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US-12622917-B2 - High-activity Wnt pathway inhibitor compound

US12622917B2US 12622917 B2US12622917 B2US 12622917B2US-12622917-B2

Abstract

Provided are a compound having the structure of formula (I) for inhibiting Wnt pathway activity, a pharmaceutical composition comprising the compound, and use of the compound in prevention and/or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

Inventors

  • Yufeng Chen
  • Keke Chen
  • Pingping LU
  • Nanhai HE
  • Peng Wu
  • Meng LV
  • Canfeng Liu
  • Han Yang
  • Kaixuan Chen
  • Wanli CHENG
  • Feifan Li
  • Youping Wang

Assignees

  • ADLAI NORTYE BIOPHARMA CO., LTD.

Dates

Publication Date
20260512
Application Date
20211027
Priority Date
20201028

Claims (10)

  1. 1 . A compound having a structure represented by formula I or a pharmaceutically acceptable salt, an isotopic derivative, end a stereoisomer thereof for inhibiting Wnt pathway activity: wherein: means existence or non-existence; R 1 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, and said R 1 can be optionally substituted by 0, 1, 2, 3 substituents selected from hydrogen, halogen, (C 1 -C 6 )alkyl, OR a , halogenated (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, halogenated (C 3 -C 6 ) cycloalkyl, cyano, SR a , halogenated (C 1 -C 6 ) alkoxy, halo (C 3 -C 6 ) cycloalkoxy, halo (C 1 -C 6 ) alkylthio, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkylthio, halo (C 3 -C 6 ) cycloalkylthio; X represents —(CR a R a′ ) m —, —(CR a R a′ ) m O(CR a R a′ ) n -, —(CR a R a′ ) m S(R a R a′ ) n ; C y represents C 6 -C 10 aryl or 5-10 membered heteroaryl, and it can be optionally substituted by 0, 1, 2, 3 substituents selected from: hydrogen, halogen, —OR a , (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, cyano, hydroxyl (C 1 -C 6 ) alkyl; R 2 represents hydrogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, hydroxyl (C 1 -C 6 ) alkyl; R 3 and R 3′ independently represent hydrogen, halogen, OR a , (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, hydroxyl (C 1 -C 6 alkyl), (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl; alternatively, R 3 and R 3′ form a 3-6 membered saturated or unsaturated ring together with the carbon atom connected to them, and the ring can also optionally contain 1 or 2 heteroatoms selected from O, S, and N; and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl, C 1 -C 6 alkyl; alternatively, R 2 , R 3 or R 2′ , R 3 form a 4-6 membered saturated or unsaturated ring together with the atoms connected to them, the ring may optionally contain 1 or 2 heteroatoms selected from O, S, and N; and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl, C 1 -C 6 alkyl; R 4 and R 4′ independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl (C 1 -C 6 alkyl), halogenated (C 1 -C 6 alkyl), (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl; alternatively, R 4 and R 4′ together form ═O; R T and R T′ each independently represent hydrogen, C 1 -C 6 alkyl, halogenated (C 1 -C 6 alkyl), hydroxyl C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, —OR a ; alternatively, R T and R T′ together form a 3-6 membered ring with the atom connected to them; wherein, when represents absence, A represents (CR L R L′ ) p , wherein R L and R L′ each independently represent hydrogen, C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, halogen, OR a , or R L and R L′ together form a 3-6 membered ring with the carbon atom connected to them, and the ring can optionally contain 0, 1, 2 heteroatoms selected from O, S, N, and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl; wherein, when represents existence, A represents CR H , wherein R H means hydrogen, C 1 -C 6 alkyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, halogen, OR a ; wherein, R a , R a′ independently represent hydrogen and C 1 -C 6 alkyl; wherein, m, n, and p each independently represent 0, 1, 2.
  2. 2 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , wherein X represents —O—, —CH 2 —, —OCH 2 or —CH 2 CH 2 —.
  3. 3 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , wherein C y represents pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, phenyl substituted by 0, 1, and 2 substituents selected from (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, halogenated (C 1 -C 6 alkyl), —OR a , halogen, cyano hydroxy (C 1 -C 6 ) alkyl; wherein, R a , R a′ each independently represent hydrogen and C 1 -C 6 alkyl.
  4. 4 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , wherein R 1 represents (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 6 -C 10 ) aryl, (5-10) membered heteroaryl, which are optionally substituted by 0, 1, 2 substituents selected from halogen, OR a , (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 alkyl); wherein, R a represents hydrogen and C 1 -C 6 alkyl.
  5. 5 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , wherein R 2 represents hydrogen or (C 1 -C 6 ) alkyl.
  6. 6 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , wherein R 3 and R 3′ each independently represent hydrogen or (C 1 -C 6 ) alkyl.
  7. 7 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , wherein R 4 and R 4′ form ═O together.
  8. 8 . The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 , selected from the group consisting of: serial serial number Compound structure number Compound structure 1 (W1 64) 2 (W1 79) 3 (W1 66) 4 (W1 69) 5 (W1 71) 6 (W1 72) 7 (W1 74) 8 (W1 75) 9 (W1 76) 10 (W1 77) 11 (W1 78) 12 (180) 13 (W1 81) 14 (W1 82) 15 (W1 83) 16 (W1 84) 17 (W1 85) 18 (W1 86) 19 (W7 5) 20 (W1 59) 21 (W1 55) 22 (W1 54 23 (W1 53) 24 (W1 50) 25 (W1 48) 26 (W1 10) 27 (W6 4) 28 (W9 4) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 (W2) 62 (W1 3) 63 (W2 2) 64 (W2 3) 65 (W3 2) 66 (W4 3) 67 (W4 6) 68 (W4 9) 69 (W5 0) 70 (W5 5) 71 (W5 6) 72 (W5 7) 73 (W8 5) 74 (W6 9) 75 (W7 7) 76 (W8 3) 77 (W8 6) 78 (W8 7) 79 (W9 5) 80 (W1 04) 81 (W1 05) 82 (W1 07) 83 (W1 16) 84 (W1 23) 85 (W1 32) 86 (W1 35) 87 (W1 36) 88 (W1 40) 89 (W1 50) 90 (W1 52) 91 (W2 21) 92 (W2 32) 93 (W2 23) 94 (W2 52) 95 (W2 53) 96 (W2 56) 97 (W3 12) 98 (W1 88) 99 (W1 93) 100 (W2 39) 101 (W2 13) 102 (W2 14) 103 (W1 95) 104 (W1 98) 105 (W1 99) 106 (W1 90) 107 (W1 92) 108 (W2 07) 109 (W2 20) 110 (W2 31) 111 (W2 41) 112 (W2 42) 113 (W2 47) 114 (W2 43) 115 (W2 44) 116 (W2 49) 117 (W2 37) 118 (W2 79) 119 (W2 55) 120 (W2 65) 121 (W2 66) 122 (W2 72) 123 (W2 76) 124 (W2 78) 125 (W2 81) 126 (W3 08) 127 (W2 80) 128 (W2 63) 129 (W3 69) 130 (W3 54) 131 (W3 66) 132 (W3 83) 133 (W3 77) 134 (W3 80) 135 (W3 82) 136 (W3 81) 137 (W3 35) 138 (W2 71) 139 (W2 68) 140 (W3 76) 141 (W2 61) 142 (W2 57) 143 (W2 77) 144 (W2 90) 145 (W3 31) 146 (W2 73) 147 (W2 74) 148 (W2 50) 149 (W2 85) 150 (W3 01) 151 (W3 32) 152 (W3 36) 153 (W2 93) 154 (W2 58 155 (W3 47) 156 (W2 64) 157 (W2 62) 158 (W2 75) 159 (W2 59) 160 (W3 62) 161 (W2 69) 162 (W2 70) 163 (W3 25) 164 (W3 26) 165 (W2 86) 166 (W2 87) 167 (W2 89) 168 (W2 98) 169 (W2 94) 170 (W3 68) 171 (W3 67) 172 (W3 05) 173 (W3 13) 174 (W3 14) 175 (W3 27) 176 (W2 96) 177 (W2 97) 178 (W3 33) 179 (W3 75) 180 (W3 86) 181 (W3 96) 182 (W3 95) 183 (W3 09) 184 (W2 82) 185 (W3 10) 186 (W3 11) 187 (W3 15) 188 (W3 16) 189 (W3 06) 190 (W3 17) 191 (W3 18) 192 (W3 24) 193 (W3 42) 194 (W3 41) 195 (W3 23) 196 (W3 44) 197 (W3 43) 198 (W3 07) 199 (W3 19) 200 (W3 20) 201 (W3 60) 202 (W3 61) 203 (W3 72) 204 (W3 74) 205 (W3 79) 206 (W3 88) 207 (W3 57) 208 (W) 209 (W) 210 (W3 71) 211 (W3 90) 212 (W3 89) 213 (W3 55) 214 (W3 92) 215 (W3 91) 216 (W3 52) 217 (W3 59) 218 (W3 39) 219 (W3 38) 220 (W3 98) 221 (W3 99) 222 (W4 02) 223 (W4 03) 224 (W4 06) 225 (W4 07) 226 (W4 11) 227 (W4 12) 228 (W4 13) 229 (W4 14) 230 (W4 15) 231 (W4 17) 232 (W4 18) 233 (W4 19) 234 (W4 20) 235 (W4 22) 236 (W4 24 237 (W4 25) 238 (W4 26) 239 (W4 27) 240 (W4 28) 241 (W4 31) 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269
  9. 9 . A pharmaceutical composition, comprising the compound or pharmaceutically acceptable salt according to claim 1 .
  10. 10 . A method for preventing and/or treating cancer, tumor, inflammatory diseases, autoimmune diseases or immune-mediated diseases, comprising administering the compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as claimed in claim 1 to a subject in need thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is the national phase of International Application No. PCT/CN2021/126539, titled “HIGH-ACTIVITY WNT PATHWAY INHIBITOR COMPOUND”, filed on Oct. 27, 2021, which claims the priority to Chinese Patent Application No. 202011175894.X, titled “HIGH-ACTIVITY WNT PATHWAY INHIBITOR COMPOUND”, filed on Oct. 28, 2020 with the China National Intellectual Property Administration, which is incorporated herein by reference in entirety. TECHNICAL FIELD The invention relates to a heterocyclic compound, in particular to a highly active Wnt pathway inhibitor and its application. BACKGROUND Wnt/β-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β-catenin is only a cytoskeleton protein that forms a complex with E-cadherin at the cell membrane to maintain the adhesion of the same type of cells and prevent cell movement. When the Wnt signaling pathway is not activated, the β-catenin in the cytoplasm is phosphorylated to form a β-catenin degradation complex with APC, Axin, and GSK3β, and the ubiquitin system is activated to degrade β-catenin through the proteasome pathway, so that the cytoplasmic β-catenin was maintained at a low level. When cells are stimulated by Wnt signal, Wnt protein binds to the specific receptor Frizzled protein on the cell membrane, and the activated Frizzled receptor recruits intracellular Disheveled protein, which inhibits the degradation activity of the β-Catenin degradation complex formed by GSK3β and other proteins, stabilizing β-Catenin protein in free state in cytoplasm. The stable accumulated β-Catenin in the cytoplasm enters the nucleus and binds to the LEF/TCF transcription factor family to initiate the transcription of downstream target genes (such as c-myc, c-jun, Cyclin D1, etc.). Transitional activation of the Wnt/β-catenin signaling pathway is closely related to the occurrence of various cancers (including colon cancer, gastric cancer, breast cancer, etc.). For example, abnormal activation of Wnt signaling pathway and nuclear accumulation of β-catenin protein widely exist in colorectal cancer, and the proliferation of colon cancer can be inhibited by inhibiting the activity of Wnt signaling pathway. APC mutations exist in more than 85% of colorectal cancers, and the mutated APC blocks the phosphorylation and degradation of β-catenin and induces the occurrence of colorectal cancer. In addition, mutations of Axin and β-catenin itself can also cause the intracellular accumulation of β-catenin and activate the Wnt/β-catenin pathway. CONTENTS OF THE INVENTION The present invention provides a compound having a structure of formula (I) for inhibiting Wnt pathway activity and pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers: wherein: means existence or non-existence;R1 represents C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, and said R1 can be optionally substituted by 0, 1, 2, 3 substituents selected from: hydrogen, halogen, ORa, halogenated (C1-C6) alkyl, (C3-C6) cycloalkyl, halogenated (C3-C6) cycloalkyl, cyano, SRa, halogenated (C1-C6) alkoxy, halo (C3-C6) cycloalkoxy, halo (C1-C6) alkylthio, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkylthio, halo (C3-C6) cycloalkylthio;X represents —(CRaRa′)m—, —(CRaRa′)m O(CRaRa′)—, —(CRaRa′)m S(RaRa)n;Cy represents C6-C10 aryl or 5-10 membered heteroaryl, and it can be optionally substituted by 0, 1, 2, 3 substituents selected from: hydrogen, halogen, —ORa, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano, hydroxyl (C1-C6) alkyl;R2 represents hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl (C1-C6) alkyl;R3 and R3′ independently represent hydrogen, halogen, ORa, (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl (C1-C6 alkyl), (C1-C6) alkoxy (C1-C6) alkyl;alternatively, R3 and R3′ form a 3-6 membered saturated or unsaturated ring together with the carbon atom connected to them, and the ring can also optionally contain 1 or 2 heteroatoms selected from O, S, and N; and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl, C1-C6 alkyl;alternatively, R2, R3 or R2′, R3 form a 4-6 membered saturated or unsaturated ring together with the atoms connected to them, the ring may optionally contain 1 or 2 heteroatoms selected from O, S, and N; and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl, C1-C6 alkyl;R4 and R4′ independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl (C1-C6 alkyl), halogenated (C1-C6 alkyl), (C1-C6) alkoxy (C1-C6) alkyl;alternatively, R4 and R4′ together form ═O;RT and RT′ each independently represent hydrogen, C1-C6 alkyl, halogenated (C1-C6 alkyl), hydroxyl C1-C6 alkyl, C3-C6 cycloalkyl, halogen, ORa;alternatively, RT and RT′ together form a 3-6 membered ring with the atom connected to them;wherein, when represents absence, A represents (CRLRL′)p, wherein RL and RL′ each independently represe