Halogen-containing compound for 5' end capping of nucleic acid and use thereof.

Abstract

Provided are halogen-containing compounds used for capping the 5' end of a nucleic acid and the use thereof, the compounds being represented by following formula (I). Also provided are the uses and effects of the compounds for nucleic acid transcription, expression, etc.

Description

Halogen-containing compound for 5' end capping of nucleic acid and use thereof. Technical Field

[0001] The present invention relates to the fields of biotechnology and synthetic chemistry, in particular to a class of nucleoside compounds and, in particular, to a halogen-containing compound for 5' end capping of a nucleic acid (RNA) and a use of the halogen-containing compound. Background of the Technique

[0002] In recent years, as the global COVID-19 situation has changed, messenger RNA (mRNA) technology and related vaccine drugs have made significant progress from the laboratory to clinical application. With the unprecedented success of the COVID-19 vaccine, market expectations for mRNA technology have increased dramatically. Application scenarios for mRNA technology have great potential for development not only in the field of infectious diseases like COVID-19, but also in preventive vaccines, therapeutic drugs, and even regenerative and cell-programming therapies.

[0003] The cap structure is a widely present RNA modification in cells that plays an important role in maintaining mRNA stability and regulating protein translation. Currently, many studies are dedicated to further chemical modification of the cap structure to further enhance the efficiency of mRNA translation while reducing its immunogenicity. Summary of the Invention Petition 870250103152, dated 11 / 11 / 2025, page 10 / 219 2 / 208

[0004] The present invention provides a halogen-containing compound for 5' end capping of a nucleic acid (RNA), a pharmaceutically acceptable solvate and stereoisomer thereof, and an use thereof. This compound has various modified or unmodified 7-methylguanine bases in the nucleoside at one end and a halogen substituent at the 2' position of the nucleoside at the other end. The use of this compound in a reaction to cap the 5' end of mRNA has a high capping rate and good transcription efficiency in vitro. At the same time, it has high translation expression efficiency at the cellular level and in vivo, such as in mice.

[0005] The present invention provides a halogen-containing compound for 5' end capping of a nucleic acid or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has a structure of Formula (I): Petition 870250103152, dated 11 / 11 / 2025, p. 11 / 219 3 / 208 O —po—pO—pO OH OH OH OpO HO O J1 RJ4J N01 THE OJ2N02 °< HOZO THE .N03 OJ3OP HOZO THE J4 OOP HO O R7 HOJ5R0 (I), in which Ro is any one selected from the group consisting of F, Cl, Br and I, Ri is a selected group from the group consisting of -H, -OH, C1-4 alkyl and C1-4 alkoxy, R2 is any one selected from the group consisting of -H, -OH, C1-6 alkyl and C1-6 alkoxy, optionally, R1 and R2 are connected to form a ring by means of a chemical bond, and -R1-R2- is any one of -(CH2)qO-, -O-(CH2)q- and (CH2)mO-(CH2)n-, where q, m, n are each independently 1, 2 or 3. R3 is any of H, -OH, -SH, -N3, -NH2, halogen, -CN, C1-6 alkoxy, Petition 870250103152, dated 11 / 11 / 2025, page 12 / 219 4 / 208 O(CH2)sCN, -SR3a, -O(CH2)pR3b, OCOR3c, O(CH2)pCOR3c, -O(CH2)tSH, O(CH2)pOH, -O(CH2)pN3 and -O(CH2)pNH2, where t, pes are, each independently, any integer from 1 to 6, R3a is C1-6 alkyl, R3b is C1-12 aryl optionally substituted with one or more R3d or C5-12 heteroaryl optionally substituted with one or more R3d, R3c is C1-10 alkyl optionally substituted with one or more R3d, C1-10 alkenyl optionally substituted with one or more R3d, C5-12 cycloalkyl optionally substituted with one or more R3d or C5-12 cycloalkenyl optionally substituted with one or more R3d, wherein R3 is optionally substituted with a or more R3e, and R3d and R3e are selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, cyano, amino, nitro, -OH and -SH, R4, R5, Re, and R7 are each independently selected from the group consisting of -H, -OH, -OCH3, halogen, -CN, and -SH. N01, N02, N03 and N04 are each independently selected from 0 or 1, J1, J2, J3, J4, and J5 are each independently selected from natural or modified pyrimidine nucleotide bases or natural or modified purine nucleotide bases. Rp1 is C1 to C1 alkyl, preferably C1 to C3 alkyl, which is optionally substituted with -SH, -N3, C2 to C1 alkenyl or C2 to C1 alkynyl. Rp2 and Rp3 are each independently selected from the group consisting of H, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, PEG, CORp4 and SO2RP4, wherein these groups are each optionally substituted with -CN, -N3, -SH or alkynyl, Rp4 is selected from the group consisting of H and C1 to C6 alkyl, and Rp2 and Petition 870250103152, dated 11 / 11 / 2025, p. 13 / 219 5 / 208 Rp3 are optionally connected to form a ring, and since, when NO1, NO2, NO3 and NO4 are all O, J5 is a guanine base, and when R2 is -OH, R3 is not a methoxy group.

[0006] In a preferred embodiment, the compound of the present invention has a structure of Formula (I'): that each group in Formula (I') has the same meaning as that described above in relation to Formula (I). In a preferred embodiment, at least one of J1, J2, J3, J4, and J5 is a modified nucleotide base, preferably a modified purine nucleotide base, more preferably a methyl-modified purine nucleotide base, and even more preferably 6-N-methyladenine. Petition 870250103152, dated 11 / 11 / 2025, p. 14 / 219 6 / 208

[0007] In a preferred embodiment, R3 is any of -H, -OH, -SH, N3, -NH2, halogen, -CN, C1-6 alkoxy, -O(CH2)pCN, -SR3a, -O(CH2)pR3b, OCOR3c, O(CH2)pCOR3c, -O(CH2)pSH, -O(CH2)pOH, -O(CH2)pN3 and -O(CH2)pNH2, where t, pes are each independently any integer from 1 to 6, preferably 1 to 4, R3a is C1-4 alkyl, R3b is C6-10 aryl optionally substituted with one or more R3d or C5-10 is heteroaryl optionally substituted with one or more R3d, R3c is C5-10 cycloalkyl optionally substituted with one or more R3d or C5-10 cycloalkenyl optionally substituted with one or more R3d groups, wherein R3 is optionally substituted with one or more R3e groups, and R3d and R3e are selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, halogen, cyano, amino, nitro, -OH and -SH groups.

[0008] In another preferred embodiment, R and R3 are any of -H, -OH, -SH, -N3, -NH2, halogen, -CN, C1-3 alkoxy, -O(CH2)pCN, -SR3a, -O(CH2)pR3b, OCOR3c, O(CH2)pCOR3c, -O(CH2)pSH, -O(CH2)pOH, -O(CH2)pN3 and -O(CH2)pNH2, where pes are each independently any integer from 1 to 3, t is any integer from 1 to 4, R3a is methyl or ethyl, R3b is C5-10 heteroaryl optionally substituted with one or two R3d, R3c is C5-10 cycloalkyl optionally substituted with one or two R3d or C5-10 cycloalkenyl optionally substituted with one or two R3d, wherein R3 is optionally replaced with one or more R3e, and R3d and R3e are selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, halogen, cyano, amino, nitro, -OH and -SH.

[0009] In another preferred embodiment, R3b is C5 or C6 heteroaryl optionally substituted with C1-4 alkyl, for example, tetrazinyl optionally substituted with C1-4 alkyl, and R3c is C5-10 cycloalkenyl Petition 870250103152, dated 11 / 11 / 2025, p. 15 / 219 7 / 208 optionally substituted with C1-4 alkyl, halogen, cyano, amino or nitro, for example, norbornenyl or cyclooctenyl optionally substituted with C1-4 alkyl, halogen, cyano, amino or nitro, and, for example, unsubstituted norbornenyl or cyclooctenyl.

[0010] In a preferred embodiment, the compound has a structure of Formula (Ia) Formula (Ib) or Formula (Ic): Petition 870250103152, dated 11 / 11 / 2025, p. 16 / 219 8 / 208 R2 R3 Ri H2NN1 VN THE' HN p—o—po—po OH OH OH Op0ho o J1 R4 THE J2 OOP HOZO R5 J5 HORo (Ic).

[0011] In a preferred embodiment, Ro is -F or -Cl and / or R4 and R5 are each independently any one selected from the group consisting of H, OH, OCH3, F, Cl, -CN and -SH and preferably any one selected from the group consisting of H, OH, OCH3 and F.

[0012] In another preferred embodiment, the compound has a structure of Formula (Id): Petition 870250103152, dated 11 / 11 / 2025, p. 17 / 219 9 / 208 that Rs' has the same meaning as described above in relation to Rs, and the remaining groups have the same meanings as defined above.

[0013] In a preferred embodiment, the compound has a structure of Formula (le) Formula (If) or Formula (Ig): Petition 870250103152, dated 11 / 11 / 2025, p. 18 / 219 10 / 208 THE HN H2N • O· O' THE II Op-OOH ' OH popO OH R4 OpO HO \ J1 R3' HO J5 Ro (If) or the HN H2N * O* O^ R3' pO-pOpOpO • OH OH OH R4zO P. THE J1 O< ho THE THE J2O HO O R5 HO THE J5Ro(Ig).

[0014] In a preferred embodiment, Ro is -F or -Cl and / or R4 and R5 are each independently any one selected from the group consisting of H, OH, OCH3, F, Cl, -CN and -SH and preferably any one selected from the group consisting of H, OH, OCH3 and F.

[0015] In a more preferred embodiment, the compound has one of the structures shown in Table 1.

[0016] In a preferred embodiment, the compound of the present invention is present in the form of a pharmaceutically acceptable salt and, preferably, Petition 870250103152, dated 11 / 11 / 2025, p. 19 / 219 11 / 208 in the form of a triethylamine salt, a sodium salt, a potassium salt, an ammonium salt or tris(hydroxymethyl)aminomethane hydrochloride.

[0017] Another aspect of the present invention relates to a use of the compound, as described above, as a capping reagent for cotranscriptional RNA in vitro.

[0018] Yet another aspect of the present invention relates to an RNA molecule that includes the compound, as described above, as a cap structure or a fragment of a cap structure.

[0019] Yet another aspect of the present invention relates to a pharmaceutical composition that includes the RNA molecule, as described above, and a pharmaceutically acceptable carrier.

[0020] The present invention also relates to a method for synthesizing an RNA molecule, which includes incubating the compound, as described above, with a polynucleotide template in order to perform template-based transcription.

[0021] The present invention further relates to a transcriptional RNA capping reaction system, which includes a polynucleotide template, the compound as described above, NTPs and an RNA polymerase.

[0022] According to some embodiments of the present invention, the compound (or cap analogue) has one of the structures shown in Table 1 below: Table 1: Petition 870250103152, dated 11 / 11 / 2025, page 20 / 219 12 / 208 Compound 4 Compound 6 Compound 7 Compound -8 Compound 9 Compound - 10 Compound 13 Compound 12 Compound 115 Compound 16 Compound 19 Compound 22 [Compasto .] R Compound 121 Compound .24 Compound 25 Compound 28 Petition 870250103152, dated 11 / 11 / 2025, page 21 / 219 13 / 208 Compound 31 Compound 38 Compound 41 Compound 44 Compound 43 Compound 46 Compound 47 Compound 49 Compound 50 Compound 52 Compound 55 Compound 56 Compound 59 Compcrsto 39 Compound 42 Compound 45 Compound 48 Compound 54 Compound 57 Compound 60 Petition 870250103152, dated 11 / 11 / 2025, page 22 / 219 14 / 208 Compound 6Έ Compound 62 Composed 63 Compound 64 Compound 73 Compound 77 Compound 75 Compound 78 Composed 80 Composed I 81 Composed 82 Compound 83 Compound 84 Compound . 85 Compound X6 Compound 87 Compound 88 Compound 89 Compound 9Cl· Petition 870250103152, dated 11 / 11 / 2025, pág. 23 / 219 15 / 208 Compound 91 Composlo 94 Compound 97 Compound 1Q0 Compound 103 Compound 106 HüF Compound 109 Compound 11 2 Compound 115 Compound 1 ] $ Compound 92 Compound 95 Compound 98 Compound lü7 Compound | 08 HO Compound 111 Compound 113 Composlo 116 Compound 119 Compound 114 Compound 120 Petition 870250103152, dated 11 / 11 / 2025, page 24 / 219 16 / 208 Compound 121 Compound 123 Compound 12-4 Compound 122 Composlo 125 Compound 127 HÜ Compound 130 Compound 128 Composlo 3.31 Compound 134 Compound 133 Compound 1 33 Compound ] 36 Compound 137 Compound 140 Compound 139 Compound 144 Compound 142 "the Compound 1 45 Compound $14 Compound 146 Compound 3 49 » OH Cn Composed Compound 150 Petition 870250103152, dated 11 / 11 / 2025, page 25 / 219 17 / 208 èn CM □ Compound 152 Compound 1 53 Compound- 151 Compound 154 Compound 1 57 Compound 1.5X Compound 156 Compound I 59 Compound 161 Compound 164 Compound 167 Compound 170 Compound 169 Compound 173 Compound 172 Compound 1 75 Compound 1 76 Compound 1 Compound 179 Compound 162 Compound 171 Compound 174 Compound 177 ISO compound Petition 870250103152, dated 11 / 11 / 2025, page 26 / 219 18 / 208 Compound ] SI Ml ' Compound 18-4 Compound 182 Composed 185 Compound 1 It8 Composed 187 Compound 5 90 Compound 191 Compound 193 Compound 196 Compound 199 Compound 198 Compound 201 Compound 2ü2 Compound 200 Compound 203 Compound 204 Compound 206 Compound 207 Compound- 205 Compound 2(18 Compound 209 Compound 2 9 D Petition 870250103152, dated 11 / 11 / 2025, page 27 / 219 19 / 208 Compound 2 11 Compound 214 Composite 217 Compound 220 Compound 221 Compound 222 Compound 223 Compound 224 Compound 225 Compound 226 Compound 229 Compound 22X HO f Compound 232 Compound 235 Compound 238 Compound 231 Compound 24U Petition 870250103152, dated 11 / 11 / 2025, page 28 / 219 20 / 208 Port 241 Compound 243 Compound 247 Compound 242 24X Compound Compound 246 Compound 251 Compound 250 Compound 253 Compound 254 Compound 255 Compound 256 Compound 257 Compound 25K Compound 259 Compound 260 Compound 261 Compound 262 Compound 263 Compound 264 Compound 265 Compound 268 Compound 269 Compound 270 Petition 870250103152, dated 11 / 11 / 2025, pág. 29 / 219 21 / 208 Compound 271 Compound 272 Compound 274 Composlo 275 Compound 27ÍÈ Composlo 279 Compound 2 S3 Compound 28S Compound 289 Compound 292 Compound 295 Compound 298 Compound 282 Composlo 290 Compound 293 Compound 296 Compound 299 Composlo 2^5 28K Compound Composlo 291 Petition 870250103152, dated 11 / 11 / 2025, page 30 / 219 22 / 208 Compound 304 Composite 305 Compound 303™ Compound 306 Compound 307 Compound 310 Compound 313 Compound 309 Compound 312 Compound 315 Compound 319 Compound 31 8 Compound 321 Compound 322 Compound 323 Compound 324 Compound 325 Compound 326 Compound I 327 Compound 328 Compound 329 Compound 330 Petition 870250103152, dated 11 / 11 / 2025, pág. 31 / 219 23 / 208 -ίΊ-ΐ-Dl· □ F Compound 331 Compound Λ4ω W ÓH ou Compound 355 Compound OH 9*1 Compound Compound I» in in Compound 346 Compound 3? pa-*ô*t on fln Compound 352 ooo -o-ü-É-D-PÍh ôh CW Compound 358 Composition 332 Compound 33 5 Compound 338 Compound 347 HO Compound 350 Compound 353 Compound 356 Compound 359 Compound 336 Compound 339 Compound 342 Compound I 345 Compound 357 Compound 3-60 Petition 870250103152, dated 11 / 11 / 2025, page 32 / 219 24 / 208 Compound 374 Compound 372 Compound 375 Compound 379 3R0 Compound Compound 378 Compound 381 Compound 382 Compound 383 Compound 384 Compound 388 Compound 386 Compound 387 Compound 389 Compound 390 Petition 870250103152, dated 11 / 11 / 2025, page 33 / 219 25 / 208 Compound 391 Compound 392 Compound 393 Compound 394 Compound 395 Compound 396 Compound 397 Compound 398 KJ 4W Compound Compound 399 Compound 402 Compound 4IJ6 Compound 409 Compound 412 Compound 415 Compound 418 Compound 408 Compound 411 Compound 4L4 Petition 870250103152, dated 11 / 11 / 2025, pág. 34 / 219 26 / 208 C-amposto 421 ο HQ Compound 424 Compound 422 I HAVE Compound 425 Compound 428 Compound 430 Compound 433 Compound 434 Compound 4.3 2 Compound 436 Compound 437 Compound 439 I HAVE Compound 440 Compound 442 Compound 445 Compound 449 Compound 450 I HAVE ' Compound 448 Petition 870250103152, dated 11 / 11 / 2025, pág. 35 / 219 27 / 208 Compound 451 Compound 452 Compound 453 Compound I 454 Compound 455 Compound 456 Compound 457 Compound 45R Compound 459 «j Compound 460 Compound 461 Compound 462 Compound 463 Compound 465 Compound 471 Compound 472 or Compound 476 Compound 474 Compound 475 Compound 478 Compound 479 Compound 477 4SG Compound Petition 870250103152, dated 11 / 11 / 2025, page 36 / 219 28 / 208 Compound 482 4R3 Compound Compound 491 Compound 492 Compound 499 Compound 497 Compound 500 Compound 498 Petition 870250103152, dated 11 / 11 / 2025, page 37 / 219 29 / 208 Compound 522 Compound 502 Compound 505 M Ccmpostn 508 Compound 511 in 3H Compound 514 Compound 517 Ϊ í 9 ί-φ-FD-POH ÍB Compound 520 Compound 528 Compound 529 Petition 870250103152, dated 11 / 11 / 2025, p. 38 / 219 30 / 208 Compound 537 Compound 540 Compound 558 Compound 532 Compound 538 MW* w Compound 541 Compound 544 547 iii iui □ ύμ «tw Compound 535 □μ pit Cn Compound Compound & P = i-ír-fo··? Compound 55-3 Compound 559 Compound 548 Compound 560 Petition 870250103152, dated 11 / 11 / 2025, p. 39 / 219 31 / 208 Compound 576 Compound 579 Compound 588 Compound 589 Compound 584 Compound 59CJ Petition 870250103152, dated 11 / 11 / 2025, page 40 / 219 32 / 208 Compound . 606 Compound 612 Compound 618 Compound 619 Compound 599 Compound 602 Compound 60? Compound 61] Compound 614 Oh oh » Ah oh Compound 620 Compound 593 Compound 596 j ip a Pn. Ρ-ύ-^-Ο Compound I 605 sh oh Ah Compound 617 Petition 870250103152, dated 11 / 11 / 2025, page 41 / 219 33 / 208 Compound 623 Compound 62] Compound 622 Compound 625 Compound 626 Compound 624 Composite 627 Compound 62 8 Compound 629 Compound 630 Compound 631 Compound 654 Compound 632 Composite. 633 Compound 637 Compound 635 Compound 638 Compound 636 Compound 639 Compound 640 Compound 645 Compound 646 Compound 647 Compound $64 Compound 649 Compound 650 Petition 870250103152, dated 11 / 11 / 2025, page 42 / 219 34 / 208 Compound 65 I Compound 653 Compound 654 Composite 657 Composlo 660 Compound 663 Compound 672 Compound 675 Compound 676 Composite 662 Compound 665 Compound 678 Compound 679 Petition 870250103152, dated 11 / 11 / 2025, page 43 / 219 35 / 208 u MO Compound 682 Compound 685 HO Compound 688 Compound 690 Compound 686 Compound 689 Compound 699 Compound 697 Compound 702 OH OH <* Compound 708 KM Oh, cut one. Compound 705 Compound 709 Petition 870250103152, dated 11 / 11 / 2025, p. 44 / 219 36 / 208 Compound 738 No. Compound 715 Compound 724 Composlo 739 Compound 740 Petition 870250103152, dated 11 / 11 / 2025, p. 45 / 219 37 / 208 Compound 768 Compound 769 Compound 770 Petition 870250103152, dated 11 / 11 / 2025, p. 46 / 219 38 / 208 Compound Compound 793 Composed Aug 796 Oh £l Ρ-α-ρ·ο-ί-c without W iH Compound 799 Made up 800 Petition 870250103152, dated 11 / 11 / 2025, p. 47 / 219 39 / 208 Compound 804 Compound 810 Compound S ] 2 Compound 819 Compound 828 Compound 801 and Χϕ-Ι^-ο Compound 807 Oh OH Compound 816 Compound £22 Compound 82–5 ooo -lo-H-cU Compound 806 Compound 809 Compound 820 Compound 812 Compound 823 Compound 824 Compound 826 Compound 827 Compound 829 Compound 830 Petition 870250103152, dated 11 / 11 / 2025, page 48 / 219 40 / 208 Compound 843 Composite 846 Compound 849 Compound 855 Compound Composite 835 Compound 83.3 the Compass 838 Composite 850 Compound 848 Compound 85] Compound 856 Composite 857 Compound 859 Compound 860 Petition 870250103152, dated 11 / 11 / 2025, page 49 / 219 41 / 208 R61 Compound Compound 879 Compound Compound 880 Compound 889 Compound 887 Compound 890 Petition 870250103152, dated 11 / 11 / 2025, page 50 / 219 42 / 208 Compound 892 Compound 898 Compound 897 i Compound 901 Compound ^96 Compound 918 Compound 919 Compound 920 Petition 870250103152, dated 11 / 11 / 2025, page 51 / 219 43 / 208 Compound 948 Compound 949 Compound 950 Petition 870250103152, dated 11 / 11 / 2025, p. 52 / 219 44 / 208 Compound 954 Compound 971 i ? Ϊ Oh, and oh Compound 978 Compound 979 Compound 98(1 Petition 870250103152, dated 11 / 11 / 2025, p. 53 / 219 45 / 208 Compound 1008 Compound 1007 Compound 1010 Petition 870250103152, dated 11 / 11 / 2025, p. 54 / 219 46 / 208 Compound 1011 Compound 10-20 Compound 1023 Compound 1026 Compound 1029 Compound 1032 Compound 1035 Compound 1038 CM there » Compound ÍH DM Òw Compound 1033 IM pH CM Compound 1039 Compound Compound Compound Compound Oh oh or Compound ]Q21 Compound Compound 1036 Compound 1025 Compound I 028 Compound 1031 Compound 1034 Compound 1037 Compound 1040 Petition 870250103152, dated 11 / 11 / 2025, page 55 / 219 47 / 208 Compound 1047 Compound 1050 Compound 1051 Compound 1053 Compound 1054 Compound 1056 Compound 1058 Compound 1062 Compound 1057 Compound 1068 Compound 1060 Compound 1061 Compound 1063 Composed 1 064 Compound I 069 Compound 1Ü67 Compound ] ()7() Petition 870250103152, dated 11 / 11 / 2025, pág. 56 / 219 48 / 208 Compound 1079 Compound] GOLD Compound 10$l Compound 1084 Compound 1083 Compound 1087 Compound 1095 Compound 1090 Compound 1093 Compound 1096 Compound 109R Compound 1099 Compound 11 00 Petition 870250103152, dated 11 / 11 / 2025, pág. 57 / 219 49 / 208 Compound 1107 Compound 1108 Compound Π10 Compound 1111 Compound 1113 Compound 1114 Compound 1 106 Compound 1116 Compound | H9 Compound 1122 Compound 1125 Compound 11 26 Compound Π 2X Compound 1129 Petition 870250103152, dated 11 / 11 / 2025, page 58 / 219 50 / 208 Compound 1134 Compound 1137 Composite 1138 Compound 1136 Compound 1143 LI41 compound Compound 1139 Compound 1] 49 Compound 1144 Compound 1152 Compound 1153 Compound 1155 Compound 1158 Compound 1159 Composite 1157 r Composite I160 Petition 870250103152, dated 11 / 11 / 2025, page 59 / 219 51 / 208 C-composite 1164 Compound 1165 Compound 11 67 Compound 9168 Compound 1166 Compound 1170 Compound 1173 Compound I 174 Compound 1178 Compound 1176 Compound 1179 Compound 1 180 Compound 1181 Compound - 1 9 82 Compound LJ 83 Compound 1184 Compound 1185 Compound ] 186 Compound 1188 Compound 1 189 Petition 870250103152, dated 11 / 11 / 2025, pág. 60 / 219 52 / 208 HQ SH Compound I ] 91 Compound ] 192 Compound I 1193 I have F Compound J194 Compound 1197 Compound 1 I 98 Composite 1199 Compound 1 209 Compound Compound 1 qh oh » Compound Compound 1212 Compound 1208 nor Compound 1211 Compound 1214 Compound 1215 Compound 1217 Compound 1218 Compound 1216 Compound 1220 Petition 870250103152, dated 11 / 11 / 2025, page 61 / 219 53 / 208 Compound 1224 Composlo 1227 Compound 1234 Compound 1232 Compound 1235 Compound 1 233 Compound Í 240 Compound 1243 Composlo 1 245 Compound 1246 Compound I 247 Compound 1248 Compound 1249 Compound 1250 Petition 870250103152, dated 11 / 11 / 2025, pág. 62 / 219 54 / 208 Compound 1251 Compound 1252 Compound 1253 Compound 1254 Compound 1255 Compound 1256 Compound 1257 Compound 1258 Compound 1259 Compound 1260 Compound 1261 Compound 1262 Compound 1263 Compound 1264 Compound 1265 Compound 1266 Compound 1267 Compound 1268 Compound L 269 Compound 1270 Compound 1271 Compound 1272 Compound 1273 Compound 1274 Compound 1 275 Compound 1276 Compound 1277 Compound 1278 Compound 1279 Compound 128ü Petition 870250103152, dated 11 / 11 / 2025, page 63 / 219 55 / 208 Compound 1282 S2Xl Composite Compound 1283 Composite 1284 Compound 1788 Composed l 289 Composite 1287 Compound 1291 Compound 1290 Composite 1294 •c Compound L293 Compound ] 296 Compound 1 297 Compound 1299 Compound 1298 Compound 1301 Composite 1302 Compound 1300 nae Compound 1304 Compound 13Ü5 Compound 1307 L309 Composite Compound 1310 Compound 1308 Petition 870250103152, dated 11 / 11 / 2025, page 64 / 219 56 / 208 Compound 1311 Compound 1314 Compound 1317 Compound 1320 Compound 1324 Compound 1325 Compound 1323 Compound 1326 Compound 1327 Composite 1330 Compound 1331 Compound 1329 Compound 1332 Compound 1333 Compound 1334 Compound 1335 Compound 1336 Compound 1337 Compound 1338 Compound 1339 Compound 1340 Petition 870250103152, dated 11 / 11 / 2025, pág. 65 / 219 57 / 208 Compound 1341 Compound 1342 Compound 1343 Compound 1 344 Compound 1345 Compound 1347 Compound 1348 Compound 1350 Compound 1351 Compound 5 353 Compound 13 56 Compound 1354 No Compound 1357 Compound 1359 Compound 1362 Compound 1360 Compound I 363 Compound 1346 1357 1355 Compound 1358 1364 Compound Compound LM 6h úh wy Compound Compound Compound 1361 Compound 1365 Compound 1366 Compound I 367 Compound 1368 Compound 1369 Compound . 1370 Petition 870250103152, dated 11 / 11 / 2025, pág. 66 / 219 58 / 208 Compound 1377 □ Compound 1380 Composed 1384 Compound 1373 Compound 1376 Compound 1379 Composed 1382 Composed Composed 1383 Composed 1386 Composed 1389 Compound 1392 Compound 1395 1385 Compound 1387 Compound 1388 dn ÒH Compound 1390 Compound 1396 Campos] 397 Composite 1391 Compound 1393 Compound 1394 M-4 [Compound] 398 IJW Compound Compound 1400 Petition 870250103152, dated 11 / 11 / 2025, page 67 / 219 59 / 208 Compound 144] 1 Compound 1402 Compound 1-403 Compound 1404 Compound 1405 Compound 1408 Compound 1407 Compound 1411 Composlo 1416 Compound 1414 Compound 1415 Compound 14] 9 Compound I 422 Compound 1425 Compound 1417 Composlo 1420 Compound 1423 Compound 1424 Compound 1427 Compound 1430 Petition 870250103152, dated 11 / 11 / 2025, page 68 / 219 60 / 208 Compound 1432 Compound 1435 Compound 1438 Compound 1437 Compound 1440 Compound 1441 Compound 1443 Compound 1446 Composite 1449 Composed [45ü Compound 1452 Compound 1433 Compound 1 436 Compound 1439 Compound 1442 Compound 1445 «á. ,*i ''p· Composite · 144K Composlo 1451 Petition 870250103152, dated 11 / 11 / 2025, page 69 / 219 61 / 208 Compound 1461 Compound 1462 Compound 1-463 Composed 1464 Compound 1465 Compound 1466 Compound 1467 Compound 1468 Compound 1469 Compound 1 470 Petition 870250103152, dated 11 / 11 / 2025, page 70 / 219 62 / 208 Compound 1471 Compound 1472 Compound 1473 Compound 1474 Compound 1477 Compound ] 480 Compound 1481 M76 Compound Compound 1479 Compound 1482 Composite 1483 Compound 1484 Compound I 486 Compound I 487 Compound 1489 Compound 1492 Compound 1494 Compound 1495 Compound 1498 Petition 870250103152, dated 11 / 11 / 2025, page 71 / 219 63 / 208 Composlo 1 502 Compound 1503 Compound 1501 Compound 1 $04 Compound 1507 Compound 1510 Composlo 1 506 wF Compound ]509 Compound 1512 Compound 1515 Compound 1516 Compound 1517 Compound 1518 Compound 1519 Composlo 1 520 Compound 1 521 Compound 152Λ Compound 1529 Compound 1524 Compound 1527 HOF Compound 1 530 Petition 870250103152, dated 11 / 11 / 2025, page 72 / 219 64 / 208 Compound 1531 Compound 1532 Compound 153.3 Compound 1535 Compound 1538 Compound 1536 Compound 1539 Petition 870250103152, dated 11 / 11 / 2025, page 73 / 219 65 / 208 Compound 1541 Compound 1 546 Compound 1 544 Compound 1 547 Compound 1550 Compound 1554 Compound 1553 Compound 1557 Compound 1556 HQ Compound 1560 CH OH in m > w Compound 1561 Compound Compound Compound 1555 Compound Compound 1564 Compound 1 566 Compound 1567 Compound 1565 Compound 1568 Compound 1569 Compound 1570 Petition 870250103152, dated 11 / 11 / 2025, page 74 / 219 66 / 208 Compound 1 576 Compound I574 Composed 1577 Compound 1 -578 Composed 1579 Compound 1580 Petition 870250103152, dated 11 / 11 / 2025, pág. 75 / 219 67 / 208 Composed 1581 Composed 1584 Compound l 587 Compound 1 590 Composed 1593 Compound 1 596 Compound 1602 I HAVE Compound 1605 Compound I 60S Composed 1582 Composed 1585 Composed 1609 Composed 1583 Compound 161Ü Petition 870250103152, dated 11 / 11 / 2025, page 76 / 219 68 / 208 rü' Compound 1611 □ Compound 1612 Compound 1614 HO Compound 161 5 Compound 1618 Compound 1620 Compound 1621 τ« * Compound 1624 Compound 1625 Compound 1626 Compound 1627 Compound 1 628 6 J629 compound Compound 1636 Composlo 1635 Compound 1638 Compound 1639 Compound 1640 Petition 870250103152, dated 11 / 11 / 2025, page 77 / 219 69 / 208 Composed 1641 Composed 1642 Composed 1643 Comp «to 11>44 Composed 1645 Composed 1647 Compound 1 648 Composed 1651 Composed 1646 nd Compound 1650 Composed 1652 Composed 1653 Composed 1654 Composed 1655 Composed 1656 Composed 1657 I HAVE Composed I 662 mS1 F Compound 3668 Composed 1669 Petition 870250103152, dated 11 / 11 / 2025, pág. 78 / 219 70 / 208 Composed 1672 Composed 1677 Compound 1C8Ü Compound 1 683 Composed 1686 Composed 1685 Composed 1689 Composed 1692 kid Composed 1690 Composed 1691 Compound I 695 Composed 1698 Composed 1699 Composlo 1700 Petition 870250103152, dated 11 / 11 / 2025, pág. 79 / 219 71 / 208 Compound 1701 Compound 1702 Composed 1704 Compound J 705 Composed 1708 Composed 1706 Compound 1710 Compound 1711 ho F Compound 1715 Compound l7|4 icB Compound 1716 Compound 1X717 Compound 1721 Compound 1725 Compound 1728 Compound | 729 Compound 1730 Petition 870250103152, dated 11 / 11 / 2025, page 80 / 219 72 / 208 Compound 1731 Compound .1734 Compound 1740 Composlo 1742 Compound 1752 Compound 1755 Compound 1758 Compound ]75ü Compound 1753 Compound 1756 Compound 1759 Compound 1745 Compound 1748 Compound 1757 Compound 1760 Petition 870250103152, dated 11 / 11 / 2025, page 81 / 219 73 / 208 Compound 1762 Composite 1,765 Compound 1763 Composed 1766 kj' Compound ] 769 Composed 1768 Compound 1771 Compound 1770 Composed in 1772 Compound 1782 Composed 1783 Composite 1,788 HÊ * Composed 1786 Composed 1789 Composed 1790 Petition 870250103152, dated 11 / 11 / 2025, pág. 82 / 219 74 / 208 □ Composed I 1793 Composed 1796 Compound 180() Composed 1803 Composed 1812 Composed 1815 Composed 1818 Ϊ ft •PWOF Composed 1806 Composed 1809 LU Compound 1 804 Composed 1810 Composed 1813 Composed 1816 Composed 1819 Composed 1799 Composed 1811 Composed 1814 Composed 181.7 Composed 1820 Petition 870250103152, dated 11 / 11 / 2025, page 83 / 219 75 / 208 Compound 182] Compound 1824 Compound 1828 Compound 1830 Compound 1 836 Compound 1844 Compound ]84fi Compound 1849 Petition 870250103152, dated 11 / 11 / 2025, page 84 / 219 76 / 208 Compound 1854 Compound 1857 Compound 1856 Compound 1858 Compound 1861 Compound 1862 Compound 1860 Compound 1863 Compound 1ÍS66 Composed 1867 Composed 1872 □ Composed 1 875 Composed 1876 Composed 1877 Composed 1878 Composed 1879 or Composed 1880 Petition 870250103152, dated 11 / 11 / 2025, pág. 85 / 219 77 / 208 Composed 188 J Compound IKK2 Composed 1886 Composed 1884 Composed 1883 Composed 1889 Composed 1887 Composed 1888 γL * Compound 1E90 Composed 1893 Cofrpostü 1896 Compound 1899 Petition 870250103152, dated 11 / 11 / 2025, page 86 / 219 78 / 208 Compound 19ΰ ] Composed in 1907 Compound 1910 Compound 1913 D Compound 1916 Composlo 1919 Compound 1902 Compound 1905 Compound 1908 Composed in 1920 Petition 870250103152, dated 11 / 11 / 2025, page 87 / 219 79 / 208 Compound 1936 Compound 1939 Compound 1940 Compound 1923 Compound 1926 Compound 1929 Compound 1938 Petition 870250103152, dated 11 / 11 / 2025, pp. 88 / 219 80 / 208 Composed 1941 Composed 1944 Composed 1950 Composed 1946 Composed 1949 I HAVE Composed 1956 Composed 1959 Compound i960 Composed 1958 Petition 870250103152, dated 11 / 11 / 2025, pág. 89 / 219 81 / 208 HjN' Μ « 'Íh j 9 & Compound Compound Composed 1962 Composed 1963 Composed 1967 Compound 1 970 Composed 1973 Composed 1976 Composed 1979 Composed 1965 Composed 1966 Composed 1968 Compound 1980 Composlo 1969 Compound 1978 Petition 870250103152, dated 11 / 11 / 2025, pp. 90 / 219 82 / 208 Composed 1985 Compound 1983 Compound 1987 Compound 1988 Composlo 19R9 Composed 1990 Compound 1991 Compound 1993 Composite I 1994 Compound 2008 Compound 2000 Compound 2003 Compound 2009 200 L Compound Compound 2004 Compound 2010 Petition 870250103152, dated 11 / 11 / 2025, page 91 / 219 83 / 208 Composed 2017 Compound 20 12 í J i OO-iS-O-PQH Ôd DH Composed 2015 Composed 2013 Composed 2016 Composed 2019 IN1 Compass 2018 Composed 2022 .*1 Composed 2020 Compound 2θ3θ Compound 2025 Compound 2028 Compound 203 1 Compound 2032 Compound 2033 Compound 2034 Composed 2035 Compound 203 R Compound 2U36 Compound 2039 Composed 2037 Composed 2040 Petition 870250103152, dated 11 / 11 / 2025, page 92 / 219 84 / 208 Compound 2042 Compound 2043 Composite 2044 Compound 2ü47 Composite 2053 Composed 2045 CM Compound 2048 Compound 2046 □ □ ç Cri OM Compound 2U49 Compound 2052 Compound 2054 Petition 870250103152, dated 11 / 11 / 2025, page 93 / 219 85 / 208 Compound 2066 Compound 21)69 Compound 2O?9 Composed 2085 Compound 2093 Petition 870250103152, dated 11 / 11 / 2025, pág. 94 / 219 86 / 208 Compound 2096 Compound 2(199 Compound 21ÜÜ Compound 2 J UJ Composed 2106 Compound 2108 Composed 2109 Composed 2110 Compound 2112 Compound 2 ] 13 Compound 2111 Compound 2118 Compound 2116 Compound 2119 Compound 2121 Compound 2122 Compound 211? ΜhΫΖM!j— rOf-OHí-O-^-O \Cl ή chi 6» w W ιμ oHa-É-aF w èw ÜH ím Compound 21 20 NHj Compound 2123 Petition 870250103152, dated 11 / 11 / 2025, page 95 / 219 87 / 208 Brief Description of the Drawings

[0023] The present invention will be further described below with reference to the accompanying drawings.

[0024] FIG. 1 illustrates fluorescence imaging of mRNA with different cap analogs in HEK293T cells.

[0025] FIG. 2 illustrates the fluorescence intensity of mRNA with different cap analogs in HEK293T cells.

[0026] FIG. 3 illustrates the fluorescence intensity of mRNA with different cap analogs in HepG2 cells.

[0027] FIG. 4 illustrates the efficiency of mRNA expression with different cap analogs in different organs. Detailed Description

[0028] The present invention provides a halogen-containing compound (cap analog or capping analog) for 5' end capping of RNA, a pharmaceutically acceptable salt, solvate and stereoisomer thereof, and a use of the halogen-containing compound. The use of this compound for capping the 5' end of mRNA has a high capping rate and good transcription efficiency in vitro. At the same time, it has a high translation expression efficiency at the cellular level.

[0029] Before further describing the present invention, several terms used in the descriptive report, examples, and appended claims are collected in the following sections. The definitions listed herein should be read and understood by those skilled in the art in light of the remainder of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning. Petition 870250103152, dated 11 / 11 / 2025, pp. 96 / 219 88 / 208 meaning that which is commonly understood by those skilled in the art to which the present invention pertains. Definition

[0030] Unless defined otherwise, when disclosing or claiming any type of range, it is intended to individually disclose or claim each possible value that the range could reasonably cover, including any subranges contained therein. For example, if the number of groups is 1 to 6, this indicates an integer within the range, and 1 to 6 is understood to include 1, 2, 3, 4, 5, and 6, and should also be understood to include subranges 1 to 5, 1 to 4, and 1 to 3.

[0031] The descriptive report of the present disclosure should be interpreted in accordance with the laws and principles of chemical bonding. In some cases, a hydrogen atom may be removed to accommodate a substituent at a given position.

[0032] The words include, contain, comprise, or similar words used in this disclosure mean that the elements preceding the word include the elements listed after the word and equivalents thereof, without excluding elements that are not described. The terms contain or include (comprises) used in this document may be broad, semi-closed, or closed. In other words, the terms also include that which essentially consists of or that which consists of.

[0033] The term “pharmaceutically acceptable”, as used in this document, means that a compound or composition is chemically and / or toxicologically compatible with the other ingredients that constitute a formulation and / or with humans or mammals for the prevention or treatment of diseases. Petition 870250103152, dated 11 / 11 / 2025, page 97 / 219 89 / 208 treatment of a disease or condition for which the compound or composition is used.

[0034] Natural or modified pyrimidine nucleotide bases include, but are not limited to, uracil, thymine, cytosine, 5-methylcytosine, 5-fluorouracil, 5-fluorocytosine and the like.

[0035] Natural or modified purine nucleotide bases include, but are not limited to, adenine, guanine, 6-N-methyladenine, 6-N,N-dimethylaminopurine, 2-N-methylguanine, 2-N,N-dimethylguanine, 7-methylguanine, and the like. The structure of 6-N-methyladenine is

[0036] The nucleotide bases, as used in this document, may be modified or substituted to provide oligonucleotides. For example, modification may be carried out by these bases or synthetic or natural nucleotide bases (e.g., inoside, thymine, xanthine, hypoxanthine, nubularin, isoguanine, or tuberculin) and optionally. Alternatively, substituted or modified analogues of any natural or synthetic base may be used.Examples include 2-adenine(halogenated), 2-(alkyl)adenine, 2-(propyl)adenine, 2-(amino)adenine, 2-(aminoalkyl)adenine, 2(aminopropyl)adenine, 2-(methylthio)-N6-(isopentenyl)adenine, 6-(alkyl)adenine, 6(methyl)adenine, 7-(deaza)adenine, 8-(alkenyl)adenine, 8-(alkyl)adenine, 8(alkynyl)adenine, 8-(amino)adenine, 8-(halogenated)adenine, 8-(hydroxy)adenine, 8-(thioalkyl)adenine, 8-(thiol)adenine, N6-(isopentyl)adenine, N6-(methyl)adenine, N6,N6-(dimethyl)adenine, 2-(alkyl)guanine, 2-(propyl)guanine, 6-(alkyl)guanine, 6-(methyl)guanine, 7-(alkyl)guanine, 7-(methyl)guanine, 7-(deaza)guanine, 8. Petition 870250103152, dated 11 / 11 / 2025, pp. 98 / 219 90 / 208 (alkyl)guanine, 8-(alkenyl)guanine, 8-(alkynyl)guanine, 8-(amino)guanine, 8-(halogenated)guanine, 8-(hydroxy)guanine, 8-(thioalkyl)guanine, 8-(thiol)guanine, N-(methyl)guanine, 2-(thio)cytosine, 3-(deaza)-5-(aza)cytosine, 3-(alkyl)cytosine, 3-(methyl)cytosine, 5-(alkyl)cytosine, 5-(alkynyl)cytosine, 5-(halogenated)cytosine, 5-(methyl)cytosine, 5-(propynyl)cytosine, 5-(propynyl)cytosine, 5-(trifluoromethyl)cytosine, 6-(azo)cytosine, N-4-(acetyl)cytosine, 3-(3-amino-3-carboxypropyl)uracil, 2(thio)uracil, 5-(methyl)-2-(thio)uracil, 5-(methylaminomethyl)-2-(thio)uracil, 4(thio)uracil, 5-(methyl)-4-(thio)uracil, 5-(methylaminomethyl)-4-(thio)uracil, 5-(methyl)2,4-(dithio)uracil, 5-(methylaminomethyl)-2,4-(dithio)uracil, 5-(2-aminopropyl)uracil, 5-(alkyl)uracil, 5-(alkynyl)uracil, 5-(allylamino)uracil, 5-(aminoallyl)uracil, 5(aminoalkyl)uracil, 5-(guanidinyl)uracil, 5-(1,3-diazol-1-alkyl)uracil 5-(cyanoalkyl)uracil, 5-(dialkylaminoalkyl)uracil, 5-(dimethylaminoalkyl)uracil,5-uracila(halogenada), 5-(metoxi)uracila, ácidouracil-5-oxoacetico, 5(metoxicarbonilmetil)-2-(tio)uracila, 5-(metoxicarbonilmetil)uracila, 5(propynil)uracila, 5-(propynil)uracila, 5-(trifluorometil)uracila, 6-(azo)uracila, dihidrouracila, 3-(metil)uracila, 5-uracila (ou seja, pseudouracila), 2(tio)pseudouracila, 4-(tio)pseudouracila, 2,4-(ditio)purina pirimidina, 5(alquil)pseudouracila, 5-(metil)pseudouracila, 5-(alquil)-2-(thio)pseudouracil, 5(methyl)-2-(thio)pseudouracil, 5-(alquil)-4-(thio)pseudouracil, 5-(methyl)-4(thio)pseudouracil, 5-(alquil)-2,4-(dithio)pseudouracil, 5-(methyl)-2,4(dithio)pseudouracila, pseudouracila 1-substituída, 2(tio)-pseudouracila 1substituída, 4-(tio)pseudouracila 1-substituída, 2,4-(ditio)pseudouracila 1substituída, 1 -(aminocarbonylvinyl)-pseudouracil, 1 -(aminocarbonylvinyl)-2(thio)pseudouracil, 1-(aminocarbonylvinyl)-4-(thio)pseudouracil, 1(aminocarbonylvinyl)-2,4-(dithio)pseudouracil, 1-(aminoalquilaminocarbonylvinyl), Petition 870250103152, dated 11 / 11 / 2025, pp. 99 / 219 91 / 208 pseudouracil, 1-(aminoalkylamino-carbonylvinyl)-2(thio)-pseudouracil, 1-(aminoalkylaminocarbonylvinyl)-4-(thio)pseudouracil, 1-(aminoalkylaminocarbonylvinyl)-2,4-(dithio)pseudouracil, 1,3-(diaza)-2-(oxo)phenoxazine-1-yl, 1-(aza)-2-(thio)-3-(aza)-phenoxazine-1-yl, 1,3-(diaza)-2-(oxo)phenothiazine-1-yl, 1-(aza)-2-(thio)-3-(aza)-phenothiazine-1-yl, 7-substituted 1,3-(diaza)-2-(oxo)phenoxazine-1-yl, 7-substituted 1-(aza)-2-(thioxo)-3-(aza)-phenoxazine-1-yl, 7-substituted 1,3-(diaza)-2-(oxo)-phenothiazine-1-yl, 1-(aza)-2-(thioxo)3-(aza)-phenothiazine-1-yl 7-substituted, 7-(aminoalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenoxazine-1-yl, 7-(aminoalkylhydroxy)-1-(aza)-2-(thioxo)-3-(aza)phenoxazine-1-yl, 7-(aminoalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenothiazine-1-yl, 7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenothiazine-1-yl, 7-(guanidinoalkylhydroxy)-1 -(aza)2-(thio)-3-(aza)-phenoxazine-1-yl, 7-(guanidinium alkylhydroxy)-1,3-(diaza)-2-(oxo)phenothiazine-1-yl, 7-(guanidinoalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenothiazine-1-yl, 1,3,5-(triaza)-2,6-(dioxa)naphthalene, inosine, xanthine, hipoxanthin, zebularin, tuberculin, isoguanosine, inosinyl, 2-aza-inosinyl, 7-deaza-inosinyl, nitroimidazolyl, nitropyrazolil, nitrobenzimidazolil, nitroindazolyl, aminoindolyl, pyrrolopyrimidinyl, 3-(methyl)isocarbostyryl, 5-(methyl)isocarbostyryl, 3-(methyl)-7(propynyl)isocarbostyryl, 7-(aza)indolyl, 6-(methyl)-7-(aza)indolyl, iminopyridinyl, 9-(methyl)-iminopyridinyl, pyrrolopyrazinil, isocarbeniryl, 7-(propynyl)isocarbeniryl, propynyl-7-(aza)indolyl, 2,4,5-(trimethyl)phenyl, 4-(methyl)indolyl, 4,6-(dimethyl)indolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, estylbenyl, tetraphenyl, pentaphenyl, difluorotolyl, 4-(fluoro)-6-(methyl)benzimidazol, 4-(methyl)benzimidazol, 6-(azo)thymine, 2-pyridona, 5-nitroindol, 3-nitropyrrol, 6-(aza)pyrimidine, 2(amino)purine, 2,6-(diamino)purine, pyrimidine 5-substitute, purine 2-substitute, Petition 870250103152, dated 11 / 11 / 2025, pág. 100 / 219 92 / 208 N6-substituted purine, O6-substituted purine, substituted 1,2,4-triazole or any O-alkylated or N-alkylated derivative thereof.

[0037] Stereoisomers refer to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0038] The expression connected to form a ring by means of a chemical bond means connecting two groups by means of a carbon-carbon bond, a carbon-oxygen bond, a carbon-nitrogen bond, a carbon-sulfur bond, or similar to form a ring structure. If necessary, the hydrogen atoms can be reduced by 1 or 2 from the corresponding group.

[0039] The optionally substituted expression means that one, two, three, or more than three hydrogen atoms in a group can be independently replaced by respective substituents. The substituents can be selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, cyano, amino, nitro, and -OH.

[0040] The term alkyl refers to a saturated linear or branched carbon chain. Preferably, the chain contains from 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably from 1 to 6 carbon atoms, most preferably from 1 to 3 carbon atoms. Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, pentyl or octyl. Alkyl is optionally substituted.

[0041] The term alkoxy includes -O-alkyl groups and alkyl groups, where the Petition 870250103152, dated 11 / 11 / 2025, pp. 101 / 219 93 / 208 The O atom is in the alkyl chain, as -CH2-O-CH3. The alkoxy contains from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, and most preferably from 1 to 3 carbon atoms. The alkoxy is optionally substituted.

[0042] The term alkenyl includes both linear and branched alkyl groups containing at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl contains from 2 to 10 carbon atoms, preferably from 2 to 6 carbon atoms, and most preferably from 2 to 3 carbon atoms. Alkenyl is optionally substituted.

[0043] The term alkynyl includes both linear and branched alkyl groups containing at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl group contains from 2 to 10 carbon atoms, preferably from 2 to 6 carbon atoms, and most preferably from 2 to 3 carbon atoms. The alkynyl group is optionally substituted.

[0044] The terms cycloalkyl, cycloalkenyl, and cycloalkynyl are used by themselves or in combination with other terms to represent cyclic forms of alkyl, alkenyl, and alkynyl, respectively. Preferably, the cyclic forms are formed by 3, 4, 5, 6, 7, 8, 9, or 10 atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopropynyl, cyclobutynyl, cyclohexynyl, cyclopentinyl, and the like. The connecting position of the cycloalkenyl or cycloalkynyl group relative to another group may be in any suitable position. The terms cycloalkyl, cycloalkenyl, and cycloalkynyl are also intended to include bicyclic, tricyclic, and polycyclic forms thereof, which may be spirocyclic or bridging rings. Cycloalkyl, cycloalkenyl, and cycloalkynyl are Petition 870250103152, dated 11 / 11 / 2025, p. 102 / 219 94 / 208 optionally replaced. Examples of cycloalkyl and cycloalkenyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3] heptyl, spiro[3,4] octyl, spiro[4,3] octyl, spiro[3,5] nonyl, spiro[5,3] nonyl, spiro [3,6] decyl, spiro [6,3] decyl, spiro [4,5] decyl, spiro [5,4] decyl, bicycle [2.2.1] heptyl, bicycle [2.2.2] octyl, adamantyl, norbornenyl and the like.

[0045] The term aryl preferably refers to a monocyclic aromatic ring containing 6 carbon atoms, a bicyclic aromatic ring system containing 10 carbon atoms, or a tricyclic aromatic ring system containing 14 carbon atoms. Examples include phenyl, naphthyl, or anthracenyl. The aryl group is optionally substituted.

[0046] The term heteroaryl preferably refers to: a five-membered monocyclic aromatic ring or a six-membered monocyclic aromatic ring in which at least one carbon atom is replaced by 1, 2, 3 or 4 (for a five-membered ring) or 1, 2, 3, 4 or 5 (for a six-membered ring) identical or different heteroatoms, the heteroatoms preferably being selected from the group consisting of O, N and S; a bicyclic aromatic ring system in which 1, 2, 3, 4, 5 or 6 carbon atoms of 8, 9, 10, 11 or 12 carbon atoms are replaced by identical or different heteroatoms, the heteroatoms preferably being selected from the group consisting of O, N and S;or an aromatic tricyclic ring system in which 1, 2, 3, 4, 5, or 6 carbon atoms of 13, 14, 15, or 16 carbon atoms are replaced by identical or different heteroatoms, and the heteroatoms are preferably selected from the group consisting of O, N, and S. Examples include oxazolyl, isoxazolyl, 1,2,5; Petition 870250103152, dated 11 / 11 / 2025, p. 103 / 219 95 / 208 oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoloxazinyl, 2,1-benzoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-Benzisothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, quinolyl, 1,2,3-benzotriazinyl or 1,2,4benzotriazinyl.

[0047] The term PEG group refers to a group in which one or more -CH2CH2-O- or CH3-CH2-O- units are connected, for example, CH3-CH2-O(CH2-CH2-O)x-, where x is selected from an integer from 0 to 6, preferably an integer from 0 to 4. The PEG group may optionally be substituted.

[0048] The term pharmaceutically acceptable salt refers to relatively non-toxic addition salts of the compound of the present disclosure. See, for example, SM Berge, et al. “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1 to 19.

[0049] Suitable pharmaceutically acceptable salts of the compound of the present disclosure may be acid addition salts of the compound of the present disclosure having a nitrogen atom in a chain or ring and having sufficient basicity, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, Petition 870250103152, dated 11 / 11 / 2025, pp. 104 / 219 96 / 208 caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanopropionic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pampic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, acid malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, Dgluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid,Sulfosalicylic acid or thiocyanic acid.

[0050] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an ammonium salt, a triethylamine salt or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with the following substances: N-methylglucamine, dimethylglucamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol. Furthermore, the basic nitrogen-containing groups can be quaternized using the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as sulfate Petition 870250103152, dated 11 / 11 / 2025, p. 105 / 219 97 / 208 dimethyl, diethyl sulfate, dibutyl sulfate and dipenyl sulfate; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromides and phenethyl bromides and the like.

[0051] Those skilled in the art might also recognize that acid addition salts of the claimed compound can be prepared by reacting the compound with a suitable inorganic or organic acid by any of numerous known methods. Alternatively, alkali metal salts and alkaline earth metal salts of the acid compound of the present disclosure can be prepared by reacting the compound with a suitable base by means of various known methods.

[0052] The present invention includes all possible salts of the compound of the present disclosure, which may be a single salt or any mixture of any proportion of the salts.

[0053] The term solvate refers to a substance formed by combining, physically linking, and / or solvating the compound of the present invention with a solvent molecule, such as a dissolvate, a monosolvate, or a hemisolvate, wherein the ratio between the solvent molecule and the compound of the present invention is about 2:1, about 1:1, or about 1:2, respectively. This physical linkage involves ionization and covalent bonding (including hydrogen bonding) to varying degrees. In some cases (for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid), the solvate can be separated. Therefore, the solvate includes separable solution and solvate phases. The compound of the present invention, together with a pharmaceutically acceptable solvent (such as water, methanol, and ethanol), can be Petition 870250103152, dated 11 / 11 / 2025, pp. 106 / 219 98 / 208 present in solvated form, and the present application is intended to cover solvated and non-solvated forms of the compound of the present invention. One of the solvates is a hydrate.

[0054] The term pharmaceutical composition as used in this application refers to a substance and / or a combination of substances used to identify, prevent or treat a condition or disease in the tissue. The pharmaceutical composition is formulated to be suitable for administration to a patient for diagnosis, prevention and / or treatment of a disease. In addition, the pharmaceutical composition refers to a combination of an active agent and an inert or active carrier that makes the composition suitable for therapeutic use.

[0055] As used in this document, the term carrier refers to a diluent, adjuvant, excipient or vehicle used together with a therapeutic agent. This pharmaceutical carrier may be a sterile liquid, such as a saline solution in water and oil, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.When the pharmaceutical composition is administered intravenously, a saline solution is a preferred carrier. A saline solution, an aqueous glucose solution, and a glycerol solution can also be used as liquid carriers, particularly as injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, ethylene glycol, water, ethanol, and the like. If necessary, the composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer. Examples of pharmaceutical carriers. Petition 870250103152, dated 11 / 11 / 2025, pp. 107 / 219 Suitable 99 / 208 ratios are described in E.W. Martin's "Remington's Pharmaceutical Sciences".

[0056] The term halogen refers to fluorine, chlorine, bromine, and iodine.

[0057] The term optionally means that this may occur or it may not occur. Examples Reagents and Models Used

[0058] The starting materials in the examples are commercially available and / or can be prepared by numerous methods well known to those skilled in the art of organic synthesis. Those skilled in the art of organic synthesis will appropriately select reaction conditions (including solvent, reaction atmosphere, reaction temperature, experiment duration, and post-treatment) in the following synthetic methods. Those skilled in the art of organic synthesis will understand that functional groups present in each part of a molecule must be compatible with the reagents and reactions provided.

[0059] All reagents and synthesized compounds can be acquired through general commercial channels in China. Suppliers include SigmaAldrich (USA), Shanghai Hongene Biotech Corporation (Trinlink Cleancap), jetMESSENGER (Polyplus-transfection®), Shanghai Titan Technology Co., Ltd., and similar companies.

[0060] Cell model: HEK293T cells were acquired from the Shanghai Cell Bank of the Chinese Academy of Sciences, and HepG2 cells were acquired from Wuhan Pricella Biotechnology Co., Ltd.

[0061] Main instruments used: Multimodal microplate reader Petition 870250103152, dated 11 / 11 / 2025, pp. 108 / 219 100 / 208 (Molecular Devices), and flow cytometer (CytoFLEX S series).

[0062] Compound preparation and identification: Nuclear magnetic resonance spectrometer (Bruker 300 MHz), liquid chromatography coupled to mass spectrometry (Agilent 6150 / 1290) and high-performance liquid chromatography (Agilent 1260).

[0063] Cell experiment: Inverted fluorescence microscope (Guangzhou Mingmei Optoelectronic Technology Co., Ltd) and cell culture incubator (Thermo Fisher Scientific).

[0064] The implementation process and beneficial effects of the present invention will be described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the implementable scope of the present invention. Final Product Summary: Petition 870250103152, dated 11 / 11 / 2025, pp. 109 / 219 101 / 208 ϊνP,'N) 2F Ίι* 2g 2h ^i^XaiLÍHÇtHr^ ΗηΐΟώ^ΟΉ^H^; UR^OCHjC&í RO is selected from the group that consists of FrCL Br and I R2 is selected from the group consisting of H. OH, OCH3, F. Cl, CHe SH IcR^SH, ΜΒ1·*ΙΙ-ζ hRi-N* if fl<-F 3h Γ,^ΊH / Χ^Χ;»] 3I UR^CHXjCCM Jh and J2 are any of the following five bases: Final Product Synthesis Method 1

[0065] In 8 ml of anhydrous DMSO, 0.4 g of compound 1 was dissolved, and 2 eq of compound 2 and 20 eq of anhydrous zinc chloride were added under argon protection. The reaction solution was stirred at room temperature (25 °C) for 24 hours under argon protection. After the reaction was completed by TLC monitoring, 150 ml of 0.25 M EDTA solution was used to terminate the reaction, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using a 0 M to 1.0 M ammonium bicarbonate eluent. The eluent containing the product was collected and freeze-dried to obtain a product. Final Product Synthesis Method 2

[0066] In 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 Petition 870250103152, dated 11 / 11 / 2025, pp. 110 / 219 In a solution of 102 / 208 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, 0.2 g of compound 2 was dissolved, and then 0.2 g of compound 1 was added to the solution. The reaction solution was stirred at room temperature (25 °C) for 16 hours. After the reaction was completed by TLC monitoring, 150 mL of 0.25 M EDTA solution was used to terminate the reaction, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using a 0 M to 1.0 M ammonium bicarbonate eluent. The eluent containing the product was collected and freeze-dried to obtain a product. Synthesis of Representative Structural Compounds Example 1 Synthesis of Compound 3 Step 1:

[0067] A 3-2 compound (2.38 g) was added to a tetrazole solution. Petition 870250103152, dated 11 / 11 / 2025, pp. 111 / 219 103 / 208 (1.76 g) in acetonitrile (63 ml) in a three-necked flask, and the atmosphere was replaced with argon three times. Then, at room temperature of 25 °C, a compound 3-1 (5 g) was dissolved in 10 ml of acetonitrile and added to the above solution. The resulting solution was stirred at room temperature of 25 °C for 1 hour. No obvious heat release was found, and TLC monitoring showed that compound 3-1 disappeared. Then, to the solution, a solution of iodine in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the solution no longer faded. After that, the reaction solution was stirred for another 0.5 hour, and TLC monitoring showed that the oxidation was complete. After adding a saturated aqueous solution (10 ml) of sodium sulfite to the reaction solution for quenching, a further 50 ml of water was added for dilution, and the mixture was extracted with dichloromethane (50 ml x 2).The organic phases were combined and washed once with water (50 ml) and concentrated to obtain a light yellow oily product 3-3 (8 g, crude product). Step 2:

[0068] Compound 3-3 (8 g, crude product) was dissolved in 40 ml of acetic acid and 10 ml of water, and the reaction solution was stirred at 25 °C for 16 hours. TLC monitoring showed that compound 3-3 disappeared and a highly polar spot was generated. The reaction solution was directly concentrated under vacuum. After concentration, appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white solid product 3-4 was obtained (2.8 g, 51% overall yield in two steps). Petition 870250103152, dated 11 / 11 / 2025, pp. 112 / 219 104 / 208 Step 3:

[0069] 28 ml of a tetrazole solution in acetonitrile (0.4 mmol / ml) were prepared. Compound 3-4 (2.8 g) was added to the above solution, and then compound A1 (3 g) was added to the solution at room temperature of 25 °C. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at room temperature of 25 °C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to below 10 °C in an ice water bath, and an iodine solution in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the reaction solution no longer faded. TLC monitoring showed that the oxidation reaction was complete. The reaction solution was quenched by the addition of 10 ml of a saturated aqueous solution of sodium sulfite, diluted with water and extracted three times with ethyl acetate.The organic phases were combined and dried over anhydrous sodium sulfate and filtered. Appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white foamy solid compound 3-6 was obtained (2.6 g, 78.2% yield). Step 4:

[0070] Compound 3-6 (2.6 g) was dissolved in methanol (30 ml) and concentrated aqueous ammonia (30 ml) was added. The resulting solution was stirred at room temperature of 25 °C for 60 hours. TLC monitoring showed that compound 3-6 was completely reacted. The reaction solution was concentrated under vacuum and concentrated again with methanol to obtain a Petition 870250103152, dated 11 / 11 / 2025, pp. 113 / 219 105 / 208 light yellow oily liquid compound 3-7 (2.4 g, crude product), which was used directly for the next step. Step 5:

[0071] Compound 3-7 (2.4 g, crude product) was dissolved in DMSO (3 mL) and triethylamine trihydrofluoride (3.5 mL) was added. The reaction solution was stirred at 50 °C for 1 hour. TLC monitoring showed that compound 3-7 was completely reacted. The reaction solution was diluted to 50 mL with water, and the pH was adjusted to 5.5 with 1 N aqueous NaOH solution. The mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an aqueous ammonium bicarbonate solution eluent from 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a target compound, amine salt 3-8 (0.8 g, 33.7% yield), which was a white solid. Step 6:

[0072] Compound 9a (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 3-8 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the Petition 870250103152, dated 11 / 11 / 2025, pp. 114 / 219 106 / 208 of the remaining liquid was freeze-dried to obtain a product, compound 5, which was an ammonium salt in the form of a white powder (65 mg).

[0073] 1H NMR (400 MHz, D2O) δ 8.08 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 5.93 (d, J = 17.9 Hz, 1H), 5.70 (d, J = 6.4 Hz, 2H), 5.28 - 5.02 (m, 1H), 4.58 - 3.99 (m, 14H), 3.84 (s, 3H), 3.00 - 2.70 (m, 3H).

[0074] 31P NMR (162 MHz, D2O) δ -0.80, -11.55, -23.03. Example 2 Synthesis of Compound 35 Step 1:

[0075] A compound 35-2 (2.07 g) was added to a solution of tetrazole (1.6 g) in acetonitrile (56 ml) in a three-necked flask, and the atmosphere was replaced with argon three times. Then, at room temperature of 25 °C, a compound 35-1 (5 g) was dissolved in 10 ml of acetonitrile and Petition 870250103152, dated 11 / 11 / 2025, pp. 115 / 219 107 / 208 added to the above solution. The resulting solution was stirred at room temperature of 25 °C for 1 hour. No obvious heat release was found, and TLC monitoring showed that compound 2-1 had disappeared. Then, iodine solution (a 0.5 mmol / ml solution was prepared by dissolving 5 g of iodine in 40 ml of the mixed solution: THF:H2O:pyridine = 8:1:1) was added dropwise until the solution no longer faded. After that, the reaction solution was stirred for another 0.5 hour, and TLC monitoring showed that the oxidation was complete. After adding aqueous Na2SO3 solution (10 ml) to the reaction solution for quenching, another 50 ml of water was added for dilution, and the mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined and washed once with water (50 ml) and concentrated to obtain a light yellow oily product 35-3 (7.5 g, crude product). Step 2:

[0076] Compound 35-3 (7.2 g, crude product) was dissolved in 40 ml of acetic acid and 10 ml of water, and the reaction solution was stirred at 25 °C for 16 hours. TLC monitoring showed that compound 35-3 disappeared and a highly polar spot was generated. The reaction solution was directly concentrated under vacuum. After concentration, appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white solid product 35-4 (2.8 g, 54.8% overall yield in two steps) was obtained. Step 3:

[0077] 28 ml of a tetrazole solution in acetonitrile (0.4 Petition 870250103152, dated 11 / 11 / 2025, pp. 116 / 219 (108 / 208 mmol / ml). Compound 35-4 (2.8 g) was added to the above solution, and then compound A1 (2.26 g) was added to the solution at room temperature of 25 °C. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at room temperature of 25 °C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to below 10 °C in an ice water bath, and an iodine solution in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the reaction solution no longer faded. TLC monitoring showed that the oxidation reaction was complete. The reaction solution was quenched by adding 10 ml of a saturated aqueous solution of sodium sulfite, diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered.Appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white foamy solid compound 35-6 was obtained (3.1 g, 93.5% yield). Step 4:

[0078] Compound 35-6 (3.1 g) was dissolved in methanol (30 ml) and concentrated aqueous ammonia (30 ml) was added. The resulting solution was stirred at room temperature of 25 °C for 60 hours. TLC monitoring showed that compound 35-6 was completely reacted. The reaction solution was concentrated under vacuum and concentrated again with methanol to obtain a light yellow oily liquid compound 35-7 (2.4 g, crude product). Step 5: Petition 870250103152, dated 11 / 11 / 2025, pp. 117 / 219 109 / 208

[0079] Compound 35-7 (2.4 g, crude product) was dissolved in DMSO (3 mL) and triethylamine trihydrofluoride (3.5 mL) was added. The reaction solution was stirred at 50 °C for 1 hour. TLC monitoring showed that compound 35-7 was completely reacted. The reaction solution was diluted to 50 mL with water, and the pH was adjusted to 5.5 with 1 N aqueous NaOH solution. The mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using 0 M to 1.0 M TEAB eluent. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a target compound, triethylamine salt 35-8 (1.5 g, 51% yield), which was a white solid. Step 6:

[0080] At room temperature (25 °C), under argon protection, compound 35-8 (500 mg), compound 9a (500 mg) and anhydrous zinc chloride (1.2 g) were added, and anhydrous DMSO (8 ml) was added with a syringe to react for 24 hours. TLC monitoring showed that most compounds were reacted. The reaction solution was added to a solution of disodium EDTA (1.6 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 35, which was an ammonium salt in the form of a white powder (120 mg).

[0081] 1H NMR (400 MHz, D2O) δ 8.25 (s, 1H), 7.98 (s, 1H), 7.59 (d, J = 7.3 Hz, 1H), 5.99 - 5.53 (m, 4H), 4.96 - 4.80 (m, 1H), 4.46 - 3.99 (m, 14H), 3.90 (s, Petition 870250103152, dated 11 / 11 / 2025, pp. 118 / 219 110 / 208 3H), 3.41 (s, 3H).

[0082] 31P NMR (162 MHz, D2O) δ -1.25, -11.58, -22.98. Example 3 Synthesis of Compound 68 Step 1:

[0083] Compound 3-2 (2.07 g) was added to a solution of tetrazole (1.6 g) in acetonitrile (56 ml) in a three-necked flask, and the atmosphere was replaced with argon three times. Then, at room temperature of 25 °C, compound 68-1 (5 g) was dissolved in 10 ml of acetonitrile and added to the above solution. The resulting solution was stirred at room temperature of 25 °C for 1 hour. No obvious heat release was found, and TLC monitoring showed that compound 68-1 disappeared. Then, in the solution, the iodine solution (a 0.5 mmol / ml solution) was prepared by dissolving 5 g of iodine in 40 ml of the mixed solution: THF:H2O:pyridine = Petition 870250103152, dated 11 / 11 / 2025, pp. 119 / 219 111 / 208 A solution of 8:1:1 was added dropwise until the solution no longer faded. After that, the reaction solution was stirred for another 0.5 hours, and TLC monitoring showed that oxidation was complete. After adding aqueous Na2SO3 solution (10 ml) to the reaction solution for quenching, another 50 ml of water was added for dilution, and the mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined and washed once with water (50 ml) and concentrated to obtain a light yellow oily product 68-3 (7.5 g, crude product). Step 2:

[0084] Compound 68-3 (7.2 g, crude product) was dissolved in 40 ml of acetic acid and 10 ml of water, and the reaction solution was stirred at 25 °C for 16 hours. TLC monitoring showed that compound 68-3 disappeared and a highly polar spot was generated. The reaction solution was directly concentrated under vacuum. After concentration, appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white solid product 68-4 (2.8 g, 54.8% overall yield in two steps) was obtained. Step 3:

[0085] 28 ml of a tetrazole solution in acetonitrile (0.4 mmol / ml) were prepared. Compound 68-4 (2.8 g) was added to the above solution, and then compound A1 (2.26 g) was added to the solution at room temperature of 25 °C. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at room temperature of 25 °C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to below Petition 870250103152, dated 11 / 11 / 2025, pp. 120 / 219 112 / 208 at 10 °C in an ice water bath, and an iodine solution in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the reaction solution no longer faded. TLC monitoring showed that the oxidation reaction was complete. The reaction solution was quenched by adding 10 ml of a saturated aqueous sodium sulfite solution, diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. Appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM:MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white foamy solid compound 68-6 was obtained (3.1 g, 93.5% yield). Step 4:

[0086] Compound 68-6 (3.1 g) was dissolved in methanol (30 ml) and concentrated aqueous ammonia (30 ml) was added. The resulting solution was stirred at room temperature of 25 °C for 60 hours. TLC monitoring showed that compound 68-6 was completely reacted. The reaction solution was concentrated under vacuum and concentrated again with methanol to obtain a light yellow oily liquid compound 68-7 (2.4 g, crude product). Step 5:

[0087] Compound 68-7 (2.4 g, crude product) was dissolved in DMSO (3 ml) and triethylamine trihydrofluoride (3.5 ml) was added. The reaction solution was stirred at 50 °C for 1 hour. TLC monitoring showed that compound 68-7 was completely reacted. The reaction solution was diluted to 50 ml with water, and the pH was adjusted to 5.5 with 1 N aqueous NaOH solution. Petition 870250103152, dated 11 / 11 / 2025, pages 121 / 219 113 / 208 The mixture was loaded onto a Sephadex DEAE column. The product was eluted via linear gradient elution using TEAB eluent at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a target compound, triethylamine 68-8 salt (1.5 g, 51% yield), which was a white solid. Step 6:

[0088] At room temperature (25 °C), under argon protection, compound 68-8 (500 mg), compound 9a (500 mg) and anhydrous zinc chloride (1.2 g) were added, and anhydrous DMSO (8 ml) was added with a syringe to react for 24 hours. TLC monitoring showed that most of the materials were reacted. The reaction solution was added to a solution of disodium EDTA (1.6 g, 80 ml of water were added) pre-cooled to 0 °C beforehand, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 68, which was an ammonium salt in the form of a white powder (120 mg).

[0089] 1H NMR (400 MHz, D2O) δ 7.75 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 5.97 (dd, J = 17.8, 2.3 Hz, 1H), 5.85 - 5.65 (m, 3H), 5.28 (ddd, J = 52.2, 4.7, 2.3 Hz, 1H), 5.01 (dt, J = 51.5, 3.4 Hz, 1H), 4.57 - 4.51 (m, 2H), 4.48 (t, J = 4.2 Hz, 1H), 4.34 (t, J = 5.1 Hz, 1H), 4.24 - 4.07 (m, 7H), 4.02 (t, J = 4.3 Hz, 2H), 3.93 (s, 3H).

[0090] 31P NMR (162 MHz, D2O) δ -1.30, -11.57 (dd, J = 25.8, 18.4 Hz), -22.98 (t, J = 18.3 Hz). Example 4 Petition 870250103152, dated 11 / 11 / 2025, pp. 122 / 219 114 / 208 Synthesis of Compound 83 Step 1:

[0091] Compound 3-2 (2.1 g) was added to a solution of tetrazole (1.6 g) in acetonitrile (56 ml) in a three-necked flask, and the atmosphere was replaced with argon three times. Then, at room temperature of 25 °C, compound 83-1 (5 g) was dissolved in 10 ml of acetonitrile and added to the above solution. The resulting solution was stirred at room temperature of 25 °C for 1 hour. No obvious heat release was found, and TLC monitoring showed that compound 83-1 disappeared. Then, iodine solution (a 0.5 mmol / ml solution was prepared by dissolving 5 g of iodine in 40 ml of the mixed solution: THF:H2O:pyridine = 8:1:1) was added dropwise until the solution no longer faded. After that, the reaction solution was stirred for another 0.5 hour, and TLC monitoring showed that oxidation was complete. After adding the aqueous solution of Petition 870250103152, dated 11 / 11 / 2025, pp. 123 / 219 115 / 208 Na2SO3 (10 ml) was added to the reaction solution for quenching, followed by 50 ml of water for dilution, and the mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined and washed once with water (50 ml) and concentrated to obtain a light yellow oily product 83-3 (7.4 g, crude product). Step 2:

[0092] Compound 83-3 (7.4 g, crude product) was dissolved in 40 ml of acetic acid and 10 ml of water, and the reaction solution was stirred at 25 °C for 16 hours. TLC monitoring showed that compound 83-3 disappeared and a highly polar spot was generated. The reaction solution was directly concentrated under vacuum. After concentration, appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white solid product 83-4 (2.8 g, 54.8% overall yield in two steps) was obtained. Step 3:

[0093] 28 ml of a tetrazole solution in acetonitrile (0.4 mmol / ml) were prepared. Compound 83-4 (2.8 g) was added to the above solution, and then compound A1 (2.26 g) was added to the solution at room temperature of 25 °C. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at room temperature of 25 °C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to below 10 °C in an ice water bath, and an iodine solution in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the reaction solution no longer faded. The Petition 870250103152, dated 11 / 11 / 2025, pp. 124 / 219 Monitoring by TLC showed that the oxidation reaction was complete. The reaction solution was quenched by adding 10 ml of a saturated aqueous solution of sodium sulfite, diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. Appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white foamy solid compound 83-6 (3.1 g, 93.5% yield) was obtained. Step 4:

[0094] Compound 83-6 (3.1 g) was dissolved in methanol (30 ml) and concentrated aqueous ammonia (30 ml) was added. The resulting solution was stirred at room temperature of 25 °C for 60 hours. TLC monitoring showed that compound 83-6 was completely reacted. The reaction solution was concentrated under vacuum and concentrated again with methanol to obtain a light yellow oily liquid compound 83-7 (2.4 g, crude product). Step 5:

[0095] Compound 83-7 (2.4 g, crude product) was dissolved in DMSO (3 mL) and triethylamine trihydrofluoride (3.5 mL) was added. The reaction solution was stirred at 50 °C for 1 hour. TLC monitoring showed that compound 83-7 was completely reacted. The reaction solution was diluted to 50 mL with water, and the pH was adjusted to 5.5 with 1 N aqueous NaOH solution. The mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using 0 M to 1.0 M TEAB eluent. Most of the water in the obtained fraction was concentrated under vacuum, and the Petition 870250103152, dated 11 / 11 / 2025, pages 125 / 219 The remaining 117 / 208 liquid was freeze-dried to obtain a target compound, triethylamine salt 83-8 (1.5 g, 51% yield), which was a white solid. Step 6:

[0096] At room temperature (25 °C), under argon protection, compound 83-8 (500 mg), compound 9a (500 mg) and anhydrous zinc chloride (1.2 g) were added, and anhydrous DMSO (8 ml) was added with a syringe to react for 24 hours. TLC monitoring showed that most of the materials were reacted. The reaction solution was added to a solution of disodium EDTA (1.6 g, 80 ml of water were added) pre-cooled to 0 °C beforehand, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 83, which was an ammonium salt in the form of a white powder (120 mg).

[0097] 1H NMR (400 MHz, D2O) δ 8.30 (d, J = 0.6 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 0.7 Hz, 1H), 6.59 - 6.30 (m, 2H), 6.23 - 6.08 (m, 1H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 5.08 - 4.90 (m, 1H), 4.68 - 4.03 (m, 12H), 3.98 (d, J = 0.7 Hz, 3H), 2.76 - 2.48 (m, 2H).

[0098] 31P NMR (162 MHz, D2O) δ -1.30, -11.57 (dd, J = 25.8, 18.4 Hz), -22.98 (t, J = 18.3 Hz). Example 5 Synthesis of Compound 90 Petition 870250103152, dated 11 / 11 / 2025, pp. 126 / 219 118 / 208 90-1 Compound 90

[0099] Compound 9a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 90-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 90, which was an ammonium salt in the form of a white powder (50 mg).

[0100] 1H NMR (400 MHz, D2O) δ 7.83 (d, J = 0.6 Hz, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.28 (ddq, J = 3.1, 1.5, 0.7 Hz, 1H), 6.20-6.13 (m, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.40 (dddd, J = 25.2, 3.5, 1.8, 0.9 Hz, 1H), 5.09 - 4.93 (m, 1H), 4.81 (dddd, J = 46.4, 7.1, 3.7, 0.7 Hz, 1H), 4.61 (ddd, J = 5.2, 2.8, 0.7 Hz, 1H), 4.41 4.05 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 2.81 - 2.38 (m, 2H).

[0101] 31P NMR (162 MHz, D2O) δ -1.17, -11.50, -22.81. Example 6 Synthesis of Compound 103 Petition 870250103152, dated 11 / 11 / 2025, pp. 127 / 219 119 / 208 3-B Compound 103

[0102] Compound 9b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 3-8 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 103, which was an ammonium salt in the form of a white powder (60 mg).

[0103] 1H NMR (400 MHz, D2O) δ 8.33 (d, J = 0.5 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.2, 1.4, 0.7 Hz, 1H), 6.17 (dq, J = 2.3, 0.8 Hz, 1H), 6.11 (dq, J = 3.1,0.8 Hz, 1H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.88 - 4.62 (m, 3H), 4.45 (dddd, J = 25.2, 6.8, 5.0, 0.7 Hz, 1H), 4.33 - 4.09 (m, 9H), 4.05 (ttd, J = 2.9, 1.5, 0.7 Hz, 1H), 3.98 (d, J = 0.7 Hz, 3H), 3.44 (d, J = 1.4 Hz, 3H), 3.08 (s, 3H).

[0104] 31P NMR (162 MHz, D2O) δ 0.60, -10.29, -21.23. Example 7 Petition 870250103152, dated 11 / 11 / 2025, pp. 128 / 219 120 / 208 Synthesis of Compound 119 11&-1 Compound 119

[0105] Compound 9b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 119-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 119, which was an ammonium salt in the form of a white powder (65 mg).

[0106] 1H NMR (400 MHz, D2O) δ 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.76 (dd, J = 7.8, 1.8 Hz, 1H), 6.17 (dt, J = 2.5, 0.7 Hz, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.85 5.73 (m, 2H), 5.53 (dddd, J = 25.2, 3.9, 1.7, 0.9 Hz, 1H), 4.89 - 4.60 (m, 3H), 4.46 - 4.02 (m, 12H), 3.98 (d, J = 0.7 Hz, 3H), 3.44 (d, J = 1.4 Hz, 3H).

[0107] 31P NMR (162 MHz, D2O) δ 0.62, -10.29, -21.22. Example 8 Synthesis of Compound 127 Petition 870250103152, dated 11 / 11 / 2025, pp. 129 / 219 121 / 208 127-1 Compound 127

[0108] Compound 9b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 127-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 127, which was an ammonium salt in the form of a white powder (82 mg).

[0109] 1H RMN (400 MHz, D2O) δ 8,29 (s, 1H), 8,24 (d, J = 0,7 Hz, 1H), 8,21 8,18 (m, 2H), 6,54 - 6,00 (m, 3H), 5,27 (dddd, J = 46,5, 7,0, 4,0, 0,6 Hz, 1H), 4,97 (dddd, J = 8,0, 4,4, 2,9, 0,7 Hz, 1H), 4,77 (tqd, J = 4,4, 1,5, 0,7 Hz, 1H), 4,71 (ddd, J = 3,9, 2,6, 0,7 Hz, 1H), 4,45 (dddd, J = 25,2, 6,8, 5,1,0,7 Hz, 1H), 4,35 (qt, J = 3,0, 0,7 Hz, 1H), 4,29 - 4,08 (m, 8H), 4,05 (ttd, J = 2,9, 1,5, 0,7 Hz, 1H), 3,98 (d, J = 0,7 Hz, 3H), 3,42 (dd, J = 18,0, 1,5 Hz, 6H), 3,08 (s, 3H).

[0110] 31P RMN (162 MHz, D2O) δ 0,60, -10,29, -21,22. Exemplo 9 Petição 870250103152, de 11 / 11 / 2025, pág. 130 / 219 122 / 208 Síntese do Composto 167

[0111] Compound 9b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 24-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 167, which was an ammonium salt in the form of a white powder (62 mg).

[0112] 1H NMR (400 MHz, D2O) δ 8.24 (d, J = 0.7 Hz, 1H), 8.20 (s, 1H), 7.81 (dd, J = 7.9, 1.8 Hz, 1H), 6.39 (ddt, J = 25.2, 4.0, 0.7 Hz, 1H), 6.17 (dq, J = 2.3, 0.7 Hz, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.56 (dddt, J = 25.3, 3.4, 1.8, 0.9 Hz, 1H), 5.43 - 4.99 (m, 3H), 4.79 - 4.65 (m, 1H), 4.56 - 4.38 (m, 2H), 4.35 - 4.06 (m, 8H), 4.05 (ddq, J = 4.6, 2.2, 1.1 Hz, 1H), 3.98 (d, J = 0.7 Hz, 3H), 3.44 (d, J = 1.4 Hz, 3H).

[0113] 31P NMR (162 MHz, D2O) δ 0.60, -10.29, -21.22. Petition 870250103152, dated 11 / 11 / 2025, pp. 131 / 219 123 / 208 Example 10 Synthesis of Compound 180 180-1 Compound 180

[0114] Compound 9b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 180-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 180, which was an ammonium salt in the form of a white powder (95 mg).

[0115] 1H NMR (400 MHz, D2O) δ 8.35 (d, J = 0.6 Hz, 1H), 8.29 (s, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.47-6.32 (m, 1H), 6.17 (dq, J = 2.3, 0.8 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.54-5.33 (m, 1H), 5.10-4.94 (m, 1H), 4.91 -4.64 (m, 2H), 4.48 - 4.03 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 3.44 (d, J = 1.4 Hz, 3H), 3.08 (s, 3H), 2.83-2.35 (m, 2H).

[0116] 31P NMR (162 MHz, D2O) δ 0.60, -10.29, -21.22. Petition 870250103152, dated 11 / 11 / 2025, pp. 132 / 219 124 / 208 Example 11 Synthesis of Compound 203 203-1 Compound 203

[0117] A compound 9c (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 203-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 203, which was an ammonium salt in the form of a white powder (95 mg).

[0118] 1H NMR (400 MHz, D2O) δ 8.33 (d, J = 0.6 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.2, 1.4, 0.7 Hz, 1H), 6.23 (dt, J = 2.3, 0.8 Hz, 1H), 6.11 (dq, J = 3.1, 0.8 Hz, 1H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 5.00 - 4.68 (m, 4H), 4.65 - 4.39 (m, 2H), 4.38 - 4.05 (m, 8H), 3.98 (d, J = 0.7 Hz, 3H), 3.08 (s, 3H).

[0119] 31P NMR (162 MHz, D2O) δ 0.60, -10.29, -21.22. Petition 870250103152, dated 11 / 11 / 2025, pp. 133 / 219 125 / 208 Example 12 Synthesis of Compound 239 239-1 Compound 239

[0120] Compound 9c (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 239-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 239, which was an ammonium salt in the form of a white powder (95 mg).

[0121] 1H NMR (400 MHz, D2O) δ 7.88 (d, J = 0.7 Hz, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 6.33 - 6.06 (m, 2H), 5.90 (d, J = 7.8 Hz, 1H), 5.53 (dddd, J = 25.2, 3.9, 1.7, 0.9 Hz, 1H), 5.03 - 4.50 (m, 6H), 4.43 - 4.07 (m, 9H), 3.98 (d, J = 0.7 Hz, 3H), 3.40 (d, J = 1.6 Hz, 3H).

[0122] 31P NMR (162 MHz, D2O) δ 0.60, -10.29, -21.22. Example 13 Petition 870250103152, dated 11 / 11 / 2025, pp. 134 / 219 126 / 208 Synthesis of Compound 260 260-1 Compound 260

[0123] Compound 9c (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 260-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 260, which was an ammonium salt in the form of a white powder (75 mg).

[0124] 1H NMR (400 MHz, D2O) δ 8.24 (d, J = 0.7 Hz, 1H), 8.20 (s, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.43 (ddq, J = 25.2, 1.6, 0.8 Hz, 1H), 6.27 - 6.20 (m, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.51 - 5.12 (m, 3H), 5.05 - 4.70 (m, 3H), 4.66 - 4.10 (m, 10H), 3.98 (d, J = 0.7 Hz, 3H).

[0125] 31P NMR (162 MHz, D2O) δ -0.90, -10.29, -21.22. Example 14 Synthesis of Compound 287 Petition 870250103152, dated 11 / 11 / 2025, pp. 135 / 219 127 / 208 287-1 Compound 287

[0126] Compound 9c (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 287-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 287, which was an ammonium salt in the form of a white powder (75 mg).

[0127] 1H NMR (400 MHz, D2O) δ 8.24 (d, J = 0.7 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J = 0.6 Hz, 1H), 6.39 (ddt, J = 25.2, 4.0, 0.7 Hz, 1H), 6.28 (ddt, J = 3.1, 1.5, 0.7 Hz, 1H), 6.26 - 6.15 (m, 1H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 5.11 - 4.79 (m, 3H), 4.65 - 4.03 (m, 10H), 3.98 (d, J = 0.7 Hz, 3H), 2.88 - 2.51 (m, 2H).

[0128] 31P NMR (162 MHz, D2O) δ-1.11,-10.31,-21.25. Example 15 Synthesis of Compound 126 Petition 870250103152, dated 11 / 11 / 2025, pp. 136 / 219 128 / 208 3-8 Compound 308

[0129] Compound 9d (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 3-8 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 308, which was an ammonium salt in the form of a white powder (60 mg).

[0130] 1H NMR (400 MHz, D2O) δ 8.28 (d, J = 0.6 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.3, 1.6, 0.9 Hz, 1H), 6.21 - 6.07 (m, 2H), 5.22 (dddd, J =46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.98 -4.68 (m, 2H), 4.57 -4.03 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 2.45 - 1.75 (m, 2H).

[0131] 31P NMR (162 MHz, D2O) δ -0.9, -10.29, -21.27. Example 16 Synthesis of Compound 326 Petition 870250103152, dated 11 / 11 / 2025, pp. 137 / 219 129 / 208 316-1 Compound 326

[0132] Compound 9d (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 326-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 326, which was an ammonium salt in the form of a white powder (60 mg).

[0133] 1H NMR (400 MHz, D2O) δ 8.29 (d, J = 1.7 Hz, 3H), 8.20 (d, J = 0.7 Hz, 1H), 6.39 (ddt, J = 25.1, 3.9, 0.7 Hz, 1H), 6.29 - 6.04 (m, 2H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 4.97 (dddd, J = 8.0, 4.4, 2.9, 0.7 Hz, 1H), 4.77 (tqd, J = 4.4, 1.5, 0.7 Hz, 1H), 4.61 -4.06 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 3.40 (d, J = 1.6 Hz, 3H), 3.08 (s, 6H), 2.56 - 1.44 (m, 2H).

[0134] 31P NMR (162 MHz, D2O) δ -0.78, -10.29, -21.22. Example 17 Synthesis of Compound 352 Petition 870250103152, dated 11 / 11 / 2025, pp. 138 / 219 130 / 208 Compound 352

[0135] Compound 9d (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 352-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 352, which was an ammonium salt in the form of a white powder (74 mg).

[0136] 1H NMR (400 MHz, D2O) δ 8.33 - 8.27 (m, 2H), 8.24 (d, J = 0.6 Hz, 1H), 8.20 (s, 1H), 6.63 - 6.28 (m, 2H), 6.17 (dt, J = 1.3, 0.7 Hz, 1H), 5.57 - 5.04 (m, 3H), 4.63 - 4.03 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 3.08 (s, 3H), 2.63 - 1.60 (m, 2H).

[0137] 31P NMR (162 MHz, D2O)-0.55, -10.32, -21.28. Example 18 Synthesis of Compound 386 Petition 870250103152, dated 11 / 11 / 2025, pp. 139 / 219 131 / 208 Compound 386

[0138] Compound 9d (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 386-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 386, which was an ammonium salt in the form of a white powder (60 mg).

[0139] 1H NMR (400 MHz, D2O) δ 8.38 - 8.22 (m, 2H), 8.18 (d, J = 0.6 Hz, 1H), 6.58 - 6.30 (m, 2H), 6.17 (t, J = 1.0 Hz, 1H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 5.10-4.83 (m, 1H), 4.60-4.07 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 3.08 (s, 3H), 2.69 - 2.46 (m, 2H), 2.34 - 1.69 (m, 2H).

[0140] 31P NMR (162 MHz, D2O) δ -0.85, -10.09, -21.23. Example 19 Synthesis of Compound 403 Petition 870250103152, dated 11 / 11 / 2025, pp. 140 / 219 132 / 208 m 403d Compound 403

[0141] A compound 10a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 403-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 403, which was an ammonium salt in the form of a white powder (55 mg).

[0142] 1H NMR (400 MHz, D2O) δ 8.40 - 8.19 (m, 2H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.2, 1.4, 0.7 Hz, 1H), 6.33 (dd, J = 2.7, 0.6 Hz, 1H), 6.11 (dq, J = 3.0, 0.7 Hz, 1H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.80 (ddd, J = 3.9, 3.1, 0.7 Hz, 1H), 4.74 (dddd, J = 7.9, 3.9, 2.9, 0.7 Hz, 1H), 4.64 (t, J = 2.8 Hz, 1H), 4.51 - 4.08 (m, 10H), 4.02 (d, J = 0.7 Hz, 2H), 3.98 (s, 3H), 3.08 (s, 3H).

[0143] 31P NMR (162 MHz, D2O) δ -0.90, -11.41, -22.93. Example 20 Synthesis of Compound 443 Petition 870250103152, dated 11 / 11 / 2025, pp. 141 / 219 133 / 208 443-1 Compound 443

[0144] Compound 70a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 443-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 443, which was an ammonium salt in the form of a white powder (70 mg).

[0145] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 7.75 (dd, J = 7.8, 1.8 Hz, 1H), 6.45 (ddq, J = 25.2, 1.6, 0.9 Hz, 1H), 6.33 (dd, J = 2.7, 0.6 Hz, 1H), 5.93 - 5.65 (m, 2H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.89 (dddd, J = 8.0, 5.4,4.6, 0.6 Hz, 1H), 4.64 (t, J = 2.8Hz, 1H), 4.51 -4.07 (m, 11H), 4.02 (d, J = 0.7 Hz, 2H), 3.98 (s, 3H), 3.47 (s, 3H).

[0146] 31P NMR (162 MHz, D2O) δ 0.50, -9.18, -10.26, -21.22. Example 21 Synthesis of Compound 467 Petition 870250103152, dated 11 / 11 / 2025, pp. 142 / 219 134 / 208 467-1 i Compound 467

[0147] Compound 70a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 467-7 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 467, which was an ammonium salt in the form of a white powder (75 mg).

[0148] 1H NMR (400 MHz, D2O) δ 8.32 - 8.10 (m, 2H), 7.81 (dd, J = 7.9, 1.8 Hz, 1H), 6.54 - 6.21 (m, 2H), 5.90 (d, J = 7.8 Hz, 1H), 5.71 - 4.98 (m, 4H), 4.73 4.09 (m, 11H), 4.02 (d, J = 0.7 Hz, 2H), 3.98 (s, 3H).

[0149] 31P NMR (162 MHz, D2O) δ -0.99, -11.40, -23.06. Example 22 Synthesis of Compound 480 Petition 870250103152, dated 11 / 11 / 2025, pp. 143 / 219 135 / 208 480-1 Compound 480

[0150] Compound 10a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 480-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 480, which was an ammonium salt in the form of a white powder (85 mg).

[0151] 1H NMR (400 MHz, D2O) δ 8.41 - 8.23 ​​(m, 2H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.43 - 6.28 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), 5.56 - 5.21 (m, 1H), 5.09 4.93 (m, 1H), 4.81 (dddd, J = 46.5, 7.1,3.7, 0.7 Hz, 1H), 4.64 (t, J = 2.8 Hz, 1H), 4.48 - 4.03 (m, 10H), 4.02 (d, J = 0.7Hz, 2H), 3.98 (d, J = 0.7 Hz, 3H), 3.08 (s, 3H), 2.79-2.46 (m, 2H).

[0152] 31P NMR (162 MHz, D2O) δ 0.60, -9.01, -10.23, -21.17. Example 23 Synthesis of Compound 501 Petition 870250103152, dated 11 / 11 / 2025, pp. 144 / 219 136 / 208

[0153] A compound 10b (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 501-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 501, which was an ammonium salt in the form of a white powder (92 mg).

[0154] 1H NMR (400 MHz, D2O) δ 8.41 - 8.14 (m, 4H), 6.39 (ddt, J = 25.3, 4.1, 0.8 Hz, 1H), 6.25 - 5.98 (m, 2H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 4.83 - 4.61 (m, 3H), 4.45 (dddd, J = 25.2, 6.8, 5.0, 0.7 Hz, 1H), 4.36 - 4.07 (m, 10H), 3.98 (d, J = 0.7 Hz, 3H), 3.69 - 3.48 (m, 2H), 3.08 (s, 6H), 2.90 - 2.61 (m, 2H), 1.84 (p, J = 6.5 Hz, 2H).

[0155] 31P NMR (162 MHz, D2O) δ 0.60, -9.10, -10.31, -21.17. Petition 870250103152, dated 11 / 11 / 2025, pp. 145 / 219 137 / 208 Example 24 Synthesis of Compound 541 Compound 541

[0156] Compound 10b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 541-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 541, which was an ammonium salt in the form of a white powder (85 mg).

[0157] 1H RMN (400 MHz, D2O) δ 8,38 - 8,21 (m, 2H), 7,75 (dd, J = 7,8, 1,8 Hz, 1H), 6,50-6,30 (m, 1H), 6,27 - 6,10 (m, 1H), 5,95 - 5,71 (m, 2H), 5,27 (dddd, J = 46,5, 7,0, 4,0, 0,6 Hz, 1H), 4,89 (dddd, J = 8,0, 5,4, 4,7, 0,6 Hz, 1H), 4,71 (ddd, J = 3,3, 2,5, 0,7 Hz, 1H), 4,52 - 4,04 (m, 12H), 3,98 (d, J = 0,7 Hz, 3H), 3,75 Petição 870250103152, de 11 / 11 / 2025, pág. 146 / 219 138 / 208 - 3,54 (m, 2H), 3,47 (d, J = 1,6 Hz, 3H), 3,08 (s, 3H), 2,90 - 2,51 (m, 2H), 1,84 (p, J = 6,5 Hz, 2H).

[0158] 31P RMN (162 MHz, D2O) δ 0,60, -9,10, -10,22, -21,17. Exemplo 25 Síntese do Composto 574 574-1 Composto 574

[0159] Compound 10b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 574-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 574, which was an ammonium salt in the form of a white powder (80 mg).

[0160] 1H NMR (400 MHz, D2O) δ 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.70 (dd, J = Petition 870250103152, dated 11 / 11 / 2025, pp. 147 / 219 139 / 208 7.4, 1.8 Hz, 1 Η), 6.29-6.11 (m, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.63 - 5.42 (m, 2H), 5.33 - 5.00 (m, 2H), 4.89 - 4.64 (m, 2H), 4.55 - 4.05 (m, 11H), 3.98 (d, J = 0.7 Hz, 3H), 3.75 - 3.50 (m, 2H), 2.89 - 2.50 (m, 2H), 1.84 (p, J = 6.5 Hz, 2H).

[0161] 31P NMR (162 MHz, D2O) δ -0.22, -9.07, -10.25, -21.27. Example 26 Synthesis of Compound 589 569-1 Compound 589

[0162] Compound 10b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 589-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 589. Petition 870250103152, dated 11 / 11 / 2025, pp. 148 / 219 140 / 208 which was an ammonium salt in the form of a white powder (58 mg).

[0163] 1H RMN (400 MHz, D2O) δ 7,93 - 7,46 (m, 2H), 6,31 - 6,11 (m, 2H), 5,90 (d, J = 7,8 Hz, 1H), 5,53 (dddd, J = 25,2, 3,9, 1,7, 0,9 Hz, 1H), 5,13 - 4,93 (m, 1H), 4,88 - 4,61 (m, 2H), 4,43 - 4,04 (m, 11H), 3,98 (d, J = 0,7 Hz, 3H), 3,70 3,28 (m, 2H), 2,79 - 2,71 (m, 2H), 2,70 - 2,46 (m, 2H), 1,84 (p, J = 6,5 Hz, 2H).

[0164] 31P RMN (162 MHz, D2O) δ 0,66, -9,13, -10,26, -21,25. Exemplo 27 Síntese do Composto 589 5B9-1 Composto 589

[0165] A compound 10c (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 589-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the Petition 870250103152, dated 11 / 11 / 2025, pp. 149 / 219 141 / 208 of the remaining liquid was freeze-dried to obtain a product, compound 589, which was an ammonium salt in the form of a white powder (88 mg).

[0166] 1H RMN (400 MHz, D2O) δ 7.97 (dd, J = 37.6, 0.6 Hz, 2H), 6.71 - 6.22 (m, 2H), 6.10 (dq, J = 1.7, 0.7 Hz, 1H), 5.22 (dddd, J = 46.4, 7.0, 1.7.0.7 Hz, 1H), 4.87 (t, J = 3.1 Hz, 1H), 4.74 (qt, J = 4.1.2.2 Hz, 2H), 4.55 - 4.10 (m, 10H), 4.02 (s, 2H), 3.98 (s, 3H), 3.66 (td, J = 5,3, 2,9 (Hz, 2H), 3.00 - 2.60 (m, 2H), 1.85 (tt, J = 6.4, 5.3 Hz, 2H).

[0167] 31P RMN (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 28 Síntese do Composto 664 6S4-1 Composto €64

[0168] Compound 10c (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 664-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution. Petition 870250103152, dated 11 / 11 / 2025, pages 150 / 219 142 / 208 using an eluent, i.e., aqueous solution of ammonium bicarbonate at 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated in vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 664, which was an ammonium salt in the form of a white powder (60 mg).

[0169] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 6.57 - 6.23 (m, 2H), 5.90 (d, J = 7.8 Hz, 1H), 5.71 - 5.42 (m, 1H), 5.39 - 5.16 (m, 2H), 4.94 - 4.67 (m, 2H), 4.56 - 4.08 (m, 10H), 4.02 (s, 2H), 3.98 (s, 3H), 3.66 (td, J = 5.3, 2.9 Hz, 2H), 2.98 - 2.65 (m, 2H), 1.85 (tt, J = 6.4, 5.3 Hz, 2H).

[0170] 31P NMR (162 MHz, D2O) δ -0.85, -10.09, -21.23. Example 29 Synthesis of Compound 706

[0171] A compound 10d (200 mg) was added to 16 ml of an aqueous solution with pH 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 706-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 ml of water were Petition 870250103152, dated 11 / 11 / 2025, pp. 151 / 219 143 / 208 added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 706, which was an ammonium salt in the form of a white powder (55 mg).

[0172] 1H NMR (400 MHz, D2O) δ 8.40 - 7.81 (m, 4H), 6.84 - 5.90 (m, 3H), 5.31 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 4.76 (dddd, J = 46.0, 3.3, 2.8, 0.7 Hz, 2H), 4.54 - 4.18 (m, 9H), 4.09 - 3.95 (m, 3H), 3.92 (d, J = 0.6 Hz, 3H), 3.56 (td, J = 6.4, 1.5 Hz, 2H), 3.23 (td, J = 6.3, 0.8Hz, 2H), 3.10 (s, 3H), 1.94 (pd, J = 6.3, 1.0 Hz, 2H).

[0173] 31P NMR (162 MHz, D2O) δ -0.90, -11.41, -22.93. Example 30 Synthesis of Compound 760 760-1 Compound 760

[0174] Compound 10d (200 mg) was added to 16 ml of an aqueous solution with pH 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 760-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution Petition 870250103152, dated 11 / 11 / 2025, pp. 152 / 219 144 / 208 was added to a solution of disodium EDTA (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 760, which was an ammonium salt in the form of a white powder (70 mg).

[0175] 1H NMR (400 MHz, D2O) δ 8.28 - 8.06 (m, 2H), 7.69 (dd, J = 7.4, 1.8 Hz, 1H), 6.47 (ddt, J = 25.2, 1.5, 0.8 Hz, 1H), 6.28 (dq, J = 2.3, 0.8 Hz, 1H), 6.15 (d, J = 7.3 Hz, 1H), 5.60 (dddt, J = 25.3, 3.6, 1.8, 0.8 Hz, 1H), 5.42 (dddd, J = 46.5, 2.8, 1.9, 0.7 Hz, 1H), 4.70 (ddd, J = 3.3, 2.5, 0.7 Hz, 1H), 4.50 - 3.96 (m, 13H), 3.92 (d, J = 0.6 Hz, 3H), 3.56 (td, J = 6.5, 1.5 Hz, 2H), 3.36 (t, J = 6.2 Hz, 2H), 1.94 (pd, J = 6.3, 1.0 Hz, 2H).

[0176] 31P NMR (162 MHz, D2O) δ 0.50, -9.18, -10.26, -21.22. Example 31 Synthesis of Compound 787 7874 Compound 787

[0177] Compound 10d (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 787-7 (200 mg) was added to the solution. A Petition 870250103152, dated 11 / 11 / 2025, pp. 153 / 219 The reaction solution 145 / 208 was stirred at room temperature (25 °C) for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 787, which was an ammonium salt in the form of a white powder (75 mg).

[0178] 1H NMR (400 MHz, D2O) δ 8.49 - 7.98 (m, 2H), 7.75 (d, J = 0.5 Hz, 1H), 6.50 - 6.32 (m, 1H), 6.28 (dtd, J = 3.2, 1.6, 0.8 Hz, 2H), 5.31 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 4.70 (ddd, J = 3.3, 2.5, 0.7 Hz, 1H), 4.52-4.19 (m, 9H), 4.14 3.95 (m, 2H), 3.94 - 3.84 (m, 4H), 3.56 (td, J = 6.4, 1.5 Hz, 2H), 3.23 (td, J = 6.3, 0.8 Hz, 2H), 2.83 - 2.48 (m, 2H), 1.94 (pd, J = 6.3, 1.0 Hz, 2H).

[0179] 31P NMR (162 MHz, D2O) δ -0.99, -11.40, -23.06. Example 32 Synthesis of Compound 828 B2B-1 Compound 828

[0180] A compound 10e (200 mg) was added to 16 ml of a solution Petition 870250103152, dated 11 / 11 / 2025, pp. 154 / 219 Aqueous solution 146 / 208 with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, was prepared, and compound 828-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature (25 °C) for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 828, which was an ammonium salt in the form of a white powder (85 mg).

[0181] 1H RMN (400 MHz, D2O) δ 8.27 (s, 1H), 8.19 (d, J = 0.6 Hz, 1H), 7.95 (d, J = 0.7 Hz, 1H), 6.63 - 6.29 (m, 3H), 5.28 (dddd, J = 46.4, 6.9, 1.6, 0.7 Hz, 1H), 4.62 (ddqd, J = 4.5, 3.7, 1.5, 0.6 Hz, 1H), 4.57 - 4.40 (m, 2H), 4.36 - 4.20 (m, 5H), 4.16 - 3.95 (m, 5H), 3.93 - 3.81 (m, 4H), 3.73 - 3.51 (m, 3H), 3.37 (d, J = 1.6 Hz, 3H), 3.23 (td, J = 6.3, 0.8 Hz, 2H), 3.10 (s, 3H), 1.95 (tt, J = 6.3, 5.3 Hz, 2H).

[0182] 31P RMN (162 MHz, D2O) δ 0.60, -9.01, -10.23, -21.17. Example 33 Síntese do Composto 880 Petition: 870250103152, on November 11, 2025, page. 155 / 219 147 / 208 883-1

[0183] Compound 10e (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 880-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 880, which was an ammonium salt in the form of a white powder (92 mg).

[0184] 1H NMR (400 MHz, D2O) δ 8.35 (d, J = 0.6 Hz, 1H), 8.27 (s, 1H), 7.69 (dd, J = 7.4, 1.8 Hz, 1H), 6.60 - 6.29 (m, 2H), 6.15 (d, J = 7.3 Hz, 1H), 5.89 - 5.26 (m, 1H), 4.52 (dd, J = 11.6, 8.5 Hz, 1H), 4.44 - 3.84 (m, 16H), 3.75 - 3.48 (m, 3H), 3.23 (td, J = 6.3, 0.8 Hz, 2H), 3.10 (s, 3H), 2.87 - 2.56 (m, 2H), 1.95 (tt, J = 6.3, 5.3 Hz, 2H).

[0185] 31P NMR (162 MHz, D2O) δ 0.60, -9.10, -10.31, -21.17. Petition 870250103152, dated 11 / 11 / 2025, pp. 156 / 219 148 / 208 Example 34 Synthesis of Compound 903 Compound 903

[0186] A compound 10f (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 903-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 903, which was an ammonium salt in the form of a white powder (85 mg).

[0187] 1H NMR (400 MHz, D2O) δ 8.48 - 8.18 (m, 2H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.2, 1.6, 0.8 Hz, 1H), 6.25 - 6.00 (m, 2H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.89 - 4.62 (m, 3H), 4.59 - 4.09 (m, 13H), 3.98 (d, J = 0.7 Hz, 3H), 3.08 (s, 3H), 2.42 (t, J = 3.0Hz, 1H).

[0188] 31P NMR (162 MHz, D2O) δ 0.60, -9.10, -10.22, -21.17. Petition 870250103152, dated 11 / 11 / 2025, pp. 157 / 219 149 / 208 Example 35 Synthesis of Compound 974 974-1 Compound 974

[0189] Compound 10f (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 974-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 974, which was an ammonium salt in the form of a white powder (80 mg).

[0190] 1H NMR (400 MHz, D2O) δ 7.76 (ddd, J = 44.0, 7.5, 1.8 Hz, 2H), 6.20 (dq, J = 2.3, 0.8 Hz, 1H), 5.97 (dd, J = 56.9, 7.5 Hz, 2H), 5.64 - 5.41 (m, 2H), 5.34 - 4.98 (m, 2H), 4.89 - 4.63 (m, 2H), 4.55 - 4.08 (m, 13H), 3.98 (d, J = 0.7 Hz, 3H), 2.42 (t, J = 3.0 Hz, 1H).

[0191] 31P NMR (162 MHz, D2O) δ -0.22, -9.07, -10.25, -21.27. Petition 870250103152, dated 11 / 11 / 2025, pp. 158 / 219 150 / 208 Example 36 Synthesis of Compound 1040 Compound 1040

[0192] A 10 g (200 mg) compound was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a 1040-1 compound (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1040, which was an ammonium salt in the form of a white powder (58 mg).

[0193] 1H NMR (400 MHz, D2O) δ 7.88 (d, J = 0.7 Hz, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.47 - 6.14 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), 5.40 (dddd, J = 25.2, 3.5, 1.8, 0.9 Hz, 1H), 5.10-4.64 (m, 4H), 4.43-4.08 (m, 12H), 4.02 (s, 2H), 3.98 (s, 3H), 3.40 (s, 3H), 2.42 (t, J = 3.0 Hz, 1H). Petition 870250103152, dated 11 / 11 / 2025, pp. 159 / 219 151 / 208

[0194] 31P NMR (162 MHz, D2O) δ 0.66, -9.13, -10.26, -21.25. Example 37 Synthesis of Compound 1087 1087-1 Compound 1087

[0195] Compound 10 g (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1087-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1087, which was an ammonium salt in the form of a white powder (88 mg).

[0196] 1H NMR (400 MHz, D2O) δ 8.31 - 8.11 (m, 2H), 7.83 (d, J = 0.6 Hz, 1H), 6.88 - 6.07 (m, 3H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 5.05 - 4.88 (m, 2H), 4.54 - 4.04 (m, 12H), 4.02 (s, 2H), 3.98 (s, 3H), 2.77 - 2.52 (m, 2H), 2.42 (t, Petition 870250103152, dated 11 / 11 / 2025, pp. 160 / 219 152 / 208 J = 3.0 Hz, 1H).

[0197] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 38 Synthesis of Compound 1108 Compound 1108

[0198] A 10h compound (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a 1108-1 compound (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1108, which was an ammonium salt in the form of a white powder (88 mg).

[0199] 1H NMR (400 MHz, D2O) δ 8.33 - 8.15 (m, 2H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.2, 1.5, 0.8 Hz, 1H), 6.32 - 5.94 (m, 2H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.83 - 4.69 (m, 2H), 4.56 (dt, J = 3.8, 0.9 Hz, 1H), 4.51 4.06 (m, 10H), 3.98 (d, J = 0.7 Hz, 3H), 3.65 (ddd, J = 3.6, 2.6, 0.6 Hz, 1H). Petition 870250103152, dated 11 / 11 / 2025, pp. 161 / 219 153 / 208

[0200] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 39 Synthesis of Compound 1130 'hH 1130-1 Compound 1130

[0201] Compound 10h (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1130-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1130, which was an ammonium salt in the form of a white powder (88 mg).

[0202] 1H NMR (400 MHz, D2O) δ 8.51 - 8.01 (m, 2H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.31 - 6.15 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), 5.56 - 5.22 (m, 1H), 4.97 (dddd, J = 8.0, 4.4, 2.9, 0.7 Hz, 1H), 4.90 - 4.69 (m, 2H), 4.56 (dt, J = 3.8, 0.9 Hz, 1H), 4.48-4.10 (m, 10H), 3.98 (s, 3H), 3.65 (ddd, J = 3.6, 2.6, 0.6 Hz, 1H), 3.40 (s, 3H), 3.08 (s, 3H). Petition 870250103152, dated 11 / 11 / 2025, pp. 162 / 219 154 / 208

[0203] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 40 Synthesis of Compound 1130 11304 Compound 1130

[0204] Compound 10h (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1130-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1130, which was an ammonium salt in the form of a white powder (88 mg).

[0205] 1H NMR (400 MHz, D2O) δ 8.51 - 8.01 (m, 2H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.31 - 6.15 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), 5.56 - 5.22 (m, 1H), 4.97 (dddd, J = 8.0, 4.4, 2.9, 0.7 Hz, 1H), 4.90 - 4.69 (m, 2H), 4.56 (dt, J = 3.8, 0.9 Hz, 1H), 4.48-4.10 (m, 10H), 3.98 (s, 3H), 3.65 (ddd, J = 3.6, 2.6, 0.6 Hz, 1H), 3.40 (s, 3H), 3.08 (s, 3H). Petition 870250103152, dated 11 / 11 / 2025, pp. 163 / 219 155 / 208

[0206] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 41 Synthesis of Compound 1140 1140-1 114D Compound

[0207] A compound 10i (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1140-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1140, which was an ammonium salt in the form of a white powder (88 mg).

[0208] 1H NMR (400 MHz, D2O) δ 8.18 (d, J = 1.3 Hz, 2H), 7.69 (dd, J = 7.4, 1.8 Hz, 1H), 6.36 - 6.26 (m, 1H), 6.20 - 6.09 (m, 2H), 5.80 - 5.38 (m, 1H), 4.82 (ddd, J = 3.9, 3.1, 0.7 Hz, 1H), 4.62 (ddd, J = 5.5, 2.8, 0.7 Hz, 1H), 4.42 - 3.95 (m, 13H), 3.92 (s, 3H).

[0209] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pp. 164 / 219 156 / 208 Example 42 Synthesis of Compound 1198 1198-1 -POPN 1 OH OH Compound 1198

[0210] A compound 10j (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1198-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1198, which was an ammonium salt in the form of a white powder (88 mg).

[0211] 1H NMR (400 MHz, D2O) δ 8.28 (d, J = 0.5 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 0.7 Hz, 1H), 6.45 (ddq, J = 25.2, 1.5, 0.8 Hz, 1H), 6.22 (dd, J = 3.1, 0.7 Hz, 1H), 6.11 (dd, J = 3.1,0.7 Hz, 1H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.86 - 4.66 (m, 2H), 4.59 - 4.39 (m, 2H), 4.36 - 4.06 (m, 9H), 3.98 (s, 3H), 2.80 (ddd, J = 5.1,4.0, 0.7 Hz, 1H).

[0212] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pp. 165 / 219 157 / 208 Example 43 Synthesis of Compound 1220 1220-1 Compound 1220

[0213] Compound 10] (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1220-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1220, which was an ammonium salt in the form of a white powder (88 mg).

[0214] 1H NMR (400 MHz, D2O) δ 8.29 (s, 1H), 8.20 (d, J = 0.7 Hz, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.32 - 6.16 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), R 1H).

[0215] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 44 Petition 870250103152, dated 11 / 11 / 2025, pp. 166 / 219 158 / 208 Synthesis of Compound 1280 12Í0-1 Compound 1ÍB0

[0216] A 10h compound (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a 1280-1 compound (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1280, which was an ammonium salt in the form of a white powder (88 mg).

[0217] 1H NMR (400 MHz, D2O) δ 8.24 (d, J = 0.7 Hz, 1H), 8.20 (s, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.43 (ddq, J = 25.2, 1.5, 0.8 Hz, 1H), 6.24 (p, J = 0.8 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.50 - 5.10 (m, 3H), 4.81 (dddd, J = 46.5, 7.1, 3.7, 0.7 Hz, 1H), 4.56 (dt, J = 3.8, 0.9 Hz, 1H), 4.48 (tdd, J = 3.5, 2.4, 0.8 Hz, 1H), 4.44 - 4.09 (m, 9H), 3.98 (s, 3H), 3.65 (ddd, J = 3.6, 2.6, 0.6 Hz, 1H).

[0218] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 45 Petition 870250103152, dated 11 / 11 / 2025, pp. 167 / 219 159 / 208 Synthesis of Compound 1307 13074 Compound 1307

[0219] A compound 10i (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1307-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1307, which was an ammonium salt in the form of a white powder (88 mg).

[0220] 1H NMR (400 MHz, D2O) δ 8.22 - 8.03 (m, 4H), 6.60 - 6.35 (m, 2H), 6.31 - 6.22 (m, 1H), 5.54 - 5.15 (m, 2H), 4.62 (ddd, J = 5.5, 2.8, 0.7 Hz, 1H), 4.51 4.01 (m, 12H), 3.92 (s, 3H).

[0221] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 46 Synthesis of Compound 1373 Petition 870250103152, dated 11 / 11 / 2025, pp. 168 / 219 160 / 208 1373-1 10k Compound 1373

[0222] A 10k compound (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a 1373-1 compound (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1373, which was an ammonium salt in the form of a white powder (88 mg).

[0223] 1H RMN (400 MHz, D2O) δ 8,40 (d, J = 0,5 Hz, 1H), 8,20 (s, 1H), 8,02 (d, J = 0,7 Hz, 1H), 6,45 (ddq, J = 25,2, 1,6, 0,8 Hz, 1H), 6,35 - 5,85 (m, 2H), 5,22 (dddd, J = 46,4, 7,0, 1,7, 0,7 Hz, 1H), 4,97 (dddd, J = 8,0, 4,4, 2,9, 0,7 Hz, 1H), 4,84 - 4,69 (m, 1H), 4,58 (ddd, J = 3,8, 1,6, 0,7 Hz, 1H), 4,45 (dddd, J = 25,2, 6,8, 5,0, 0,7 Hz, 1H), 4,36 - 4,30 (m, 2H), 4,30 - 4,05 (m, 7H), 3,98 (s, 3H), 3,61 (dddd, J = 3,8, 2,6, 1,8, 1,1 Hz, 1H), 3,40 (s, 3H), 2,09 (s, 3H).

[0224] 31P RMN (162 MHz, D2O) δ 0,85, -9,12, -10,24, -21,26. Exemplo 47 Petição 870250103152, de 11 / 11 / 2025, pág. 169 / 219 161 / 208 Síntese do Composto 1400 140Ú-1 Composto 1400

[0225] Compound 10k (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1400-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1400, which was an ammonium salt in the form of a white powder (88 mg).

[0226] 1H NMR (400 MHz, D2O) δ 8.43 - 8.11 (m, 2H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.43 (ddq, J = 25.2, 1.6, 0.8 Hz, 1H), 6.20 (dt, J = 1.6, 0.8 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.49 - 5.13 (m, 3H), 4.81 (dddd, J = 46.5, 7.1, 3.7, 0.7 Hz, 1H), 4.58 (ddd, J = 3.8, 1.6, 0.7 Hz, 1H), 4.48 (tdd, J = 3.5, 2.4, 0.8 Hz, 1H), 4.42 4.03 (m, 9H), 3.98 (s, 3H), 3.61 (dddd, J = 3.8, 2.5, 1.8, 1.1 Hz, 1H), 2.09 (s, 3H).

[0227] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 48 Petition 870250103152, dated 11 / 11 / 2025, pág. 170 / 219 162 / 208 Síntese do Composto 1421 1421-1 ο ο II II Ο-Ρ-Ο-Ρ-Ν> OH OH Compound 1421

[0228] Compound 10h (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1421-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1421, which was an ammonium salt in the form of a white powder (88 mg).

[0229] 1H NMR (400 MHz, D2O) δ 8.51 - 7.89 (m, 4H), 6.46 - 6.31 (m, 2H), 6.24 (p, J = 0.8 Hz, 1H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 5.08 - 4.88 (m, 1H), 4.56 (dt, J = 3.8, 0.9 Hz, 1H), 4.52 - 4.38 (m, 2H), 4.36 - 4.04 (m, 8H), 3.98 (s, 3H), 3.65 (ddd, J = 3.6, 2.6, 0.6Hz, 1H), 3.08 (s, 3H), 2.80 - 2.52 (m, 2H).

[0230] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 49 Synthesis of Compound 1449 Petition 870250103152, dated 11 / 11 / 2025, pp. 171 / 219 163 / 208 Compound 1449

[0231] Compound 10i (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1449-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1449, which was an ammonium salt in the form of a white powder (88 mg).

[0232] 1H NMR (400 MHz, D2O) δ 8.40 - 8.08 (m, 2H), 7.59 - 7.18 (m, 2H), 6.48 - 6.34 (m, 1H), 6.24 (dq, J = 4.7, 0.8 Hz, 1H), 5.98 (dddt, J = 25.2, 4.0, 1.7, 0.8 Hz, 1H), 4.72 (ddd, J = 7.4, 4.7, 0.7 Hz, 1H), 4.49 - 3.97 (m, 12H), 3.95 - 3.80 (m, 4H), 3.10 (s, 3H), 2.93 - 2.53 (m, 2H).

[0233] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 50 Synthesis of Compound 1449 Petition 870250103152, dated 11 / 11 / 2025, pp. 172 / 219 164 / 208 1449-1 Compound 1449

[0234] Compound 10i (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1449-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1449, which was an ammonium salt in the form of a white powder (88 mg).

[0235] 1H NMR (400 MHz, D2O) δ 8.40 - 8.08 (m, 2H), 7.59 - 7.18 (m, 2H), 6.48 - 6.34 (m, 1H), 6.24 (dq, J = 4.7, 0.8 Hz, 1H), 5.98 (dddt, J = 25.2, 4.0, 1.7, 0.8 Hz, 1H), 4.72 (ddd, J = 7.4, 4.7, 0.7 Hz, 1H), 4.49 - 3.97 (m, 12H), 3.95 - 3.80 (m, 4H), 3.10 (s, 3H), 2.93 - 2.53 (m, 2H).

[0236] 31P NMR (162 MHz, D2O) δ 0.85, -9.12, -10.24, -21.26. Example 51 Synthesis of Compound 1495 Petition 870250103152, dated 11 / 11 / 2025, pp. 173 / 219 165 / 208 1455-1 Compound 1495

[0237] A compound 101 (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1495-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1495, which was an ammonium salt in the form of a white powder (88 mg).

[0238] 1H NMR (400 MHz, D2O) δ 8.30 (d, J = 0.6 Hz, 1H), 8.20 (s, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.55-6.34 (m, 1H), 6.16 (dq, J = 2.2, 0.8 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.40 (dddd, J = 25.2, 3.4, 1.8, 0.9 Hz, 1H), 5.12 - 4.93 (m, 1H), 4.81 (dddd, J = 46.5, 7.1,3.7, 0.7 Hz, 1H), 4.41 - 4.04 (m, 11H), 3.98 (s, 3H), 3.63 (ddd, J =4.6, 3.1,0.7 Hz, 1H), 2.81 -2.48 (m, 2H).

[0239] 31P NMR (162 MHz, D2O) δ 0.85, -10.30, -21.26. Example 52 Synthesis of Compound 1580 Petition 870250103152, dated 11 / 11 / 2025, pp. 174 / 219 166 / 208 1580-1 Compound 1580

[0240] Compound 10k (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1580-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1580, which was an ammonium salt in the form of a white powder (88 mg).

[0241] 1H NMR (400 MHz, D2O) δ 7.73 (ddd, J = 24.9, 7.2, 1.8 Hz, 2H), 6.35 6.15 (m, 2H), 6.03 (dd, J = 12.2, 7.2 Hz, 2H), 5.40 (dddd, J = 25.2, 3.5, 1.8, 0.9 Hz, 1H), 5.10 (ddddd, J = 8.3, 6.4, 4.5, 3.7, 0.7 Hz, 1H), 4.81 (dddd, J = 46.5, 7.1, 3.7, 0.7 Hz, 1H), 4.58 (dddd, J = 3.8, 1.6, 0.7Hz, 1H), 4.39 - 4.00 (m, 10H), 3.98 (s, 3H), 3.74 - 3.47 (m, 1H), 2.61 - 2.28 (m, 2H), 2.09 (s, 3H).

[0242] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Example 53 Síntese do Composto 1581 Petition 870250103152, dated 11 / 11 / 2025, pág. 175 / 219 167 / 208 1581-1 Composed 1581

[0243] A compound 11a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1581-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1581, which was an ammonium salt in the form of a white powder (88 mg).

[0244] 1H RMN (400 MHz, D2O) δ 8,33 - 7,87 (m, 2H), 7,60 (dd, J = 7,4, 1,8 Hz, 1H), 6,49 - 6,23 (m, 2H), 6,15 - 5,73 (m, 2H), 5,27 (dddd, J = 46,5, 7,0, 4,0, 0,6 Hz, 1H), 5,00 (dd, J = 3,2, 2,5 Hz, 1H), 4,80 - 4,62 (m, 1H), 4,53 - 4,32 (m, 4H), 4,31 - 4,10 (m, 6H), 4,09 (s, 2H), 3,98 (s, 3H), 3,96 (d, J = 3,2 Hz, 1H), 3,08 (s, 3H).

[0245] 31P RMN (162 MHz, D2O) δ 0,85, -10,24, -21,26. Exemplo 54 Síntese do Composto 1617 Petição 870250103152, de 11 / 11 / 2025, pág. 176 / 219 168 / 208 NH 1β1Τ-4 Composto 1617

[0246] A compound 11b (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1617-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1617, which was an ammonium salt in the form of a white powder (88 mg).

[0247] 1H NMR (400 MHz, D2O) δ 8.27 (s, 1H), 8.22 - 8.17 (m, 2H), 8.14 (d, J = 0.6 Hz, 1H), 6.60 - 6.31 (m, 3H), 5.31 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 4.81 (dd, J = 4.8, 2.0 Hz, 1H), 4.66 - 4.54 (m, 2H), 4.46 (dddd, J = 25.2, 6.8, 5.0, 0.7 Hz, 1H), 4.36 - 4.21 (m, 6H), 4.19 - 3.99 (m, 4H), 3.92 (d, J = 0.6 Hz, 3H), 3.83 (dd, J = 11.3, 8.5 Hz, 1H), 3.37 (s, 3H), 3.10 (s, 3H).

[0248] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Example 55 Petition 870250103152, dated 11 / 11 / 2025, pp. 177 / 219 169 / 208 Synthesis of Compound 1660 1680-1 Compound 1660

[0249] A compound 11c (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1660-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1660, which was an ammonium salt in the form of a white powder (88 mg).

[0250] 1H NMR (400 MHz, D2O) δ 7.88 (d, J = 0.7 Hz, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.51 - 6.18 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), 5.40 (dddd, J = 25.2, 3.5, 1.8, 0.9 Hz, 1H), 5.05 - 4.59 (m, 4H), 4.48 - 4.09 (m, 9H), 4.04 - 3.82 (m, 6H), 3.40 (s, 3H).

[0251] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Example 56 Synthesis of Compound 1698 Petition 870250103152, dated 11 / 11 / 2025, pp. 178 / 219 170 / 208 1698-1 Compound 1698

[0252] A compound 11d (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1698-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1698, which was an ammonium salt in the form of a white powder (88 mg).

[0253] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 7.81 (dd, J = 7.3, 1.8 Hz, 1H), 6.63 - 6.39 (m, 2H), 6.18 - 5.82 (m, 2H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 4.89 (dddd, J = 8.0, 5.4, 4.6, 0.6 Hz, 1H), 4.59 - 4.28 (m, 6H), 4.25 - 4.03 (m, 7H), 3.98 (s, 3H), 3.46 (s, 3H), 3.11 (d, J = 3.1 Hz, 1H).

[0254] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Example 57 Synthesis of Compound 1728 Petition 870250103152, dated 11 / 11 / 2025, pp. 179 / 219 171 / 208 11e Compound 1728

[0255] A compound 11e (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 1728-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1728, which was an ammonium salt in the form of a white powder (88 mg).

[0256] 1H RMN (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 7.81 (dd, J = 7.3, 1.8 Hz, 1H), 6.73 - 6.18 (m, 2H), 6.18 - 5.82 (m, 2H), 5.22 (dddd, J = 46.4, 7.0, 1.7, 0.7 Hz, 1H), 5.02 - 4.79 (m, 2H), 4.58 - 4.28 (m, 5H), 4.27 - 4.01 (m, 7H), 3.98 (s, 3H), 3.93 (dq, J = 2.9, 1.5 Hz, 1H), 3,46 (s, 3H), 2.10 (d, J = 1.4 Hz, 3H).

[0257] 31P RMN (162 MHz, D2O) δ 0.85, -10.24, -21.26. Exemplo 58 Síntese do Composto 1897 Petition: 870250103152, on November 11, 2025, page. 180 / 219 172 / 208 1B97-1 Composto 1897

[0258] Compound 11a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1897-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1897, which was an ammonium salt in the form of a white powder (88 mg).

[0259] 1H NMR (400 MHz, D2O) δ 8.32 - 8.11 (m, 2H), 7.76 (dd, J = 7.0, 1.8 Hz, 1H), 6.46 - 6.31 (m, 2H), 6.25 (dddd, J = 5.2, 3.3, 1.7, 0.8 Hz, 1H), 6.01 (d, J = 7.2 Hz, 1H), 5.27 (dddd, J = 46.5, 7.0, 4.0, 0.6 Hz, 1H), 5.10 (ddddd, J = 8.3, 6.4, 4.5, 3.7, 0.7 Hz, 1H), 5.00 (dd, J = 3.2, 2.5Hz, 1H), 4.54 - 4.30 (m, 3H), 4.26 4.17 (m, 4H), 4.13 - 4.01 (m, 4H), 3.98 (d, J = 0.7 Hz, 3H), 3.96 (d, J = 3.2 Hz, 1H), 2.60 - 2.26 (m, 2H).

[0260] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pág. 181 / 219 173 / 208 Example 59 Síntese do Composto 1907 1907Ί Composed 1907

[0261] Compound 11b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 1907-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1907, which was an ammonium salt in the form of a white powder (88 mg).

[0262] 1H NMR (400 MHz, D2O) δ 8.18 (s, 1H), 8.14 (d, J = 0.6 Hz, 1H), 7.75 (d, J = 0.5 Hz, 1H), 6.49 (dd, J = 2.0, 0.7 Hz, 1H), 6.47 - 6.35 (m, 1H), 6.28 (ddq, J=3.0, 1.4, 0.7Hz, 1H), 5.31 (dddd, J=46.5, 7.0, 4.0, 0.6Hz, 1H), 4.81 (dd, J=4.8, 2.0Hz, 1H), 4.58 (dd, J= 11.3, 8.5Hz, 1H), 4.50-4.39 (m, 1H), 4.37-4.19 (m, 6H), 4.14 - 3.98 (m, 3H), 3.96 - 3.76 (m, 5H), 2.92 - 2.35 (m, 2H).

[0263] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pp. 182 / 219 174 / 208 Example 60 Synthesis of Compound 1925 1925-1 Compound 1925

[0264] Compound 11c (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 1925-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1925, which was an ammonium salt in the form of a white powder (88 mg).

[0265] 1H NMR (400 MHz, D2O) δ 8.30 (d, J = 0.5 Hz, 1H), 8.20 (s, 1H), 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 6.42 - 6.36 (m, 1H), 6.31 (dd, J = 2.0, 0.6 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.48-5.29 (m, 1H), 5.18-4.94 (m, 1H), 4.81 (dddd, J = 46.5, 7.1, 3.7, 0.7 Hz, 1H), 4.66 (t, J = 2.2 Hz, 1H), 4.46 - 4.05 (m, 9H), 4.02 - 3.90 (m, 6H), 2.92-2.35 (m, 2H). Petition 870250103152, dated 11 / 11 / 2025, pp. 183 / 219 175 / 208

[0266] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Example 61 Synthesis of Compound 1978 Compound 1978

[0267] Compound 11e (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 1978-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1978, which was an ammonium salt in the form of a white powder (88 mg).

[0268] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 7.76 (dd, J = 7.0, 1.8 Hz, 1H), 6.54 - 6.35 (m, 2H), 6.25 (dddd, J = 5.2, 3.3, 1.7, 0.8 Hz, 1H), 6.01 (d, J = 7.2 Hz, 1H), 5.37 - 5.03 (m, 2H), 4.88 (dd, J = 3.1,2.0 Hz, 1H), 4.57 - 4.29 (m, 3H), 4.26 - 4.01 (m, 8H), 3.98 (d, J = 0.7 Hz, 3H), 3.93 (dq, J = 3.0, 1.5 Hz, Petition 870250103152, dated 11 / 11 / 2025, pp. 184 / 219 176 / 208 1H), 2.71 - 2.26 (m, 2H), 2.10 (s, 3H).

[0269] 31P NMR (162 MHz, D2O) δ 0.85, -10.24, -21.26. Example 62 Synthesis of Compound 1981 1981-1 Composite 1981

[0270] Compound 9a (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 1981-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1981, which was an ammonium salt in the form of a white powder (88 mg).

[0271] 1H NMR (400 MHz, D2O) δ 8.30 - 8.00 (m, 2H), 6.39 (ddd, J = 25.2, 4.0, 0.7 Hz, 1H), 6.25 - 5.90 (m, 1H), 5.28 (dddd, J = 46.5, 4.9, 4.1,0.6 Hz, 1H), 4.69 - 4.49 (m, 2H), 4.35 (ddd, J = 5.3, 3.7, 0.7 Hz, 1H), 4.30 - 4.07 (m, 6H), 3.98 (d, J = 0.7 Hz, 3H). Petition 870250103152, dated 11 / 11 / 2025, pp. 185 / 219 177 / 208

[0272] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 63 Synthesis of Compound 1988 1988-1 Composite 1988

[0273] Compound 9b (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 1988-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1988, which was an ammonium salt in the form of a white powder (88 mg).

[0274] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 6.43 (ddd, J = 25.2, 1.5,0.8 Hz, 1H), 6.17 (dt, J = 2.5, 0.7 Hz, 1H), 5.61 -5.11 (m, 1H), 4.96 - 4.44 (m, 2H), 4.30-4.22 (m, 4H), 4.21 -4.10 (m, 2H), 4.06 (dtt, J = 4.2, 2.1, 1.1 Hz, 1H), 3.98 (s, 3H), 3.44 (s, 3H).

[0275] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pp. 186 / 219 178 / 208 Example 64 Synthesis of Compound 1992 HO F 1992-1 Compound 1992

[0276] Compound 9c (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 1992-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1992, which was an ammonium salt in the form of a white powder (88 mg).

[0277] 1H NMR (400 MHz, D2O) δ 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 6.44 - 6.09 (m, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.53 (dddd, J = 24.4, 3.9, 1.8, 0.9 Hz, 1H), 5.00 - 4.94 (m, 1H), 4.88 - 4.80 (m, 1H), 4.78 - 4.69 (m, 1H), 4.60 (dtd, J = 3.8, 2.7, 0.8 Hz, 1H), 4.57-4.51 (m, 1H), 4.33 (ddd, J = 8.5, 3.7, 1.6 Hz, 2H), 4.25-4.12 (m, 3H), 3.98 (s, 3H).

[0278] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pp. 187 / 219 179 / 208 Example 65 Synthesis of Compound 1996 HO-PO OH 1996-1 Compound 1996

[0279] Compound 9d (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 1996-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 1996, which was an ammonium salt in the form of a white powder (88 mg).

[0280] 1H NMR (400 MHz, D2O) δ 8.18 (s, 1H), 8.14 (d, J = 0.6 Hz, 1H), 6.41 (ddq, J = 25.2, 4.0, 0.8 Hz, 1H), 6.31 - 6.22 (m, 1H), 5.45 - 4.99 (m, 1H), 4.79 4.50 (m, 2H), 4.46 - 4.05 (m, 7H), 3.92 (s, 3H).

[0281] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 66 Synthesis of Compound 2005 Petition 870250103152, dated 11 / 11 / 2025, pp. 188 / 219 180 / 208 O HQ-P-0 OH 2005-1 Compound 2005

[0282] A compound 9e (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 2005-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2005, which was an ammonium salt in the form of a white powder (88 mg).

[0283] 1H NMR (400 MHz, D2O) δ 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 6.24 (p, J = 0.8 Hz, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.74 - 5.30 (m, 1H), 4.89 - 4.64 (m, 1H), 4.60 - 4.43 (m, 2H), 4.43 - 4.37 (m, 1H), 4.36 - 4.11 (m, 5H), 3.98 (s, 3H), 3.65 (ddd, J = 3.6, 2.6, 0.6 Hz, 1H).

[0284] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 67 Synthesis of Compound 2010 Petition 870250103152, dated 11 / 11 / 2025, pp. 189 / 219 181 / 208 5? HO-PO OH 2010-1 2D1D compound

[0285] A compound 9f (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 2010-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2010, which was an ammonium salt in the form of a white powder (88 mg).

[0286] 1H NMR (400 MHz, D2O) δ 7.70 (dd, J = 7.3, 1.8 Hz, 1H), 6.18 (dq, J = 2.5, 0.8 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.40 (dddt, J = 25.1, 3.4, 1.6, 0.8Hz, 1H), 4.83 (dddd, J = 46.3, 5.2, 3.7, 0.6Hz, 1H), 4.68 (ddd, J = 3.2, 2.4, 0.7Hz, 1H), 4.59 - 4.42 (m, 1H), 4.30 - 4.07 (m, 7H), 3.98 (d, J = 0.7 Hz, 3H), 3.59 (p, J = 5.9 Hz, 2H), 1.24 (t, J = 6.0 Hz, 3H).

[0287] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 68 Synthesis of Compound 2020 Petition 870250103152, dated 11 / 11 / 2025, pp. 190 / 219 182 / 208 HO-PD OH 2020-1 Compound 2020

[0288] Compound 10k (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 2020-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2020, which was an ammonium salt in the form of a white powder (88 mg).

[0289] 1H NMR (400 MHz, D2O) δ 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 6.21 (dq, J = 1.5, 0.8 Hz, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.62 - 5.35 (m, 1H), 5.00 - 4.69 (m, 1H), 4.62 - 4.41 (m, 2H), 4.36 - 4.11 (m, 6H), 3.98 (d, J = 0.7 Hz, 3H), 3.69 - 3.47 (m, 1H), 2.09 (d, J = 1.4 Hz, 3H).

[0290] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 69 Synthesis of Compound 2025 Petition 870250103152, dated 11 / 11 / 2025, pp. 191 / 219 183 / 208 2025-1 Compound 2025

[0291] Compound 10d (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 2025-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2025, which was an ammonium salt in the form of a white powder (88 mg).

[0292] 1H NMR (400 MHz, D2O) δ 7.95 (d, J = 0.7 Hz, 1H), 6.49 (ddt, J = 25.2, 1.5, 0.8 Hz, 1H), 6.28 (dq, J = 2.3, 5.8 Hz, 1Hz, 1H), δ = 46.3, 5.0, 1.6, 0.7 Hz, 1H), 4.70 (ddd, J = 3.3, 2.5, 0.7 Hz, 1H), 4.58 (dddd, J = 25.2, 4.9, 3.1, 0.6 Hz, 4.4, 4.5 Hz), (m 4.13 (qt, J = 3.1,0.8 Hz, 1H), 3.98 (ddd, J = 3.1,2.3, 0.6 Hz, 1H), 3.92 (d, J = 0.6 Hz, 3H), 3.56 (td, J = 6.4, 1.5 Hz, J 6.3, 0.8 Hz, 2H), 1.94 (pd, J = 6.3, 1.0 Hz, 2H).

[0293] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Petition 870250103152, of 11 / 11 / 2025, p. 192 / 219 184 / 208 Example 70 Compound Synthesis 2028 □ HO-PO OH 2028-1 Composite 2028

[0294] Compound 10b (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 2028-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2028, which was an ammonium salt in the form of a white powder (88 mg).

[0295] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 6.43 (ddd, J = 25.2, 1.5, 0.8 Hz, 1H), 6.27 - 6.03 (m, 1H), 5.54 - 5.05 (m, 1H), 4.71 (ddd, J = 3.3, 2.5, 0.7 Hz, 1H), 4.59 - 4.45 (m, 1H), 4.37 - 4.06 (m, 7H), 3.98 (d, J = 0.7 Hz, 3H), 3.76 - 3.46 (m, 2H), 3.06 - 2.68 (m, 2H), 1.84 (p, J = 6.5 Hz, 2H).

[0296] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Petition 870250103152, dated 11 / 11 / 2025, pp. 193 / 219 185 / 208 Example 71 Synthesis of Compound 2031 2031*1 Compound 2031

[0297] Compound 10f (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 2031-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2031, which was an ammonium salt in the form of a white powder (88 mg).

[0298] 1H NMR (400 MHz, D2O) δ 7.70 (dd, J = 7.3, 1.8 Hz, 1H), 6.20 (dt, J = 2.3, 0.7 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H), 5.40 (dddd, J = 25.2, 3.5, 1.7, 0.8 Hz, 1H), 4.97 - 4.69 (m, 2H), 4.59 - 4.41 (m, 1H), 4.35 - 4.09 (m, 9H), 3.98 (d, J = 0.7 Hz, 3H), 2.42 (t, J = 3.0 Hz, 1H).

[0299] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 72 Petition 870250103152, dated 11 / 11 / 2025, pp. 194 / 219 186 / 208 Synthesis of Compound 2037 2037 1 OH Compound 2037

[0300] Compound 10a (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 2037-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2037, which was an ammonium salt in the form of a white powder (88 mg).

[0301] 1H NMR (400 MHz, D2O) δ 8.42 - 8.05 (m, 2H), 6.55 - 6.15 (m, 2H), 5.28 (dddd, J = 46.4, 7.0, 3.0, 0.7 Hz, 1H), 4.64 (t, J = 2.8 Hz, 1H), 4.55-4.19 (m, 7H), 4.00 (dd, J = 12.9, 0.7 Hz, 5H).

[0302] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 73 Synthesis of Compound 2038 Petition 870250103152, dated 11 / 11 / 2025, pp. 195 / 219 187 / 208 2033-1 Compound 2038

[0303] A compound 12a (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 2038-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2038, which was an ammonium salt in the form of a white powder (88 mg).

[0304] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 6.43 (ddt, J = 25.2, 1.6, 0.8 Hz, 1H), 6.27 - 5.99 (m, 1H), 5.24 (dddd, J = 46.5, 5.1, 1.7, 0.6 Hz, 1H), 4.86 - 4.45 (m, 2H), 4.36 - 4.07 (m, 7H), 3.98 (d, J = 0.7 Hz, 3H), 3.83 - 3.48 (m, 2H), 3.09 - 2.90 (m, 2H), 2.79 (s, 3H), 2.55 - 2.18 (m, 2H).

[0305] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 74 Synthesis of Compound 2039 Petition 870250103152, dated 11 / 11 / 2025, pp. 196 / 219 188 / 208 O 2039 Compound 2039

[0306] A compound 12b (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 2039-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2039, which was an ammonium salt in the form of a white powder (88 mg).

[0307] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 6.43 (ddd, J = 25.2, 1.6, 0.8 Hz, 1H), 6.27 - 5.70 (m, 3H), 5.42 - 5.07 (m, 1H), 5.00 - 4.81 (m, 2H), 4.65 - 4.43 (m, 2H), 4.37 - 4.10 (m, 5H), 3.98 (d, J = 0.7 Hz, 3H), 3.38 (ttdd, J = 5.3,4.2, 1.8, 1.0 Hz, 1H), 3.11 -2.53 (m, 2H), 2.14 -1.79 (m, 2H), 1.62-1.17 (m, 2H).

[0308] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 75 Petition 870250103152, dated 11 / 11 / 2025, pp. 197 / 219 189 / 208 Synthesis of Compound 2040 2040'1 Compound 2040

[0309] A compound 12c (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and a compound 2040-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2040, which was an ammonium salt in the form of a white powder (88 mg).

[0310] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 6.43 (ddd, J = 25.2, 1.5, 0.8 Hz, 1H), 6.26 - 6.03 (m, 1H), 5.69 - 5.39 (m, 2H), 5.31 - 5.07 (m, 1H), 4.84 - 4.67 (m, 2H), 4.63 - 4.46 (m, 1H), 4.28 - 4.06 (m, 7H), 3.98 (d, J = 0.7 Hz, 3H), 3.89 - 3.69 (m, 2H), 2.58 (td, J = 7.2, 2.9 Hz, 2H), 2.26 - 1.11 (m, 10H).

[0311] 31P NMR (162 MHz, D2O) δ -10.25, -21.23. Petition 870250103152, dated 11 / 11 / 2025, pp. 198 / 219 190 / 208 Example 76 Synthesis of Compound 2050 HO-PO Oh -OpOPOpO—X o, ,,-N OH OH OH \ / NMi Compound 2050

[0312] Compound 11c (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 2050-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2050, which was an ammonium salt in the form of a white powder (88 mg).

[0313] 1H NMR (400 MHz, D2O) δ 8.02 (d, J = 0.7 Hz, 1H), 6.65 - 6.28 (m, 2H), 5.39 - 5.11 (m, 1H), 4.87 (t, J = 3.1 Hz, 1H), 4.65 - 4.47 (m, 1H), 4.39 - 4.21 (m, 5H), 4.15 (d, J = 3.1 Hz, 1H), 4.02 (s, 2H), 3.98 (d, J = 0.7 Hz, 3H), 3.66 (td, J = 5.3, 2.9 Hz, 2H), 2.96 - 2.52 (m, 2H), 1.85 (tt, J = 6.4, 5.3 Hz, 2H). Petition 870250103152, dated 11 / 11 / 2025, pp. 199 / 219 191 / 208

[0314] 31P NMR (162 MHz, D2O) δ -10.21, -21.25. Example 77 Synthesis of Compound 2051 2051 -1

[0315] Compound 11e (250 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and compound 2051-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2051, which was an ammonium salt in the form of a white powder (88 mg).

[0316] 1H NMR (400 MHz, D2O) δ 7.95 (d, J = 0.7 Hz, 1H), 6.71 - 6.22 (m, 2H), 5.31 (dddd, J = 46.3, 5.0, 1.6, 0.7 Hz, 1H), 4.67 - 4.45 (m, 2H), 4.42 - 4.21 (m, 2H), 4.13 (qt, J = 3.1,0.8 Hz, 1H), 4.06 - 3.85 (m, 7H), 3.76 - 3.53 (m, 3H), 3.36 Petition 870250103152, dated 11 / 11 / 2025, pp. 200 / 219 192 / 208 (t, J = 6.2 Hz, 2H), 1.95 (tt, J = 6.3, 5.3 Hz, 2H).

[0317] 31P NMR (162 MHz, D2O) δ -10.34, -21.36. Example 78 Synthesis of Compound 2054 2C54-1 Compound 2054

[0318] Compound 11b (250 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and compound 2054-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2054, which was an ammonium salt in the form of a white powder (88 mg).

[0319] 1H NMR (400 MHz, D2O) δ 7.95 (d, J = 0.7 Hz, 1H), 6.49 (dd, J = 2.0, 0.7 Hz, 1H), 6.44-6.19 (m, 1H), 5.31 (dddd, J = 46.4, 6.9, 3.5, 0.8 Hz, 1H), 4.81 (dd, J = 4.8, 2.0 Hz, 1H), 4.58 (dd, J = 11.3, 8.5 Hz, 1H), 4.42 (dddd, J = 25.2, 7.1, 3.2, 0.7 Hz, 1H), 4.36 - 4.23 (m, 3H), 4.14 - 3.99 (m, 3H), 3.92 (d, J = 0.6 Hz, Petition 870250103152, dated 11 / 11 / 2025, pp. 201 / 219 193 / 208 3H), 3.83 (dd, J = 11.3, 8.5 Hz, 1H).

[0320] 31P NMR (162 MHz, D2O) δ -10.24, -21.16. Example 79 Synthesis of Compound 2064

[0321] A compound 2064-2 (2.38 g) was added to a solution of tetrazole (1.76 g) in acetonitrile (63 ml) in a three-necked flask, and the atmosphere was replaced with argon three times. Then, at room temperature of 25 °C, a material 2064-1 (5 g) was dissolved in 10 ml of acetonitrile and added to the above solution. The resulting solution was stirred at room temperature of 25 °C for 1 hour. No obvious heat release was found, and TLC monitoring showed that material 2064-1 disappeared. Then, to the solution, a solution of iodine in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the solution no longer faded. After that, the reaction solution was stirred for a further 0.5 hour. Petition 870250103152, dated 11 / 11 / 2025, pp. 202 / 219 194 / 208 and TLC monitoring showed that oxidation was complete. After adding an aqueous solution (10 ml) of saturated sodium sulfite to the reaction solution for quenching, a further 50 ml of water was added for dilution, and the mixture was extracted with dichloromethane (50 ml x 2). The organic phases were combined and washed once with water (50 ml) and concentrated to obtain a light yellow oily product 2064-3 (8 g, crude product).

[0322] Compound 2064-3 (8 g, crude product) was dissolved in 40 ml of acetic acid and 10 ml of water, and the reaction solution was stirred at 25 °C for 16 hours. TLC monitoring showed that compound 2064-3 disappeared and a highly polar spot was generated. The reaction solution was directly concentrated under vacuum. After concentration, appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white solid product 2064-4 was obtained (2.8 g, 51% overall yield in two steps).

[0323] 28 ml of a tetrazole solution in acetonitrile (0.4 mmol / ml) were prepared. Compound 2064-4 (2.8 g) was added to the above solution, and then compound A1 (3 g) was added to the solution at room temperature of 25 °C.The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at room temperature (25 °C) for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to below 10 °C in an ice water bath, and an iodine solution in pyridine / tetrahydrofuran / water (0.5 mmol / ml, pyridine:tetrahydrofuran:water = 1:8:1) was added dropwise until the reaction solution no longer faded. TLC monitoring showed that the oxidation reaction was complete. A. Petition 870250103152, dated 11 / 11 / 2025, pages 203 / 219 The reaction solution 195 / 208 was quenched by adding 10 ml of a saturated aqueous solution of sodium sulfite, diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. Appropriate amounts of silica gel and DCM were added and mixed with the sample, followed by purification (40 g normal phase column, EA, 10 min, DCM: MeOH, 10% to 20%, for 20 min, flow rate: 30 ml / min). After concentration, a white foamy solid compound 2064-6 was obtained (2.6 g, 78.2% yield).

[0324] Compound 2064-6 (2.6 g) was dissolved in methanol (30 ml) and concentrated aqueous ammonia (30 ml) was added. The resulting solution was stirred at room temperature of 25 °C for 60 hours. TLC monitoring showed that raw material 2064-6 was completely reacted. The reaction solution was concentrated under vacuum and concentrated again with methanol to obtain a light yellow oily liquid compound 2064-7 (2.4 g, crude product), which was used directly for the next step.

[0325] Compound 2064-7 (2.4 g, crude product) was dissolved in DMSO (3 mL) and triethylamine trihydrofluoride (3.5 mL) was added. The reaction solution was stirred at 50 °C for 1 hour. TLC monitoring showed that raw material 2064-7 was completely reacted. The reaction solution was diluted to 50 mL with water, and the pH was adjusted to 5.5 with 1 N aqueous NaOH solution. The mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., 0 M to 1.0 M aqueous ammonium bicarbonate solution. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a target compound, amine salt 2064-8 (0.8 g, 33.7%). Petition 870250103152, dated 11 / 11 / 2025, pages 204 / 219 196 / 208 yield), which was a white solid.

[0326] Compound 9a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and 2064-8 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a solution of disodium EDTA (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the obtained fraction was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2064, which was an ammonium salt in the form of a white powder (65 mg).

[0327] 1H NMR (400 MHz, D2O) δ 8.33 (s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 6.25 (t, J = 0.7 Hz, 1H), 6.16 (dt, J = 3.0, 0.7 Hz, 1H), 6.11 (dq, J = 3.0, 0.7 Hz, 1H), 4.80 (ddd, J = 3.8, 2.9, 0.7 Hz, 1H), 4.74 (dddd, J = 7.9, 3.9, 2.9, 0.7 Hz, 1H), 4.61 (ddd, J = 5.2, 2.8, 0.7 Hz, 1H), 4.55 - 4.43 (m, 1H), 4.41 - 4.32 (m, 2H), 4.30 - 4.09 (m, 9H), 3.98 (d, J = 0.7 Hz, 3H), 3.08 (s, 3H).

[0328] 31P NMR (162 MHz, D2O) δ -0.80, -11.55, -23.03. Example 80 Synthesis of Compound 2078 Petition 870250103152, dated 11 / 11 / 2025, pp. 205 / 219 197 / 208 2078-1 HSN 2D7& Compound

[0329] Compound 10a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and 2078-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2078, which was an ammonium salt in the form of a white powder (55 mg).

[0330] 1H NMR (400 MHz, D2O) δ 8.39 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 6.49 (dq, J = 1.5, 0.7 Hz, 1H), 6.32 - 6.09 (m, 2H), 5.30 (ddd, J = 2.6, 1.8, 0.7 Hz, 1H), 5.25 (ddd, J = 3.6, 2.9, 0.7 Hz, 1H), 4.72 - 4.60 (m, 2H), 4.56 - 4.46 (m, 2H), 4.44 - 4.36 (m, 2H), 4.33 (d, J = 2.8Hz, 1H), 4.27 - 4.07 (m, 6H), 4.05 - 3.96 (m, 4H), 3.11 (s, 3H).

[0331] 31P NMR (162 MHz, D2O) δ -0.90, -11.50, -22.95. Example 81 Synthesis of Compound 2092 Petition 870250103152, dated 11 / 11 / 2025, pp. 206 / 219 198 / 208 2ÚÔ2-1 Compound 2092

[0332] Compound 10a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and 2092-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2092, which was an ammonium salt in the form of a white powder (65 mg).

[0333] 1H NMR (400 MHz, D2O) δ 8.19 (s, 1H), 8.08 (s, 1H), 6.37 - 6.19 (m, 2H), 6.09 (dd, J = 2.8, 0.8 Hz, 1H), 4.97 (ddd, J = 4.4, 2.9, 0.7 Hz, 1H), 4.76 4.70 (m, 1H), 4.64 (t, J = 2.8 Hz, 1H), 4.55 - 4.45 (m, 3H), 4.44 - 4.35 (m, 2H), 4.33 (d, J = 2.8 Hz, 1H), 4.26 - 4.06 (m, 6H), 4.05 - 3.97 (m, 4H), 3.39 (s, 3H).

[0334] 31P NMR (162 MHz, D2O) δ -0.95, -11.70, -22.75. Example 82 Synthesis of Compound 2098 Petition 870250103152, dated 11 / 11 / 2025, pp. 207 / 219 199 / 208 Compound 2098 203B-1

[0335] Compound 9a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and 2098-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution at 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2098, which was an ammonium salt in the form of a white powder (70 mg).

[0336] 1H NMR (400 MHz, D2O) δ 8.42 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 6.15 (dq, J =4.1,0.7 Hz, 1H), 6.10 (dd, J = 2.9, 0.7 Hz, 1H), 6.01 (ddd, J = 2.7, 1.7, 0.8 Hz, 1H), 5.91 (d, J = 7.8 Hz, 1H), 5.02 - 4.88 (m, 1H), 4.77 (dddd, J = 5.9, 4.3, 1.5, 0.7 Hz, 1H), 4.55 (ddd, J = 5.3, 2.9, 0.6 Hz, 1H), 4.48 (qt, J = 3.3, 0.8 Hz, 1H), 4.36 (ddd, J = 7.3, 2.8, 0.6 Hz, 1H), 4.30 - 4.04 (m, 10H), 4.02 (s, 3H), 3.39 (s, 3H).

[0337] 31P NMR (162 MHz, D2O) δ -0.95, -11.70, -22.75. Example 83 Petition 870250103152, dated 11 / 11 / 2025, pp. 208 / 219 200 / 208 Synthesis of Compound 2110 9 9 OPOPOPO Oh oh oh 2110-1 Compound 2110

[0338] Compound 9b (200 mg) was added to 16 mL of an aqueous solution with a pH of 7.0, containing 0.2 mol / L N-methylmorpholine and 0.2 mol / L manganous chloride, and 2110-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 mL of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2110, which was an ammonium salt in the form of a white powder (70 mg).

[0339] 1H NMR (400 MHz, D2O) δ 8.41 (s, 1H), 8.18 (s, 1H), 6.31 (dd, J = 1.4, 0.8 Hz, 1H), 6.13 (dd, J = 2.5, 0.8 Hz, 1H), 4.72 - 4.53 (m, 2H), 4.35 - 4.06 (m, 8H), 4.02 (s, 3H), 3.38 (s, 3H).

[0340] 31P NMR (162 MHz, D2O) δ -10.24, -21.26. Example 84 Synthesis of Compound 2123 Petition 870250103152, dated 11 / 11 / 2025, pp. 209 / 219 201 / 208 2123-1 Compound 2123

[0341] Compound 10a (200 mg) was added to 16 ml of an aqueous solution with a pH of 7.0, containing 0.2 mol / l N-methylmorpholine and 0.2 mol / l manganous chloride, and 2123-1 (200 mg) was added to the solution. The reaction solution was stirred at room temperature of 25 °C for 16 hours. TLC monitoring showed that a product was generated. The reaction solution was added to a disodium EDTA solution (1.4 g, 80 ml of water were added) pre-cooled to 0 °C, and the mixture was loaded onto a Sephadex DEAE column. The product was eluted by linear gradient elution using an eluent, i.e., aqueous ammonium bicarbonate solution from 0 M to 1.0 M. Most of the water in the fraction obtained was concentrated under vacuum, and the remaining liquid was freeze-dried to obtain a product, compound 2123, which was an ammonium salt in the form of a white powder (50 mg).

[0342] 1H NMR (400 MHz, D2O) δ 7.62 (dd, J = 7.4, 1.8 Hz, 1H), 6.24 (dd, J = 2.7,0.6 Hz, 1H), 6.12 (ddt, J = 2.6, 1.6, 0.7 Hz, 1H), 5.96 (d, J = 7.3 Hz, 1H),4.64 (t, J = 2.8 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.42 (ddd, J = 5.3, 2.4, 0.7 Hz, 1H), 4.39 (d, J = 11.6 Hz, 1H), 4.33 (d, J = 2.8Hz, 1H), 4.27 (td, J = 5.1,0.7 Hz, 1H), 4.21 - 4.05 (m, 4H), 4.04 - 3.96 (m, 4H).

[0343] 31P NMR (162 MHz, D2O) δ-10.70, -20.75. Example 85 Petition 870250103152, dated 11 / 11 / 2025, pp. 210 / 219 202 / 208 Detection of mRNA synthesis efficiency with cap a) A plasmid was linearized and a DNA template was purified. b) Capping analogs of the present invention and Comparative Example 1 Trilink CleanCap, cap analogs of Comparative Example 2 and Comparative Example 3 were used to synthesize mRNA by in vitro transcription, respectively. Comparative Example 1 was commercially acquired, and Comparative Example 2 and Comparative Example 3 were obtained according to the method disclosed in WO2022 / 036858. Comparative Example 1 Comparative Example 2 Petition 870250103152, dated 11 / 11 / 2025, pages 211 / 219 203 / 208 Comparative Example 3

[0344] The minimal reaction system for preparing mRNA used in the present invention is shown in Table 1. Table 1 In vitro transcription system Components Dosage T7 RNA polymerase 4 μΙ (200 U) RNase inhibitor 0.5 μΙ (20 U) Inorganic pyrophosphatase 1 μΙ (0.5 U) ATPa 100 mM 1.5 μΙ CTPa 100 mM 1.5 μΙ GTPa 100 mM 1.5 μΙ ψΤΡ at 100 mM 1.5 μΙ 100 mM cap analogue 1.5 μΙ 10 μΙ buffer 2 μΙ DNA template 1 μΙ Water 4 μΙ Total 20 μΙ Petition 870250103152, dated 11 / 11 / 2025, pages 212 / 219 204 / 208 c) During the experiment, the above reagents were thoroughly mixed and incubated at 37 °C. After 4 hours, deoxyribonuclease (DNase) was added and incubated for 30 minutes to remove the DNA template. After digestion, the LiCI solution was added, pre-cooled, and centrifuged at 16,000 rpm for 15 minutes to remove the supernatant. 70% ethanol was added and centrifuged to remove the supernatant again, and then a certain amount of enzyme-free water was added for storage. The purified mRNA sample was then quantitatively detected using Nanodrop One, as shown in Table 2 below. The experimental results show that the yield of the product in mRNA synthesis using the halogenated cap analogs in the present invention is improved compared to the comparative examples. Table 2 - Amount (mg) of final product obtained per 1 ml of mRNA synthesis reaction system Number of components 8 68 168 173 433 458 468 33 Example Comparative 2 Quantity of product 4.7 5.8 5.6 5.2 4.9 4.8 5.3 5.3 4.2 Number of components 58 76 101 158 408 1982 2017 2037 2058 Quantity of product 5.5 5.4 5.3 4.9 5.7 5.8 5.8 5.5 4.6 d) After the purified mRNA was treated with enzymatic cleavage, the oligonucleotide fragments of different sizes were separated and Petition 870250103152, dated 11 / 11 / 2025, pp. 213 / 219 205 / 208 identified by liquid chromatography coupled to mass spectrometry (LC-MS), providing exact molecular weight information of the enzyme-cleaved fragments. Combined with the theoretical enzyme-cleaved molecular weight and the assignment, the sample capping efficiency can be obtained.

[0345] The capping efficiency of mRNA synthesized by the cap analogs of the present invention was between 90% and 98%. From the purified capped mRNA, the compounds of the present invention all showed good capping efficiency. Example 86 Evaluation of the Efficiency of Fluorescent Green Protein mRNA Expression with Different Capping Analogs in Different Cells

[0346] The present invention tested the mRNA expression efficiency of capped green fluorescent protein in HEK293T and HepG2 cells. A GFP coding sequence of green fluorescent protein was used as a DNA template, and the cap analogs of the present invention were used as materials for in vitro mRNA transcription. Then, different mRNA products were transfected into cells, and finally, fluorescent proteins in the cells were detected by flow cytometry.

[0347] Different cells described above were placed in plates in 2 χ 105 cells (96-well plate).

[0348] 300 μl of mRNA buffer were uniformly mixed with 6 μg of RNA, and then 6 μl of a transfection reagent (JetMESENG-ER) were added and mixed uniformly. After leaving for 10 min, the mixture was Petition 870250103152, dated 11 / 11 / 2025, pp. 214 / 219 206 / 208 was added to the cells in each well, and transfection medium (Opti-MEM) was supplemented to reach 2 ml / well. The cells were cultured at 37 °C and 5% CO2 for 6 h.

[0349] After the transfection medium was replaced with a fresh complete medium and cultured for 24 h under the same conditions, the fluorescence intensity of GFP was observed using a fluorescence microscope. The results are shown in FIG. 1, from which it can be clearly seen that the mRNA expression efficiency in the present invention is greater than that of the comparative examples.

[0350] After the transfected cells were cultured for 24 h, the cells were treated and then detected by flow cytometry (CytoFLEX S series). The detected fluorescence intensity was proportional to the translation efficiency of the target protein. The results of the analysis are shown in FIGS. 2 and 3.

[0351] FIG. 2 is a graph of fluorescence intensity analysis of mRNA-encoding green fluorescent protein with different cap analogs in HEK293T cells; the horizontal geometric axis is the digital compound number of the cap analogs, and the vertical geometric axis is a fluorescence intensity value detected by flow cytometry. Compared to Comparative Examples 1 and 2, the fluorescence intensity values ​​of the cap analogs in the present invention in HEK293T cells were more prominent. For example, the average fluorescence intensity value of compound 468 was 1.5 times that of Comparative Example 2 and 1.6 times that of Comparative Example 1, and the average fluorescence intensity value of compound 158 was 1.3 times that of Petition 870250103152, dated 11 / 11 / 2025, pages 215 / 219 207 / 208 Comparative Example 2 is 1.4 times that of Comparative Example 1.

[0352] FIG. 3 is a statistical graph of mRNA fluorescence intensity with different cap analogs in Hep G2 cells. In comparison, the mRNA translation and protein expression efficiency of the cap analogs of the present invention in Hep G2 cells is higher than that of the comparative examples. The protein expression levels of fluorinated nucleoside dimer cap analogs such as compound 1982 and fluorinated nucleoside tetramer cap analogs such as 2057 were also significantly enhanced. Example 87 Testing the Efficiency of Expression of mRNA Synthesized by Different Cap Analogs in Mice a) The cap analogs of the present invention were used to prepare coding luciferase mRNA, and the obtained mRNA was diluted in a citric acid buffer at pH 4.0. The cationic lipids DLin-MC3-DMA, DSPC, cholesterol, and PEG lipids (DMG-PEG2000) were dissolved in ethanol at a molar ratio of 50:10:38.5:1.5. b) Two 5 ml syringes were filled with 3 ml of mRNA buffer and 1 ml of lipid solution, respectively, and then loaded into a microfluidic injection pump, and the pump flow rate was adjusted. The collected product was placed in a dialysis bag and ultrafiltered and concentrated to an optimal concentration. Then, the lipid nanoparticles were filtered through a sterile 0.22 μm filter and stored for use. c) Lipid mRNA luciferase nanoparticles containing 5 μg of mRNA were injected into female Balb / c mice aged 6 to 8 years. Petition 870250103152, dated 11 / 11 / 2025, pp. 216 / 219 208 / 208 weeks via caudal vein injection. Each type of luciferase mRNA lipid nanoparticle was injected into 5 mice for parallel experiments. A luciferase substrate was injected 24 hours later and detected using a PerkinElmer small animal imaging system. The luminescence intensity was proportional to the translation efficiency of the effective target protein. The relative mRNA fluorescence intensity in different mouse organs is shown in FIG. 4. The mRNA expression efficiency with different halogenated cap analogs of the present invention in different organs was significantly higher than that of the comparative examples.

Claims

1. Compound for capping the 5' end of a nucleic acid or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is characterized by having a structure of Formula (I): (I), wherein Ro is any one selected from the group consisting of F, Cl, Br and I, Ri is a group selected from the group consisting of -H, -OH, Petition 870250082359, 12 / 09 / 2025, p. 12 / 382 2 / 11 C1-4 alkyl and C1-4 alkoxy, R2 is any one selected from the group consisting of -H, OH, C1-6 alkyl and C1-6 alkoxy, optionally, R1 and R2 are connected to form a ring by means of a chemical bond, and -R1-R2- is any one of -(CH2)qO-, -O-(CH2)q and -(CH2)mO-(CH2)n-, where q, men are each independently 1, 2 or 3, R3 is any one of H, -OH, -SH, -N3, -NH2, halogen, -CN, C1-6 alkoxy, -O(CH2)sCN, -SR3a, -O(CH2)pR3b, OCOR3c, O(CH2)pCOR3c, -O(CH2)tSH, O(CH2)pOH, -O(CH2)pN3 and -O(CH2)pNH2, where t, pes are, each one,independently any integer from 1 to 6; R3a is C1-6 alkyl; R3b is C6-12 aryl optionally substituted with one or more R3d or C5-12 heteroaryl optionally substituted with one or more R3d; R3c is C1-10 alkyl optionally substituted with one or more R3d, C1-10 alkenyl optionally substituted with one or more R3d, C5-12 cycloalkyl optionally substituted with one or more R3d or C5-12 cycloalkenyl optionally substituted with one or more R3d; where R3 is optionally substituted with one or more R3e; R3d and R3e are selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, cyano, amino, nitro, -OH and -SH; R4, R5, R6 and R7 are each independently selected from the group consisting of -H, -OH, -OCH3, halogen, CN and -SH; NO1, NO2, NO3 and NO4 are each independently selected from O or I; Petition 870250082359, dated 12 / 09 / 2025, p. 13 / 382 3 / 11; J1, J2, J3, J4 and J5 are eachindependently selected from natural or modified pyrimidine nucleotide bases or natural or modified purine nucleotide bases, Rp1 is C1 to C6 alkyl, preferably C1 to C3 alkyl, which is optionally substituted with -SH, -N3, C2 to C6 alkenyl or C2 to C6 alkynyl, Rp2 and Rp3 are each independently selected from the group consisting of H, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, a PEG group, CORp4 and SO2RP4, wherein these groups are each optionally substituted with -CN, N3, -SH or alkynyl, Rp4 is selected from the group consisting of H and C1 to C6 alkyl, and Rp2 and Rp3 are optionally connected to form a ring, provided that, when N01, NO2, NO3, and NO4 are all O, J5 is a guanine base, and when R2 is -OH, R3 is not a methoxy group.

2. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to claim 1, the compound being characterized by having a structure of Formula (I'): Petition 870250082359, dated 12 / 09 / 2025, page 14 / 382 4 / 11 wherein each group in Formula (I') has a meaning equal to that described in claim 1.

3. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to claim 1 or 2, characterized in that at least one of J1, J2, J3, J4 and J5 is a modified nucleotide base, preferably a modified purine nucleotide base, more preferably a methyl-modified purine nucleotide base, and even more preferably 6-N-methyladenine.

4. A pharmaceutically acceptable compound or salt, solvate or stereoisomer thereof, according to any one of claims 1 to 3, characterized in that Petition 870250082359, dated 12 / 09 / 2025, p. 15 / 382 5 / 11 R3 is any of -H, -OH, -SH, -N3, -NH2, halogen, -CN, C1-6 alkoxy, -O(CH2)pCN, -SR3a, -O(CH2)pR3b, OCOR3c, O(CH2)pCOR3c, -O(CH2)pSH, O(CH2)pOH, -O(CH2)pN3 and -O(CH2)pNH2, where t, pes are each independently any integer from 1 to 6, preferably 1 to 4; R3a is C1-4 alkyl; R3b is C6-10 aryl optionally substituted with one or more R3d or C5-10 heteroaryl optionally substituted with one or more R3d; R3c is C5-10 cycloalkyl optionally substituted with one or more R3d or C5-10 cycloalkenyl optionally substituted with one or more R3d, where R3 is optionally substituted with one or more R3e; and R3d and R3e are selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, halogen, cyano, amino, nitro,-OH and -SH, preferably, R3 is any one of -H, -OH, -SH, -N3, -NH2, halogen, -CN, C1-3 alkoxy, -O(CH2)pCN, -SR3a, -O(CH2)pR3b, OCOR3c, O(CH2)pCOR3c, -O(CH2)pSH, -O(CH2)pOH, -O(CH2)pN3 and -O(CH2)pNH2, where pes are each independently any integer from 1 to 3, t is any integer from 1 to 4, R3a is methyl or ethyl, R3b is C5-10 heteroaryl optionally substituted with one or two R3d, R3c is C5-10 cycloalkyl optionally substituted with one or two R3d or C5-10 cycloalkenyl optionally substituted with one or two R3d, wherein R3 is optionally substituted with one or R3e, and R3d and R3e are selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, halogen, cyano, amino, nitro, -OH and -SH, more preferably, R3b is C5 or C6 heteroaryl optionally substituted with C1-4 alkyl, for example, tetrazinyl optionally substituted with C1-4 alkyl, and R3c is C5-10 cycloalkenyl optionally substituted.from 12 / 09 / 2025, page 16 / 382 6 / 11 substituted with C1-4 alkyl, halogen, cyano, amino or nitro, for example, norbornenil or cyclooctenyl optionally substituted with C1-4 alkyl, halogen, cyano, amino or nitro, and, for example, unsubstituted norbornenil or cyclooctenyl.

5. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to any one of claims 1 to 4, wherein the compound is characterized by having a structure of Formula (Ia), Formula (Ib) or Formula (Ic): Petition 870250082359, dated 12 / 09 / 2025, page 17 / 382 7 / 11 R2R3 Γχ Ri H2Nk no / / Tn hn. JL Π N + O xo—po—p—O—pO OH OH OH OXO HO O J1 R4 O J2 O OP HOZ OO J5 HO Ro (Ic).

6. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to claim 5, characterized in that Ro is -F or -Cl and / or R4 and R5 are each independently any one selected from the group consisting of H, OH, OCH3, F, Cl, -CN and -SH and, preferably, any one selected from the group consisting of H, OH, OCH3 and F.

7. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to any one of claims 1 to 4, wherein the compound is characterized by having a structure of Formula (Id): Petition 870250082359, dated 12 / 09 / 2025, page 18 / 382 8 / 11 wherein Rs' has a meaning equal to that of R3 defined in claim 1 or 4, and the remaining groups have the same meanings as those described in claims 1 to 4.

8. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to claim 7, wherein the compound is characterized by having a structure of Formula (Ie), Formula (If) or Formula (Ig): Petition 870250082359, dated 12 / 09 / 2025, p. 19 / 382 9 / 11 9. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to claim 8, characterized in that Petition 870250082359, dated 12 / 09 / 2025, p. 20 / 382 10 / 11 that Ro is -F or -Cl and / or R4 and R5 are each independently any one selected from the group consisting of H, OH, OCH3, F, Cl, -CN and -SH and preferably any one selected from the group consisting of H, OH, OCH3 and F.

10. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, according to claim 1, wherein the compound is characterized by having one of the structures shown in Table 1 of the description.

11. A compound or a solvate or stereoisomer thereof, according to any one of claims 1 to 10, wherein the compound is characterized by being present in the form of a pharmaceutically acceptable salt and, preferably, in the form of a triethylamine salt, a sodium salt, a potassium salt, an ammonium salt or tris(hydroxymethyl)aminomethane hydrochloride.

12. Use of the compound as defined in any one of claims 1 to 11, characterized by being used as an in vitro cotranscriptional RNA capping reagent.

13. RNA molecule characterized by comprising: the compound as defined in any one of claims 1 to 11 as a cap structure or a fragment of a cap structure.

14. Pharmaceutical composition characterized by comprising: the RNA molecule as defined in claim 13; and a pharmaceutically acceptable carrier. Petition 870250082359, dated 12 / 09 / 2025, page 21 / 382 11 / 11 15. Method for synthesizing an RNA molecule, the method being characterized by comprising: incubating the compound as defined in any one of claims 1 to 11 with a polynucleotide template in order to perform template-based transcription.

16. Transcriptional RNA capping reaction system characterized by comprising: a polynucleotide template; the compound as defined in any one of claims 1 to 11; NTPs; and an RNA polymerase.

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