Methods of treating cancer associated with reduced interleukin 1 beta expression

Abstract

The present disclosure relates to methods of treating cancer comprising administering to a subject an IRAK4 modifying compound wherein the subject has irregular expression of a gene associated with NF-KB.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480064154.9 (22) Application Date 2024.10.25 (30) Priority Data 63 / 546016 2023.10.27 US (85) PCT International Application Entering National Phase Date 2026.04.03 (86) PCT International Application Application Data PCT / US2024 / 052925 2024.10.25 (87) PCT International Application Publication Data WO2025 / 090844 EN 2025.05.01 (71) Applicant: Corliss Corporation, Address: Massachusetts, USA (72) Inventors: M. Severini, G. Chowdhury, M.E. Lane, D.C. Nicole, S.M. Carlyle (74) Patent Agency: China Patent Agency (Hong Kong) Limited, 72001 Patent Attorneys: Wang Yingyu, Yang Sijie (51) Int.Cl. A61K 31 / 424 (2006.01) A61K 31 / 428 (2006.01) A61K 31 / 39 (2006.01) A61K 31 / 5377 (2006.01) C07D 413 / 14 (2006.01) C07D 498 / 04 (2006.01) C07D 513 / 04 (2006.01) A61P 35 / 00(2006.01) A61P 35 / 02(2006.01) (54) Invention Title: Method for Treating Cancer Associated with Decreased Interleukin-1β Expression (57) Abstract: This disclosure relates to a method for treating cancer, the method comprising administering an IRAK4 modified compound to a subject, wherein the subject has irregular expression of a gene associated with NF-κB. Claims: 21 pages Description: 37 pages Drawings: 11 pages CN 121969366 A 2026.05.01 CN 1 21 96 93 66 A 1. A method for treating cancer in a subject, the method comprising administering an IRAK4 modified compound to the subject, wherein the subject has decreased expression of interleukin-1β or immediate early response gene 3. 2. The method of claim 1, wherein the subject has decreased expression of interleukin-1β. 3. The method of claim 2, wherein the subject has decreased expression of interleukin-1β compared to a subject without cancer. 4. The method of claim 2, wherein the subject has reduced expression of interleukin-1 β compared to a subject with cancer. 5. The method of claim 1, wherein the subject has reduced expression of immediate early response gene 3.6. The method of claim 5, wherein the expression of the immediate early response gene 3 is reduced in the subject compared to a subject without cancer. 7. The method of claim 5, wherein the expression of the immediate early response gene 3 is reduced in the subject compared to a subject with cancer. 8. The method of any one of claims 1-7, the method comprising: obtaining a biological sample from the subject; determining the expression level of interleukin-1β or the immediate early response gene 3 in the biological sample; comparing the expression level of one or more genes with a reference expression level; and if the expression level of the one or more genes is lower than the reference expression level, administering the IRAK4 modifying compound. 9. The method of claim 8, the method comprising determining the expression level of interleukin-1β in the biological sample. 10. The method of claim 8 or 9, the method comprising determining the expression level of the immediate early response gene 3 in the biological sample. 11. The method of any one of claims 8-10, wherein the biological sample comprises tissue (e.g., bone marrow). 12. The method of any one of claims 8-11, wherein the biological sample comprises blood (e.g., a peripheral blood sample). 13. The method of any one of claims 1-12, wherein the method further comprises administering an interleukin-1 blocker to the subject. 14. The method of claim 13, wherein the interleukin-1 blocker is an interleukin-1 receptor antagonist. 15. The method of claim 13 or 14, wherein the interleukin-1 blocker is an interleukin-1 receptor antagonist protein or a homolog thereof. 16. The method of any one of claims 13-15, wherein the interleukin-1 blocker is analysin. 17. The method of claim 13, wherein the interleukin-1 blocker is a soluble decoy receptor. 18. The method of claim 13 or 17, wherein the interleukin-1 blocker is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of a human interleukin-1 receptor component (IL-1R1) and an IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1. 19. The method of any one of claims 13, 17, or 18, wherein the interleukin-1 blocker is linacip. Claims 1 / 21 page 2 CN 121969366 A 20. The method of claim 13, wherein the interleukin-1 blocker is an IL-1β neutralizing antibody. 21. The method of claim 13 or 20, wherein the interleukin-1 blocker is kanamycin. 22. The method of claim 13 or 20, wherein the interleukin-1 blocker is gemvozumab.23. The method of claim 13 or 20, wherein the interleukin-1 blocker is LY2189102. 24. The method of claim 13, wherein the interleukin-1 blocker is an IL-1α neutralizing antibody. 25. The method of claim 13 or 24, wherein the interleukin-1 blocker is MABp1. 26. The method of claim 13, wherein the interleukin-1 blocker is an interleukin-1 receptor 1 blocking antibody. 27. The method of claim 13 or 26, wherein the interleukin-1 blocker is MEDI-8968. 28. The method of claim 13, wherein the interleukin-1 blocker is a caspase 1 inhibitor. 29. The method of any one of claims 1-28, further comprising administering an agent that inhibits NF-κB activity. 30. The method of any one of claims 1-29, wherein the IRAK4 modifying compound is an IRAK4 inhibitor. 31. The method of any one of claims 1-29, wherein the IRAK4 modifying compound is an IRAK4 degrading agent. 32. The method according to claim 31, wherein the IRAK4 degrading agent is KT-474. 33. The method of claim 30, wherein the IRAK4 inhibitor has a structure represented by formula I: (I) or a pharmaceutically acceptable salt thereof; wherein X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2, or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently halogenated or optionally substituted heterocyclic in each occurrence; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, hydroxyalkyl, or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, or -NRaRb; wherein the substituent is alkyl, amino, halogenated, or hydroxyl; R3 is alkyl or hydroxyl in each occurrence; Ra and Rb are independently hydrogen, alkyl, acyl, or heterocyclic; “m” and “n” are independently 0, 1, or 2; and “p” is 0 or 1. 34. The method of claim 33, wherein A is O or S; AY is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogen or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic or -NRaRb; "m" is 0; and "n" is 1. 35. The method of claim 33, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic;R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogenated, or hydroxyl; “m” and “n” are independently 0, 1, or 2; and “p” is 0 or 1. 36. The method according to any one of claims 33-35, wherein: . 37. The method according to any one of claims 33-36, wherein Z is aryl, a 5-membered heterocyclic group, or a 6-membered heterocyclic group. 38. The method according to any one of claims 33-37, wherein Z is an optionally substituted heterocyclic group selected from: phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanecycloyl, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene, dihydropyranyl and azabicyclic [3.2.1] Octyl; each of the heterocyclic groups is optionally substituted with an alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, or -NRaRb; and Ra and Rb are independently hydrogen, alkyl, or acyl. 39. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IA): Claim 3 / 21 page 4 CN 121969366 A (IA) or a pharmaceutically acceptable salt thereof. 40. The method of claim 39, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogen, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NRaRb; "m" is 0; and "n" is 1. 41. The method of claim 39, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogen, or hydroxyl; and "m" and "n" are independently 0, 1, or 2.42. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IB): (IB) or a pharmaceutically acceptable salt thereof. 43. The method of claim 42, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogen, or hydroxyl; and “m” and “n” are independently 0, 1, or 2. 44. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IC): Claims 4 / 21 page 5 CN 121969366 A (IC) or a pharmaceutically acceptable salt thereof. 45. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NRaRb; and Ra and Rb are independently hydrogen or acyl. 46. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, aminoalkyl, halogen, or -NRaRb; and Ra and Rb are independently hydrogen or acyl. 47. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, aminoalkyl, halogen, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic. 48. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic. 49. The method according to any one of claims 33-44, wherein R1 is pyridinyl, pyrazolyl, pyrrolidinyl, or piperidinyl. 50. The method according to any one of claims 33-44, wherein R1 is an optionally substituted pyrazolyl group, wherein the substituent is alkyl, hydroxyl, or -NRaRb. 51. The method according to any one of claims 33-44, wherein R1 is a halogen. 52. The method according to any one of claims 33-51, wherein R2 is hydrogen, cycloalkyl, heterocyclic, or -NRaRb. 53. The method according to any one of claims 33-51, wherein R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogen, or hydroxyl. 54. The method according to any one of claims 33-51, wherein R2 is an optionally substituted heterocyclic group, wherein the optional substituent is selected from amino, halogen, or hydroxyl.The heterocyclic group is selected from: piperidinyl, pyrrolyl, morpholinyl, piperazine, aziridine, pyrazolyl, furanyl, or azirbiscyclic [3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl, or amino. 55. The method according to any one of claims 33-51, wherein R2 is piperidinyl, pyrrolyl, morpholinyl, or piperazine. 56. The method according to any one of claims 33-51, wherein R2 is hydrogen. 57. The method according to any one of claims 33-51, wherein R2 is cycloalkyl. 58. The method according to claim 57, wherein R2 is cyclopropyl. 59. The method according to any one of claims 33-58, wherein R3 is alkyl. 60. The method according to any one of claims 33-59, wherein m is 0 and p is 1. 61. The method according to any one of claims 33-59, wherein m is 0 or 2, and p is 0 or 1. 62. The method of claim 30, wherein the IRAK4 inhibitor is selected from: (Claims 5 / 21, page 6, CN 121969366 A; Claims 6 / 21, page 7, CN 121969366 A; Claims 7 / 21, page 8, CN 121969366 A; Claims 8 / 21, page 9, CN 121969366 A; Claims 9 / 21, page 10, CN 121969366 A) or pharmaceutically acceptable salts or stereoisomers thereof. 63. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. 64. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt of [missing information]. 65. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. (Claims 10 / 21, page 11, CN 121969366 A) 66. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt of [missing information]. 67. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. 68. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt. 69. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. 70. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt. 71. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. 72. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt. 73. The method of claim 30, wherein the IRAK4 inhibitor is [missing information].74. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt of claim 11 / 21 (CN 121969366 A). 75. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. 76. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt of [missing information]. 77. The method of claim 30, wherein the IRAK4 inhibitor is [missing information]. 78. The method of claim 30, wherein the IRAK4 inhibitor is a pharmaceutically acceptable salt of [missing information]. 79. The method of any one of claims 33-78, wherein the method comprises administering 100 mg to 400 mg of the IRAK4 inhibitor to the subject twice daily. 80. The method of any one of claims 33-78, wherein the method comprises administering 200 mg to 400 mg of the IRAK4 inhibitor to the subject twice daily. 81. The method of any one of claims 33-78, wherein the method comprises administering 250 mg to 350 mg of the IRAK4 inhibitor to the subject twice daily. 82. The method according to any one of claims 33-78, wherein the method comprises administering to the subject twice daily an IRAK4 inhibitor of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. 83. The method according to any one of claims 33-78, wherein the method comprises administering to the subject twice daily an IRAK4 inhibitor of 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. 84. The method according to any one of claims 33-78, wherein the method comprises administering to the subject twice daily about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 400 mg of the IRAK4 inhibitor. 85. The method according to any one of claims 33-78, wherein the method comprises administering to the subject twice daily about 100 mg of the IRAK4 inhibitor. 86. The method according to any one of claims 33-78, wherein the method comprises administering to the subject twice daily about 100 mg of the IRAK4 inhibitor. (Claims 12 / 21 pages 13 CN 121969366 A)87. The method of any one of claims 33-78, wherein the method comprises administering about 200 mg of the IRAK4 inhibitor to the subject twice daily. 88. The method of any one of claims 33-78, wherein the method comprises administering about 225 mg of the IRAK4 inhibitor to the subject twice daily. 89. The method of any one of claims 33-78, wherein the method comprises administering about 250 mg of the IRAK4 inhibitor to the subject twice daily. 90. The method of any one of claims 33-78, wherein the method comprises administering about 275 mg of the IRAK4 inhibitor to the subject twice daily. 91. The method of any one of claims 33-78, wherein the method comprises administering about 300 mg of the IRAK4 inhibitor to the subject twice daily. 92. The method of any one of claims 33-78, wherein the method comprises administering about 325 mg of the IRAK4 inhibitor to the subject twice daily. 93. The method of any one of claims 33-78, wherein the method comprises administering about 350 mg of the IRAK4 inhibitor to the subject twice daily. 94. The method of any one of claims 33-78, wherein the method comprises administering about 375 mg of the IRAK4 inhibitor to the subject twice daily. 95. The method of any one of claims 33-78, wherein the method comprises administering about 400 mg of the IRAK4 inhibitor to the subject twice daily. 96. The method of any one of claims 33-78, wherein the method comprises administering to the subject once daily an IRAK4 inhibitor of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. 97. The method of any one of claims 33-78, wherein the method comprises administering to the subject once daily an IRAK4 inhibitor of about 25 mg. 98. The method of any one of claims 33-78, wherein the method comprises administering to the subject once daily an IRAK4 inhibitor of about 50 mg. 99. The method of any one of claims 33-78, wherein the method comprises administering to the subject once daily an IRAK4 inhibitor of about 75 mg. 100. The method according to any one of claims 33-78, the method comprising administering the medication to the subject once daily.101. The method of any one of claims 33-78, wherein the method comprises administering about 125 mg of the IRAK4 inhibitor to the subject once daily. 102. The method of any one of claims 33-78, wherein the method comprises administering about 150 mg of the IRAK4 inhibitor to the subject once daily. 103. The method of any one of claims 33-78, wherein the method comprises administering about 175 mg of the IRAK4 inhibitor to the subject once daily. 104. The method of any one of claims 33-78, wherein the method comprises administering about 200 mg of the IRAK4 inhibitor to the subject once daily. Claims 13 / 21 pages 14 CN 121969366 A 105. The method of any one of claims 33-78, wherein the method comprises administering about 225 mg of the IRAK4 inhibitor to the subject once daily. 106. The method of any one of claims 33-78, wherein the method comprises administering about 250 mg of the IRAK4 inhibitor to the subject once daily. 107. The method of any one of claims 33-78, wherein the method comprises administering about 275 mg of the IRAK4 inhibitor to the subject once daily. 108. The method of any one of claims 33-78, wherein the method comprises administering about 300 mg of the IRAK4 inhibitor to the subject once daily. 109. The method of any one of claims 33-78, wherein the method comprises administering about 325 mg of the IRAK4 inhibitor to the subject once daily. 110. The method of any one of claims 33-78, wherein the method comprises administering about 350 mg of the IRAK4 inhibitor to the subject once daily. 111. The method of any one of claims 33-78, wherein the method comprises administering about 375 mg of the IRAK4 inhibitor to the subject once daily. 112. The method of any one of claims 33-78, wherein the method comprises administering about 400 mg of the IRAK4 inhibitor to the subject once daily. 113. The method of any one of claims 33-78, wherein the method comprises administering about 425 mg of the IRAK4 inhibitor to the subject once daily. 114. The method of any one of claims 33-78, wherein the method comprises administering about 450 mg of the IRAK4 inhibitor to the subject once daily. 115. The method of any one of claims 33-78, wherein the method comprises administering about 425 mg of the IRAK4 inhibitor to the subject once daily.116. The method of any one of claims 33-78, wherein the method comprises administering about 500 mg of the IRAK4 inhibitor to the subject once daily. 117. The method of any one of claims 1-116, wherein the IRAK4 modified compound is administered orally to the subject. 118. The method of any one of claims 33-78, wherein the method comprises administering about 50 mg of the IRAK4 inhibitor to the subject once daily. 119. The method of any one of claims 33-78, wherein the method comprises administering about 75 mg of the IRAK4 inhibitor to the subject once daily. 120. The method of any one of claims 33-78, wherein the method comprises administering about 100 mg of the IRAK4 inhibitor orally to the subject twice daily. 121. The method of any one of claims 33-78, wherein the method comprises administering about 125 mg of the IRAK4 inhibitor orally to the subject twice daily. 122. The method of any one of claims 33-78, wherein the method comprises orally administering about 150 mg of the IRAK4 inhibitor to the subject twice daily. 123. The method of any one of claims 33-78, wherein the method comprises orally administering about 175 mg of the IRAK4 inhibitor to the subject twice daily. 124. The method of any one of claims 33-78, wherein the method comprises orally administering about 200 mg of the IRAK4 inhibitor to the subject twice daily. 125. The method of any one of claims 33-78, wherein the method comprises orally administering about 225 mg of the IRAK4 inhibitor to the subject twice daily. 126. The method of any one of claims 33-78, wherein the method comprises orally administering about 250 mg of the IRAK4 inhibitor to the subject twice daily. 127. The method of any one of claims 33-78, wherein the method comprises orally administering about 275 mg of the IRAK4 inhibitor to the subject twice daily. 128. The method of any one of claims 33-78, wherein the method comprises orally administering about 300 mg of the IRAK4 inhibitor to the subject twice daily. 129. The method of any one of claims 33-78, wherein the method comprises orally administering about 325 mg of the IRAK4 inhibitor to the subject twice daily. 130. The method of any one of claims 33-78, wherein the method comprises administering about 300 mg of the IRAK4 inhibitor to the subject twice daily.131. The method of any one of claims 33-78, wherein the method comprises orally administering to the subject about 375 mg of the IRAK4 inhibitor twice daily. 132. The method of any one of claims 33-78, wherein the method comprises orally administering to the subject about 400 mg of the IRAK4 inhibitor twice daily. 133. The method of any one of claims 1-132, wherein the method comprises additionally administering to the subject 75 mg / m² of azacitidine once daily. 134. The method of any one of claims 1-29, wherein the IRAK4 modifying compound is PF-06650833. 135. The method of any one of claims 1-29, wherein the IRAK4 modifying compound is BAY 1830839. 136. The method of any one of claims 1-135, wherein the method further comprises co-administering to the subject a BCL-2 inhibitor. 137. The method of claim 136, wherein the BCL-2 inhibitor is venetoc. 138. The method of claim 137, wherein the method comprises administering 400 mg of venetoclax daily. 139. The method of claim 137, wherein the venetoclax is administered orally. 140. The method of claim 137, wherein the method comprises administering 400 mg of venetoclax orally daily. 141. The method of any one of claims 1-140, wherein the method further comprises administering a BTK inhibitor to the subject in combination. 142. The method of claim 141, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, évorabutinib, ONO-4059, spetinib, or HM7 1224. 143. The method of claim 142, wherein the BTK inhibitor is acalabrutinib. 144. The method of claim 143, wherein the method comprises administering 200 mg of acalabrutinib daily. 145. The method of claim 143, wherein the acalabrutinib is administered orally. 146. The method of claim 143, wherein the method comprises oral administration of 200 mg of acalabrutinib daily. 147. The method of claim 142, wherein the BTK inhibitor is ibrutinib. 148. The method of claim 147, wherein the method comprises oral administration of 420 mg of ibrutinib daily. Claims 15 / 21 pages 16 CN 121969366 A 149. The method of claim 147, wherein the method comprises oral administration of 560 mg of ibrutinib daily.150. The method of claim 147, wherein the ibrutinib is administered orally. 151. The method of claim 147, wherein the method comprises administering 420 mg of ibrutinib orally daily. 152. The method of claim 147, wherein the method comprises administering 560 mg of ibrutinib orally daily. 153. The method of claim 142, wherein the BTK inhibitor is zanubrutinib. 154. The method of claim 153, wherein the method comprises administering 160 mg of zanubrutinib twice daily. 155. The method of claim 153, wherein the method comprises administering 320 mg of zanubrutinib once daily. 156. The method of claim 153, wherein the zanubrutinib is administered orally. 157. The method of claim 153, wherein the method comprises administering 160 mg of zanubrutinib orally twice daily. 158. The method of claim 153, wherein the method comprises administering 320 mg of zanubrutinib orally once daily. 159. The method of any one of claims 1-158, wherein the cancer is a hematologic malignancy. 160. The method of claim 159, wherein the hematologic malignancy is non-Hodgkin's lymphoma. 161. The method of claim 159, wherein the hematologic malignancy is leukemia. 162. The method of claim 159, wherein the hematologic malignancy is lymphoma. 163. The method according to any one of claims 159-162, wherein the hematologic malignancy is myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphocytic 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), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma. 164. The method of claim 159, wherein the hematologic malignancy is myeloid leukemia. 165. The method of claim 159, wherein the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia). 166. The method of claim 159, wherein the hematologic malignancy is acute myeloid leukemia (e.g., AML).167. The method of claim 166, wherein the AML is primary AML. 168. The method of claim 166, wherein the AML is secondary AML. 169. The method of any one of claims 166-168, wherein the AML is treatment-related AML. 170. The method of claim 159, wherein the hematologic malignancy is myelodysplastic syndrome. 171. The method of claim 170, wherein the myelodysplastic syndrome is high-grade. 172. The method of claim 170, wherein the myelodysplastic syndrome is low-grade. 173. The method of any one of claims 170-172, wherein the myelodysplastic syndrome is high-risk. 174. The method of claim 159, wherein the hematologic malignancy is lymphocytic leukemia (e.g., acute lymphoblastic leukemia). 175. The method of claim 159, wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL). 176. The method of claim 175, wherein the CLL is a high-risk CLL. 177. The method of claim 159, wherein the hematologic malignancy is a small lymphocytic lymphoma (SLL). 178. The method of claim 159, wherein the hematologic malignancy is a follicular lymphoma. 179. The method of claim 159, wherein the hematologic malignancy is a diffuse large B-cell lymphoma (DLBCL). 180. The method of claim 159, wherein the hematologic malignancy is an activated B-cell-like (ABC) DLBCL. 181. The method of claim 159, wherein the hematologic malignancy is a germinal center B-cell-like (GCB) DLBCL. 182. The method of any one of claims 179-181, wherein the DLBCL is extranodal. 183. The method of any one of claims 179-181, wherein the DLBCL is an extranodal leg lymphoma, an extranodal testicular lymphoma, or an extranodal nonspecific (NOS) lymphoma. 184. The method of claim 159, wherein the hematologic malignancy is mantle cell lymphoma. 185. The method of claim 159, wherein the hematologic malignancy is Waldenström macroglobulinemia. 186. The method of claim 159, wherein the hematologic malignancy is multiple myeloma. 187. The method of claim 159, wherein the hematologic malignancy is marginal zone lymphoma. 188. The method of claim 159, wherein the hematologic malignancy is Burkitt lymphoma.189. The method of claim 159, wherein the hematologic malignancy is a non-Burkita high-grade B-cell lymphoma. 190. The method of claim 159, wherein the hematologic malignancy is an extranodal marginal zone B-cell lymphoma. 191. The method of claim 159, wherein the hematologic malignancy is a transformed high-grade B-cell lymphoma (HGBL). 192. The method of claim 159, wherein the hematologic malignancy is a lymphoplasmacytic lymphoma (LPL). 193. The method of claim 159, wherein the hematologic malignancy is a CNS lymphoma. 194. The method of claim 193, wherein the CNS lymphoma is a primary CNS lymphoma (PCNSL). 195. The method of claim 159, wherein the hematologic malignancy is a MALT lymphoma. 196. The method of any one of claims 159-195, wherein the hematologic malignancy is relapsed. 197. The method of any one of claims 159-196, wherein the hematologic malignancy is refractory. 198. The method according to any one of claims 1-158, wherein 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, melanoma, epidermal cancer, prostate cancer, and head and neck cancer. 199. The method according to any one of claims 1-158, wherein the cancer is pancreatic cancer. 200. The method according to any one of claims 1-158, wherein the cancer is colon cancer. 201. The method according to any one of claims 198-200, wherein the cancer is a solid tumor. 202. The method according to any one of claims 198-201, wherein the cancer is recurrent. 203. The method according to any one of claims 198-202, wherein the cancer is refractory. 204. The method according to any one of claims 1-203, wherein the cancer is resistant to treatment with BTK inhibitors. 205. The method of claim 204, wherein the cancer is resistant to treatment with ibrutinib, acalatinib, zanubrutinib, évorabutinib, ONO-4059, spetinib, or HM7 1224. 206. The method of claim 205, wherein the cancer is resistant to treatment with ibrutinib. 207. The method of claim 205, wherein the cancer is resistant to treatment with acalatinib. 208. The method of any one of claims 1-207, wherein the subject is an adult.209. The method of any one of claims 1-208, wherein the subject has previously received at least one anticancer therapy (e.g., an anticancer therapy or an anti-inflammatory therapy). 210. The method of claim 209, wherein the subject has previously received one anticancer therapy. 211. The method of claim 209, wherein the subject has previously received two anticancer therapies. 212. The method of claim 209, wherein the subject has previously received three anticancer therapies. 213. The method of claim 209, wherein the subject has previously received four anticancer therapies. 214. The method of claim 209, wherein the subject has previously received five anticancer therapies. 215. The method according to any one of claims 209-214, wherein the at least one anticancer therapy comprises: an antiCD20 antibody, nitrogen mustard, a steroid, a purine analog, a DNA topoisomerase inhibitor, a DNA intercalating agent, 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, a BTK inhibitor, a glutaminase inhibitor, a steroid, or a methylating agent; or a combination thereof. 216. The method of any one of claims 209-215, wherein the anticancer therapy comprises: ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, opzomib, ixazomib, acalatinib, zanubrutinib, IMO-08400, ederaris, ibritex, CB-839, fludarabine, or thalidomide; or combinations thereof. 217. The method of any one of claims 209-216, wherein the anticancer therapy comprises dexamethasone. 218. The method of any one of claims 209-216, wherein the anticancer therapy comprises ibrutinib. 219. The method of any one of claims 209-216, wherein the anticancer therapy comprises ibrutinib and rituximab. 220. The method of any one of claims 209-216, wherein the anticancer therapy comprises bendamustine. 221. The method of any one of claims 209-216, wherein the anticancer therapy comprises bendamustine and rituximab. 222. The method of any one of claims 209-216, wherein the anticancer therapy comprises bortezomib. 223. The method of any one of claims 209-216, wherein the anticancer therapy comprises bortezomib and dexamethasone. 224. The method of any one of claims 209-216, wherein the anticancer therapy comprises bortezomib and rituximab.225. The method of any one of claims 209-216, wherein the anticancer therapy comprises bortezomib, rituximab, and dexamethasone. 226. The method of any one of claims 209-216, wherein the anticancer therapy comprises chlorambucil. 227. The method of any one of claims 209-216, wherein the anticancer therapy comprises cladribine. Claims 18 / 21 pages 19 CN 121969366 A 228. The method of any one of claims 209-216, wherein the anticancer therapy comprises cladribine and rituximab. 229. The method of any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). 230. The method of any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, prednisone, and rituximab (i.e., CPR). 231. The method of any one of claims 209-216, wherein the anticancer therapy comprises fludarabine. 232. The method of any one of claims 209-216, wherein the anticancer therapy comprises fludarabine and rituximab. 233. The method of any one of claims 209-216, wherein the anticancer therapy comprises fludarabine, cyclophosphamide, and rituximab. 234. The method of any one of claims 209-216, wherein the anticancer therapy comprises rituximab. 235. The method of any one of claims 209-216, wherein the anticancer therapy comprises rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). 236. The method of any one of claims 209-216, wherein the anticancer therapy comprises thalidomide. 237. The method of any one of claims 209-216, wherein the anticancer therapy comprises thalidomide and rituximab. 238. The method of any one of claims 209-216, wherein the anticancer therapy comprises venetoclax. 239. The method of any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). 240. The method of any one of claims 209-216, wherein the anticancer therapy comprises a hypomethylating agent. 241. The method of any one of claims 1-240, wherein the subject has previously received at least six cycles of a hypomethylating agent. 242. The method of any one of claims 1-241, wherein the subject has previously received etoposide chemotherapy.243. The method of any one of claims 1-242, wherein the subject has previously received a bone marrow transplant. 244. The method of any one of claims 1-243, wherein the subject has previously received a hematopoietic cell transplant. 245. The method of any one of claims 1-244, wherein the subject has previously received a stem cell transplant. 246. The method of any one of claims 1-245, wherein the subject has previously received an autologous stem cell transplant. 247. The method of any one of claims 1-246, wherein the subject has previously received an allogeneic stem cell transplant. 248. The method of any one of claims 1-247, wherein the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning). 249. The method of any one of claims 1-248, wherein the subject has previously received re-induction therapy. Claims 19 / 21 pages 20 CN 121969366 A 250. The method of any one of claims 1-249, wherein the subject has previously achieved a partial response. 251. The method of any one of claims 1-250, wherein the subject has previously achieved a good partial response. 252. The method of any one of claims 1-251, wherein the subject has previously achieved a complete response. 253. The method of any one of claims 1-252, wherein the subject has a mutation in RICTOR. 254. The method of claim 253, wherein the subject has an N1065S mutation in RICTOR. 255. The method of any one of claims 1-254, wherein the subject has a mutation in MYD88. 256. The method of claim 255, wherein the subject has an L265P mutation in MYD88. 257. The method of any one of claims 1-256, wherein the subject has a mutation in TET2. 258. The method of any one of claims 1-257, wherein the subject does not have a mutation in CXCR4. 259. The method of any one of claims 1-257, wherein the subject has a mutation in CXCR4. 260. The method of any one of claims 1-259, wherein the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or splice variant). 261. The method of any one of claims 1-260, wherein the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or splice variant).262. The method of any one of claims 1-261, wherein the subject has a mutation in FLT3 kinase (e.g., insertion, deletion, loss, or internal tandem repeat). 263. The method of claim 262, wherein the mutation in FLT3 kinase is selected from: internal tandem repeat (ITD); mutations in D835, F691, K663, or N841; and combinations of ITD and mutations in D835, F691, K663, or N841. 264. The method of claim 263, wherein the mutation in FLT3 kinase is D835H. 265. The method of claim 263, wherein the mutation in FLT3 kinase is D835V. 266. The method of claim 263, wherein the mutation in FLT3 kinase is D835Y. 267. The method of claim 263, wherein the mutation in FLT3 kinase is K663Q. 268. The method of claim 263, wherein the mutation in FLT3 kinase is N841I. 269. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and D835V. 270. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and F691L. 271. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and D835Y. 272. The method of any one of claims 1-271, wherein the subject has a mutation in STAG2 (e.g., insertion, deletion, or loss). 273. The method of any one of claims 1-272, wherein the subject has a mutation in DNMT3A (e.g., insertion, deletion, or loss). 274. The method of any one of claims 1-273, wherein the subject has a mutation in BCOR (e.g., insertion, deletion, or loss). 275. The method of any one of claims 1-274, wherein the subject has a mutation in WT1 (e.g., insertion, deletion, or loss). 276. The method of any one of claims 1-275, wherein the subject has a mutation in NRAS (e.g., insertion, deletion, or loss). Claims 20 / 21, Page 21, CN 121969366 A 277. The method according to any one of claims 1-276, wherein the subject shows early progress. 278. The method according to any one of claims 1-277, wherein the subject has not previously received a BTK inhibitor. 279. The method according to any one of claims 1-278, wherein the subject achieves a partial response after administration of the IRAK4 modified compound.280. The method of any one of claims 1-279, wherein the subject achieves a good partial response after administration of the IRAK4 modified compound. 281. The method of any one of claims 1-279, wherein the subject achieves a complete response after administration of the IRAK4 modified compound. 282. The method of any one of claims 1-281, wherein IL-1-induced signaling is reduced in the subject after administration of the IRAK4 modified compound. 283. The method of any one of claims 1-282, wherein cytokine production is reduced in the subject after administration of the IRAK4 modified compound. 284. The method of any one of claims 1-283, wherein the IRAK4 modified compound is administered until disease progression or unacceptable toxicity occurs. 285. The method of any one of claims 209-284, wherein the subject has previously received a BTK inhibitor for cancer treatment. Claims 21 / 21 pages 22 CN 121969366 A Method for treating cancers associated with decreased interleukin 1β expression

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 546,016, filed October 27, 2023, the contents of which are incorporated herein by reference in their entirety. Background Art

[0002] Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) is a serine / threonine kinase that plays an important role in signal transduction via Toll / IL-1 receptors (TIRs). Various IRAK enzymes are key components in signal transduction pathways mediated by interleukin-1 receptors (IL-1Rs) and Toll-like receptors (TLRs) (Janssens, S. et al., Mol. Cell. 11, 2003, 293–302). There are four members in the mammalian IRAK family: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a central kinase domain that mediates interactions with MyD88 family adaptor proteins. IRAK proteins and MyD88 have been shown to play roles in transducing signals other than those derived from the IL-1R receptor, including those triggered by the IL-18 receptor (Kankaraj et al., J. Exp. Med. 189(7):1999, 1129-38) and those triggered by the activation of the LPS receptor (Yang et al., J. Immunol. 163, 1999, 639-643). Of the four members of the mammalian IRAK family, IRAK4 is considered the “mother IRAK.” Under overexpression conditions, all IRAKs can mediate nuclear factor-κB (NF-κB) activation.Activation of stress-induced mitogen-activated protein kinase (MAPK) and the signaling cascade amplification. However, only IRAK-1 and IRAK4 showed active kinase activity. Although IRAK-1 kinase activity may be unnecessary for its function in IL-1-induced NF-KB activation (Kankaraj et al., J. Exp. Med. 187(12), 1998, 2073–2079) and (Xiaoxia Li et al., Mol. Cell. Biol. 19(7), 1999, 4643–4652), IRAK4 signal transduction requires its kinase activity (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). Given the central role of IRAK4 in Toll-like / IL-1R signaling and immune protection, IRAK4 inhibitors have been considered valuable therapeutic agents for inflammatory diseases, sepsis, and autoimmune diseases (Wietek C et al., Mol. Interv. 2: 2002, 212–215).

[0003] Mice lacking IRAK4 survived and showed complete elimination of the production of inflammatory cytokines in response to IL-1, IL-18, or LPS (Suzuki et al., Nature, 416(6882), 2002, 750–756). Similarly, human patients lacking IRAK4 were severely immunocompromised and unresponsive 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., J Exp Med 204: 2007, 1025–36) and (Kawagoe T et al., J Exp Med 204(5): 2007, 1013–1024), demonstrating that IRAK4 kinase activity is essential for cytokine production, MAPK activation, and the induction of NF-κB-regulated genes in response to TLR ligands (Koziczak-Holbro M et al., J Biol Chem; 282(18): 2007; 13552–13560). Inactivation of IRAK4 kinase (IRAK4 KI) in mice resulted in resistance to EAE due to a reduction in inflammatory cells infiltrating the CNS and antigen specificity.Decreased IL-17 production mediated by sex CD4+ T cells (Kirk A et al., The Journal of Immunology, 183(1), 2009, 568-577).

[0004] Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in adults, with an estimated 80,000 new cases and 20,000 deaths in the United States in 2023. The molecular pathology driving NHL is diverse, but a common theme is the overactivity of the NF-κB signaling pathway. Specific molecular changes driving this pathway in NHL subsets have been identified. For example, diffuse large B-cell lymphoma (hereinafter also referred to as “DLBCL”) is an aggressive lymphoma that can occur in or outside the lymphatic system, in the gastrointestinal tract, testes, thyroid gland, skin, breast, bone, or brain. DLBCL is a cancer of B cells, which are white blood cells responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma in adults, occurring in 7–8 cases per 100,000 people each year. This cancer primarily occurs in older individuals, with a median age of diagnosis of approximately 70 years, but it can also occur in children and young adults in rare cases. DLBCL is an aggressive tumor, and the first symptom of the disease is usually the observation of a rapidly growing mass. The five-year survival rate is only 58%. DLBCL has subtypes named according to their cellular origin and includes germinal center B-cell-like (GCB) and activated B-cell-like (ABC). They are distinguished by their poor prognosis and, in some cases, require specific treatments.

[0005] Acute myeloid leukemia (AML) is one of the most common forms of leukemia in adults, with approximately 20,000 new cases diagnosed each year. AML remains a highly fatal disease, with a five-year survival rate of only 28.3%. Interleukin-1 receptor-associated kinase 4 (IRAK4) has been shown to be a potential therapeutic target for human AML. Although AML is a heterogeneous disease, common characteristics of leukemia blasts include high proliferative potential, increased stem cell self-renewal, and arrested differentiation in a relatively immature state within the mitotic pool. It is also generally believed that specific genetic mutations present in AML cells can guide treatment and determine the patient's potential survival time.

[0006] Myelodysplastic syndromes are conditions that can occur when hematopoietic cells in the bone marrow become abnormal. The main clinical problems in these diseases are the morbidity caused by blood cell reduction and the likelihood of MDS developing into AML. In the general population, the incidence of MDS is approximately 4.9 per 100,000 people per year. High-risk MDS (hrMDS) is defined as having a high risk of developing AML.The risk is high, with an IPSS score ≥2.5 and immature blasts possibly comprising more than 5% of the cells in the bone marrow. Low blood cell counts may lead to anemia, neutropenia, or thrombocytopenia. HrMDS has a greater risk of progression to AML and shorter survival, with a median survival of only 0.8 years when patients are untreated. Most MDS diagnoses are low-risk MDS (LR-MDS). Although LR-MDS has a lower risk of death in the short term, it is associated with a high risk of anemia and treatment complications, leading to a high mortality rate (Brunner, AM et al., Blood Cancer J. 12:166 (2022)).

[0007] Another example of NHL is Waldenström macroglobulinemia (WM). WM is a non-Hodgkin lymphoma that affects two types of B cells, lymphoplasmacytic cells and plasma cells. WM is characterized by high levels of circulating antibodies, immunoglobulin M (IgM), which are produced and secreted by cells involved in the disease. WM is a rare disease, with only about 1,500 cases per year in the United States. There is no single, universally accepted treatment for WM, and clinical outcomes vary significantly due to gaps in our understanding of the molecular basis of the disease. Objective response rates are high (>80%), but complete response rates are low (0%–15%).

[0008] Other types of non-Hodgkin 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. Non-Hodgkin lymphoma can be caused by a variety of factors, such as infectious agents (Epstein-Barr virus, hepatitis C virus, and human T-cell leukemia virus), radiation and chemotherapy, and autoimmune diseases. As a population, non-Hodgkin lymphoma affects 2.1% of the U.S. population in their lifetime. The percentage of people who survive more than five years after diagnosis is 71%.

[0009] Targeting intratumoral immune cells with immune checkpoint inhibitors has enabled new treatment options for many cancers. Although several other targets are under development, major clinically approved treatments focus on programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways. These treatments have been shown to be effective for both Hodgkin's lymphoma and non-Hodgkin's lymphoma, although not all patients respond to these therapies.

[0010] In view of the above, there is a clear and unmet need for additional therapies for the treatment of cancer and other IRAK4-related diseases. Specification 2 / 37 pages 24 CN 121969366 A Summary of the Invention

[0011] In some aspects, this disclosure provides a method of treating a subject with cancer, the method comprising administering an IRAK4-modified...Compounds, wherein the subject has irregular expression of genes associated with NF-κB. Figure Descriptions

[0012] Figure 1 is a graph showing the difference in IL1B expression in patients with hRMDS before and after treatment with emavusertib. IL1B expression was significantly higher in patients who did not respond to emavusertib ("non-responders") both before treatment ("baseline") and during treatment ("On_Tx") compared to hRMDS patients who responded to emavusertib ("responders") (P≤0.01).

[0013] Figure 2 is a graph showing the difference in IER3 expression in patients with hRMDS before and after treatment with emavusertib. IER3 expression was significantly higher in patients who did not respond to emavusertib ("non-responders") both before treatment ("baseline") and during treatment ("On_Tx") compared to hRMDS patients who responded to emavusertib ("responders") ("non-responders") (P≤0.01).

[0014] Figure 3 is a graph showing the difference in IL1B expression in patients before and after receiving emavusertib treatment for AML. IL1B expression was significantly higher in patients who did not respond to emavusertib (“non-responders”) both before treatment (“baseline”) and during treatment (“On_Tx”) compared to AML patients who responded to emavusertib (“responders”) (P≤0.01).

[0015] Figure 4 is a graph showing the difference in IER3 expression in patients before and after receiving emavusertib treatment for AML. IER3 expression was significantly higher in patients who did not respond to emavusertib (“non-responders”) both before treatment (“baseline”) and during treatment (“On_Tx”) compared to AML patients who responded to emavusertib (“responders”) (P=0.57).

[0016] Figure 5 is a graph showing the difference in CCL4 expression in patients with AML compared to patients with high-risk MDS. Compared with hrMDL patients, CCL4 expression was lower in AML patients both before treatment (“baseline”) and during treatment (“On_Tx”) (P ≤ 0.01).

[0017] Figure 6 shows the differential expression of genes in the IRAK4 / NF-KB pathway, highlighting the alterations in gene expression due to diagnosis, treatment status, and response.

[0018] Figure 7 shows Hallmark pathway analysis in AML and MDS patients treated with emavusertib.

[0019] Figure 8 shows a gene enrichment map of the Hallmark G2M checkpoint pathway.

[0020] Figure 9 shows a gene enrichment map of the Hallmark E2F target pathway.

[0021] Figure 10 shows a gene enrichment map of the Hallmark heme metabolism pathway.

[0022] Figure 11 shows a gene enrichment map of TNF-α / NF-KB signaling. Detailed Description

[0023] Results from an ongoing Phase 1 study demonstrated the clinical activity of the IRAK4 inhibitor emavusertib in patients with AML and high-risk MDS. To support the development of effective emavusertib treatment regimens, a study was conducted to monitor changes in gene expression in pre-treatment and post-treatment samples obtained from AML and high-risk MDS. Clinical response data showed that patients who responded to emavusertib treatment had reduced levels of IL1B and IER3 (targets of NF-KB) expression compared to non-responders. This disclosure relates to a method of treating cancer with emavusertib and other IRAK4 inhibitors or degraders, wherein the subject has altered expression of genes associated with NF-KB.

[0024] In some aspects, this disclosure provides a method of treating a subject with cancer, the method comprising administering an IRAK4-modifying compound to the subject, wherein the subject has reduced expression of interleukin-1β or immediate early response gene 3.

[0025] In some preferred embodiments, the expression of interleukin-1β in the subject is reduced.

[0026] In some embodiments, the expression of interleukin-1β in the subject is reduced compared to the subject without cancer.

[0027] In some embodiments, the expression of interleukin-1β in the subject is reduced compared to the subject with cancer.

[0028] In some embodiments, the expression of immediate early response gene 3 in the subject is reduced.

[0029] In some embodiments, the expression of immediate early response gene 3 in the subject is reduced compared to the subject without cancer.

[0030] In some embodiments, the expression of immediate early response gene 3 in the subject is reduced compared to the subject with cancer.

[0031] In another embodiment, the method includes: obtaining a biological sample from a subject; determining the expression level of interleukin-1β or immediate early response gene 3 in the biological sample; comparing the expression level of the one or more genes with a reference expression level; and administering an IRAK4 modifying compound.

[0032] In some embodiments, the method includes determining the expression level of interleukin-1β in the biological sample.

[0033] In some embodiments, the method includes determining the expression level of immediate early response gene 3 in the biological sample.

[0034] In some embodiments, the biological sample includes tissue (e.g., bone marrow).

[0035] In some embodiments, the biological sample includes blood (e.g., a peripheral blood sample).

[0036] In some embodiments, the method includes administering an interleukin-1 blocker to the subject.

[0037] In some embodiments, the interleukin-1 blocker is an interleukin-1 receptor antagonist.

[0038] In some embodiments, the interleukin-1 blocker is an interleukin-1 receptor antagonist protein or a homolog thereof.

[0039] In some preferred embodiments, the interleukin-1 blocker is anakinra.

[0040] In some embodiments, the interleukin-1 blocker is a soluble decoy receptor.

[0041] In some embodiments, the interleukin-1 blocker is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of a human interleukin-1 receptor component (IL-1R1) and an IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1.

[0042] In some preferred embodiments, the interleukin-1 blocker is rilonacept.

[0043] In some embodiments, the interleukin-1 blocker is an IL-1β neutralizing antibody.

[0044] In some preferred embodiments, the interleukin-1 blocker is canakinumab.

[0045] In some embodiments, the interleukin-1 blocker is gemovizumab.

[0046] In some embodiments, the interleukin-1 blocker is LY2189102.

[0047] In some embodiments, the interleukin-1 blocker is an IL-1α neutralizing antibody.

[0048] In some embodiments, the interleukin-1 blocker is MABp1.

[0049] In some embodiments, the interleukin-1 blocker is an interleukin-1 receptor 1 blocking antibody.

[0050] In some embodiments, the interleukin-1 blocker is MEDI-8968.

[0051] In some embodiments, the interleukin-1 blocker is a caspase 1 inhibitor.

[0052] In some embodiments, the method further includes administering an agent that inhibits the activity of NF-κB.

[0053] In some embodiments, the IRAK4-modifying compound is an IRAK4 inhibitor. In other embodiments, the IRAK4-modifying compound is an IRAK4 degrader.

[0054] IRAK4 inhibitors In a broad sense, the methods disclosed herein can be performed with any IRAK4 inhibitor. For example, these methods can be performed using the IRAK4 inhibitors disclosed in the specification, page 4 / 37, 26 CN 121969366 A, PCT / IB2015 / 050119, PCT / IB2015 / 050217, PCT / IB2015 / 0054620, PCT / IB2016 / 054203 and / or PCT / IB2016 / 054229. The contents of each of the foregoing international applications (in particular the IRAK4 inhibitors disclosed therein) are incorporated herein by reference in their entirety.

[0055] In some embodiments, the IRAK4 inhibitor is represented by formula I: (I) or a pharmaceutically acceptable salt thereof; wherein X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently halogenated or optionally substituted heterocyclic in each occurrence; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, hydroxyalkyl or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NRaRb; wherein the substituent is alkyl, amino, halogenated or hydroxyl; R3 is alkyl or hydroxyl in each occurrence; Ra and Rb are independently hydrogen, alkyl, acyl or heterocyclic; “m” and “n” are independently 0, 1 or 2; “p” is 0 or 1.

[0056] In some embodiments, A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogen or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic or -NRaRb; "m" is 0; and "n" is 1.

[0057] In other embodiments, A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic or -NRaRb, wherein the substituent is selected from amino, halogen or hydroxyl; "m" and "n" are independently 0, 1 or 2; and "p" is 0 or 1.

[0058] In some embodiments, is: . Specification 5 / 37 page 27 CN 121969366 A

[0059] In some embodiments, Z is aryl or 5-membered heterocyclic or 6-membered heterocyclic. In some embodiments, Z is an optionally substituted heterocyclic group selected from: phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxohexylcycloyl, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydroPyranyl and azirbicyclo[3.2.1]octyl; these heterocyclic groups are each optionally substituted with alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl or -NRaRb; and Ra and Rb are independently hydrogen, alkyl or acyl.

[0060] In some embodiments, the IRAK4 inhibitor is represented by formula (IA): (IA) or a pharmaceutically acceptable salt thereof. In some embodiments, A is O or S; Y is -CH2- or O; R1 is independently halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogen or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl or heterocyclic group; R2 is hydrogen, cycloalkyl, heterocyclic or -NRaRb; "m" is 0; and "n" is 1. In other embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl or heterocyclic group; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or -NRaRb, wherein the substituent is selected from amino, halogen or hydroxyl; and "m" and "n" are independently 0, 1 or 2.

[0061] In some embodiments, the IRAK4 inhibitor is represented by formula (IB): (IB) or a pharmaceutically acceptable salt thereof. In some embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogenated, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NRaRb; and "n" is 1. In other embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogenated, or hydroxyl; and "m" and "n" are independently 0, 1, or 2.

[0062] In some embodiments, the IRAK4 inhibitor is represented by formula (IC): (IC) or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NRaRb; and Ra and Rb are independently hydrogen or acyl. In other embodiments, R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, aminoalkyl, halogen, or -NRaRb; and Ra and Rb are independently hydrogen or acyl.In some embodiments, R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, or -NRaRb; wherein Ra and Rb are independently hydrogen, alkyl, or heterocyclic. In some embodiments, R1 is pyridinyl, pyrazolyl, pyrrolidinyl, or piperidinyl. In some embodiments, R1 is an optionally substituted pyrazolyl group, wherein the substituent is alkyl, hydroxy, or -NRaRb. In other embodiments, R1 is halogen.

[0064] In some embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogen, or hydroxyl. In some embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NRaRb, wherein the substituent is selected from amino, halogen, or hydroxyl. In some embodiments, R2 is an optionally substituted heterocyclic group selected from: piperidinyl, pyrrolyl, morpholinyl, piperazine, azirrobutyl, pyrazolyl, furanyl, or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl, or amino. In some embodiments, R2 is piperidinyl, pyrrolyl, morpholinyl, or piperazine. In other embodiments, R2 is hydrogen. In yet another embodiment, it is cycloalkyl. In some embodiments, R2 is cyclopropyl.

[0065] In some embodiments, R3 is alkyl.

[0066] In some embodiments, m is 0 and p is 1. In other embodiments, m is 0 or 2, and p is 0 or 1.

[0067] In some embodiments, the IRAK4 inhibitor is selected from: (Page 7 / 37, CN 121969366 A), (Page 8 / 37, CN 121969366 A), (Page 9 / 37, CN 121969366 A), (Page 10 / 37, CN 121969366 A), (Page 11 / 37, CN 121969366 A), (Page 12 / 37, CN 121969366 A), or pharmaceutically acceptable salts or stereoisomers thereof.

[0068] In some preferred embodiments, the IRAK4 inhibitor is [missing information]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [missing information].

[0069] In some preferred embodiments, the IRAK4 inhibitor is [missing information]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [missing information].

[0070] In some preferred embodiments, the IRAK4 inhibitor is [missing information]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt.

[0071] In some preferred embodiments, the IRAK4 inhibitor is [missing information]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt.

[0072] In some preferred embodiments, the IRAK4 inhibitor is [specification missing]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [specification missing] (pages 13 / 37, CN 121969366 A).

[0073] In some preferred embodiments, the IRAK4 inhibitor is [specification missing]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [specification missing].

[0074] In some preferred embodiments, the IRAK4 inhibitor is [specification missing]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [specification missing].

[0075] In some preferred embodiments, the IRAK4 inhibitor is [specification missing]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [specification missing].

[0076] In some preferred embodiments, the IRAK4 inhibitor is [specification missing]. In other embodiments, the IRAK4 inhibitor is a pharmaceutically acceptable salt of [specification missing].

[0077] Generally, the compounds set forth herein can be administered in any amount or manner that elicits a desired response in a subject. Example: For instance, on page 14 / 37 of the specification, CN 121969366 A, a subject may be given 100 mg to 400 mg of an IRAK4 inhibitor selected from the compounds described herein, twice daily, or 200 mg to 1000 mg of an IRAK4 inhibitor once daily. In some embodiments, a subject is given 100 mg to 400 mg of an IRAK4 inhibitor twice daily. In some embodiments, a subject is given 200 mg to 400 mg of an IRAK4 inhibitor twice daily. In some preferred embodiments, a subject is given 250 mg to 350 mg of an IRAK4 inhibitor twice daily. In some implementations, the subject is given approximately 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg of an IRAK4 inhibitor twice daily. In some implementations, the subject is given approximately 50 mg, 100 mg, 200 mg, or 300 mg of an IRAK4 inhibitor twice daily. In some implementations, the subject is given approximately 50 mg of an IRAK4 inhibitor twice daily. In other implementations, the subject is given approximately 50 mg of an IRAK4 inhibitor twice daily.In another embodiment, approximately 200 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 225 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 250 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 275 mg of the IRAK4 inhibitor is administered to the subject twice daily. In a particularly preferred embodiment, approximately 300 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 325 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 350 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 375 mg of the IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, approximately 400 mg of the IRAK4 inhibitor is administered to the subject twice daily.

[0078] In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 50 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 75 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 100 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 125 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 150 mg.

[0079] In some preferred embodiments, the IRAK4 inhibitor or degrader is administered orally to the subject. In some embodiments, about 50 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 200 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 250 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In a particularly preferred embodiment, about 300 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 325 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 350 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, the IRAK4 inhibitor or degrader is administered orally to the subject twice daily.Approximately 375 mg of an IRAK4 inhibitor or degrader. In other embodiments, approximately 400 mg of an IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, approximately 50 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 75 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 100 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 125 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 150 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily.

[0080] In other embodiments, the IRAK4 inhibitor is PF-06650833 or BAY 1830839. Specification 15 / 37 pages 37 CN 121969366 A

[0081] IRAK4 degrader In some embodiments, the method includes administering an IRAK4 degrader. In some embodiments, the IRAK4 degrader is KT-474.

[0082] Combination therapy In some embodiments of the methods disclosed herein, the method further includes administering an IL-1β inhibitor or antagonist to a subject. In some embodiments, the IL-1β inhibitor is an antibody targeting IL-1β. In some preferred embodiments, the IL-1β inhibitor is kanamycin. In some embodiments, the IL-1β inhibitor is a protein having at least 90% sequence identity with an interleukin-1 receptor antagonist protein (IL-1RN). In some preferred embodiments, the IL-1β inhibitor is anakinin. In some embodiments, the IL-1β inhibitor is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of a human interleukin-1 receptor component (IL-1R1) and an IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1. In some preferred embodiments, the IL-1β inhibitor is linacip.

[0083] In some embodiments of the method disclosed herein, the method further includes co-administering a BCL-2 inhibitor to the subject. In some preferred embodiments, the BCL-2 inhibitor is venetoclax. In some embodiments, the method further includes administering 400 mg of venetoclax daily. In some embodiments, venetoclax is administered orally. In some preferred embodiments, the method further includes administering 400 mg of venetoclax orally daily.

[0084] In other embodiments, the method further includes co-administering a BTK inhibitor to the subject. In some embodimentsIn this embodiment, the BTK inhibitor is ibrutinib, acalatinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224. In some embodiments, the BTK inhibitor is ibrutinib, acalatinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224. In some embodiments, the BTK inhibitor is acalatinib. In some embodiments, the method includes administering 200 mg of acalatinib daily. In some embodiments, acalatinib is administered orally. In some embodiments, the method includes administering 200 mg of acalatinib orally daily. In some preferred embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the method includes administering 420 mg of ibrutinib daily. In other embodiments, the method includes administering 420 mg of ibrutinib daily. In some embodiments, ibrutinib is administered orally. In some preferred embodiments, ibrutinib is administered orally at a dose of 420 mg daily. In other preferred embodiments, the method includes administering 560 mg ibrutinib daily. In some embodiments, the BTK inhibitor is zanubrutinib. In some embodiments, the method includes administering 160 mg zanubrutinib twice daily. In other embodiments, the method includes administering 320 mg zanubrutinib once daily. In some embodiments, zanubrutinib is administered orally. In some embodiments, the method includes administering 160 mg zanubrutinib orally twice daily. In other embodiments, the method includes administering 320 mg zanubrutinib orally once daily. In some embodiments, the method further includes the combined administration of one or more of the following: ABT-737, BAY-1143572, 5-fluorouracil, abiraterone acetate, acetylcholine, trastuzumab emtansine, afatinib, interleukin, alectinib, alemtuzumab, retinoic acid, aminolevulinic acid, anastrozole, aprepitant, arsenic trioxide, Erwinia chrysogenum asparaginase, atezolizumab, axitinib, azacitidine, belistat, bendamustine, benzyl isothiocyanate, bevacizumab, bexarotin, bicalutamide, bleomycin. Bonatumumab, Bortezomib, Bosutinib, Bentuximab, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Cetuximab, Chloramic acid mustard, Cisplatin, Clofabrab, Cobitinib, Cupannixicin, Crizotinib, Cyclophosphamide, Cytarabine, Dabrafenib, Dacarbazine, Actinomycin D, Daramonumab, Dasatinib, Dasorubicin, Decitabine, Defibrinolytic sodium, Degarelix, Denisil interleukin, Dexamethasone, Dexrazoxen, Dihydrotestosterone (DHT), Dituximab, Docetaxel, Doxorubicin, Elotuzumab, EltrombopagEnzalutamide, epirubicin, elebulin mesylate, erlotinib, etoposide, everolimus, exemestane, exemestane (instructions for use, pages 16 / 37, 38, CN 121969366, A), filgrastim, fludarabine phosphate, flutamide, fulvestrant, fulvestrant, gefitinib, gemcitabine, gemtuzumab, gemtuzumab ozomicin, glucuronidase, goserelin acetate, hydroxyurea, tiimomab, ibrutinib Idarubicin, Adalaris, Ifosfamide, Imatinib, Imiquimod, Interferon α-2b, Ipilimumab, Irinotecan, Ixaspirone, Ixazomib, Lanreotide, Lapatinib, Lenalidomide, Lenvatinib, Letrozole, Leucovorin, Leuprorelin, Lomustine, Nitrogen Mustard, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Navitoclax, Nexituzumab, Neraribine Netutopeptide, Nilotinib, Nilumet, Nivolumab, Obinutuzumab, Ofamumab, Olaparib, Homoharringtonide Mesylate, Osimertinib, Oxaliplatin, Ozomicin, Paclitaxel, Palbociclib, Palivmin, Pamidronate, Panitumumab, Pabistat, Pazopanib, Pegaspargase, Pegylated Interferon Alpha-2b, Pembrolizumab, Pemetrexed, Pertuzumab, Prexafo, Pomalidomide, Ponatinib, Pratretinoinxa Prednisone, procarbazine, propranolol, radium-223 dichloride, raloxifene, ramucirumab, raburicase, regorafenib, rituximab, lorapipetine, romidesin, romistachytin, ruxolitinib, staximab, sipuleucel-T, sorafenib, sunitinib, talimumab, tamoxifen, temozolomide, tesimolimus, thalidomide, thioguanine, thiotepa, tepiramycin, topotecan, toremifene, toremifene, tosimomab, trabectedin, trametinib, trastuzumab, retinoic acid, trifluorouridine, triacetinib, vandetanib, vemurafenib, venetoclax, vincristine, vinorelbine, vemodega, vorinostat, aflibercept, zoledronic acid, and their pharmaceutically acceptable salts. In some embodiments, the second therapeutic agent is one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

[0085] Diseases and Symptoms The methods disclosed herein relate to the treatment of cancer. In some embodiments, the cancer is a hematologic malignancy, such as leukemia or lymphoma, for example, non-Hodgkin's lymphoma. In some embodiments, the hematologic malignancy is myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphocytic 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), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma. In some embodiments, the hematologic malignancy is myeloid leukemia. In other embodiments, the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In some embodiments, the hematologic malignancy is acute myeloid leukemia (e.g., AML). In some embodiments, the AML is primary AML. In other embodiments, the AML is secondary AML. In other embodiments, the hematologic malignancy is myelodysplastic syndrome. In some embodiments, the myelodysplastic syndrome is high-grade. In other embodiments, myelodysplastic syndrome is low-grade. In some embodiments, myelodysplastic syndrome is high-risk. In other embodiments, myelodysplastic syndrome is low-risk. In yet another embodiment, the hematologic malignancy is lymphocytic leukemia (e.g., acute lymphoblastic leukemia). In other embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, CLL is high-risk CLL. In other embodiments, the hematologic malignancy is small lymphocytic lymphoma (SLL). In other embodiments, the hematologic malignancy is follicular lymphoma. In other embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In other embodiments, the hematologic malignancy is activated B-cell-like (ABC) DLBCL. In other embodiments, the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL. In some embodiments, DLBCL is extranodal. In some embodiments, DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma. In other embodiments, page 17 / 37 of document 39, CN 121969366 A, the hematologic malignancy is mantle cell lymphoma. In another embodiment, the hematologic malignancy is Waldenström macroglobulinemia. In another embodiment, the hematologic malignancy is multiple myeloma. In another embodiment, the hematologic malignancy is marginal zone lymphoma. In another embodiment, the hematologic malignancy is Burkitt lymphoma. In another embodiment, the hematologic malignancy is non-Burkitt high-grade B-cell lymphoma. In another embodiment, the hematologic malignancy is extranodal marginal zone B-cell lymphoma. In another embodiment, the hematologic malignancy is transformed high-grade B-cell lymphoma.(HGBL). In other embodiments, the hematologic malignancy is lymphoplasmacytic lymphoma (LPL). In other embodiments, the hematologic malignancy is CNS lymphoma. In other embodiments, the CNS lymphoma is primary CNS lymphoma (PCNSL). In other embodiments, the hematologic malignancy is MALT lymphoma. In some embodiments, the hematologic malignancy is relapsed or refractory.

[0086] In some embodiments, the subject has previously received BTK inhibitors for cancer treatment. In some embodiments, the hematologic malignancy is resistant to BTK inhibitor treatment. In some embodiments, the hematologic malignancy is resistant to BTK inhibitor treatment as a single therapy. In some embodiments, the hematologic malignancy is resistant to ibrutinib, acalabrutinib, zanubrutinib, edovabrutinib, ONO-4059, spetinib, or HM7 1224. In some preferred embodiments, the hematologic malignancy is resistant to ibrutinib treatment. In some embodiments, the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, stomach cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, melanoma, prostate cancer, and head and neck cancer. In some preferred embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is colon cancer. In some embodiments, the cancer is a solid tumor. In various such embodiments, the cancer may be relapsed or refractory. In some embodiments, the above-mentioned cancers are resistant to treatment with BTK inhibitors. In some embodiments, the above-mentioned cancers are resistant to treatment with BTK inhibitors as monotherapy. In some embodiments, the cancers are resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, évorabutinib, ONO-4059, spetinib, or HM7 1224. In some preferred embodiments, the cancers are resistant to treatment with ibrutinib.

[0087] In some embodiments, the subject is an adult.

[0088] In some embodiments, the IRAK4 inhibitor or degrader is administered orally once daily at a dose of about 50 mg; and the cancer is DLBCL. In some embodiments, the DLBCL is relapsed or refractory.

[0089] In some embodiments, the IRAK4 inhibitor or degrader is administered orally once daily at a dose of about 50 mg; and the cancer is FL. In some embodiments, the FL is relapsed or refractory.

[0090] In some embodiments, the IRAK4 inhibitor or degrader is administered orally once daily at a dose of about 300 mg; and the cancer is WM. In some embodiments, the WM is relapsed or refractory.

[0091] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 50 mg; andAnd the cancer is DLBCL. In some embodiments, DLBCL is relapsed or refractory.

[0092] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 300 mg; and the cancer is LPL. In some embodiments, LPL is relapsed or refractory.

[0093] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 300 mg; and the cancer is GCB DLBCL. In some embodiments, GCB DLBCL is relapsed or refractory.

[0094] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 400 mg; and the cancer is ABC DLBCL. In some embodiments, ABC DLBCL is relapsed or refractory.

[0095] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 400 mg; and the cancer is MZL. In some embodiments, MZL is relapsed or refractory. Instructions for Use, Pages 18 / 37, 40, CN 121969366 A

[0096] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 300 mg; and the cancer is MZL. In some embodiments, the MZL is relapsed or refractory.

[0097] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of about 300 mg; and the cancer is MALT. In some embodiments, the MALT is relapsed or refractory.

[0098] In some embodiments, the IRAK4 inhibitor or degrader is administered continuously (e.g., emavusertib is administered without a withdrawal period). In other embodiments, the IRAK4 inhibitor or degrader is administered intermittently (e.g., emavusertib is administered continuously, with one or more withdrawal periods interrupted). In some embodiments, each withdrawal period lasts for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some preferred embodiments, the withdrawal period lasts for 7 days. In another preferred embodiment, the IRAK4 inhibitor or degrader is administered daily for three weeks, followed by a one-week withdrawal period, optionally followed by three weeks of daily administration and a one-week withdrawal period, which may be repeated further. In some embodiments, the above dosing regimen is continued, alternating between dosing and withdrawal periods, until a change in disease status is observed (e.g., until a complete response, partial response, or unacceptable toxicity is observed). Methods of treating certain diseases and conditions with emavusertib are disclosed in PCT / US2021 / 030192 and PCT / US23 / 21812, the contents of which are incorporated herein by reference in their entirety.

[0099] Existing Therapies: The methods disclosed herein can be used as first-line therapies or applied to patients who have failed to achieve a partial or complete response using one or more prior anticancer or anti-inflammatory therapies. In some embodiments, the subject has previously received at least one anticancer therapy. In some embodiments, the patient has previously received one anticancer therapy. In other embodiments, the patient has previously received two anticancer therapies. In other embodiments, the patient has previously received three anticancer therapies. In other embodiments, the patient has previously received four anticancer therapies. In other embodiments, the patient has previously received five anticancer therapies. In some embodiments, at least one anticancer therapy comprises: an antiCD20 antibody, nitrogen mustard, a steroid, a purine analog, a DNA topoisomerase inhibitor, a DNA intercalating agent, 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, a BTK inhibitor, a glutaminase inhibitor, or a methylating agent; or a combination thereof. In some embodiments, the anticancer therapy includes: ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, ederaris, umbrelasib, CB-839, fludarabine, or thalidomide; or combinations thereof. In some embodiments, the anticancer therapy includes ibrutinib. In some embodiments, the anticancer therapy includes ibrutinib and rituximab. In some embodiments, the anticancer therapy includes bendamustine. In some embodiments, the anticancer therapy includes bendamustine and rituximab. In some embodiments, the anticancer therapy includes bortezomib. In some embodiments, the anticancer therapy includes bortezomib and dexamethasone. In some embodiments, the anticancer therapy includes bortezomib and rituximab. In some embodiments, the anticancer therapy includes bortezomib, rituximab, and dexamethasone. In some embodiments, chlorambucil. In some embodiments, the anticancer therapy includes cladribine. In some embodiments, the anticancer therapy includes cladribine and rituximab. In some embodiments, the anticancer therapy includes cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In some embodiments, the anticancer therapy includes cyclophosphamide, prednisone, and rituximab (i.e., CPR). In some embodiments, the anticancer therapy includes fludarabine. In some embodiments, the anticancer therapy includes fludarabine and rituximab. In some embodiments, the anticancer therapy includes fludarabine, cyclophosphamide, and rituximab. In some preferred embodiments, the anticancer therapy comprises chlorambucil.Rituximab. In some preferred embodiments, the anticancer therapy comprises rituximab. In some embodiments, the anticancer therapy comprises rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In some embodiments, the anticancer therapy comprises thalidomide. In some embodiments, the anticancer therapy comprises thalidomide and rituximab. In some embodiments, the anticancer therapy comprises venetoclax. In some embodiments, the anticancer therapy comprises cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In some embodiments, the anticancer therapy comprises a hypomethylating agent. In some embodiments, the subject has previously received at least 6 cycles of a hypomethylating agent. In some embodiments, the anticancer therapy comprises any of the foregoing combinations, for example, the subject may first receive rituximab and then subsequently receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

[0100] The subject may also have received or be prepared for other non-chemotherapy treatments, such as surgery, radiation therapy, or bone marrow transplantation. In some embodiments, the subject has previously received etoposide chemotherapy. In some embodiments, the subject has previously received a bone marrow transplant. In some embodiments, the subject has previously received a stem cell transplant. In some embodiments, the subject has previously received an autologous stem cell transplant. In some embodiments, the subject has previously received an allogeneic stem cell transplant. In some embodiments, the subject has previously received a hematopoietic cell transplant. In some embodiments, the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning). In some embodiments, the subject has previously received re-induction therapy.

[0101] The subject may also have previously shown favorable results to prior therapy and only require additional treatment later. In some embodiments, the subject has previously achieved a partial response. In some embodiments, the subject has previously achieved a good partial response. In some embodiments, the subject has previously achieved a complete response. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is refractory.

[0102] In some embodiments, the subject has not previously received a BTK inhibitor for cancer treatment.

[0103] In some embodiments, the subject has previously received one or more immune checkpoint inhibitors for cancer treatment.

[0104] The subject may also have one or more pre-existing or developed genetic mutations that make the subject's cancer more or less resistant to the therapy. In some embodiments, the subject has a mutation in the RICTOR. In some embodiments, the subject has the N1065S mutation in the RICTOR. In some preferred embodiments, the subject has the MYD88 mutation.The subject has a mutation in MYD88. In some, even more preferred, embodiments, the subject has an L265P mutation in MYD88. In some embodiments, the subject has a mutation in TET2. In some embodiments, the subject does not have a mutation in CXCR4. In other embodiments, the subject has a mutation in CXCR4. In some preferred embodiments, the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or splice variant mutation). In some preferred embodiments, the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or splice variant mutation). In some preferred embodiments, the subject has a mutation in FLT3 kinase (e.g., insertion, deletion, loss, or internal tandem repeat). In some preferred embodiments, the FLT3 kinase mutation is selected from one or more of the following: internal tandem repeat (ITD), mutation in D835, mutation in F691, mutation in K663, and / or mutation in N841. In some embodiments, the FLT3 kinase mutation includes the D835H mutation. In some embodiments, the FLT3 kinase mutation includes the D835V mutation. In some embodiments, the mutation in the FLT3 kinase includes the D835Y mutation. In some embodiments, the mutation in the FLT3 kinase includes the K663Q mutation. In some embodiments, the mutation in the FLT3 kinase includes the N841I mutation. In some embodiments, the mutation in the FLT3 kinase includes ITD and D835V mutations. In some embodiments, the mutation in the FLT3 kinase includes ITD and F691L mutations. In some embodiments, the mutation in the FLT3 kinase includes ITD and D835Y mutations. In some embodiments, the subject has a mutation in STAG2 (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in DNMT3A (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in BCOR (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in WT1 (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in NRAS (e.g., on page 42 of CN 121969366 A). In some embodiments, the subject shows early progression.

[0105] In some embodiments, the subject achieves a partial response after administration of the compound. In some embodiments, the subject achieves a good partial response after administration of the compound. In other embodiments, the subject achieves a complete response after administration of the compound. In some embodiments, the subject achieves a partial response within 7 days of receiving the compound. In some embodiments, the subject achieves a good partial response within 7 days of receiving the compound. In some embodiments,Subjects achieved a complete response within 7 days of receiving the compound. In some embodiments, the subject's tumor volume decreased by approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95%. In some embodiments, the subject's tumor volume decreased by 5%. In some embodiments, the subject's tumor volume decreased by 10%. In some embodiments, the subject's tumor volume decreased by 15%. In some embodiments, the subject's tumor volume decreased by 20%. In some embodiments, the subject's tumor volume decreased by 25%. In some embodiments, the subject's tumor volume decreased by 30%. In some embodiments, the subject's tumor volume decreased by 35%. In some embodiments, the subject's tumor volume decreased by 40%. In some embodiments, the subject's tumor volume decreased by 45%. In some embodiments, the subject's tumor volume decreased by 50%. In some embodiments, the subject's tumor volume decreased by 55%. In some embodiments, the subject's tumor volume decreased by 60%. In some embodiments, the tumor volume of the subject is reduced by 65%. In some embodiments, the tumor volume of the subject is reduced by 70%. In some embodiments, the tumor volume of the subject is reduced by 80%. In some embodiments, the tumor volume of the subject is reduced by 85%. In some embodiments, the tumor volume of the subject is reduced by 90%. In some embodiments, the tumor volume of the subject is reduced by 95%.

[0106] Pharmaceutical Composition The compositions and methods of the present invention can be used to treat individuals in need. In some embodiments, the individuals are mammals such as humans, or non-human mammals. When administered to animals (such as humans), the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, the compounds of the present 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 carriers such as ethylene glycol, glycerin, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (i.e., routes that avoid transport or diffusion across the epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, excipients can be selected to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules (including spray capsules and gelatin capsules), granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems.For example, skin patches. The composition may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0107] Pharmaceutically acceptable carriers may contain physiologically acceptable agents, which, for example, act to stabilize, increase solubility, or increase the absorption of compounds such as those of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. For example, the choice of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which compounds such as those of the present invention may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0108] As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0109] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” and harmless to the patient in the sense of compatibility with other components of the formulation. Some examples of materials that can be used 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 gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (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 glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate. (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) Phosphate buffer solution; and (21) Other non-toxic and compatible substances used in pharmaceutical preparations.

[0110] The pharmaceutical composition (formulation) can be administered to a subject via any of a variety of routes of administration, including oral (e.g., as an lavage in an aqueous or non-aqueous solution or suspension, tablets, capsules (including spray capsules and gelatin capsules), pills, powders, granules, or pastes applied to the tongue); absorption through the oral mucosa (e.g., sublingual); subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment, or spray applied to the skin). The compound can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions applicable thereto can be found, for example, in U.S. Patent Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 and the patents referenced therein.

[0111] Formulations can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific manner of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, in one hundred percent, this amount is from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0112] Methods for preparing these formulations or compositions include the step of associating an active compound (such as the compound of the present invention) with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by uniformly and tightly associating the compound of the present invention with a liquid carrier or a finely chopped solid carrier or both, and then, if desired, shaping the product.

[0113] Formulations of the present invention suitable for oral administration may be in the form of capsules (including spray capsules and gelatin capsules), granules, pills, tablets, lozenges (using a flavoring base, typically sucrose and gum arabic or tragacanth), lyophilized forms, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The composition or compound may also be administered as pills, granules, or pastes.

[0114] To prepare solid dosage forms (capsules (including spray capsules and gelatin capsules), tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, which are pharmaceutically acceptable...Acceptable carriers include sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and sodium carbonate; (5) solution blockers, such as paraffin. (6) Absorption enhancers, such as quaternary ammonium compounds; (7) Wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; (10) Complexing agents, such as modified and unmodified cyclodextrins; and (11) Coloring agents. In the case of capsules (including spray capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules that use excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0115] Tablets may be made by compression or molding, optionally using one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0116] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated pills, capsules (including spray capsules and gelatin capsules), pellets, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the field of pharmaceutical formulation. They can also be formulated using, for example, different proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a slow or controlled release of the active ingredient therein, thereby providing the desired release profile. They can be sterilized, for example, by filtration through a bacterial trap filter, or by adding a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain an opaque agent and may be compositions that release the active ingredient, either only or preferably, in a specific portion of the gastrointestinal tract, optionally in a delayed manner. Examples of encapsulation compositions that can be used include polymers and waxes. If suitable, the active ingredient may also be in a microencapsulated form together with one or more of the excipients described above.

[0117] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof.

[0118] In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents, and preservatives.

[0119] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragali gum, and mixtures thereof.

[0120] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. The active compound may be mixed with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required under aseptic conditions.

[0121] In addition to the active compound, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragali gum, cellulose derivatives, polyethylene glycol, organosilicon, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0122] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0123] Transdermal patches have the added advantage of providing the body with controlled delivery of the compounds of the present invention. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0124] As used herein, the phrases “parenteral administration” and “administered parenterally” refer to a route of administration other than enteral and local administration, typically by injection,And including but not limited to intravenous injection, intramuscular injection, intra-arterial injection, intrathecal injection, intracapsular injection, intraorbital injection, intracardiac injection, intradermal injection, intraperitoneal injection, tracheal injection, subcutaneous injection, subcutaneous injection, intra-articular injection, subcapsular injection, subarachnoid injection, spinal injection, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0125] Examples of suitable aqueous and non-aqueous carriers for use in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. For example, appropriate flowability can be maintained by using coating materials such as lecithin, maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0126] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by adding various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenolic sorbic acid, etc. It may also be necessary to include isotonic agents in the composition, such as sugars, sodium chloride, etc. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0127] In some cases, to prolong the action of a drug, it is necessary to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of a drug depends on its dissolution rate, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil carrier.

[0128] Injectable long-acting formulations are prepared by forming a microencapsulated matrix of the test compound in a biodegradable polymer such as polylactide-polyglycolic acid. The release rate of the drug can be controlled depending on the ratio of drug to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Long-acting injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues.

[0129] For use in the methods of the present invention, the active compound can be administered alone or as a pharmaceutical composition comprising, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0130] The introduction method can also be provided by a rechargeable or biodegradable device. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including biodegradable and non-degradable polymers, can be used to form implants that sustainably release compounds at specific target sites.

[0131] The actual dose level of the active ingredient in the pharmaceutical composition can be varied to obtain an amount of active ingredient that is non-toxic to the patient and effectively achieves the desired therapeutic response for a specific patient, group, and route of administration.

[0132] The selected dose level will depend on a variety of factors, including the activity of the specific compound or combination of compounds used or its esters, salts or amides, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health status and medical history of the patient being treated, and similar factors well known in the medical field.

[0133] A physician or veterinarian with general skill in the art can readily determine and prescribe a therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may initially use a dose of the pharmaceutical composition or compound below the required level to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. A “therapeutically effective amount” refers to a concentration of compound sufficient to produce the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject’s weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient’s condition, the condition being treated, the stability of the compound, and, if necessary, other types of therapeutic agents administered with the compound of the present invention. A larger total dose can be delivered by multiple administrations. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al., (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814–1882, incorporated herein by reference).

[0134] Generally, the appropriate daily dose of the active compound used in the compositions and methods of the present invention will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose generally depends on the factors described above.

[0135] If desired, the effective daily dose of the active compound may be administered in one, two, three, four, five, six or more sub-dose intervals throughout the day, optionally in unit dosage form. In some embodiments of the invention, the active compound may be administered two or three times daily. In a preferred embodiment, the active compound will be administered once daily.

[0136] Patients receiving this treatment are any animals in need, including primates, specifically humans; as well as other mammals such as horses, cattle, pigs, sheep, cats, and dogs; poultry; and pets in general.

[0137] In some embodiments, the compounds of the present invention may be used alone or in combination with another type of therapeutic agent.

[0138] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In some embodiments, the contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the intended salts of the present invention include, but are not limited to, L-arginine, benzylamine, benzathine, betaine, calcium hydroxide, choline, tannin, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hepatoamide, 1H-imidazolium, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In some embodiments, the intended salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In some embodiments, the intended salts of the present invention include, but are not limited to, 1-hydroxy-2-naphtholic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, caprylic acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (caprylic acid), carbonic acid, cinnamic acid, citric acid, cyclohexylaminoethanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, d-glucanonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutamate, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, and undecanoic acid salt. Specification 25 / 37 pages 47 CN 121969366 A

[0139] Pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of these solvates can also be prepared. The source of such solvates can be from the crystallization solvent, inherent in the preparation solvent or crystallization solvent, or unrelated to such solvents.

[0140] Wetting agents, emulsifiers, and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromatizers, preservatives, and antioxidants may also be present in the composition.

[0141] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0142] Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques described herein relating to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry are those well-known and commonly used in the art.

[0143] Unless otherwise stated, the methods and techniques of this disclosure are generally practiced according to conventional methods known in the art and methods described in the various general and more specific references cited and discussed in this specification. See, for example, “Principles of Neural Science”, McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th Edition”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition”, WH Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th Edition”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0144] Unless otherwise defined herein, chemical terms used herein are used in accordance with conventional usage in the art, “The McGraw-Hill Dictionary of Chemical Terms”, Parker S.,Ed., McGraw-Hill, San Francisco, CA (1985) is an example.

[0145] All of the foregoing and any other publications, patents and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, this specification (including its specific definitions) shall prevail.

[0146] The term “agent” is used herein to mean a chemical compound (such as an organic or inorganic compound, a mixture of compounds), a biological macromolecule (such as a nucleic acid, an antibody (including portions thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies), a protein or a portion thereof, such as a peptide, lipid, carbohydrate), or an extract made from biological material such as bacteria, plants, fungi or animal (especially mammalian) cells or tissues. For example, an agent includes agents with known structures and agents with unknown structures. The ability of such agents to inhibit AR or promote AR degradation may make them suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0147] “Patient,” “subject,” or “individual” are used interchangeably to refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock (including cattle, pigs, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0148] “Treating a condition or patient” means taking measures to obtain a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, the reduction or improvement of one or more symptoms or conditions, a reduction in the severity of the disease, a stable (i.e., non-worsening) disease state, prevention of disease spread, delay or slowing of disease progression, improvement or relief of the disease state, and relief (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean an extended lifespan compared to the expected lifespan without treatment.

[0149] The term “prevention” is recognized in the art and is well known in the art when used in relation to conditions such as local recurrence (e.g., pain), diseases such as cancer, syndromes such as heart failure, or any other medical condition, and includes the administration of a composition that, relative to a subject who has not received the composition, reduces the frequency of the subject’s medical condition symptoms or delays their onset. Thus, cancer prevention includes, for example, relative to an untreated control population, In a population receiving prophylactic treatment, the number of detectable cancer growths is reduced, and / or the onset of detectable cancer growths is delayed in a treated population relative to an untreated control population, for example, by delaying a statistically and / or clinically significant amount.

[0150] The substance, compound, or other treatment may be “administered” to the subject using one of a variety of methods known to those skilled in the art.The administration of a substance or agent, or a compound or agent, is described as "administration". For example, a compound or agent may be administered intravenously, via artery, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and percutaneously (by absorption, e.g., via a skin catheter). A compound or agent may also be suitably introduced via a rechargeable or biodegradable polymer device or other device, such as patches and pumps, or formulations that provide a prolonged, slow, or controlled release of the compound or agent. For example, administration may be performed once, multiple times, and / or over one or more prolonged time periods.

[0151] For example, a suitable method of administering a substance, compound, or agent to a subject will also depend on, for example, the subject's age and / or physical condition, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally, for example, by ingestion. In some embodiments, the orally administered compound or agent is administered in a slow-release or sustained-release formulation, or using a device for such slow-release or sustained-release.

[0152] As used herein, the phrase “combined 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 remains effective in the body (e.g., both agents are effective for the patient simultaneously, which may include synergistic effects of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or as separate formulations. Thus, an individual receiving such treatment may benefit from the combined effect of different therapeutic agents.

[0153] The “therapeutic effective amount” or “therapeutic effective dose” of a drug or agent is the amount of drug or agent that will have the expected therapeutic effect when administered to a subject. A complete therapeutic effect may not necessarily be achieved by administering a single dose, but may only occur after a series of doses. Therefore, a therapeutic effective amount may be administered in one or more doses. The precise effective amount required by the subject will depend, for example, the subject’s body type, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The effective amount under given conditions can be readily determined by routine experiments.

[0154] As used herein, the terms “optional” or “optionally” mean that an event or condition described below may or may not occur, and the description includes instances of the event or condition occurring as well as instances of it not occurring. For example, “optionally substituted alkyl” means that the alkyl group may be substituted as well as that the alkyl group is not substituted.

[0155] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods set forth below. If the substituent itself is substituted by more than one group, these should be understood.Multiple groups can be on the same carbon or different carbons, as long as a stable structure is produced.

[0156] As used herein, the term "optionally substituted" means that one to six hydrogen groups in a given structure are replaced by a group of a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-AO-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen groups in a given structure are replaced by the above-described substituents. More preferably, one to three hydrogen groups are replaced by the substituents described above. It should be understood that the substituents can be further substituted.

[0157] As used herein, the term "alkyl" refers to a saturated aliphatic group, including but not limited to C1-C10 straight-chain alkyl or C1-C10 branched alkyl. Preferably, an "alkyl" group refers to a C1-C6 straight-chain alkyl group or a C1-C6 branched alkyl group. Most preferably, an "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C4 branched alkyl group. Examples of "alkyl" 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. The "alkyl" group may optionally be substituted.

[0158] The term "acyl" is recognized in the art and refers to a group represented by the general formula alkyl C(O)-, preferably alkyl C(O)-.

[0159] The term "amide" is recognized in the art and refers to an amino group substituted with an acyl group and may be, for example, represented by the formula alkyl C(O)NH-.

[0160] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula alkyl C(O)O-, preferably alkyl C(O)O-.

[0161] The term "alkoxy" refers to an alkyl group having an oxygen atom attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0162] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0163] The term "alkyl" refers to a saturated aliphatic group, which includes straight-chain alkyl, branched alkyl, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In a preferred embodiment, the straight-chain or branched alkyl group has 30 or fewer carbon atoms in its main chain (e.g., C1-30 for straight chains and C3-30 for branched chains), and more preferably 20 or fewer.

[0164] Furthermore, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter referring to an alkyl moiety having a substituent with a hydrogen atom on one or more carbons of a hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0165] The terms “Cxy” or “Cx-Cy”, when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, are intended to include carbon atoms in a chain containing groups from x to y. C0 alkyl indicates a hydrogen atom at the terminal position of the group, or a bond if internal. For example, C1-6 alkyl groups contain one to six carbon atoms in the chain.

[0166] As used herein, the term “alkylamino” refers to an amino group substituted with at least one alkyl group.

[0167] As used herein, the term “alkoxythio” refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0168] As used herein, the term "amide" refers to a group wherein R9 and R10 each independently represent a hydrogen or hydrocarbon group, or R9 and R10 together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in the ring structure.

[0169] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, for example, this part can be represented by the following formula: [Specification 28 / 37 pages 50 CN 121969366 A], wherein R9, R10, and R10' each independently represent a hydrogen or hydrocarbon group, or R9 and R10 together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in the ring structure.

[0170] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0171] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0172] As used herein, the term “aryl” includes a substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is a carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes a polycyclic system having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0173] The term “carbamate” is recognized in the art and refers to a group, wherein R9 and R10 independently represent a hydrogen or hydrocarbon group.

[0174] As used herein, the term “carbocyclic alkyl” refers to an alkyl group substituted by a carbocyclic group.

[0175] The term “carbocyclic” includes 5- to 7-membered monocyclic and 8- to 12-membered bicyclic. Each ring of a bicyclic carbocyclic ring may be selected from saturated, un...Saturated and aromatic rings. A carbide ring includes a bicyclic molecule in which one, two, or three or more atoms are shared between two rings. The term “fused carbide ring” refers to a bicyclic carbide ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbide ring may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbide ring, provided that the valence allows. Exemplary “carbide rings” 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 carbocyclic rings include naphthane, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” can be substituted at any one or more positions capable of carrying a hydrogen atom.

[0176] As used herein, the term “carbocyclic alkyl” refers to an alkyl group substituted with a carbocyclic group.

[0177] The term “carbonate” is recognized in the art and refers to the group -OCO2-.

[0178] As used herein, the term “carboxyl” refers to a group represented by the formula -CO2H.

[0179] The term “cycloalkyl” includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4-membered to 8-membered rings, more preferably 4-membered to 6-membered rings. The term "cycloalkyl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is cycloalkyl, and a substituent (e.g., R100) is attached to the cycloalkyl ring. For example, other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline, etc.

[0180] As used herein, the term "ester" refers to the group -C(O)OR9, wherein R9 represents a hydrocarbon group.

[0181] As used herein, the term "ether" refers to a hydrocarbon group attached to another hydrocarbon group by means of oxygen. Thus, the ether substituent of the hydrocarbon group may be hydrocarbon-O-. Ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic rings. Ethers include an "alkoxyalkyl" group, which can be represented by the general formula alkyl-O-alkyl. Specification 29 / 37 pages 51 CN 121969366 A

[0182] As used herein, the terms "halo" and "halogen" refer to halogens and include chlorine, fluorine, bromine, and iodine.

[0183] As used herein, the terms “heteroalkyl” and “heteroaryl” refer to alkyl groups substituted with heteroaryl groups.

[0184] The terms “heteroaryl” and “heteroaryl” include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “heteroaryl” also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is an aromatic heterocyclic ring, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.

[0185] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0186] As used herein, the term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group.

[0187] The terms "heterocyclic group," "heterocyclic," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclic group" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is heterocyclic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. For example, heterocyclic groups include piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0188] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms without =O or =S substituents and generally has at least one carbon-hydrogen bond and is predominantly a carbon backbone, but may optionally include heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on the connecting carbon) and ethoxy (which is connected by oxygen rather than carbon) are not considered hydrocarbon groups. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

[0189] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

[0190] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, ynyl, or alkoxy, the term "lower" is intended to include groups having ten or fewer atoms in the substituents, preferably six or fewer atoms. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms, preferably six or fewer carbon atoms. In some embodiments, the acyl group defined herein...The substituents, such as alkyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, are 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 hydroxyalkyl and aralkyl in the cited example (in which case, for example, when calculating the carbon atom in the alkyl substituent, the atom in the aryl group is not counted).

[0191] The terms “polycyclic,” “polycyclic,” and “polycyclic” refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) wherein two or more atoms are shared by two adjacent rings, for example, the ring is a “fused ring.” Each ring of a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring of a polycyclic compound contains 3 to 10 atoms in the ring, preferably 5 to 7.

[0192] The term “sulfate” is recognized in the art and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0193] The term “sulfonamide” is recognized in the art and refers to a group represented by the following general formula (see specification 30 / 37, page 52, CN 121969366 A), wherein R9 and R10 independently represent hydrogen or a hydrocarbon group.

[0194] The term “sulfoxide” is recognized in the art and refers to the group -S(O)-.

[0195] The term “sulfonate” is recognized in the art and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0196] The term “sulfone” is recognized in the art and refers to the group -S(O)2-.

[0197] The term “substituted” refers to a portion having a substituent with a hydrogen substituted group on one or more carbons of the main chain. It should be understood that “substituted” or “replaced by” includes the implicit condition that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, which does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. For a suitable organic compound, permissible substituents may be one or more, the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compound described herein that satisfy the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphates, phosphonates, hypophosphonates, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, and azides.The substituted moiety includes thioalkyl, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, aralkyl, or aromatic or aromatic heterocyclic moiety. Those skilled in the art will understand that, where appropriate, the substituted portion of the hydrocarbon chain can itself be substituted.

[0198] As used herein, the term “thioalkyl” refers to an alkyl group substituted with a thiol group.

[0199] As used herein, the term “thioester” refers to the group -C(O)SR9 or -SC(O)R9, where R9 represents a hydrocarbon group.

[0200] As used herein, the term “thioether” is equivalent to an ether, where oxygen is substituted with sulfur.

[0201] The term “urea” is recognized in the art and can be represented by the following general formula, where R9 and R10 independently represent hydrogen or a hydrocarbon group.

[0202] As used herein, the term “modulation” includes inhibition or suppression of a function or activity (such as cell proliferation) and enhancement of a function or activity.

[0203] The phrase “pharmaceutically acceptable” is recognized in the art. In some embodiments, this term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that, within reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and which are commensurate with a reasonable benefit / risk ratio.

[0204] “Pharmaceutically acceptable salt” or “salt” herein refers to an acid addition salt or base addition salt that is suitable for or compatible with the treatment of a patient.

[0205] As used herein, the term “pharmaceutically acceptable acid addition salt” refers to any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monoacid salts or diacid salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts of Formula I compounds are more soluble in water and a wide variety of hydrophilic organic solvents and typically exhibit higher melting points compared to their free basic forms. The selection of suitable salts is known to those skilled in the art. Other non-pharmaceuticalally acceptable salts, such as oxalates, can be used to isolate Formula I compounds for laboratory use or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0206] As used herein, the term “pharmaceutically acceptable base addition salt” refers to any non-toxic organic or inorganic base addition salt of any acid compound or any intermediate thereof represented by Formula I. Exemplary inorganic bases forming suitable salts include lithium hydroxide, sodium, potassium, calcium, magnesium, or barium. Exemplary organic bases forming suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or ammonia. The selection of suitable salts is known to those skilled in the art.

[0207] Many compounds that can be used in the methods and compositions of this disclosure have at least one stereocenter in their structure. The stereocenter may be present in an R or S configuration, and the use of the R and S designations is consistent with the rules described in Pure Appl. Chem. (1976), 45, 11-30. This disclosure covers all stereoisomers, such as enantiomeric and diastereomeric forms of compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0208] Furthermore, some compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, this disclosure includes mixtures and individual isomers.

[0209] Some compounds may also exist in tautomeric forms. These forms, while not explicitly indicated in the formulas described herein, are intended to be included within the scope of this disclosure.

[0210] A “prodrug” or “pharmaceuticalally acceptable prodrug” means a compound that, upon administration, is metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of this disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protective) group on the functional portion of an active compound. Prodrugs include compounds that can be oxidized, reduced, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation to produce an active compound. Examples of prodrugs using esters or aminophosphates as biologically unstable or cleavable (protective) groups are disclosed in U.S. Patent Nos. 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 compounds of Formula I. This disclosure includes prodrugs of the compounds described herein within its scope. Conventional procedures for selecting and preparing suitable prodrugs are described, for example, in “Design of Prodrugs”, Ed.H. Bundgaard, Elsevier, 1985.

[0211] As used herein, the phrase “pharmaceuticalally acceptable carrier” refers to pharmaceutically acceptable materials, compositions, or carriers, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that can be used to formulate medicaments for pharmaceutical or therapeutic purposes.

[0212] The terms “logarithm of solubility,” “LogS,” or “logS” as used herein are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is generally accompanied by poor absorption. The LogS value is the unit stripping logarithm (base 10) of solubility measured in mol / L.

[0213] As used herein, “expression” refers individually and / or cumulatively to one or more biological processes that result in the production of a nucleic acid sequence according to the encoded agent. Expression specifically includes either or both of transcription and translation. For example, the expression of a DNA sequence can result in the production of RNA and / or protein. In another example, the expression of an RNA sequence results in the production of a polypeptide (e.g., protein). A cell, tissue, biological sample, or subject that produces the encoded agent may be said to express the encoded agent. Specification 32 / 37 pages 54 CN 121969366 A

[0214] As used herein, the phrase “expression product” refers to the expressed product. Expression products specifically include transcription products (i.e., RNA) and translation products (i.e., polypeptides).

[0215] As used herein, the phrases “expression level” and “level of expression” refer to the level and / or prevalence of expression of an expression product. For example, expression level refers to the level and / or prevalence of an expression product and / or its precursor within a cell, tissue, biological sample, or subject. For example, the expression level of a gene can be measured by measuring the prevalence (i.e., presence) and / or level of its transcription product (e.g., RNA) and / or measuring the prevalence and / or level of its translation product (e.g., polypeptide). For example, the expression level of a protein can be measured by measuring the prevalence (i.e., presence) and / or level of its transcription precursor (e.g., mRNA) and / or measuring the prevalence and / or level of the protein and / or its components (e.g., peptide fragments).

[0216] As used herein, the term “AZA” refers to azacitidine.

[0217] As used herein, the term “VEN” refers to venetoclax.

[0218] As used herein, the term “BID” means twice-daily administration of the drug.

[0219] As used herein, the term “QD” means daily administration of the drug.

[0220] As used herein, the term “CR” means complete response.

[0221] As used herein, the term “CRi” means CR with incomplete hematologic recovery.

[0222] As used herein, the term “CRh” means CR with partial hematologic recovery.

[0223] As used herein, the term “mCR” means complete bone marrow response.

[0224] As used herein, the term “OS” means overall survival.

[0225] As used herein, the term “PR” means partial response.

[0226] As used herein, the term “MTD” means maximum tolerated dose.

[0227] As used herein, the term “RP2D” refers to the recommended phase 2 dose.

[0228] As used herein, the term “ANC” refers to the absolute neutrophil count.

[0229] The term “WBC” refers to the white blood cell count.

[0230] Examples The invention will now be described in general terms and will be more readily understood by referring to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0231] Exemplary methods and compounds related to this disclosure can be found in U.S. Patent Nos. 10 / 160,753, 10 / 758,518 and 11 / 419,875; U.S. Application No. 17 / 680,995; and pending PCT patent applications US21 / 59668, US2021 / 030192, WO22 / 031330 and US23 / 21812; the contents of which are incorporated herein by reference in their entirety.

[0232] Example 1: Exemplary performance targets and endpoints of emavusertib in subjects with AML or MDS who have received or have not received prior BCL-2 therapy Phase 1 (monotherapy) / Phase 1b (combination therapy) Primary targets • Phase 1: Determine the MTD and RP2D of emavusertib in patients with AML or intermediate, high, or very high risk MDS (hrMDS) based on safety and tolerability, dose-limiting toxicities, and pharmacokinetic and pharmacodynamic studies. • Phase 1b: Determine the MTD and RP2D of emavusertib in treatment-naïve patients with AML or hrMDS in combination with AZA or in relapsed / refractory patients after first-line treatment, based on safety and tolerability, dose-limiting toxicities, and pharmacokinetic and pharmacodynamic studies. Phase 1 (monotherapy) / Phase 1b (combination therapy) Primary endpoints Prescription 33 / 37 pages 55 CN 121969366 A • MTD (defined as the highest dose with a dose-limiting toxicity rate <33% in the first treatment cycle in at least 6 patients [time range: 28 days]) • RP2D (determined by the sponsor in consultation with the CSC, considering all aspects of safety, tolerability, bioactivity, pharmacokinetics, and preliminary efficacy in the trial population [time range: 24 months]) • Safety measured by adverse events, ECG, chemical and hematological laboratory values, vital signs, and physical examination. • Pharmacokinetic parameters of emavusertib characterized using non-compartmental analysis and appropriate pharmacokinetic models. • Assessment of anticancer activity. • Secondary endpoints for Phase 1 (monotherapy) / Phase 1b (combination therapy).• Pharmacokinetic parameters of emavusertib were measured using Cmax, Cmin, Tmax, AUC0-24, AUC0-inf, and T1 / 2 (time range 24 months). • Clinical response assessment in AML or hrMDS is as follows: ○AML: Proportion of patients achieving CR+CRh; Proportion of patients achieving CRi, CR, or CRh. ○hrMDS: Overall response rate of CR+PR+mCR. ○ Infusion independence: Phase 1 (monotherapy) / Phase 1b (combination therapy) Exploratory endpoints: • Assess the potential association between target-related biomarkers, selected genetic mutations, gene expression profiles, cell origin, or other molecular taxonomic subtypes and antileukemic activity. • Assess the pharmacodynamic effects of emavusertib on selected biomarkers in peripheral blood and bone marrow. • Further assessment of the anticancer activity of RP2D. Phase 1 (monotherapy) / Phase 1b (combination therapy) Exploratory endpoints: • RNA expression profiling, DNA / RNA sequencing, and proteomic analysis can be performed on peripheral blood and / or tumor samples. IRAK4 / NF-κB pathway status, differentiation markers / apoptosis, etc., to analyze changes induced by the study treatment and to identify potential predictive biomarkers.

[0233] • Clinical response assessment in AML or hrMDS is as follows: ○ Duration of response (DOR) ○ Time to response ○ Overall survival (OS) Study Design This is a phase 1, open-label dose-escalation and cohort expansion study of emavusertib, in which emavusertib is used as monotherapy in patients with AML or MDS, in combination with AZA in treatment-naïve adult patients with AML or hrMDS after first-line treatment, or in combination with VEN in patients with relapsed / refractory AML or hrMDS.

[0234] The phase 1 dose-escalation (monotherapy) portion is for patients with AML and hrMDS.

[0235] In the phase 1b portion of this study (combination therapy), patients with AML or hrMDS receive emavusertib in combination with azacitidine (AZA) or venetoclax (VEN). Patients currently receiving combination therapy and benefiting from treatment should continue the study according to the protocol at a dose of 300 mg BID or lower. Instructions for Use, 34 / 37 pages, 56 CN 121969366 A

[0236] This study employed a Clinical Safety Committee (CSC), whose task was to review all available safety information. The CSC was responsible for determining whether to increase the dose level or whether to initiate a new dose level. The CSC also defined whether a waiting period was required for any or all patients recruited into the new cohort.

[0237] Phase 1 Dose Escalation (Monotherapy) The starting dose level was 200 mg BID, which was determined to be safe and capable of achieving the relevant drug exposure levels.And it has shown signs of biological activity and clinical efficacy in the study of emavusertib-101. Three patients with AML or MDS will be recruited at the specified dose. If none of the first 3 patients experience dose-limiting toxicity during the first cycle, the patients may be enrolled at the next higher dose level. If one of the first 3 patients experiences dose-limiting toxicity, the dose level may be applied to the other 3 patients.

[0238] If two or three of the first 6 patients experience dose-limiting toxicity, the dose level will be considered above the MTD, and further recruitment will be conducted at a lower dose level. Any adverse event that leads to dose reduction or discontinuation is considered a dose-limiting toxicity unless the adverse event is clearly disease-related only. Provisional dose levels are summarized in Table 1.

[0239] Table 1: Provisional dose levels of Emavusertib for AML and MDS *If the MTD is not reached at dose level 2, a higher dose level may be tested. The CSC will determine these levels after reviewing all available data.

[0240] Phase 1b (Combination Therapy) Emavusertib + AZA The starting dose level of emavusertib will be 200 mg BID, administered for 21 days in a 28-day cycle (days 1–21). Details of dose escalation are provided below. AZA 75 mg / m2 will be administered intravenously (IV) or subcutaneously (SC) 7 times in 7 doses over a 28-day cycle (e.g., starting on day 1, administered consecutively for 7 times, or divided doses with 5–2 rest days at the weekend), in accordance with local prescribing information (Table 2).

[0241] Note: • If toxicity occurs, the AZA dose will be reduced to 50 mg / m2 or lower according to the label.

[0242] • The expected emavusertib doses will be 200 mg, 300 mg, 400 mg BID; DL-1 and DL-2 decreasing; 150 mg, 100 mg, administered for 21 days in a 28-day cycle.

[0243] Table 2: Dosage levels of Emavusertib + Azacitidine. Instructions for Use, 35 / 37 pages, 57 CN 121969366 A

[0244] Emavusertib + VEN The starting dose level of emavusertib will be 200 mg BID, continued for 21 days in a 28-day cycle (days 1-21). Details of dose escalation are provided below. According to the product label, VEN will be administered orally at the same time daily (day 1), increasing to 400 mg within 3 days, continued for 21 days in a 28-day cycle. The second and subsequent cycles begin from the target dose level (Table 3).

[0245] Note: • The expected emavusertib dose will be 200 mg, 300 mg, 400 mg BID; DL-1, DL-2 decreasing: 150 mg,100 mg, administered for 21 days in a 28-day cycle • VEN, using a labeled dosing regimen, with the second and subsequent cycles starting at the target dose level.

[0246] ○ Bone marrow assessment and continuous safety assessment 2 weeks after administration can shorten the cycle length to 14 days ○ Reduce the starting dose and target dose level according to the label to adjust for drug-drug interactions, and reduce the dose according to the label.

[0247] Table 3: Dosage levels of Emavusertib + Venetoclax.

[0248] Example 2: Exemplary results of RNA sequencing applied to clinical samples from a Phase 1 / 2a trial Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid malignancies that exhibit a dynamic and diverse mutational landscape as the disease progresses. Mutations in the spliceosome (e.g., mutations in splicing factors SF3B1 and U2AF1) drive overexpression of the highly active long isotype of interleukin-1 receptor-associated kinase 4 (IRAK4), upstream signaling activation of NFκB, triggering inflammation, tumorigenesis, and cancer cell survival. NFκB target genes CCL4, IL1B, and IER3 are highly expressed in patients with MDS and AML and are associated with poor prognosis. Emavusertib is a potent oral inhibitor of IRAK4 and FLT3 kinases, and its efficacy has been demonstrated in preclinical models of leukemia.

[0249] In a phase 1 / 2 trial of Example 1, patients with relapsed / refractory (R / R) AML or high-risk MDS were treated with emavusertib. Batch RNA sequencing of mononuclear cells from bone marrow or peripheral blood of 26 AML patients and 16 MDS patients (including 24 paired samples) was performed at Tempus Laboratories (Chicago, IL) using the Illumina NGS platform (San Diego, CA). RNA-seq quality control was performed using FASTQC V0.11.8 and low-quality reads were removed using Trimgalore V0.6.3. The raw counts were normalized to total reads by calculating log2CPM (counts per million). Based on actual response data, including changes in myeloid blast count, patients were classified as responders or non-responders.

[0250] Previous studies on NF-κB target genes (CCL4, IL1B, and IER3) previously associated with AML / MDS pathophysiology and prognosis showed significant differences between samples.

[0251] As shown in Figures 1 and 2, high-risk MDS patients who responded to emavusertib showed decreased IL1B and IER3 expression levels (P≤0.01 and P≤0.01, respectively). As shown in Figures 3 and 4, AML patients who responded to emavusertib...IL1B and IER3 expression levels were decreased (P≤0.01 and P=0.57, respectively). On average, IL1B and IER3 expression were lower in responders than in non-responders before and during treatment for AML and hrMDS, suggesting that low IL1B and / or low IER3 expression may predict response to emavusertib treatment. This suggests that IRAK4 inhibition may affect genes associated with the development and pathophysiology of AML / MDS. Previous clinical studies support the findings that IL1B and IER3 are important prognostic biomarkers for AML / MDS.

[0252] Therefore, if IL1B expression level is used as an adjunct to the diagnosis of AML or MDS, patients with low IL1B expression levels would be candidates for initial treatment with emavusertib, while patients with high IL1B expression levels would be candidates for combination therapy with emavusertib in combination with IL-1β inhibitors or degraders.

[0253] Additionally, as shown in Figure 5, CCL4, a chemokine known to be associated with the pathophysiology of heme malignancies, was expressed at higher levels in patients with MDS than in patients with AML. In both baseline and treatment-associated patient samples, patients with MDS exhibited significantly higher CCL4 expression compared to those with AML (P≤0.05). Other downstream chemokines associated with AML / MDS (e.g., CCL3) of IRAK4 showed similar differential expression patterns, as shown in Figure 6.

[0254] As shown in Figure 7, pathway analysis also revealed significant downregulation of the Hallmark G2M checkpoint (Figure 8), Hallmark E2F target (Figure 9), and Hallmark heme metabolism (Figure 10) pathways in treatment-associated samples from AML / MDS patients (all FDR p values ​​<0.005, normalized enrichment fractions = -3.39, -1.97, and -2.17, respectively), indicating a reduction in cell cycle proliferation and metabolic markers. Notably, E2F2 was reduced in the treated samples compared to baseline samples with a log2FC of approximately 1.3. These results suggest that emavusertib potentially downregulates pathways associated with heme metabolism, proliferation, and cell cycle regulation, such as E2F-related genes. Additionally, pathway analysis revealed a significant upregulation of TNF-α signaling via NF-κB, indicating increased apoptosis (Figure 11). In summary, the MDS revealed specific predictive biomarkers associated with clinical response to emavusertib, with non-responders exhibiting higher IL1B and IER3 expression compared to responders. Furthermore, the chemokine CCL4 showed higher expression in hrMDS compared to AML, reflecting an associated increase in inflammatory status.In addition, compared with baseline, in AML / MDS patients treated with emavusertib, the G2M checkpoint, E2F target, and heme metabolism Hallmark pathways were negatively enriched, indicating that these pathways were downregulated by emavusertib, while TNF-α / NF-KB signaling was upregulated, indicating increased apoptosis. The data presented herein demonstrate that emavusertib increases apoptosis / cell death and reduces cell proliferation and cell cycle. Overall, these data support the use of emavusertib to target the IRAK4 / NF-KB pathway in hematologic malignancies.

[0255] All publications and patents mentioned herein are incorporated herein by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In the event of conflict, this application (including any definitions herein) shall prevail.

[0256] Equivalent Embodiments Although specific embodiments of the invention have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon reading this description and the following claims. The full scope of this invention should be determined by referring to the full scope of the claims and their equivalents, as well as the description and such variations. Instruction manual page 37 / 37, 59 CN 121969366 A, Figure 1; Instruction manual figure 1 / 11 page, 60 CN 121969366 A, Figure 2; Instruction manual figure 2 / 11 page, 61 CN 121969366 A, Figure 3; Instruction manual figure 3 / 11 page, 62 CN 121969366 A, Figure 4; Instruction manual figure 4 / 11 page, 63 CN 121969366 A, Figure 5; Instruction manual figure 5 / 11 page, 64 CN 121969366 A, Figure 6; Instruction manual figure 6 / 11 page, 65 CN 121969366 A, Figure 7; Instruction manual figure 7 / 11 page, 66 CN 121969366 A, Figure 8; Instruction manual figure 8 / 11 page, 67 CN 121969366 A, Figure 9; Instruction manual figure 9 / 11 page, 68 CN 121969366 A, Figure 10 Figure 11, Appendix 11, Page 69, CN 121969366 A; Figure 12, Appendix 11, Page 70, CN 121969366 A

Claims

1. A method of treating a subject with cancer, the method comprising administering an IRAK4 modified compound to the subject, wherein the expression of interleukin-1β or immediate early response gene 3 in the subject is reduced.

2. The method according to claim 1, wherein the expression of interleukin-1β in the subject is reduced.

3. The method of claim 2, wherein the subject has reduced expression of interleukin-1β compared to a subject without cancer.

4. The method of claim 2, wherein the subject has reduced expression of interleukin-1β compared to a subject with cancer.

5. The method of claim 1, wherein the expression of the immediate early response gene 3 in the subject is reduced.

6. The method of claim 5, wherein the expression of the immediate early response gene 3 is reduced in the subject compared to a subject without cancer.

7. The method of claim 5, wherein the expression of the immediate early response gene 3 is reduced in the subject compared to the subject with cancer.

8. The method according to any one of claims 1-7, the method comprising: Biological samples are obtained from the subject; the expression level of interleukin-1β or immediate early response gene 3 in the biological samples is determined; the expression level of one or more genes is compared with a reference expression level; and if the expression level of one or more genes is lower than the reference expression level, the IRAK4 modified compound is administered.

9. The method of claim 8, wherein the method comprises determining the expression level of interleukin-1β in the biological sample.

10. The method of claim 8 or 9, wherein the method comprises determining the expression level of the immediate early response gene 3 in the biological sample.

11. The method according to any one of claims 8-10, wherein the biological sample comprises tissue (e.g., bone marrow).

12. The method according to any one of claims 8-11, wherein the biological sample comprises blood (e.g., a peripheral blood sample).

13. The method according to any one of claims 1-12, wherein the method further comprises administering an interleukin-1 blocker to the subject.

14. The method of claim 13, wherein the interleukin-1 blocker is an interleukin-1 receptor antagonist.

15. The method according to claim 13 or 14, wherein the interleukin-1 blocker is an interleukin-1 receptor antagonist protein or a homolog thereof.

16. The method according to any one of claims 13-15, wherein the interleukin-1 blocker is analytein.

17. The method of claim 13, wherein the interleukin-1 blocker is a soluble decoy receptor.

18. The method of claim 13 or 17, wherein the interleukin-1 blocker is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of a human interleukin-1 receptor component (IL-1R1) and an IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1.

19. The method according to any one of claims 13, 17 or 18, wherein the interleukin-1 blocker is linasip.

20. The method of claim 13, wherein the interleukin-1 blocker is an IL-1β neutralizing antibody.

21. The method according to claim 13 or 20, wherein the interleukin-1 blocker is kanamycin.

22. The method according to claim 13 or 20, wherein the interleukin-1 blocker is givozoline.

23. The method according to claim 13 or 20, wherein the interleukin-1 blocker is LY2189102.

24. The method of claim 13, wherein the interleukin-1 blocker is an IL-1α neutralizing antibody.

25. The method according to claim 13 or 24, wherein the interleukin-1 blocker is MABp1.

26. The method of claim 13, wherein the interleukin-1 blocker is an interleukin-1 receptor 1 blocking antibody.

27. The method according to claim 13 or 26, wherein the interleukin-1 blocker is MEDI-8968.

28. The method of claim 13, wherein the interleukin-1 blocker is a caspase-1 inhibitor.

29. The method according to any one of claims 1-28, wherein the method further comprises administering an agent that inhibits the activity of NF-KB.

30. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is an IRAK4 inhibitor.

31. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is an IRAK4 degrading agent.

32. The method according to claim 31, wherein the IRAK4 degrading agent is KT-474.

33. The method of claim 30, wherein the IRAK4 inhibitor has a structure represented by formula I: (I) or a pharmaceutically acceptable salt thereof; wherein X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2, or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently halogenated or optionally substituted heterocyclic in each occurrence; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, hydroxyalkyl, or -NR. a R b R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents are alkyl, amino, halogen, or hydroxyl; R3 is alkyl or hydroxyl in each occurrence; R a and R b Independently hydrogen, alkyl, acyl or heterocyclic; "m" and "n" are independently 0, 1 or 2; and "p" is 0 or 1.

34. The method of claim 33, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; and R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogenated, or -NR group. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b "m" is 0; and "n" is 1.

35. The method of claim 33, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; "m" and "n" are independently 0, 1 or 2; and "p" is 0 or 1.

36. The method according to any one of claims 33-35, wherein for: 。 37. The method according to any one of claims 33-36, wherein Z is an aryl, a 5-membered heterocyclic group, or a 6-membered heterocyclic group.

38. The method according to any one of claims 33-37, wherein Z is an optionally substituted heterocyclic group selected from: phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl Oxazoalkyl, thiazoalkyl, pyrazolalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanecycloyl, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl and azabicyclo[3.2.1]octyl; each of the heterocyclic groups is optionally surrounded by an alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl or -NR a R b Replace; and R a and R b It can be hydrogen, alkyl, or acyl on its own.

39. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IA): (IA) or its pharmaceutically acceptable salt.

40. The method of claim 39, wherein A is O or S; Y is -CH2- or O; and R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogenated, or -NR group. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b "m" is 0; and "n" is 1.

41. The method of claim 39, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; and "m" and "n" are independently 0, 1 or 2.

42. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IB): (IB) or its pharmaceutically acceptable salt.

43. The method of claim 42, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; and "m" and "n" are independently 0, 1 or 2.

44. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IC): (IC) or its pharmaceutically acceptable salt.

45. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NR. a R b And R a and R b It can be hydrogen or acyl group independently.

46. ​​The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, aminoalkyl, halogen, or -NR. a R b And R a and R b It can be hydrogen or acyl group independently.

47. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; and said substituent is an alkyl, aminoalkyl, halogen, or -NR. a R b ;where R a and R b It can be hydrogen, alkyl, or heterocyclic group independently.

48. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; and said substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b It can be hydrogen, alkyl, or heterocyclic group independently.

49. The method according to any one of claims 33-44, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl.

50. The method according to any one of claims 33-44, wherein R1 is an optionally substituted pyrazolyl group, wherein the substituent is an alkyl, hydroxyl, or -NR group. a R b .

51. The method according to any one of claims 33-44, wherein R1 is a halogen.

52. The method according to any one of claims 33-51, wherein R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b .

53. The method according to any one of claims 33-51, wherein R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen or hydroxyl groups.

54. The method according to any one of claims 33-51, wherein R2 is an optionally substituted heterocyclic group selected from: piperidinyl, pyrrolidinyl, morpholinyl, piperazineyl, aziridine, pyrazolyl, furanyl or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl or amino.

55. The method according to any one of claims 33-51, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazineyl.

56. The method according to any one of claims 33-51, wherein R2 is hydrogen.

57. The method according to any one of claims 33-51, wherein R2 is a cycloalkyl group.

58. The method of claim 57, wherein R2 is cyclopropyl.

59. The method according to any one of claims 33-58, wherein R3 is an alkyl group.

60. The method according to any one of claims 33-59, wherein m is 0 and p is 1.

61. The method according to any one of claims 33-59, wherein m is 0 or 2, and p is 0 or 1.

62. The method of claim 30, wherein the IRAK4 inhibitor is selected from: Or their pharmaceutically acceptable salts or stereoisomers.

63. The method of claim 30, wherein the IRAK4 inhibitor is 。 64. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

65. The method of claim 30, wherein the IRAK4 inhibitor is 。 66. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

67. The method of claim 30, wherein the IRAK4 inhibitor is 。 68. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

69. The method of claim 30, wherein the IRAK4 inhibitor is 。 70. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

71. The method of claim 30, wherein the IRAK4 inhibitor is 。 72. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

73. The method of claim 30, wherein the IRAK4 inhibitor is 。 74. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

75. The method of claim 30, wherein the IRAK4 inhibitor is 。 76. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

77. The method of claim 30, wherein the IRAK4 inhibitor is 。 78. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

79. The method according to any one of claims 33-78, the method comprising administering 100 mg to 400 mg of the IRAK4 inhibitor to the subject twice daily.

80. The method according to any one of claims 33-78, the method comprising administering 200 mg to 400 mg of the IRAK4 inhibitor to the subject twice daily.

81. The method according to any one of claims 33-78, the method comprising administering 250 mg to 350 mg of the IRAK4 inhibitor to the subject twice daily.

82. The method according to any one of claims 33-78, the method comprising administering to the subject twice daily an IRAK4 inhibitor of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

83. The method according to any one of claims 33-78, the method comprising administering to the subject twice daily an IRAK4 inhibitor of 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.

84. The method according to any one of claims 33-78, the method comprising administering to the subject twice daily an IRAK4 inhibitor of about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 400 mg.

85. The method according to any one of claims 33-78, the method comprising administering about 100 mg of the IRAK4 inhibitor to the subject twice daily.

86. The method according to any one of claims 33-78, the method comprising administering about 150 mg of the IRAK4 inhibitor to the subject twice daily.

87. The method according to any one of claims 33-78, the method comprising administering about 200 mg of the IRAK4 inhibitor to the subject twice daily.

88. The method according to any one of claims 33-78, the method comprising administering about 225 mg of the IRAK4 inhibitor to the subject twice daily.

89. The method according to any one of claims 33-78, the method comprising administering about 250 mg of the IRAK4 inhibitor to the subject twice daily.

90. The method according to any one of claims 33-78, the method comprising administering about 275 mg of the IRAK4 inhibitor to the subject twice daily.

91. The method according to any one of claims 33-78, the method comprising administering about 300 mg of the IRAK4 inhibitor to the subject twice daily.

92. The method according to any one of claims 33-78, the method comprising administering about 325 mg of the IRAK4 inhibitor to the subject twice daily.

93. The method according to any one of claims 33-78, the method comprising administering about 350 mg of the IRAK4 inhibitor to the subject twice daily.

94. The method according to any one of claims 33-78, the method comprising administering about 375 mg of the IRAK4 inhibitor to the subject twice daily.

95. The method according to any one of claims 33-78, the method comprising administering about 400 mg of the IRAK4 inhibitor to the subject twice daily.

96. The method according to any one of claims 33-78, the method comprising administering to the subject once daily about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the IRAK4 inhibitor.

97. The method according to any one of claims 33-78, the method comprising administering about 25 mg of the IRAK4 inhibitor to the subject once daily.

98. The method according to any one of claims 33-78, the method comprising administering about 50 mg of the IRAK4 inhibitor to the subject once daily.

99. The method according to any one of claims 33-78, the method comprising administering about 75 mg of the IRAK4 inhibitor to the subject once daily.

100. The method according to any one of claims 33-78, the method comprising administering about 100 mg of the IRAK4 inhibitor to the subject once daily.

101. The method according to any one of claims 33-78, the method comprising administering about 125 mg of the IRAK4 inhibitor to the subject once daily.

102. The method according to any one of claims 33-78, the method comprising administering about 150 mg of the IRAK4 inhibitor to the subject once daily.

103. The method according to any one of claims 33-78, the method comprising administering about 175 mg of the IRAK4 inhibitor to the subject once daily.

104. The method according to any one of claims 33-78, the method comprising administering about 200 mg of the IRAK4 inhibitor to the subject once daily.

105. The method according to any one of claims 33-78, the method comprising administering about 225 mg of the IRAK4 inhibitor to the subject once daily.

106. The method according to any one of claims 33-78, the method comprising administering about 250 mg of the IRAK4 inhibitor to the subject once daily.

107. The method according to any one of claims 33-78, the method comprising administering about 275 mg of the IRAK4 inhibitor to the subject once daily.

108. The method according to any one of claims 33-78, the method comprising administering about 300 mg of the IRAK4 inhibitor to the subject once daily.

109. The method according to any one of claims 33-78, the method comprising administering about 325 mg of the IRAK4 inhibitor to the subject once daily.

110. The method according to any one of claims 33-78, the method comprising administering about 350 mg of the IRAK4 inhibitor to the subject once daily.

111. The method according to any one of claims 33-78, the method comprising administering about 375 mg of the IRAK4 inhibitor to the subject once daily.

112. The method according to any one of claims 33-78, the method comprising administering about 400 mg of the IRAK4 inhibitor to the subject once daily.

113. The method according to any one of claims 33-78, the method comprising administering about 425 mg of the IRAK4 inhibitor to the subject once daily.

114. The method according to any one of claims 33-78, the method comprising administering about 450 mg of the IRAK4 inhibitor to the subject once daily.

115. The method according to any one of claims 33-78, the method comprising administering about 475 mg of the IRAK4 inhibitor to the subject once daily.

116. The method according to any one of claims 33-78, the method comprising administering about 500 mg of the IRAK4 inhibitor to the subject once daily.

117. The method according to any one of claims 1-116, wherein the IRAK4 modified compound is administered orally to the subject.

118. The method according to any one of claims 33-78, the method comprising administering about 50 mg of the IRAK4 inhibitor to the subject once daily.

119. The method according to any one of claims 33-78, the method comprising administering about 75 mg of the IRAK4 inhibitor to the subject once daily.

120. The method according to any one of claims 33-78, the method comprising orally administering about 100 mg of the IRAK4 inhibitor to the subject twice daily.

121. The method according to any one of claims 33-78, the method comprising orally administering about 125 mg of the IRAK4 inhibitor to the subject twice daily.

122. The method according to any one of claims 33-78, the method comprising orally administering about 150 mg of the IRAK4 inhibitor to the subject twice daily.

123. The method according to any one of claims 33-78, the method comprising orally administering about 175 mg of the IRAK4 inhibitor to the subject twice daily.

124. The method according to any one of claims 33-78, the method comprising orally administering about 200 mg of the IRAK4 inhibitor to the subject twice daily.

125. The method according to any one of claims 33-78, the method comprising orally administering about 225 mg of the IRAK4 inhibitor to the subject twice daily.

126. The method according to any one of claims 33-78, the method comprising orally administering about 250 mg of the IRAK4 inhibitor to the subject twice daily.

127. The method according to any one of claims 33-78, the method comprising orally administering about 275 mg of the IRAK4 inhibitor to the subject twice daily.

128. The method according to any one of claims 33-78, the method comprising orally administering about 300 mg of the IRAK4 inhibitor to the subject twice daily.

129. The method according to any one of claims 33-78, the method comprising orally administering about 325 mg of the IRAK4 inhibitor to the subject twice daily.

130. The method according to any one of claims 33-78, the method comprising orally administering about 350 mg of the IRAK4 inhibitor to the subject twice daily.

131. The method according to any one of claims 33-78, the method comprising orally administering about 375 mg of the IRAK4 inhibitor to the subject twice daily.

132. The method according to any one of claims 33-78, the method comprising orally administering about 400 mg of the IRAK4 inhibitor to the subject twice daily.

133. The method according to any one of claims 1-132, the method comprising administering an additional 75 mg / m² to the subject once daily. 2 Azacitidine.

134. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is PF-06650833.

135. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is BAY1830839.

136. The method according to any one of claims 1-135, wherein the method further comprises administering a BCL-2 inhibitor to the subject in combination.

137. The method of claim 136, wherein the BCL-2 inhibitor is venetoc.

138. The method of claim 137, wherein the method comprises administering 400 mg of venetoc daily.

139. The method of claim 137, wherein the venetoc is administered orally.

140. The method of claim 137, wherein the method comprises oral administration of 400 mg of venetoclax daily.

141. The method according to any one of claims 1-140, wherein the method further comprises administering a BTK inhibitor to the subject in combination.

142. The method of claim 141, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spetinib, or HM7 1224.

143. The method of claim 142, wherein the BTK inhibitor is acalabrutinib.

144. The method of claim 143, wherein the method comprises administering 200 mg of acalabrutinib daily.

145. The method of claim 143, wherein the acalatinib is administered orally.

146. The method of claim 143, wherein the method comprises oral administration of 200 mg of acalabrutinib daily.

147. The method of claim 142, wherein the BTK inhibitor is ibrutinib.

148. The method of claim 147, wherein the method comprises administering 420 mg of ibrutinib daily.

149. The method of claim 147, wherein the method comprises administering 560 mg of ibrutinib daily.

150. The method of claim 147, wherein the ibrutinib is administered orally.

151. The method of claim 147, wherein the method comprises oral administration of 420 mg of ibrutinib daily.

152. The method of claim 147, wherein the method comprises oral administration of 560 mg of ibrutinib daily.

153. The method of claim 142, wherein the BTK inhibitor is zanubrutinib.

154. The method of claim 153, wherein the method comprises administering 160 mg of zanubrutinib twice daily.

155. The method of claim 153, wherein the method comprises administering 320 mg of zanubrutinib once daily.

156. The method of claim 153, wherein the zanubrutinib is administered orally.

157. The method of claim 153, wherein the method comprises orally administering 160 mg of zanubrutinib twice daily.

158. The method of claim 153, wherein the method comprises oral administration of 320 mg of zanubrutinib once daily.

159. The method according to any one of claims 1-158, wherein the cancer is a hematologic malignancy.

160. The method of claim 159, wherein the hematologic malignancy is non-Hodgkin's lymphoma.

161. The method of claim 159, wherein the hematologic malignancy is leukemia.

162. The method of claim 159, wherein the hematologic malignancy is lymphoma.

163. The method according to any one of claims 159-162, wherein the hematologic malignancy is myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphocytic 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), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma.

164. The method of claim 159, wherein the hematologic malignancy is myeloid leukemia.

165. The method of claim 159, wherein the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia).

166. The method of claim 159, wherein the hematologic malignancy is acute myeloid leukemia (e.g., AML).

167. The method of claim 166, wherein the AML is primary AML.

168. The method of claim 166, wherein the AML is secondary AML.

169. The method according to any one of claims 166-168, wherein the AML is treatment-related AML.

170. The method of claim 159, wherein the hematologic malignancy is myelodysplastic syndrome.

171. The method of claim 170, wherein the myelodysplastic syndrome is high-grade.

172. The method of claim 170, wherein the myelodysplastic syndrome is low-grade.

173. The method according to any one of claims 170-172, wherein the myelodysplastic syndrome is high-risk.

174. The method of claim 159, wherein the hematologic malignancy is lymphocytic leukemia (e.g., acute lymphoblastic leukemia).

175. The method of claim 159, wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL).

176. The method of claim 175, wherein the CLL is a high-risk CLL.

177. The method of claim 159, wherein the hematologic malignancy is small lymphocytic lymphoma (SLL).

178. The method of claim 159, wherein the hematologic malignancy is follicular lymphoma.

179. The method of claim 159, wherein the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL).

180. The method of claim 159, wherein the hematologic malignancy is activated B-cell-like (ABC) DLBCL.

181. The method of claim 159, wherein the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL.

182. The method according to any one of claims 179-181, wherein the DLBCL is external.

183. The method according to any one of claims 179-181, wherein the DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma.

184. The method of claim 159, wherein the hematologic malignancy is mantle cell lymphoma.

185. The method of claim 159, wherein the hematologic malignancy is Waldenström macroglobulinemia.

186. The method of claim 159, wherein the hematologic malignancy is multiple myeloma.

187. The method of claim 159, wherein the hematologic malignancy is marginal zone lymphoma.

188. The method of claim 159, wherein the hematologic malignancy is Burkitt lymphoma.

189. The method of claim 159, wherein the hematologic malignancy is a non-Burkett high-grade B-cell lymphoma.

190. The method of claim 159, wherein the hematologic malignancy is extranodal marginal zone B-cell lymphoma.

191. The method of claim 159, wherein the hematologic malignancy is a transformed high-grade B-cell lymphoma (HGBL).

192. The method of claim 159, wherein the hematologic malignancy is lymphoplasmacytic lymphoma (LPL).

193. The method of claim 159, wherein the hematologic malignancy is a CNS lymphoma.

194. The method of claim 193, wherein the CNS lymphoma is primary CNS lymphoma (PCNSL).

195. The method of claim 159, wherein the hematologic malignancy is MALT lymphoma.

196. The method according to any one of claims 159-195, wherein the hematologic malignancy is recurrent.

197. The method according to any one of claims 159-196, wherein the hematologic malignancy is refractory.

198. The method according to any one of claims 1-158, wherein the cancer is selected from: brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, stomach cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, melanoma, epidermal cancer, prostate cancer, and head and neck cancer.

199. The method according to any one of claims 1-158, wherein the cancer is pancreatic cancer.

200. The method according to any one of claims 1-158, wherein the cancer is colon cancer.

201. The method according to any one of claims 198-200, wherein the cancer is a solid tumor.

202. The method according to any one of claims 198-201, wherein the cancer is recurrent.

203. The method according to any one of claims 198-202, wherein the cancer is refractory.

204. The method according to any one of claims 1-203, wherein the cancer is resistant to treatment with a BTK inhibitor.

205. The method of claim 204, wherein the cancer is resistant to treatment with ibrutinib, acalatinib, zanubrutinib, evobrutinib, ONO-4059, spetinib, or HM7 1224.

206. The method of claim 205, wherein the cancer is resistant to treatment with ibrutinib.

207. The method of claim 205, wherein the cancer is resistant to treatment with acalabrutinib.

208. The method according to any one of claims 1-207, wherein the subject is an adult.

209. The method according to any one of claims 1-208, wherein the subject has previously received at least one anticancer therapy (e.g., anticancer therapy or anti-inflammatory therapy).

210. The method of claim 209, wherein the subject has previously received an anticancer therapy.

211. The method of claim 209, wherein the subject has previously received two anticancer therapies.

212. The method of claim 209, wherein the subject has previously received three anticancer therapies.

213. The method of claim 209, wherein the subject has previously received four anticancer therapies.

214. The method of claim 209, wherein the subject has previously received five anticancer therapies.

215. The method according to any one of claims 209-214, wherein the at least one anticancer therapy comprises: Anti-CD20 antibody, nitrogen mustard, steroid, purine analog, DNA topoisomerase inhibitor, DNA intercalating agent, microtubule inhibitor, BCL-2 inhibitor, proteasome inhibitor, Toll-like receptor inhibitor, kinase inhibitor, SRC kinase inhibitor, PI3K kinase inhibitor, BTK inhibitor, glutaminase inhibitor, steroid or methylating agent; or combinations thereof.

216. The method according to any one of claims 209-215, wherein the anticancer therapy comprises: Ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, opzomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, ederaris, erblisse, CB-839, fludarabine, or thalidomide; or combinations thereof.

217. The method according to any one of claims 209-216, wherein the anticancer therapy comprises dexamethasone.

218. The method according to any one of claims 209-216, wherein the anticancer therapy comprises ibrutinib.

219. The method according to any one of claims 209-216, wherein the anticancer therapy comprises ibrutinib and rituximab.

220. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bendamustine.

221. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bendamustine and rituximab.

222. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib.

223. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib and dexamethasone.

224. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib and rituximab.

225. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib, rituximab, and dexamethasone.

226. The method according to any one of claims 209-216, wherein the anticancer therapy comprises chlorambucil.

227. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cladribine.

228. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cladribine and rituximab.

229. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R).

230. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, prednisone, and rituximab (i.e., CPR).

231. The method according to any one of claims 209-216, wherein the anticancer therapy comprises fludarabine.

232. The method according to any one of claims 209-216, wherein the anticancer therapy comprises fludarabine and rituximab.

233. The method according to any one of claims 209-216, wherein the anticancer therapy comprises fludarabine, cyclophosphamide, and rituximab.

234. The method according to any one of claims 209-216, wherein the anticancer therapy comprises rituximab.

235. The method according to any one of claims 209-216, wherein the anticancer therapy comprises rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

236. The method according to any one of claims 209-216, wherein the anticancer therapy comprises thalidomide.

237. The method according to any one of claims 209-216, wherein the anticancer therapy comprises thalidomide and rituximab.

238. The method according to any one of claims 209-216, wherein the anticancer therapy comprises venetoclax.

239. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD).

240. The method according to any one of claims 209-216, wherein the anticancer therapy comprises a hypomethylating agent.

241. The method according to any one of claims 1-240, wherein the subject has previously received at least 6 cycles of a hypomethylating agent.

242. The method according to any one of claims 1-241, wherein the subject has previously received etoposide chemotherapy.

243. The method according to any one of claims 1-242, wherein the subject has previously received a bone marrow transplant.

244. The method according to any one of claims 1-243, wherein the subject has previously received a hematopoietic cell transplant.

245. The method according to any one of claims 1-244, wherein the subject has previously received a stem cell transplant.

246. The method according to any one of claims 1-245, wherein the subject has previously received an autologous stem cell transplant.

247. The method according to any one of claims 1-246, wherein the subject has previously received an allogeneic stem cell transplant.

248. The method according to any one of claims 1-247, wherein the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning).

249. The method according to any one of claims 1-248, wherein the subject has previously received re-induction therapy.

250. The method according to any one of claims 1-249, wherein the subject has previously achieved a partial response.

251. The method according to any one of claims 1-250, wherein the subject has previously achieved a good partial response.

252. The method according to any one of claims 1-251, wherein the subject has previously achieved a complete response.

253. The method according to any one of claims 1-252, wherein the subject has a mutation in the RICTOR.

254. The method of claim 253, wherein the subject has the N1065S mutation in the RICTOR.

255. The method according to any one of claims 1-254, wherein the subject has a mutation in MYD88.

256. The method of claim 255, wherein the subject has the L265P mutation in MYD88.

257. The method according to any one of claims 1-256, wherein the subject has a mutation in TET2.

258. The method according to any one of claims 1-257, wherein the subject does not have a mutation in CXCR4.

259. The method according to any one of claims 1-257, wherein the subject has a mutation in CXCR4.

260. The method according to any one of claims 1-259, wherein the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or spliceosome mutation).

261. The method according to any one of claims 1-260, wherein the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or spliceosome mutation).

262. The method according to any one of claims 1-261, wherein the subject has a mutation in FLT3 kinase (e.g., insertion, deletion, loss, or internal tandem duplication).

263. The method of claim 262, wherein the mutation of the FLT3 kinase is selected from: internal tandem repeat (ITD); mutations in D835, F691, K663, or N841; and combinations of ITD and mutations in D835, F691, K663, or N841.

264. The method of claim 263, wherein the mutation in the FLT3 kinase is D835H.

265. The method of claim 263, wherein the mutation in the FLT3 kinase is D835V.

266. The method of claim 263, wherein the mutation in the FLT3 kinase is D835Y.

267. The method of claim 263, wherein the mutation in the FLT3 kinase is K663Q.

268. The method of claim 263, wherein the mutation in the FLT3 kinase is N841I.

269. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and D835V.

270. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and F691L.

271. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and D835Y.

272. The method according to any one of claims 1-271, wherein the subject has a mutation in STAG2 (e.g., insertion, deletion, or loss).

273. The method according to any one of claims 1-272, wherein the subject has a mutation in DNMT3A (e.g., insertion, deletion, or loss).

274. The method according to any one of claims 1-273, wherein the subject has a mutation in BCOR (e.g., insertion, deletion, or loss).

275. The method according to any one of claims 1-274, wherein the subject has a mutation in WT1 (e.g., insertion, deletion, or loss).

276. The method according to any one of claims 1-275, wherein the subject has a mutation in NRAS (e.g., insertion, deletion, or loss).

277. The method according to any one of claims 1-276, wherein the subject shows early progress.

278. The method according to any one of claims 1-277, wherein the subject has not previously received a BTK inhibitor.

279. The method according to any one of claims 1-278, wherein the subject achieves a partial response after administration of the IRAK4 modified compound.

280. The method according to any one of claims 1-279, wherein the subject achieves a good partial response after administration of the IRAK4 modified compound.

281. The method according to any one of claims 1-279, wherein the subject achieves a complete response after administration of the IRAK4 modified compound.

282. The method according to any one of claims 1-281, wherein after administration of the IRAK4 modified compound, the subject's IL-1-induced signal transduction is reduced.

283. The method according to any one of claims 1-282, wherein the subject’s cytokine production is reduced after administration of the IRAK4 modified compound.

284. The method according to any one of claims 1-283, wherein the IRAK4 modified compound is administered until disease progression or unacceptable toxicity occurs.

285. The method according to any one of claims 209-284, wherein the subject has previously received a BTK inhibitor for cancer treatment.

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