PTH treatment of chronic kidney disease

Abstract

The present application relates to a PTH compound for use in preventing chronic kidney disease (CKD) in a subject at risk of suffering from CKD or for use in treating a subject suffering from CKD, and related aspects thereof.

Description

Technical Field

[0001] This application relates to a PTH compound for the prevention of CKD in subjects at risk of developing chronic kidney disease (CKD) or for the treatment of subjects with CKD, and related aspects. Background Technology

[0002] Chronic hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, and a deficiency or insufficiency of parathyroid hormone (PTH) production. In the absence of PTH, mechanisms regulating calcium transport and phosphate reabsorption in the PTH-receptor-rich tubules are dysregulated, disrupting the kidney's primary role in controlling calcium and phosphate homeostasis. Patients with chronic hypoparathyroidism managed with conventional therapy (consisting of oral calcium and active vitamin D) have an increased risk of renal complications. Studies have shown that compared to patients without hypoparathyroidism, those with chronic hypoparathyroidism have a higher risk of developing chronic kidney disease (CKD), faster CKD stage progression, a higher risk of progressing to end-stage renal disease (ESKD), and a faster decline in estimated glomerular filtration rate (eGFR). Therefore, patients receiving conventional treatment for hypoparathyroidism need close monitoring for symptoms and comorbidities, including the development of chronic kidney disease, the risk of kidney stones, and kidney calcification.

[0003] Although a growing body of research supports an increased risk of renal complications in patients with chronic hypoparathyroidism, the underlying mechanisms of this risk in the pathophysiology of hypoparathyroidism remain unknown. Chronic hypoparathyroidism is usually controlled with conventional therapy aimed at maintaining serum calcium concentrations at the lower limit of the normal range (i.e., 8.0–8.5 mg / dL; Adv Ther (2021) 38:1876–1888 1885).

[0004] Chen et al. (J Clin Endocrinol Metab. 2020; 105: e3557-65) recently reported that in a study of patients with chronic hypoparathyroidism, during a 5-year follow-up period, the eGFR of patients who did not receive recombinant human PTH 1-84 (Natpara®) decreased by 8.0 ml / min / 1.73 m 2 In contrast, patients receiving rhPTH 1-84 treatment had stable or only slightly improved eGFR, suggesting that hormone replacement therapy can improve declining eGFR.

[0005] Compared with patients without hypoparathyroidism, patients with chronic hypoparathyroidism had a significantly increased risk of developing CKD stage 3 or higher. Compared with patients without hypoparathyroidism, patients with chronic hypoparathyroidism also had a significantly increased risk of progressing to higher CKD stages and to ESKD (Adv Ther (2021) 38: 1876-1888 1885).

[0006] Therefore, more effective treatments are needed for chronic kidney disease, especially for patients with hypoparathyroidism. Summary of the Invention

[0007] The purpose of this application is to overcome these shortcomings, at least in part.

[0008] This objective is achieved using PTH compounds, which are used to prevent chronic kidney disease (CKD) in subjects at risk of developing CKD or to treat subjects who already have CKD.

[0009] Surprisingly, in subjects with CKD, particularly those with hypoparathyroidism and eGFR less than 60 ml / min / 1.73 m 2 In subjects with CKD, administration of PTH compounds (such as PTH compounds that prolong receptor signaling by at least 10 times compared to PTH 1-84) resulted in sustained improvement in eGFR, while similar subjects receiving conventional therapy showed a decrease in eGFR.

[0010] In this application, the terms used have the following meanings.

[0011] As used herein, the terms “within normal” and “within normal range” for serum calcium (sCa) refer to calcium levels typically found in subjects of a given species, sex, and age. In humans, normal serum calcium levels typically correspond to a range of 8.3 mg / dL (albumin-adjusted) to 10.6 mg / dL (albumin-adjusted). The term “albumin-adjusted” for serum calcium levels refers to the correction of measured serum calcium levels for albumin-bound calcium according to the following formula: Albumin-adjusted serum calcium (mg / dL) = measured total Ca (mg / dL) + 0.8 (4.0 - serum albumin [g / dL]).

[0012] Serum calcium levels within the normal range are also known as "normal calcium levels".

[0013] As used herein, the term "starting dose" refers to the dose of PTH compound administered to a subject when first starting treatment with a PTH compound, i.e., a dose to which the subject has not previously received a PTH compound. It should be understood that the subject may continue with such an starting dose for a period of time (e.g., days, weeks, or months) or throughout the course of treatment, or the dose may be increased or decreased based on certain events (e.g., the occurrence of hypocalcemia or hypercalcemia).

[0014] As used in this article, the term "mean" refers to a simple (equally weighted) arithmetic mean, which can be obtained by summing all the variables in the dataset and then dividing the result by the number of variables.

[0015] If hypoparathyroidism persists for at least six months, the subject is said to have “chronic hypoparathyroidism.” In this article, the terms “subject” and “patient” are used synonymously.

[0016] As used in this article, the term “mean improvement” for eGFR refers to the mean improvement in eGFR measured in the subject population.

[0017] As used herein, the term "PTH" refers to all PTH peptides, such as PTH peptides derived from mammalian species, particularly PTH peptides derived from human and mammalian species, more specifically PTH peptides derived from human and mouse species, and their variants, analogs, orthologs, homologs, and derivatives and fragments thereof, characterized by increased serum calcium and renal phosphorus secretion and decreased serum phosphorus and renal calcium secretion. The term "PTH" also refers to all PTHrP peptides, such as the peptide of SEQ ID NO:121, which bind to and activate a common PTH / PTHrPl receptor. In some embodiments, the term "PTH" refers to the PTH peptide of SEQ ID NO:51 and its variants, homologs, and derivatives, which exhibit substantially the same biological activity, namely, increased serum calcium and renal phosphorus secretion and decreased serum phosphorus and renal calcium secretion. In some embodiments, the term "PTH" refers to the PTH peptide of SEQ ID NO:51.

[0018] In some implementations, the term "PTH" refers to one of the following polypeptide sequences: SEQ ID NO:1 (PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ SEQ ID NO:2 (PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS SEQ ID NO:3 (PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK SEQ ID NO:4 (PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA SEQ ID NO:5 (PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK SEQ ID NO:6 (PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT SEQ ID NO:7 (PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL SEQ ID NO:8 (PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV SEQ ID NO:9 (PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN SEQ ID NO:10 (PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV SEQ ID NO:11 (PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD SEQ ID NO:12 (PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA SEQ ID NO:13 (PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK SEQ ID NO:14 (PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD SEQ ID NO:15 (PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA SEQ ID NO:16 (PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE SEQ ID NO:17 (PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG SEQ ID NO:18 (PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL SEQ ID NO:19 (PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS SEQ ID NO:20 (PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK SEQ ID NO:21 (PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE SEQ ID NO:22 (PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH SEQ ID NO:23 (PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES SEQ ID NO:24 (PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE SEQ ID NO:25 (PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV SEQ ID NO:26 (PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL SEQ ID NO:27 (PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV SEQ ID NO:28 (PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN SEQ ID NO:29 (PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED SEQ ID NO:30 (PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE SEQ ID NO:31 (PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK SEQ ID NO:32 (PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK SEQ ID NO:33 (PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR SEQ ID NO:34 (PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP SEQ ID NO:35 (PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR SEQ ID NO:36 (PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ SEQ ID NO:37 (PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS SEQ ID NO:38 (PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG SEQ ID NO:39 (PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA SEQ ID NO:40 (PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD SEQ ID NO:41 (PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR SEQ ID NO:42 (PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP SEQ ID NO:43 (PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA SEQ ID NO:44 (PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL SEQ ID NO:45 (PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP SEQ ID NO:46 (PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA SEQ ID NO:47 (PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG SEQ ID NO:48 (PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL SEQ ID NO:49 (PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA SEQ ID NO:50 (PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV SEQ ID NO:51 (PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF SEQ ID NO:52 (PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN SEQ ID NO:53 (PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH SEQ ID NO:54 (PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV SEQ ID NO:55 (PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD SEQ ID NO:56 (PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ SEQ ID NO:57 (PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL SEQ ID NO:58 (PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK SEQ ID NO:59 (PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK SEQ ID NO:60 (PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR SEQ ID NO:61 (amidated PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ; where the C-terminus is amidated. SEQ ID NO:62 (amidated PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS; where the C-terminus is amidated. SEQ ID NO:63 (amidated PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK; where the C-terminus is amidated. SEQ ID NO:64 (amidated PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA; where the C-terminus is amidated. SEQ ID NO:65 (amidated PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK; where the C-terminus is amidated. SEQ ID NO:66 (amidated PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT; where the C-terminus is amidated. SEQ ID NO:67 (amidated PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL; where the C-terminus is amidated. SEQ ID NO:68 (amidated PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV; where the C-terminus is amidated. SEQ ID NO:69 (amidated PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN; where the C-terminus is amidated. SEQ ID NO:70 (amidated PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV; where the C-terminus is amidated. SEQ ID NO:71 (amidated PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD; where the C-terminus is amidated. SEQ ID NO:72 (amidated PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA; where the C-terminus is amidated. SEQ ID NO:73 (amidated PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK; where the C-terminus is amidated. SEQ ID NO:74 (amidated PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD; where the C-terminus is amidated. SEQ ID NO:75 (amidated PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA; where the C-terminus is amidated. SEQ ID NO:76 (amidated PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE; where the C-terminus is amidated. SEQ ID NO:77 (amidated PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG; where the C-terminus is amidated. SEQ ID NO:78 (amidated PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL; where the C-terminus is amidated. SEQ ID NO:79 (amidated PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS; where the C-terminus is amidated. SEQ ID NO:80 (amidated PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK; where the C-terminus is amidated. SEQ ID NO:81 (amidated PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE; where the C-terminus is amidated. SEQ ID NO:82 (amidated PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH; where the C-terminus is amidated. SEQ ID NO:83 (amidated PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES; where the C-terminus is amidated. SEQ ID NO:84 (amidated PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE; where the C-terminus is amidated. SEQ ID NO:85 (amidated PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV; where the C-terminus is amidated. SEQ ID NO:86 (amidated PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL; where the C-terminus is amidated. SEQ ID NO:87 (amidated PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV; where the C-terminus is amidated. SEQ ID NO:88 (amidated PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN; where the C-terminus is amidated. SEQ ID NO:89 (amidated PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED; where the C-terminus is amidated. SEQ ID NO:90 (amidated PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE; where the C-terminus is amidated. SEQ ID NO:91 (amidated PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK; where the C-terminus is amidated. SEQ ID NO:92 (amidated PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK; where the C-terminus is amidated. SEQ ID NO:93 (amidated PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR; where the C-terminus is amidated. SEQ ID NO:94 (amidated PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP; where the C-terminus is amidated. SEQ ID NO:95 (Amide-modified PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR; where the C-terminus is amidated. SEQ ID NO:96 (amidated PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ; where the C-terminus is amidated. SEQ ID NO:97 (amidated PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS; where the C-terminus is amidated. SEQ ID NO:98 (amidated PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG; where the C-terminus is amidated. SEQ ID NO:99 (amidated PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA; where the C-terminus is amidated. SEQ ID NO:100 (amidated PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD; where the C-terminus is amidated. SEQ ID NO:101 (amidated PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR; where the C-terminus is amidated. SEQ ID NO:102 (amidated PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP; where the C-terminus is amidated. SEQ ID NO:103 (amidated PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA; where the C-terminus is amidated. SEQ ID NO:104 (amidated PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL; where the C-terminus is amidated. SEQ ID NO:105 (amidated PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP; where the C-terminus is amidated. SEQ ID NO:106 (amidated PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA; where the C-terminus is amidated. SEQ ID NO:107 (amidated PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG; where the C-terminus is amidated. SEQ ID NO:108 (amidated PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL; where the C-terminus is amidated. SEQ ID NO:109 (amidated PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA; where the C-terminus is amidated. SEQ ID NO:110 (amidated PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV; where the C-terminus is amidated. SEQ ID NO:111 (amidated PTH 1-34) jSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF; where the C-terminus is amidated. SEQ ID NO:112 (amidated PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN; where the C-terminus is amidated. SEQ ID NO:113 (amidated PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH; where the C-terminus is amidated. SEQ ID NO:114 (amidated PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV; where the C-terminus is amidated. SEQ ID NO:115 (amidated PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD; where the C-terminus is amidated. SEQ ID NO:116 (amidated PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ; where the C-terminus is amidated. SEQ ID NO:117 (amidated PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL; where the C-terminus is amidated. SEQ ID NO:118 (amidated PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK; where the C-terminus is amidated. SEQ ID NO:119 (amidated PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK; where the C-terminus is amidated. SEQ ID NO:120 (amidated PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR; where the C-terminus is amidated. SEQ ID NO:121 (PTHrP) AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH And sequences that have at least 90% homology with it, such as at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0019] The terms "PTH molecule" and "PTH moiety" also include poly(amino acid) conjugates having the above-described sequences, but which have a backbone comprising amide and non-amide linkages, such as ester bonds, for example, peptides. Peptides are chains of amino acid residues in which the backbone comprises amide (peptide) bonds and ester bonds. Therefore, as used herein, the term "side chain" refers to a portion attached to the α-carbon of an amino acid moiety (if the amino acid moiety is linked by an amine bond, as in proteins and peptides), or to any carbon-containing portion attached to the backbone of the poly(amino acid) conjugate (e.g., in the case of peptides). In some embodiments, the term "PTH" refers to a sequence having a backbone formed by amide (peptide) bonds.

[0020] As used in this article, the terms “release half-life” and “half-life” refer to the time required for half of the PTH molecules or PTH fraction in a sustained-release PTH compound or PTH prodrug to be released under physiological conditions (i.e., aqueous buffer, pH 7.4, 37°C).

[0021] As used herein, the term "peptide" refers to a chain of at least two and up to 50 amino acid monomeric moieties (also referred to as "amino acid residues") linked by peptide (amide) links. The amino acid monomers may be selected from the group consisting of protein amino acids and non-protein amino acids, and may be D- or L-type amino acids. The term "peptide" also includes peptide mimics, such as peptides, β-peptides, cyclic peptides, and condensed peptides, encompassing peptide mimic chains with up to 50 monomeric moieties. As used herein, the term "protein" refers to a chain of more than 50 amino acid monomeric chains (also referred to as "amino acid residues") linked by peptide links, preferably with no more than 12,000 amino acid monomers linked by peptide links, such as no more than 10,000 amino acid monomers, no more than 8,000 amino acid monomers, no more than 5,000 amino acid monomers, or no more than 2,000 amino acid monomers. For simplicity, the PTH moieties and PTH molecules are generally referred to as "proteins" herein.

[0022] The term "physiological conditions" as used in this article refers to an aqueous buffer solution with pH 7.4 and 37°C.

[0023] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more active ingredients (such as at least one PTH compound) and one or more excipients, as well as any product directly or indirectly produced by the combination, compounding, or aggregation of two or more components of the composition, or by the dissociation of one or more components, or by other types of reactions or interactions of one or more components. Therefore, the pharmaceutical composition used in this application covers any composition formed by mixing one or more PTH compounds and pharmaceutically acceptable excipients.

[0024] As used herein, the term "excipient" refers to a diluent, adjuvant, or carrier used for the administration of a therapeutic substance (such as a drug or prodrug). Such pharmaceutical excipients can be sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an example of an excipient when the pharmaceutical composition is administered orally. Physiological saline and glucose aqueous solutions are examples of excipients when the pharmaceutical composition is administered intravenously. In some embodiments, saline solutions and glucose-glycerol aqueous solutions are used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. If desired, the pharmaceutical composition may also contain small amounts of wetting agents or emulsifiers, pH buffers, such as acetates, succinates, tris(hydroxymethyl)aminomethane (TRIS), carbonates, phosphates, HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid), MES (2-( NThese pharmaceutical compositions may contain morpholino(ethanesulfonic acid), or surfactants such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or amino acids such as glycine, lysine, or histidine. These pharmaceutical compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, or sustained-release formulations. Pharmaceutical compositions may be formulated as suppositories and contain conventional binders and excipients such as triglycerides. Oral formulations may contain standard excipients such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions will contain a therapeutically effective amount of the drug or biologically active portion, as well as an appropriate amount of excipients to provide a suitable form of administration for the subject. The formulation should be appropriate to the method of administration.

[0025] As used herein, the term "liquid composition" refers to a mixture comprising a water-soluble PTH compound and one or more solvents, such as water.

[0026] The term "suspension composition" refers to a mixture comprising at least one water-insoluble PTH compound and one or more solvents (such as water).

[0027] As used herein, the term "dried composition" refers to a pharmaceutical composition provided in a dried form. Suitable drying methods include spray drying and lyophilization, i.e., freeze-drying. The residual moisture content of such a dried composition, determined according to the Karl Fischer method, is at most 10%, and less than 5% or less than 2%. In some embodiments, such a dried pharmaceutical composition is dried by lyophilization.

[0028] As used in this article, the term "drug" refers to a substance used to treat, cure, prevent, or diagnose a disease, or to otherwise enhance physical or mental health, such as PTH. If a drug is conjugated to another part, the portion of the resulting product derived from the drug is referred to as the "drug portion".

[0029] As used herein, the term "prodrug" refers to a covalently conjugated compound in which the drug moiety is reversibly covalently linked to a specific protecting group via a reversible linker moiety (also called a "reversible prodrug linker moiety" or "reversible linker moiety"), which is reversibly linked to the bioactive moiety, and in which the specific protecting group alters or eliminates undesirable properties in the parent molecule. This also includes enhancing desired properties of the drug and inhibiting undesirable characteristics. This specific non-toxic protecting group is called a "carrier." The prodrug releases the reversibly covalently bound drug moiety in the form of the corresponding drug. In other words, a prodrug is a conjugated compound containing a drug moiety reversibly covalently linked to a carrier moiety via a reversible linker moiety, the covalent reversible conjugation of the carrier to the reversible linker moiety can occur directly or via a spacer group. Such a conjugated compound releases the pre-conjugated drug moiety in the form of free, unmodified drug.

[0030] "Reversible ligation" refers to a ligation that is degradable (i.e., cleaved) under physiological conditions (pH 7.4, 37°C aqueous buffer) in the absence of an enzyme, with a half-life ranging from 1 hour to 3 months, in some embodiments from 1 hour to 2 months, in some embodiments from 1 hour to 1 month, in some embodiments from 1 hour to 3 weeks, in some embodiments from 1 hour to 2 weeks, in some embodiments from 12 hours to 2 weeks, and in some embodiments from 12 hours to 1 week. Therefore, stable ligation is a ligation with a half-life exceeding three months under physiological conditions (pH 7.4, 37°C aqueous buffer) in the absence of an enzyme.

[0031] The term "traceless prodrug linker" or "traceless linker" as used in this article refers to a reversible prodrug linker, in which the linker portion reversibly covalently connects the drug moiety to the carrier, releasing the drug in its free form upon lysis. The term "free form" of the drug as used in this article refers to the drug in its unmodified, pharmacologically active form.

[0032] As used herein, the term "reagent" refers to a chemical compound containing at least one functional group that can react with the functional group of another chemical compound or drug. It should be understood that drugs containing functional groups (such as primary or secondary amines or hydroxyl functional groups) are also reagents.

[0033] As used herein, the term "part" refers to a portion of a molecule that lacks one or more atoms compared to the corresponding reagent. For example, if a reagent of formula "HXH" reacts with another reagent and becomes part of the reaction product, the corresponding part of the reaction product has the structure "HX-" or "-X-", where each "-" indicates a connection to another part. Thus, the drug part is released from the prodrug and becomes the drug.

[0034] It should be understood that if a chemical structure is provided of a set of atoms that are attached to at least one other part or interrupt a part, then unless otherwise expressly specified, the chemical structure may be attached to, or interrupted by, said at least one other part in any direction. For example, the part "-C(O)N(R) 1 "-" can be connected to two parts, or to a break part, such as "-C(O)N(R) 1 )-” or “-N(R 1 )C(O)-". Similarly, some It can connect to two parts, or it can be used as... Or as Interrupt a section.

[0035] As used herein, the term "functional group" refers to a group of atoms that can react with other groups of atoms. Functional groups include, but are not limited to, the following groups: carboxylic acids, primary or secondary amines, maleimides, thiols, sulfonic acids, carbonates, carbamates, hydroxyl groups, aldehydes, ketones, hydrazines, isocyanates, isothiocyanates, phosphoric acids, phosphonic acids, haloacetyl groups, haloalkyl groups, acryloyl groups, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfuric acids, vinyl sulfones, vinyl ketones, diazonides, ethylene oxides, and cycloheximides.

[0036] Where a PTH compound contains one or more acidic or basic groups, this application also contains its corresponding pharmaceutically or toxicologically acceptable salt, particularly a pharmaceutically usable salt. Therefore, according to this application, PTH compounds containing acidic groups can be used as, for example, alkali metal salts, alkaline earth metal salts, or ammonium salts. More precisely, examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts containing ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. According to this application, PTH compounds (containing one or more basic groups, i.e., protonable groups) can be present and used in the form of addition salts with inorganic or organic acids. Examples of suitable acids include: hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfanilic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Other methods for converting basic groups to cations are known to those skilled in the art, such as aminoalkylation, to produce a positively charged ammonium group and a suitable equilibrium ion of the salt. If the PTH compound contains both acidic and basic groups, this application also includes an inner salt or betaine (zwitterion) in addition to the salt forms described above. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these compounds with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with other salts. This application also includes salts of all compounds that, due to low physiological compatibility, are not directly applicable to pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or to prepare pharmaceutically acceptable acceptors.

[0037] The term “pharmaceutically acceptable” refers to a substance that will not cause harm when administered to a subject, and in some implementations refers to a substance that has been approved by a regulatory agency (such as the EMA (Europe) and / or the FDA (USA) and / or any other national regulatory agency) for use in animals, and particularly for use in humans.

[0038] As used herein, the terms “about” or “approximately” in combination with numerical values ​​are used to indicate a range from which no more than 10% (inclusive) of the value is added to or subtracted from the value, in some embodiments no more than 8% (inclusive) of the value is added to or subtracted from the value, in some embodiments no more than 5% (inclusive) of the value is added to or subtracted from the value, and in some embodiments no more than 2% (inclusive) of the value is added to or subtracted from the value. For example, the phrase "about 200" or "approximately 200" is used to refer to a range of 200 + / - 10% (inclusive), i.e., 180 to 220 (inclusive); in some embodiments, a range of 200 + / - 8% (inclusive), i.e., 184 to 216 (inclusive); in some embodiments, a range of 200 + / - 5% (inclusive), i.e., 190 to 210 (inclusive); and in some embodiments, a range of 200 + / - 2% (inclusive), i.e., 196 to 204 (inclusive). It should be understood that giving a percentage such as "about 20%" or "approximately 20%" does not mean "20% + / - 10%", i.e., a range of 10-30% (inclusive), but rather "about 20%" or "approximately 20%" represents a range of 18-22%, i.e., a value of 20 + / - 10% (inclusive).

[0039] As used herein, the term "polymer" refers to a molecule comprising repeating structural units (i.e., monomers) linked by chemical bonds in a linear, cyclic, branched, cross-linked, or dendritic manner, or a combination thereof, which may be synthetic, biologically derived, or a combination of both. It should be understood that polymers may also contain one or more other chemical groups and / or portions, such as, for example, one or more functional groups. In some embodiments, the molecular weight of the soluble polymer is at least 0.5 kDa, for example, at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, in some embodiments, its molecular weight is up to 1000 kDa, such as up to 750 kDa, up to 500 kDa, up to 300 kDa, up to 200 kDa, or up to 100 kDa. It should be understood that for water-insoluble polymers (such as hydrogels), a meaningful molecular weight range cannot be provided. It should be understood that peptides or proteins are also polymers in which amino acids are repeating structural units, although the side chains of each amino acid may be different.

[0040] As used herein, the term "polymer" refers to a reagent or portion comprising one or more polymers or polymer portions. Polymer reagents or portions may also optionally comprise one or more other portions, which in some embodiments are selected from the group consisting of: • C1-50 Alkyl, C 2-50 alkenyl, C 2-50 alkynyl group, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups, 8- to 11-membered heterobicyclic groups, phenyl, naphthyl, indenyl, indenyl, and tetrahydronaphthyl; and • Selected links from the following group, The dashed lines indicate connections to other parts or reagents, and -R and -R a The following are selected independently of each other: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

[0041] Those skilled in the art will understand that the polymer products obtained from the polymerization reaction do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, the molecular weight range, molecular weight, monomer quantity range, and monomer quantity in the polymer used herein refer to index-average molecular weight and number-average monomer, that is, the arithmetic mean of the molecular weight of the polymer or polymer fraction and the arithmetic mean of the monomer quantity of the polymer or polymer fraction.

[0042] Therefore, in a polymer portion containing "x" monomer units, any integer given for "x" corresponds to the arithmetic mean of the monomers. For any integer range given for "x", the integer range in which the monomer arithmetic mean lies is provided. The integer "x" given as "approximately x" means that the monomer arithmetic mean is within the integer range of x + / - 10%, which in some embodiments is x + / - 8%, in some embodiments is x + / - 5%, and in some embodiments is x + / - 2%.

[0043] The term “number-average molecular weight” as used in this article refers to the ordinary arithmetic mean of the molecular weight of individual polymers.

[0044] As used herein, the term "water-soluble" in relation to PTH compounds means that at least 1 gram of a PTH compound can dissolve in 1 liter of water at 20°C to form a homogeneous solution. Therefore, the term "insoluble in water" in relation to PTH compounds means that less than 1 g of a PTH compound can dissolve in 1 liter of water at 20°C to form a homogeneous solution.

[0045] As used herein, the term “PEG-based” means that the portion or reagent contains PEG. In some embodiments, the PEG-based portion or reagent contains at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w) PEG, such as at least 60% (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as at least 90% (w / w) PEG, such as at least 95%. The remaining weight percentage of the PEG-based portion or reagent is other portions, which in some embodiments are selected from the following portions and links: • C 1-50 Alkyl, C 2-50 alkenyl, C 2-50 alkynyl group, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups, 8- to 11-membered heterobicyclic groups, phenyl, naphthyl, indenyl, indenyl, and tetrahydronaphthyl; and • Links selected from the following group: in Dashed lines indicate connections to other parts or reagents, and -R and -R a The following are selected independently of each other: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

[0046] As used in this article, the term "substitution" refers to the replacement of one or more -H atoms in a molecule or part by different atoms or groups of atoms, which are called "substituents".

[0047] In some embodiments, one or more further optional substituents are independently selected from the group consisting of: halogens, -CN, -COOR. x1 -OR x1 -C(O)R x1 -C(O)N(R) x1 R x1a -S(O)2N(R) x1 R x1a ), -S(O)N(R x1 R x1a -S(O)2R x1 -S(O)R x1 -N(R) x1 )S(O)2N(Rx1a R x1b ), -SR x1 -N(R) x1 R x1a -NO2, -OC(O)R x1 -N(R) x1 )C(O)R x1a -N(R) x1 )S(O)2R x1a -N(R) x1 )S(O)R x1a -N(R) x1 )C(O)OR x1a -N(R) x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different -R groups. x2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 (R) x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; -R x1 -R x1a -R x1b Select independently from the following groups: -H, -T 0 C 1-50 Alkyl, C 2-50alkenyl and C 2-50 Alkyne group; wherein, -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different -R groups. x2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 -; -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-,-S-,-N(R x3 )-,-OC(OR x3 (R) x3a )-,-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; Each T 0 Independently selected from the group consisting of: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups and 8- to 11-membered heterobicyclic groups; wherein each T 0 Independently and optionally by one or more identical or different -R x2 replace; Each -R x2 Independently select from the following groups: halogen, -CN, oxo (=O), -COOR x4 -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each -R x3 -R x3a -R x4 -R x4a -R x4b Select independently from the following groups: -H and C 1-6 Alkyl; wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0048] In some embodiments, one or more further optional substituents are independently selected from the group consisting of: halogen, -CN, -COOR. x1 -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a, -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne group; wherein, -T 0 C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally surrounded by one or more identical or different -R groups. x2 Replace, and where C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-,-S-,-N(R x3 )-,-OC(OR x3 (R) x3a )-,-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; Each -R x1 -R x1a -R x1b -R x3 -R x3a Independently selected from the following groups: -H, halogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; Each T 0 Independently selected from the group consisting of: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups and 8- to 11-membered heterobicyclic groups; wherein each T 0 Independently and optionally by one or more identical or different -R x2 replace; Each -R x2Independently selected from the following groups: halogen, -CN, oxo (=O), -COOR x4 -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each -R x4 -R x4a -R x4b Independently selected from the following groups: -H, halogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; In some embodiments, one or more further optional substituents are independently selected from the group consisting of: halogen, -CN, -COOR. x1 -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 Rx1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group; wherein -T 0 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more identical or different -R groups. x2 Replace, and where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-,-S-,-N(R x3 )-,-OC(OR x3 (R) x3a )-,-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; Each -R x1 -Rx1a -R x1b -R x2 -R x3 -R x3a Independently selected from the following groups: -H, halogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; Each T 0 Independently selected from the group consisting of: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups and 8- to 11-membered heterobicyclic groups; wherein each T 0 Independently and optionally by one or more identical or different -R x2 replace.

[0049] In some embodiments, up to six -H atoms of the optionally substituted molecule are substituted independently by substituents, for example: five -H atoms are substituted independently by substituents, four -H atoms are substituted independently by substituents, three -H atoms are substituted independently by substituents, two -H atoms are substituted independently by substituents, or one -H atom is substituted by a substituent.

[0050] The term “interruption” refers to the insertion of a portion between two carbon atoms, or—if the insertion is at one of the ends of the portion—between a carbon atom or heteroatom and a hydrogen atom, and in some embodiments, between a carbon atom and a hydrogen atom.

[0051] The term "C" as used alone or in combination in this article 1-4 "Alkyl" refers to a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. If present at the end of the molecule, the straight-chain or branched carbon atoms... 1-4 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. When the two parts of the molecule are connected by C... 1-4 When alkyl groups are connected, such C 1-4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-4 Each hydrogen atom on the alkyl carbon can optionally be substituted with a substituent as defined above. Optionally, C 1-4 Alkyl groups can be interrupted by one or more of the following components.

[0052] As used alone or in combination in this article, the term "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. If present at the end of the molecule, both straight-chain and branched C atoms are considered alkyl. 1-6Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. When the two parts of the molecule are connected by C... 1-6 When alkyl groups are connected, such C 1-6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-6 Each hydrogen atom on carbon can optionally be substituted with a substituent as defined above. Optionally, C 1-6 Alkyl groups can be interrupted by one or more of the following components.

[0053] Therefore, "C" 1-10 Alkyl", C 1-20 "alkyl" or "C" 1-50 "Alkyl" refers to an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, where C 1-10 C 1-20 Or C 1-50 Each hydrogen atom of carbon may optionally be substituted with a substituent as defined above. Optionally, C 1-10 Or C 1-50 Alkyl groups can be interrupted by one or more of the following components.

[0054] As used alone or in combination in this article, the term "C" 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond and having 2 to 6 carbon atoms. If present at the end of the molecule, it is, for example, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. When the two parts of the molecule are connected by a carbon-carbon double bond, the alkenyl group is considered to be a carbon atom. 2-6 When alkenyl groups are linked, such C 2-6 An example of an alkenyl group is -CH=CH-. C 2-6 Each hydrogen atom of the alkenyl moiety may optionally be substituted with a substituent as defined above. Optionally, C 2-6 The alkenyl group can be interrupted by one or more parts as defined below.

[0055] Therefore, the term "C" used alone or in combination 2-10 "alkenyl", "C" 2-20 "Alkenyl" or "C" 2-50 "Alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms. 2-10 alkenyl, C 2-20alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may optionally be substituted with a substituent as defined above. Optionally, C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 The alkenyl group can be interrupted by one or more parts as defined below.

[0056] As used alone or in combination in this article, the term "C" 2-6 An "alkynyl group" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond and having 2 to 6 carbon atoms. If present at the end of the molecule, it is, for example, -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. An example is -C≡C- when two moles of the molecule are linked by an alkynyl group. 2-6 Each hydrogen atom of the alkynyl group may optionally be substituted with a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 The alkynyl group can be interrupted by one or more parts as defined below.

[0057] Therefore, as the term "C" is used alone or in combination in this article... 2-10 "Alkyne", "C" 2-20 "Alkyne" and "C" 2-50 "Alkyne" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 alkynyl group, C 2-20 alkynyl group and C 2-50 Each hydrogen atom of the alkynyl group may optionally be substituted with a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 alkynyl group, C 2-20 alkynyl group and C 2-50 The alkynyl group can be interrupted by one or more parts as defined below.

[0058] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 alkenyl, C 2-10 alkenyl, C 2-20 alkenyl, C 2-50 alkenyl, C 2-6 alkynyl group, C 2-10 alkynyl group, C 2-20 alkenyl or C 2-50 The alkynyl group may optionally be interrupted by one or more portions, which in some embodiments are selected from the group consisting of: in Dashed lines indicate connections to other parts or reagents; and -R and -R a The following are selected independently of each other: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

[0059] The term "C" used in this article 3-10 "Cycloalkyl" refers to a cyclic alkyl chain, saturated or unsaturated, having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom on a cycloalkyl carbon can be substituted by a substituent as defined above. The term "C" 3-10 "Cycloalkyl" also includes bridged bicyclic compounds, such as norbornane or norbornene.

[0060] The term "8- to 30-membered carbon polycyclic group" or "8- to 30-membered carbon polycyclic" refers to a cyclic portion of two or more rings having 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom, and may contain a maximum number of double bonds (aromatic or non-aromatic rings, fully saturated, partially saturated, or unsaturated). In some embodiments, an 8- to 30-membered carbon polycyclic compound refers to a cyclic portion of two, three, four, or five rings; in other embodiments, it refers to a cyclic portion of two, three, or four rings.

[0061] As used herein, the terms “3- to 10-membered heterocyclic group” or “3- to 10-membered heterocycle” refer to a ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, which may contain up to a maximum number of double bonds (aromatic or non-aromatic rings, which may be fully saturated, partially saturated, or unsaturated), wherein at least one to four ring atoms are substituted with heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule by a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to: aziridine, ethylene oxide, thiohexacyclopropane, aziridine, ethylene oxide, thiohexacyclopropane, aziridine, oxacyclobutane, oxacyclobutane, thiohexacyclobutane, furan, thiophene, pyrrole, pyrroleline, imidazole, imidazoleline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazazole, isothiazoline, thiazoline, thiadiazole, thiadizoline, tetrahydrofuran, tetrahydrothiophene, pyrrole, imidazole, pyrazoline, oxazoline, isoxazoline, thiazoline, isothiazoline, thiazoline, isothiazoline, thiadizoline, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazole, pyridine, pyrazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazolium, triazole, triazolidine, tetrazolidine, diazacycloheptane, azazoline, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclic group can be substituted by a substituent as defined below.

[0062] As used herein, the term "8-11 membered heterocyclic group" or "8-11 membered heterocyclic" refers to the heterocyclic portion of two rings having 8 to 11 ring atoms, wherein the two rings share at least one ring atom and may contain at most a maximum number of double bonds (aromatic or non-aromatic rings, which may be fully saturated, partially saturated or unsaturated), wherein at least one ring atom and at most six ring atoms are substituted by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule by a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicyclic compounds include: indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoimidazolium, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzozazazoline, purine, and pteridine. The term 8- to 11-membered heterocyclic also includes spirocyclic structures with two rings, such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridged heterocyclic compounds, such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom on the carbon of an 8- to 11-membered heterobicyclic group or 8- to 11-membered heterobicyclic compound can be substituted with substituents as defined below.

[0063] Similarly, the terms "8 to 30-membered heterocyclic group" or "8 to 30-membered heterocyclic ring" refer to a heterocyclic portion of two or more rings having 8 to 30 ring atoms, in some embodiments three, four or five rings, wherein two adjacent rings share at least one ring atom, and may contain at most a maximum number of double bonds (aromatic or non-aromatic rings, which are fully saturated, partially saturated or unsaturated), wherein at least one to at most 10 ring atoms are substituted with heteroatoms selected from the group consisting of sulfur (including -S(O)- and -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule by a carbon or nitrogen atom.

[0064] It should be understood that the expression "R" is related to a portion of the following structure. x / R y They bond together with the atoms to which they are attached to form C. 3-10 cycloalkyl or 3 to 10-membered heterocyclic groups It refers to R x and R y The following structure is formed: , Where R is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic rings.

[0065] It should also be understood that the expression "R" is related to a portion of the following structure. x / R y It connects with the atoms to which it is attached to form a ring A” It refers to R x and R y The following structure is formed: .

[0066] As used herein, "halogen" refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine or chlorine.

[0067] Generally speaking, the term "comprise" or "comprising" also encompasses "consist of" or "consisting of".

[0068] In some implementations, PTH compounds are used to treat subjects with CKD.

[0069] In some implementations, PTH compounds are used to prevent CKD in subjects at risk of developing CKD.

[0070] In some implementations, the subject at risk of or with CKD is a mammalian subject, such as a human subject, or an adult or child subject. In some implementations, the subject is a male human subject. In some implementations, the subject is a female human subject. In some implementations, the subject with CKD also has hypoparathyroidism, such as chronic hypoparathyroidism. Chronic hypoparathyroidism can be caused by surgery, genetic factors, immune system-related parathyroid damage, or idiopathic hypoparathyroidism. In some implementations, the subject has chronic hypoparathyroidism due to surgery. In some implementations, the subject has chronic hypoparathyroidism due to thyroid surgery. In some implementations, the subject has chronic hypoparathyroidism due to parathyroid surgery. In some implementations, the subject has chronic hypoparathyroidism due to genetic factors. In some implementations, the subject has chronic hypoparathyroidism due to type I autosomal dominant hypocalcemia. In some implementations, the subject has chronic hypoparathyroidism due to immune-related damage to the parathyroid glands. In some implementations, the subject has idiopathic chronic hypoparathyroidism.

[0071] In some implementations, subjects receive standard therapy, namely active vitamin D and calcium supplementation, before starting treatment with the PTH compound. Such standard therapy is typically administered orally.

[0072] In some implementations, renal function in subjects at risk of or with CKD is assessed by at least one blood and / or urine test before administration of an effective dose of the PTH compound.

[0073] In some implementations, renal function in subjects at risk of or with CKD is assessed at least twice: once at baseline before the first administration of the PTH compound, and once after one or more doses of the PTH compound. Appropriately, the second assessment is performed after multiple administrations (multiple doses), such as after at least two weeks, at least four weeks, or at least two months of treatment. The second assessment may be performed after two weeks, four weeks, six weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or one year of treatment.

[0074] Appropriate blood and urine tests are known in the art. An exemplary blood test for assessing CKD is a serum creatinine blood test, which measures the amount of creatinine in the blood. For example, an appropriate urine test for assessing chronic kidney disease is the urine albumin to creatinine ratio (UACR). Blood and / or urine tests can also be used to determine the estimated glomerular filtration rate (eGFR). Appropriate methods for determining eGFR are known in the art, such as the Dietary Modification for Kidney Disease (MDRD) formula, a four-variable MDRD form based on serum creatinine, age, race, and sex, or the original MDRD form, which also includes blood urea nitrogen and albumin levels. Depending on the degree of kidney damage, subjects can be classified into stage 1 (normal), stage 2 (mild), stage 3 (moderate), stage 4 (severe), or stage 5 (end-stage kidney disease) based on the following eGFR-based classification:

[0075] Blood and / or urine tests may include: (i) determining specific parameters in the subject's blood and / or urine samples, such as determining creatinine in the blood or determining the albumin-to-creatinine ratio in the urine; and (ii) comparing that parameter to a reference value. If the reference value indicates that the person is at risk of developing CKD or has CKD, treatment with a PTH compound may be initiated.

[0076] In some implementations, eGFR is an indication of CKD.

[0077] In some implementations, the subject has a phase 3 or worse eGFR indication, i.e., less than 60 ml / min / 1.73 m 2 eGFR.

[0078] In some implementations, subjects at risk of CKD who start treatment with the PTH compound have a stage 1 or 2 eGFR indication, i.e., a normal eGFR or a slightly decreased eGFR, and do not progress to stage 3 for at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, at least 15 years, or at least until the end of treatment with the PTH compound.

[0079] In some implementations, subjects with CKD who start treatment with the PTH compound have a phase 3 eGFR indication, i.e., a moderate decline in eGFR, and do not progress to phase 4 for at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, at least 15 years, or at least until the end of treatment with the PTH compound.

[0080] In some implementations, subjects with CKD who start treatment with the PTH compound have a stage 4 eGFR indication, i.e., a severe decline in eGFR, and who have not progressed to stage 5 for at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, at least 15 years, or at least until the end of treatment with the PTH compound.

[0081] In some implementations, treatment with PTH compounds prevents patients with CKD from progressing to the next higher CKD stage, i.e., from stage 3 to stage 4 or from stage 4 to stage 5, for at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, at least 15 years, or at least until the end of treatment with PTH compounds.

[0082] In some implementations, the subjects have hypoparathyroidism, such as chronic hypoparathyroidism.

[0083] In some implementations, treatment with PTH compounds slows the progression of CKD by, for example, 2, 3, 4, 6, 7, 8, 9, or 10 times compared to standard of care (i.e., oral calcium and active vitamin D) or PTH 1-84, particularly in subjects with hypoparathyroidism (such as chronic hypoparathyroidism). In some implementations, treatment with PTH compounds prevents progression to end-stage renal disease, particularly in subjects with hypoparathyroidism (such as chronic hypoparathyroidism).

[0084] Treatment with PTH compounds improves eGFR in subjects. In some embodiments, treatment with PTH compounds results in an average improvement in eGFR of at least 5 ml / min / 1.73 m 2 At least 6 ml / min / 1.73 m 2 At least 7 ml / min / 1.73m 2 At least 8 ml / min / 1.73 m 2 At least 9 ml / min / 1.73 m 2 At least 10 ml / min / 1.73 m 2 Or at least 11 ml / min / 1.73 m 2In some embodiments, such mean improvement in eGFR is achieved within 26 weeks of treatment with the PTH compound. In some embodiments, mean improvement may be achieved within 52 weeks of treatment. In some embodiments, mean improvement may be measured after at least 110 weeks of treatment with the PTH compound. In some embodiments, the increase in mean eGFR is sustained, meaning it lasts for a long period of time, such as six months, one year, two years, three years, five years, ten years, as long as the treatment with the PTH compound lasts, or until the end of the subject's life.

[0085] In some implementations, baseline eGFR < 60 mL / min / 1.73 m 2 The mean increase in eGFR in the subjects was numerically higher than baseline eGFR ≥60 mL / min / 1.73 m 2 Therefore, in some implementations, subjects with CKD are defined as those with eGFR < 60 mL / min / 1.73 m 2 Subjects treated with PTH compounds who had eGFR indications in phases 3, 4, or 5.

[0086] Surprisingly, it was found that, in particular, eGFR below 60 ml / min / 1.73 m 2 Subjects benefited from treatment with PTH compounds because they showed a particularly high increase in eGFR.

[0087] In some embodiments, treatment with PTH compounds reduces or eliminates the occurrence of kidney stones. In some embodiments, treatment with PTH compounds reduces or eliminates the occurrence of renal calcification.

[0088] In some implementations, patients treated with PTH compounds do not require administration of active vitamin D. In some implementations, patients treated with PTH compounds are treated independently of routine therapy (supplementation with active vitamin D and ≤600 mg / day of calcium). In some implementations, patients treated with PTH compounds maintain normal serum calcium levels. In some implementations, patients treated with PTH compounds may regain normal serum calcium levels.

[0089] In some implementations, the PTH compound is administered multiple times. Treatment for CKD can begin after diagnosis, or, in the case of a patient with hypoparathyroidism, after a diagnosis of hypoparathyroidism. The PTH compound can be administered, for example, daily or weekly. Treatment can continue for six months, one year, two years, three years, five years, ten years, or until medically indicated or until the end of the subject's life.

[0090] The PTH compound can be administered to subjects daily. The PTH compound can also be administered to subjects weekly.

[0091] In some embodiments, a single dose of the PTH compound prolongs receptor signaling time by at least 10-fold, at least 15-fold, or at least 20-fold compared to a single equimolar dose of PTH 1-84. Such a PTH compound may or may not have a prolonged circulating half-life in the blood. A prolonged circulating half-life is a circulating half-life in the blood that is at least 10-fold longer than the circulating half-life of PTH 1-84 in each case measured after a single administration, wherein the doses of the PTH compound and PTH 1-84 are equimolar (with respect to PTH).

[0092] In some embodiments, the PTH compound is a peptide. In some embodiments, the PTH compound is the peptide of SEQ ID NO: 122, also known as AZP-3601 or eneboparatide: AVAEIQLMHQRAKWIQDARRRAFLHKLIAEIHTAEI In some embodiments, the PTH compound is a water-insoluble compound, and in some embodiments, the compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, and microspheres. One or more PTH drugs may be non-covalently intercalated into or covalently conjugated to such crystals, nanoparticles, microparticles, nanospheres, and microspheres. Covalent conjugation may be a stable conjugation, i.e., conjugation through stable bonds, or it may be a reversible conjugation, i.e., conjugation to such crystals, nanoparticles, microparticles, nanospheres, and microspheres through reversible bonds.

[0093] In some embodiments, the PTH compound is a crystal containing at least one PTH molecule. In some embodiments, the PTH compound is a nanoparticle containing at least one PTH molecule. In some embodiments, the PTH compound is a microparticle containing at least one PTH molecule. In some embodiments, the PTH compound is a nanosphere containing at least one PTH molecule. In some embodiments, the PTH compound is a microsphere containing at least one PTH molecule. In some embodiments, the compound is a vesicle containing at least one PTH molecule, such as a micelle, liposome, or polymer vesicle.

[0094] In some embodiments, the PTH compound is a water-insoluble PTH compound comprising at least one non-covalently intercalated PTH molecule in a water-insoluble polymer. In some embodiments, such a water-insoluble polymer comprises polymers selected from the group consisting of: 2-methacryloyloxyethyl phosphocholine, polyacrylic acid, polyacrylate, polyacrylamide, polyalkoxy polymers, polyamides, polyamide amines, polyamino acids, polyanhydrides, polyasparagine, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactone, polycarbonate, polycyanoacrylate, polydimethacrylamide, polyester, polyethylene, polyethylene glycol, polyethylene oxide, polyethyl phosphate, polyethyl oxazoline, polyglycolic acid, hydroxyethyl polyacrylate, polyhydroxyethyl oxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, and polyhydroxypropyl methacrylate. Polyhydroxypropyl oxazoline, polyimide carbonate, polylactic acid, polylactic acid-glycolic acid copolymer, polymethacrylamide, polymethacrylate, polymethyloxazoline, polyorganophosphoric acid nitrile, polyorthoester, polyoxazoline, polypropylene glycol, polysiloxane, polyurethane, polyvinyl alcohol, polyvinylamine, polyvinyl methyl ether, polyvinylpyrrolidone, silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnose-galacturonic acid polysaccharide, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and its copolymers. In some embodiments, the water-insoluble polymer is poly(lactic acid-glycolic acid copolymer) (PLGA).

[0095] In some embodiments, the PTH compound is a conjugate or a pharmaceutically acceptable salt thereof, comprising a carrier moiety Z', one or more moieties -L 2 -L 1 -D is conjugated to this carrier portion, where each -L 2 - Independently absent or a spacer subpart; each -L 1 - is an independent linker portion, -D is reversibly covalently attached to this linker portion; each -D is an independent PTH portion; and Z' is a hydrogel. Such a long-acting PTH compound is a sustained-release PTH compound. -D, -L 1 -、-L 2 The specific implementation plan for - and Z' is described elsewhere in this article.

[0096] In some implementations, the PTH compound is water-soluble.

[0097] In some embodiments, the PTH compound has formula (Ia) or (Ib). (Ia) (Ib), in Each -D is a separate PTH part; Each -L 1 -A separate connector portion that is reversibly covalently connected to -D; Each -L 2 - It either does not exist alone or is a spacer sub-part; Each -Z is a separate carrier portion, such as a fatty acid derivative or polymer; x is an integer selected from the following group: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25; and y is an integer selected from the following groups: 2, 3, 4, and 5.

[0098] In some embodiments, the PTH compound has formula (Ia). In some embodiments, the PTH compound has formula (Ia), where x is selected from the group consisting of 1, 2, 3, and 4. In some embodiments, the PTH compound has formula (Ia), where x is 1.

[0099] In some embodiments, the PTH compound has formula (Ib). In some embodiments, the PTH compound has formula (Ib), where y is selected from the group consisting of 2, 3, and 4.

[0100] -D、-L 1 -、-L 2 The implementation schemes for - and Z' are described elsewhere in this document.

[0101] In some embodiments, -D is the PTH portion, which comprises sequences having at least 90% homology with sequences selected from the group consisting of, such as sequences having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:2 ... NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68,SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122.,

[0102] In certain embodiments, -D is a PTH moiety comprising a sequence having at least 95% homology to a sequence selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122.,

[0103] In certain embodiments, -D is a PTH moiety comprising a sequence selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76,SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122.,

[0104] In some embodiments, -D is the PTH portion, which comprises sequences having at least 90% homology with sequences selected from the group consisting of, such as sequences having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology: SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:5 ...50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120 and SEQ ID NO:122.

[0105] In some embodiments, -D is the PTH portion, which comprises a sequence having 95% homology with a sequence selected from the group consisting of: SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:10 ...9, SEQ ID NO:99, SEQ ID NO:99, SEQ ID NO:99, SEQ ID NO:99, SEQ ID NO:99, SEQ ID NO:99, SEQ ID NO:99, SEQ ID NO:99, NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120 and SEQ ID NO:122.

[0106] In certain embodiments, -D is selected from the group consisting of: SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120 and SEQ ID NO:122.

[0107] In some embodiments, -D is a PTH portion comprising sequences having at least 90% homology with sequences selected from the group consisting of sequences having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology: SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:122.

[0108] In some implementations, -D is the PTH portion, which contains sequences having 95% homology to sequences selected from the group consisting of: SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:122.

[0109] In some implementations, -D is the PTH portion, which comprises sequences selected from the group consisting of: SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:122.

[0110] In some embodiments, -D is a PTH portion comprising sequences having at least 90% homology with sequences selected from the group consisting of sequences having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology: SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:122.

[0111] In some implementations, -D is the PTH portion, which contains sequences having 95% homology with sequences selected from the group consisting of: SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112 and SEQ ID NO:122.

[0112] In some implementations, -D is selected from the group consisting of: SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112 and SEQ ID NO:122.

[0113] In some embodiments, -D is SEQ ID NO:50. In some embodiments, -D is SEQ ID NO:52. In some embodiments, -D is SEQ ID NO:110. In some embodiments, -D is SEQ ID NO:111. In some embodiments, -D is SEQ ID NO:112. In some embodiments, -D is SEQ ID NO:111. In some embodiments, -D is SEQ ID NO:122.

[0114] In some implementations, -D is SEQ ID NO:51.

[0115] In some implementations, -D is SEQ ID NO:122: AVAEIQLMHQRAKWIQDARR RAFLHKLIAEIHTAEI Partial -L 1 - Functional groups that can be conjugated to the side chains of amino acid residues of -D, N-terminal amine functional groups conjugated to -D, C-terminal carboxyl functional groups conjugated to -D, or nitrogen atoms in the main chain of a polypeptide chain conjugated to -D. The connection to the N-terminus or C-terminus can be direct or indirect via the corresponding amine or carboxyl functional groups, respectively, wherein the spacer portion is first conjugated to the -L group of the spacer portion. 1 - Conjugated amine or carboxyl functional groups.

[0116] In some implementations, -L 1 -Conjugated to -D via a functional group selected from the group consisting of: carboxylic acids, primary amines, secondary amines, maleimides, thiols, sulfonic acids, carbonates, carbamates, hydroxyl groups, aldehydes, ketones, hydrazines, isocyanates, isothiocyanates, phosphoric acids, phosphonic acids, haloacetyl groups, alkyl halides, acryloyl groups, aryl fluorides, hydroxylamines, sulfates, disulfides, vinyl sulfones, vinyl ketones, diazonides, ethylene oxides, guanidines, and cyclohexylimides. In some embodiments, -L 1 -Conjugated to -D via functional groups selected from the group consisting of hydroxyl, primary amine, secondary amine, and guanidine. In some embodiments, -L 1 -Conjugated to -D via primary or secondary amine functional groups. In some embodiments, -L 1 - Conjugated to -D via primary amine functional groups. It should be understood that not every functional group is present in protein amino acids, and may be introduced only through one or more post-translational modifications, or may be derived from non-protein amino acids.

[0117] In some implementations, -L 1- A functional group conjugated to the side chain of a protein amino acid residue of the -D group. In some embodiments, the protein amino acid is selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, and arginine. In some embodiments, the protein amino acid is selected from the group consisting of lysine, aspartic acid, arginine, and serine. In some embodiments, the protein amino acid is selected from the group consisting of lysine, arginine, and serine. In some embodiments, -L 1 -A functional group conjugated to the histidine side chain of -D. In some embodiments, -L 1 -A functional group conjugated to the -D lysine side chain. In some embodiments, -L 1 -A functional group conjugated to the -D tryptophan side chain. In some embodiments, -L 1 -A functional group conjugated to the -D serine side chain. In some embodiments, -L 1 -A functional group conjugated to the -D threonine side chain. In some embodiments, -L 1 -A functional group conjugated to the -D tyrosine side chain. In some embodiments, -L 1 -A functional group conjugated to the -D aspartic acid side chain. In some embodiments, -L 1 -A functional group conjugated to the -D glutamic acid side chain. In some embodiments, -L 1 - Functional groups conjugated to the arginine side chain of -D. It should be understood that not every -D moiety may contain all of these amino acid residues.

[0118] In some implementations, -L 1 - Directly or indirectly conjugated to the N-terminal amine functional group of -D, wherein the spacer portion is first conjugated to the spacer portion -L 1 -Conjugated amine functional groups. In some embodiments, -L 1 - Directly conjugated to the N-terminal amine functional group of -D. In some embodiments, -L 1 - Directly or indirectly conjugated to the C-terminal functional group of -D via the corresponding carboxyl functional group, wherein the spacer portion first conjugates to the spacer portion -L 1 -A conjugated carboxyl functional group. In some embodiments, -L 1 - Directly conjugated to the N-terminal amine functional group of -D.

[0119] -L 1 - Parts can be concatenated with -D using any type of connection, as long as it is reversible. In some implementations, -L 1- Linked to -D via a group selected from: amides, esters, carbamates, acetals, acetalamines, imines, oximes, hydrazones, disulfides, and acylguanidines. In some embodiments, -L 1 - Linked to -D via a group selected from: amides, esters, carbamates, and acylguanidines. It should be understood that some of these linkages are irreversible in themselves, but in this application, -L... 1 The adjacent groups contained in - make these connections reversible. In some embodiments, -L 1 - Linked to -D via ester linkage. In some embodiments, -L 1 - Linked to -D via a urethane ester. In some embodiments, -L 1 - Linked to -D via acylguanidine. In some embodiments, -L 1 -Linked with -D via amide linkage.

[0120] -L 1 - Part is a reversible prodrug connector from which the drug (i.e., PTH) can be released in its free form; that is, it is a traceless prodrug connector. Suitable prodrug connectors are known in the art, such as the reversible prodrug connector portions disclosed in WO 2005 / 099768 A2, WO2006 / 136586 A2, WO 2011 / 089216 A1 and WO 2013 / 024053 A1 (which are incorporated herein by reference in their entirety).

[0121] In some implementations, -L 1 - The reversible prodrug connector described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1 (which are incorporated herein by reference in their entirety).

[0122] In some implementations, -L 1 -Disclosed in WO 2009 / 095479 A2. Therefore, in some embodiments, -L 1 - Partially possesses equation (II): , The dashed line indicates the connection to the nitrogen, hydroxyl, or thiol of -D; -X- is selected from the following group: -C(R) 4 R 4a )-;-N(R 4 )-;-O-;-C(R 4 R 4a )-C(R 5 R 5a)-;-C(R 5 R 5a )-C(R 4 R 4a )-;-C(R 4 R 4a )-N(R 6 )-;-N(R 6 )-C(R 4 R 4a )-;C(R 4 R 4a )-O-;-OC(R 4 R 4a -; and -C(R) 7 R 7a )-; X 1 Selected from the following groups: C; and S(O); -X 2 -Selected from the following group:-C(R) 8 R 8a -; and -C(R) 8 R 8a )-C(R 9 R 9a )-; =X 3 Selected from the following groups: =O; =S; and =N-CN; -R 1 -R 1a -R 2 -R 2a -R 4 -R 4a -R 5 -R 5a -R 6 -R 8 -R 8a -R 9 、 and -R 9a Independently selected from the following groups: -H; and C 1-6 alkyl; -R 3 and -R 3a Independently selected from the following groups: -H; and C 1-6 Alkyl group, provided that it is -R 3 -R 3a If one of them is not -H or neither is -H, they pass through SP. 3 - Hybridized carbon atoms are attached to N; -R 7 Selected from the following group: -N(R) 10 R 10a ) and -NR 10 -(C=O)-R11 ; -R 7a -R 10 -R 10a and -R 11 They are selected independently from the following groups: -H; and C. 1-6 alkyl; Optional, -R 1a / -R 4a Yes, -R 1a / -R 5a Yes, -R 1a / -R 7a Yes, -R 4a / -R 5a Pair and -R 8a / -R 9a One or more pairs of bonds form chemical bonds; Optionally, add -R 1 / -R 1a Yes, -R 2 / -R 2a Yes, -R 4 / -R 4a Yes, -R 5 / -R 5a Yes, -R 8 / -R 8a Pair and -R 9 / -R 9a One or more pairs of atoms in a pair are bonded together with the atoms they are attached to, forming C. 3-10 cycloalkyl; or 3 to 10-membered heterocyclic groups; Optional, -R 1 / -R 4 Yes, -R 1 / -R 5 Yes, -R 1 / -R 6 Yes, -R 1 / -R 7a Yes, -R 4 / -R 5 Yes, -R 4 / -R 6 Yes, -R 8 / -R 9 Pair and -R 2 / -R 3 One or more pairs of atoms in a pair connect together to form a ring A; Optionally, R 3 / R 3a They connect with the nitrogen atoms to form 3 to 10-membered heterocyclic groups; A is selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetranaphthyl, C3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups; and 8- to 11-membered heterobicyclic groups; Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atom marked with an asterisk in (II) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0123] In some implementations, -L in formula (II) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0124] In some implementations, -L in formula (II) 1 - Not to be further replaced.

[0125] It should be understood that if -R in equation (II) is taken as... 3 / -R 3a When these atoms are bonded together with the nitrogen atoms they are attached to, forming 3- to 10-membered heterocycles, only the sp atoms directly bonded to the nitrogen atoms can form. 3 - Hybridized carbon atoms form such 3 to 10-membered heterocycles. In other words, -R 3 / -R 3a The 3- to 10-membered heterocycles formed together with the nitrogen atom they are attached to have the following structures: , in The dashed line indicates the relationship with -L 1 - The connection of the rest of the parts; The ring contains 3 to 10 atoms, including one nitrogen atom; and R # and R ## Represents sp 3 - Hydrogenated carbon atoms.

[0126] It should also be understood that 3- to 10-membered heterocycles can be further replaced.

[0127] From equation (II) -R 3 / -R 3a Exemplary embodiments of suitable 3- to 10-membered heterocycles formed together with the nitrogen atoms to which they are attached are as follows: in Dashed lines indicate connections to the rest of the molecule; and -R is selected from the following group: -H and C 1-6 alkyl.

[0128] -L in formula (II) 1 - It can be optionally further substituted. Generally, any substituent can be used as long as it does not affect the cleavage principle, that is, the hydrogen atoms marked with an asterisk in formula (II) are not substituted, and the part of formula (II) The nitrogen atom is still part of a primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a Independent of each other, or through sp 3 -Hybridized carbon atoms are connected to -N<.

[0129] In one implementation, -R of formula (II) 1 or -R 1a -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 2 or -R 2a -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 3 or -R 3a -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 4 -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 5 or -R 5a -L 2 -Z or -L 2 -Z' is replaced. In another embodiment, -R in formula (II) 6 -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 7 or -R 7a -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 8 or -R 8a -L 2 -Z or -L 2 -Z' is replaced. In another implementation, -R in formula (II) is replaced. 9 or -R 9a -L2 -Z or -L 2 -Z' is used instead. In another implementation, -R 10 -L 2 -Z or -L 2 -Z' is used instead. In another implementation, -R 11 -L 2 -Z or -L 2 -Z' is replaced. In some implementations, -R in formula (II) is replaced. 3 -L 2 -Z or -L 2 -Z' replaces it.

[0130] In some implementations, -X- in formula (II) is selected from the group consisting of: -C(R 4 R 4a )-,-N(R 4 )- and -C(R 7 R 7a In some implementations, -X- in equation (II) is -C(R) 4 R 4a In some implementations, -X- in equation (II) is -C(R) 7 R 7a )-.

[0131] In some implementations, -R of formula (II) 7 For -NR 10 -(C=O)-R 11 .

[0132] In some implementations, -R of formula (II) 7a Selected from -H, methyl, and ethyl. In some embodiments, -R of formula (II) 7a It is -H.

[0133] In some implementations, -R 10 Selected from -H, methyl, and ethyl. In some embodiments, -R 10 It is a methyl group.

[0134] In some implementations, -R 11 Selected from -H, methyl, and ethyl. In some embodiments, -R 11 -H. In some implementations, -R 11 -L 2 -Z or -L 2 -Z' replaces it.

[0135] In some implementations, -X- in equation (II) is -N(R) 4 )-.

[0136] In some implementations, -R 4 Selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R 4 It is -H.

[0137] In some implementations, X of formula (II) 1 The answer is C.

[0138] In some implementations, equation (II) = X 3 =O.

[0139] In some implementations, -X of formula (II) 2 -for-C(R) 8 R 8a )-.

[0140] In some implementations, -R of formula (II) 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (II) 8 and -R 8a At least one of them is -H. In some embodiments, -R in formula (II) 8 and -R 8a All are -H.

[0141] In some implementations, -R of formula (II) 1 and -R 1a It is independently selected from the group consisting of -H, methyl, and ethyl.

[0142] In some implementations, -R of formula (II) 1 and -R 1a At least one of them is -H. In some embodiments, -R in formula (II) 1 and -R 1a It is -H.

[0143] In some implementations, -R of formula (II) 1 and -R 1a At least one of them is a methyl group. In some embodiments, -R of formula (II) 1 and -R 1a All are methyl groups.

[0144] In some implementations, -R of formula (II) 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (II) 2 and -R 2a At least one of them is -H. In some embodiments, -R in formula (II)2 and -R 2a All are H.

[0145] In some implementations, -R of formula (II) 3 and -R 3a It is independently selected from the group consisting of: -H, methyl, ethyl, propyl, and butyl.

[0146] In some implementations, -R of formula (II) 3 and -R 3a At least one of them is a methyl group. In some embodiments, -R of formula (II) 3 For methyl, -R of formula (II) 3a It is -H.

[0147] In some implementations, -R of formula (II) 3 and -R 3a All are -H.

[0148] In some embodiments, -D is formed via a nitrogen atom with -L of formula (II) by forming an amide bond. 1 -connect.

[0149] In some implementations, -L 1 - Partially possesses the formula (Ila-i): (IIa-i), in The dashed line represents the connection between the nitrogen atom and -D via an amide bond; -R 1 -R 1a -R 2 -R 2a -R 3 -R 3a -R 4 and -X 2 - As defined in equation (II); and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and Where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atom marked with an asterisk in formula (IIa-i) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0150] It should be understood that in equation (Ila-i) -R 3 -R 3aIf one of them is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0151] In some implementations, the -L of formula (Ila-i) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0152] In some implementations, the -L part of formula (Ila-i) 1 - Not to be further replaced.

[0153] In some implementations, the -R of formula (Ila-i) 1 and -R 1a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-i) 1 and -R 1a At least one of them is a methyl group. In some embodiments, the -R of formula (Ila-i) 1 and -R 1a All are methyl groups.

[0154] In some implementations, the -R of formula (Ila-i) 4 Selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-i) 4 It is -H.

[0155] In some implementations, the -X of formula (Ila-i) 2 -for-C(R) 8 R 8a )-.

[0156] In some implementations, the -R of formula (Ila-i) 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-i) 8 and -R 8a At least one of them is -H. In some embodiments, -R of formula (Ila-i) 8 and -R 8a All are -H.

[0157] In some implementations, the -R of formula (Ila-i) 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-i) 2 and -R 2aAt least one of them is -H. In some embodiments, -R of formula (Ila-i) 2 and -R 2a All are H.

[0158] In some implementations, the -R of formula (Ila-i) 3 and -R 3a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -R of formula (Ila-i) 3 and -R 3a At least one of them is -H. In some embodiments, -R of formula (Ila-i) 3 and -R 3a All are -H.

[0159] In some implementations, -L 1 - Partially possesses the formula (Ila-ii): (IIa-ii), The dashed lines represent the connection between the nitrogen atom and -D via amide bonds; -R 2 -R 2a -R 3 -R 3a and -X 2 - As defined in equation (II); and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and Where -L 1 -Optionally, it can be further substituted, provided that the hydrogen atom marked with an asterisk in formula (Ila-ii) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0160] It should be understood that in equation (Ila-ii) -R 3 -R 3a In the case where one is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0161] In some implementations, -L in formula (Ila-ii) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0162] In some implementations, -L in formula (Ila-ii) 1- Some parts will not be further replaced.

[0163] In some implementations, the -X of formula (Ila-ii) 2 -for-C(R) 8 R 8a )-.

[0164] In some implementations, the -R of formula (Ila-ii) 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-ii) 8 and -R 8a At least one of them is -H. In some embodiments, -R of formula (Ila-ii) 8 and -R 8a All are -H.

[0165] In some implementations, the -R of formula (Ila-ii) 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-ii) 2 and -R 2a At least one of them is -H. In some embodiments, -R of formula (Ila-ii) 2 and -R 2a All are H.

[0166] In some implementations, the -R of formula (Ila-ii) 3 and -R 3a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -R of formula (Ila-ii) 3 and -R 3a At least one of them is -H. In some embodiments, -R of formula (Ila-ii) 3 and -R 3a All are -H.

[0167] In some implementations, -L 1 - Partially possesses the formula (Ila-ii'): (IIa-ii'), in The dashed line represents the connection between the nitrogen atom and -D via an amide bond; The dashed line marked with an asterisk indicates -L 2 - connection; -R 2 -R 2a -R 3a and -X2 - As defined in equation (II); and Among them, -L 1 -Optionally, it may be further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIa-ii') are not substituted by substituents.

[0168] It should be understood that in equation (Ila-ii') -R 3a In the case of non-H, they are via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0169] In some implementations, the -L of formula (Ila-ii') 1 - Some parts will not be further replaced.

[0170] In some implementations, the -X of formula (Ila-ii') 2 -for-C(R) 8 R 8a )-.

[0171] In some implementations, the -R of formula (Ila-ii') 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-ii') 8 and -R 8a At least one of them is -H. In some embodiments, -R in formula (Ila-ii') 8 and -R 8a All are -H.

[0172] In some implementations, the -R of formula (Ila-ii') 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ila-ii') 2 and -R 2a At least one of them is -H. In some embodiments, -R of formula (Ila-ii') 2 and -R 2a All are H.

[0173] In some implementations, the -R of formula (Ila-ii') 3a Selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In one embodiment, -R of formula (Ila-ii') 3a Yes, it's -H.

[0174] In some implementations, -L 1 - Partially possesses formula (Ila-iii): (IIa-iii), in The dashed line represents the connection between the nitrogen atom and the -D atom via an amide bond; and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atom marked with an asterisk in formula (Ila-iii) is not replaced by -L 2 -Z or -L 2 -Z or substituent substitution.

[0175] It should be understood that in equation (Ila-iii) -R 3 -R 3a If one of them is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0176] In some implementations, -L of formula (Ila-iii) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0177] In some implementations, -L of formula (Ila-iii) 1 - Some parts will not be further replaced.

[0178] In some implementations, -L 1 - Partially possesses the formula (Ila-iii'): (IIa-iii'), in The dashed line represents the connection between the nitrogen atom and -D via an amide bond; The dashed line marked with an asterisk indicates -L 2 - connection; and Where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIa-iii') are not substituted by substituents.

[0179] It should be understood that the nitrogen adjacent to the dashed line marked with an asterisk in equation (IIa-iii') is obtained through sp 3 -Hybridized carbon atoms are attached to -L 2 -

[0180] In some implementations, the part -L of formula (Ila-iii') 1 - Not to be further replaced.

[0181] In some implementations, -L 1 - Partially possesses the formula (Ilb-ii): (IIb-ii), The dashed lines represent the connection between the nitrogen atom and -D via amide bonds; -R 2 -R 2a -R 3 -R 3a and -X 2 - As defined in equation (II); and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further substituted, provided that the hydrogen atom marked with an asterisk in formula (Ilb-ii) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0182] It should be understood that in equation (Ilb-ii) -R 3 -R 3a If one of them is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0183] In some implementations, the -L of formula (Ilb-ii) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0184] In some implementations, the -L of formula (Ilb-ii) 1 - Some parts will not be further replaced.

[0185] In some implementations, the -X of formula (Ilb-ii) 2 -for-C(R) 8 R 8a )-.

[0186] In some implementations, the -R of formula (Ilb-ii) 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ilb-ii) 8 and -R 8a At least one of them is -H. In some embodiments, -R of formula (Ilb-ii) 8and -R 8a All are -H.

[0187] In some implementations, the -R of formula (Ilb-ii) 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (Ilb-ii) 2 and -R 2a At least one of them is -H. In some embodiments, -R of formula (Ilb-ii) 2 and -R 2a All are H.

[0188] In some implementations, the -R of formula (Ilb-ii) 3 and -R 3a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -R of formula (Ilb-ii) 3 and -R 3a At least one of them is -H. In some embodiments, -R of formula (Ilb-ii) 3 and -R 3a All are -H.

[0189] In some implementations, -L 1 - Partially possesses the formula (Ilb-iia): (IIb-iia), The dashed lines represent the connection between the nitrogen atom and -D via amide bonds; -R 2 -R 2a -R 3 -R 3a and -X 2 - As defined in equation (II); and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further substituted, provided that the hydrogen atom marked with an asterisk in formula (IIa-iia) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0190] It should be understood that in equation (IIb-iia) -R 3 -R 3a If one of them is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0191] In some implementations, the -L of formula (Ilb-iia) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0192] In some implementations, the -L of formula (Ilb-iia) 1 - Some parts will not be further replaced.

[0193] In some implementations, the -X of formula (Ilb-iia) 2 -for-C(R) 8 R 8a )-.

[0194] In some implementations, the -R of formula (IIb-iia) 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (IIb-iia) 8 and -R 8a At least one of them is -H. In some embodiments, -R of formula (IIb-iia) 8 and -R 8a All are -H.

[0195] In some implementations, the -R of formula (IIb-iia) 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (IIb-iia) 2 and -R 2a At least one of them is -H. In some embodiments, -R of formula (IIb-iia) 2 and -R 2a All are H.

[0196] In some implementations, the -R of formula (IIb-iia) 3 and -R 3a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -R of formula (IIb-iia) 3 and -R 3a At least one of them is -H. In some embodiments, -R of formula (IIb-iia) 3 and -R 3a All are -H.

[0197] In some implementations, -L 1 - Partially possesses the formula (IIb-ii'): (IIb-ii'), in The dashed line represents the connection between the nitrogen atom and -D via an amide bond; The dashed line marked with an asterisk indicates -L 2 - connection; -R 2 -R 2a -R 3a and -X 2 - As defined in equation (II); and Where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIb-ii') are not substituted by substituents.

[0198] It should be understood that -R in equation (IIb-ii') 3a In the case of non-H, they are via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0199] In some implementations, the -L of formula (IIb-ii') 1 - Some parts will not be further replaced.

[0200] In some implementations, -X of formula (IIb-ii') 2 -for-C(R) 8 R 8a )-.

[0201] In some implementations, -R of formula (IIb-ii') 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (IIb-ii') 8 and -R 8a At least one of them is -H. In some embodiments, -R of formula (IIb-ii') 8 and -R 8a All are -H.

[0202] In some implementations, -R of formula (IIb-ii') 2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (IIb-ii') 2 and -R 2a At least one of them is -H. In some embodiments, -R of formula (IIb-ii') 2 and -R 2a All are H.

[0203] In some implementations, -R of formula (IIb-ii') 3a Selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -R of formula (IIb-ii') 3a It is -H.

[0204] In some implementations, -L 1 - Partially possesses the formula (IIb-iia'): (IIb-iia'), in The dashed line represents the connection between the nitrogen atom and -D via an amide bond; The dashed line marked with an asterisk indicates -L 2 - connection; -R 2 -R 2a -R 3a and -X 2 - As defined in equation (II); and Where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIb-iia') are not substituted by substituents.

[0205] It should be understood that -R in equation (IIb-iia') 3a In the case of non-H, they are via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0206] In some implementations, the -L of formula (IIb-iia') 1 - Some parts will not be further replaced.

[0207] In some implementations, the -X of formula (IIb-iia') 2 -for-C(R) 8 R 8a )-.

[0208] In some implementations, the -R of formula (IIb-iia') 8 and -R 8a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (IIb-iia') 8 and -R 8a At least one of them is -H. In some embodiments, -R of formula (IIb-iia') 8 and -R 8a All are -H.

[0209] In some implementations, the -R of formula (IIb-iia')2 and -R 2a Independently selected from the group consisting of -H, methyl, and ethyl. In some embodiments, -R of formula (IIb-iia') 2 and -R 2a At least one of them is -H. In some embodiments, -R of formula (IIb-iia') 2 and -R 2a All are H.

[0210] In some implementations, the -R of formula (IIb-iia') 3a Selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -R of formula (IIb-iia') 3a It is -H.

[0211] In some implementations, -L 1 - Some of them have equation (IIb-iii): (IIb-iii), in The dashed line represents the connection between the nitrogen atom and the -D atom via an amide bond; and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atom marked with an asterisk in formula (IIb-iii) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0212] It should be understood that in equation (IIb-iii) -R 3 -R 3a If one of them is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0213] In some implementations, -L of formula (IIb-iii) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0214] In some implementations, -L of formula (IIb-iii) 1 - Some parts will not be further replaced.

[0215] In some implementations, -L 1 - Some of them have the formula (IIb-iiia): (IIb-iiia), in The dashed line represents the connection between the nitrogen atom and the -D atom via an amide bond; and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atom marked with an asterisk in formula (IIb-iiia) is not replaced by -L 2 -Z or -L 2 -Z' or substituent substitution.

[0216] It should be understood that in equation (IIb-iiia) -R 3 -R 3a If one of them is not -H or neither is -H, they are transmitted via sp 3 - Hybridized carbon atoms are connected to their bonded N atoms.

[0217] In some implementations, -L of formula (IIb-iiia) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0218] In some implementations, -L of formula (IIb-iiia) 1 - Some parts will not be further replaced.

[0219] In some implementations, -L 1 - Partially possesses the formula (IIb-iii'): (IIa-iii'), in The dashed line represents the connection between the nitrogen atom and the -D atom via an amide bond; and The dashed line marked with an asterisk indicates -L 2 - connection; Where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIa-iii') are not substituted by substituents.

[0220] It should be understood that the nitrogen adjacent to the dashed line marked with an asterisk in equation (IIa-iii') is obtained through sp 3 -Hybridized carbon atoms are attached to -L 2 -

[0221] In some implementations, -L of formula (IIa-iii') 1 - Some parts will not be further replaced.

[0222] In some implementations, -L 1 - Partially possesses the formula (IIb-iiia'): (IIa-iiia'), in The dashed line represents the connection between the nitrogen atom and -D via an amide bond; The dashed line marked with an asterisk indicates -L 2 - connection; and Where -L 1 -Optionally, it may be further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIa-iiia') are not substituted by substituents.

[0223] It should be understood that the nitrogen adjacent to the dashed line marked with an asterisk in formulas (IIa-iiia') is obtained through sp 3 -Hybridized carbon atoms are attached to -L 2 -

[0224] In some implementations, -L of formula (IIa-iiia') 1 - Some parts will not be further replaced.

[0225] In some implementations, -L 1 -Disclosed in WO2016 / 020373A1. Therefore, in some embodiments, -L 1 - Partially possesses equation (III): (III), in Dashed lines indicate primary or secondary amines or hydroxyl groups connected to -D via amide or ester linkages, respectively; -R 1 -R 1a -R 2 -R 2a -R 3 and -R 3a They are selected independently from the following groups: -H, -C(R) 8 R 8a R 8b ), -C(=O)R 8 -C≡N, -C(=NR) 8 )R 8a -CR 8 (=CR 8a R 8b ), -C≡CR 8 and -T; -R 4 -R 5 and -R5a They are selected independently from the following groups: -H, -C(R) 9 R 9a R 9b ) and -T; al and a2 are independently 0 or 1; Each -R 6 -R 6a -R 7 -R 7a -R 8 -R 8a -R 8b -R 9 -R 9a and -R 9b They are selected independently from the following groups: -H, halogen, -CN, -COOR 10 -OR 10 , -C(O)R 10 , -C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)2R 10 , -S(O)R 10 , -N(R 10 )S(O)2N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO2, -OC(O)R 10 , -N(R 10 )C(O)R 10a , -N(R 10 )S(O)2R 10a , -N(R 10 )S(O)R 10a , -N(R 10 )C(O)OR 10a , -N(R 10 )C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 Alkyne group; wherein -T, C 1-20 Alkyl, C 2-20 alkenyl and C 2-20The alkynyl group is optionally surrounded by one or more identical or different -R groups. 11 Replace, and where C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 -, -S(O)2-, -S(O)-, -N(R) 12 )S(O)2N(R 12a )-,-S-,-N(R 12 )-,-OC(OR 12 (R) 12a )-,-N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-; Each -R 10 -R 10a and -R 10b Select independently from the following groups: -H, -T, C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 Alkyne group; wherein -T, C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally surrounded by one or more identical or different -R groups. 11 Replace, and where C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 -, -S(O)2-, -S(O)-, -N(R) 12 )S(O)2N(R 12a )-,-S-,-N(R 12 )-,-OC(OR 12 (R) 12a )-,-N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-; Each T is independently selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups, and 8- to 11-membered heterobicyclic groups; wherein each T is independently and optionally surrounded by one or more identical or different -R groups. 11 replace; Each -R 11 They are independently selected from: halogen, -CN, oxo (=O), -COOR 13 -OR 13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O)2N(R 13 R 13a ), -S(O)N(R 13 R 13a ), -S(O)2R 13 , -S(O)R 13 , -N(R 13 )S(O)2N(R 13a R 13b ), -SR 13 , -N(R 13 R 13a ), -NO2, -OC(O)R 13 , -N(R 13 )C(O)R 13a , -N(R 13 )S(O)2R 13a , -N(R 13 )S(O)R 13a , -N(R 13 )C(O)OR 13a , -N(R 13 )C(O)N(R 13a R 13b ), -OC(O)N(R 13 R 13a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each -R 12 -R 12a -R 13 -R 13a and -R 13b Select independently from the following groups: -H and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Optionally, add -R 1 / -R1a Yes, -R 2 / -R 2a Yes, -R 3 / -R 3a Yes, -R 6 / -R 6a Pair and -R 7 / -R 7a One or more pairs of atoms in a pair are bonded together with the atoms they are attached to, forming C. 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups; Optionally, add -R 1 / -R 2 Yes, -R 1 / -R 3 Yes, -R 1 / -R 4 Yes, -R 1 / -R 5 Yes, -R 1 / -R 6 Yes, -R 1 / -R 7 Yes, -R 2 / -R 3 Yes, -R 2 / -R 4 Yes, -R 2 / -R 5 Yes, -R 2 / -R 6 Yes, -R 2 / -R 7 Yes, -R 3 / -R 4 Yes, -R 3 / -R 5 Yes, -R 3 / -R 6 Yes, -R 3 / -R 7 Yes, -R 4 / -R 5 Yes, -R 4 / -R 6 Yes, -R 4 / -R 7 Yes, -R 5 / -R 6 Yes, -R 5 / -R 7 Pair and -R 6 / -R 7 One or more pairs of atoms in a ring connect together with the atoms they are attached to, forming a ring A; A is selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetranaphthyl, C 3-10Cycloalkyl, 3- to 10-membered heterocyclic groups, and 8- to 11-membered heterobicyclic groups; Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0226] -L of formula (III) 1 -Optional further substituents may be used as described above in some embodiments.

[0227] In some implementations, -L of formula (III) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0228] In some implementations, -L of formula (III) 1 - Not to be further replaced.

[0229] In some implementations, -L 1 -As disclosed in EP1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2 and US8618124B2 (which are incorporated herein by reference in their entirety).

[0230] In some implementations, -L 1 -As disclosed in US8946405B2 and US8754190B2 (which are incorporated herein by reference in their entirety). Therefore, in some embodiments, -L 1 - Possessing formula (IV): (IV), in The dashed line indicates a connection to -D, and the connection is achieved through a functional group of -D selected from the group consisting of -OH, -SH and NH2. m is 0 or 1; -R 1 and -R 2 At least one or two of them are independently selected from the group consisting of: -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 -S(O)R 3 -S(O)2R 3 and -SR 4 -R 1 and -R 2One and only one of them is selected from the group consisting of: -H, optionally substituted alkyl, optionally substituted aralkyl and optionally substituted heteroaralkyl; -R 3 Selected from the following group: -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 9 and -N(R) 9 )2; -R 4 Selected from the group consisting of: optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; Each -R 5 Independently selected from the group consisting of: -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaryl; -R 9 Selected from the group consisting of -H and optionally substituted alkyl groups; -Y- does not exist and -X- is -O- or -S-; or -Y- is -N(Q)CH2-, -X- is -O-; Q is selected from the group consisting of: optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl. Optional, -R 1 and -R 2 They can be connected to form 3 to 8-membered rings; and Optional, -R 9 It forms a heterocycle together with the nitrogen it is attached to; Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0231] Only in the context of formula (IV) do the terms used have the following meanings: As used herein, the term "alkyl" includes a straight-chain, branched, or cyclic saturated hydrocarbon group having 1 to 8 carbon atoms (or, in some embodiments, 1 to 6 or 1 to 4 carbon atoms).

[0232] The term "alkoxy" includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar groups.

[0233] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.

[0234] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.

[0235] The term "aryl" includes aromatic hydrocarbon groups having 6 to 18 carbon atoms, such as 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracene. The term "heteroaryl" includes aromatic rings having 3 to 15 carbon atoms and containing at least one N, O, or S atom, such as aromatic rings containing 3 to 7 carbon atoms and containing at least one N, O, or S atom, including groups such as pyrrole, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indole, and indole.

[0236] In some cases, the alkenyl, ynyl, aryl, or heteroaryl moiety can be coupled to the rest of the molecule via an alkylene linker. In those cases, the substituent is referred to as alkenylalkyl, ynylalkyl, aralkyl, or heteroaryl, indicating that the alkylene moiety is located between the alkenyl, ynyl, aryl, or heteroaryl moiety and the molecule coupled with the alkenyl, ynyl, aryl, or heteroaryl group.

[0237] The term "halogen" includes bromine, fluorine, chlorine, and iodine.

[0238] The term "heterocyclic" refers to a 4- to 8-membered aromatic or non-aromatic ring comprising 3 to 7 carbon atoms and at least one N, O, or S atom. Examples are piperidinyl, piperazine, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as exemplary groups provided by the term "heteroaryl" above.

[0239] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or other rings, each optionally further substituted. Optional substituents on any group (including the above groups) include halogen, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, wherein each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atoms they are attached to form a ring.

[0240] In some implementations, -L in formula (IV) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0241] In some implementations, the -L of formula (IV) 1 - Not to be further replaced.

[0242] In some implementations, -L 1-As disclosed in WO2013 / 036857A1 (which is incorporated herein by reference in its entirety). Therefore, in some embodiments, -L 1 -Having the formula (V): (V), in The dashed line represents the connection between the -D amine functional group and -D; -R 1 Selected from the group consisting of: optionally substituted C1-C6 straight-chain, branched, or cyclic alkyl groups; optionally substituted aryl groups; optionally substituted heteroaryl groups; alkoxy groups; and -NR groups. 5 2; -R 2 Selected from the group consisting of: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; -R 3 Selected from the group consisting of: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; -R 4 Selected from the group consisting of: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; Each -R 5 The groups are independently selected from the group consisting of: -H; optionally substituted C1-C6 alkyl groups; optionally substituted aryl groups; and optionally substituted heteroaryl groups; or when both -R groups are ... 5 When the group can be cycloalkyl or heterocycloalkyl; Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0243] Only in the context of formula (V) do the terms used have the following meanings: "alkyl," "alkenyl," and "alkynyl" refer to straight-chain, branched, or cyclic hydrocarbon groups having 1 to 8 carbon atoms (or, in some embodiments, 1 to 6 or 1 to 4 carbon atoms), wherein the alkyl group is a saturated hydrocarbon, the alkenyl group contains one or more carbon-carbon double bonds, and the alkynyl group contains one or more carbon-carbon triple bonds. Unless otherwise stated, these contain 1 to 6 carbon atoms.

[0244] "Aryl" includes aromatic hydrocarbon groups with 6-18 carbon atoms, such as 6-10 carbon atoms, including phenyl, naphthyl, anthracene, and similar groups. "Heteroaryl" includes aromatic rings containing 3-15 carbon atoms (such as 3-7 carbon atoms containing at least one N, O, or S atom), including pyrrole, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indole, indole, and similar groups.

[0245] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group containing one or more substituents that replace one or more hydrogen atoms. Substituents are typically selected from halogens (including F, Cl, Br, and I); lower alkyl groups (including straight-chain, branched, and cyclic); lower haloalkyl groups (including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl); OH; lower alkoxy groups (including straight-chain, branched, and cyclic); SH; lower alkylthio groups (including straight-chain, branched, and cyclic); amino, alkylamino, dialkylamino, silyl (including alkylsilyl, alkoxysilyl, and arylsilyl); nitro; cyano; carbonyl; carboxylic acids, carboxylic esters, carboxylic amides, and aminocarbonyl. ; aminoacyl; carbamate; urea; thiocarbamate; thiourea; ketone; sulfone; sulfonamide; aryl, including phenyl, naphthyl and anthracene; heteroaryl, including five-membered heteroaryl, including such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiazol, thiadiazole, triazole, oxadiazole and tetraazole; six-membered heteroaryl, including pyridine, pyrimidine and pyrazine; and fused heteroaryl, including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole and benzoisothiazole.

[0246] In some implementations, -L of formula (V) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0247] In some implementations, -L of formula (V) 1 - Not to be further replaced.

[0248] In some implementations, -L 1 -As disclosed in US7585837B2 (which is incorporated herein by reference in its entirety). Therefore, in some embodiments, -L 1 -With formula (VI): (VI), in The dashed line represents the connection between the -D amine functional group and -D; R 1 and R 2Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkylaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 amino, ammonium, carboxyl, PO3H2 and OPO3H2; R 3 R 4 and R 5 Independently selected from the group consisting of hydrogen, alkyl, and aryl; Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0249] Suitable substituents for formula (VI) are alkyl groups (such as C... 1-6 alkyl), alkenyl (such as C) 2-6 alkenyl), ynyl (such as C) 2-6 Alkynyl, aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroynyl, heteroaryl (such as 4- to 7-membered aromatic heterocycles) or halogen moiety.

[0250] Only in the context of formula (VI) do the terms used have the following meanings: The terms “alkyl,” “alkoxy,” “alkoxyalkyl,” “aryl,” “alkylaryl,” and “aralkyl” refer to: alkyl groups having 1 to 8 carbon atoms, such as 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, and butyl; and aryl groups having 6 to 10 carbon atoms, such as phenyl and naphthyl. The term “halogen” includes bromine, fluorine, chlorine, and iodine.

[0251] In some implementations, the -L of formula (VI) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0252] In some implementations, the -L of formula (VI) 1 - Not to be further replaced.

[0253] W02002 / 089789A1 (which is incorporated herein by reference in its entirety) discloses -L 1 - A further preferred embodiment. Therefore, the preferred portion -L 1 - Possessing equation (VII): (VII), in The dashed line represents the connection between the -D amine functional group and -D; L1 is a bifunctional linker group. Y1 and Y2 are independently O, S, or NR. 7 ; R 2 R 3 R 4 R 5 R 6 and R 7 Independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6 Hexaalkoxy; Ar is the part that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group when it is included in formula (VII); X is a chemical bond or a portion actively transported to the target cell, a hydrophobic portion, or a combination thereof. y is 0 or 1; Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0254] Only in the context of formula (VII) do the terms used have the following meanings: The term "alkyl" should be understood to include, for example, straight-chain, branched, substituted C-chains. 1-12 Alkyl (including alkoxy), C 3-8 Cycloalkyl or substituted cycloalkyl, etc.

[0255] The term “substituted” should be understood to include the addition or replacement of one or more atoms contained in a functional group or compound with one or more different atoms.

[0256] Substituted alkyl groups include carboxylalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl groups; substituted cycloalkyl groups include moieties such as 4-chlorocyclohexyl; aryl groups include moieties such as naphthyl; substituted aryl groups include moieties such as 3-bromophenyl; aralkyl groups include moieties such as tolyl; heteroalkyl groups include moieties such as ethylthiophene; substituted heteroalkyl groups include moieties such as 3-methoxythiophene; alkoxy groups include moieties such as methoxy; phenoxy groups include moieties such as 3-nitrophenoxy. Halogenation should be understood to include fluorine, chlorine, iodine, and bromine.

[0257] In some implementations, -L of formula (VII) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0258] In some implementations, -L of formula (VII) 1 - Not to be further replaced.

[0259] In some implementations, -L 1 - Substructure containing the following formula (VIII) (VIII), in The dashed line marked with an asterisk indicates the connection between the nitrogen atom and the -D atom via an amide bond; Unmarked dashed lines indicate a connection to -L 1 - the rest; and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0260] In some implementations, -L of formula (VIII) 1 -by a part-L 2 -Z or -L 2 -Z' replaces it.

[0261] In some implementations, -L of formula (VIII) 1 - Not to be further replaced.

[0262] In some implementations, -L 1 -Including the substructure of the following formula (IX) (IX), in The dashed line marked with an asterisk indicates the connection between the nitrogen atom of -D and the carbamate bond; Unmarked dashed lines indicate a connection to -L 1 - the rest; and Where -L 1 -by at least one -L 2 -Z or -L 2 -Z' replaces, and where -L 1 -Optionally, it can be further replaced.

[0263] In some implementations, -L of formula (IX) 1-by a part-L 2 -Z or -L 2 -Z' replaces it.

[0264] In some implementations, -L of formula (IX) 1 - Not to be further replaced.

[0265] In some implementations, -L 1 - It has the structure disclosed in WO2020 / 206358 A1. Therefore, in some embodiments, -L 1 - Partially possesses the formula (X): (X), in The unmarked dashed line indicates a connection to -D; The dashed line marked with an asterisk indicates -L 2 -Z or -L 2 -Z' connection; n is an integer selected from the following group: 0, 1, 2, 3, 4, 5, and 6; -R 1 and -R 2 Independently an electron-withdrawing group, alkyl group, or -H, wherein -R 1 and -R 2 At least one of them is an electron-withdrawing group; Each -R 4 Independently C1-C3 alkyl, or two -R 4 Together with the carbon atoms they are attached to, they form 3 to 6-membered rings; and When -D is the drug moiety linked by an amine, -Y- is absent; Or, when -D is the drug moiety linked by phenol, alcohol, thiol, thiophenol, imidazole, or non-basic amine, -Y- is -N(R) 6 CH 2- ;where -R 6 It is an optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0266] In some embodiments, n in equation (X) is an integer selected from 1, 2, 3, 4, 5, and 6. In some embodiments, n in equation (X) is an integer selected from 1, 2, and 3. In some embodiments, n in equation (X) is an integer selected from 0, 1, 2, and 3. In some embodiments, n in equation (X) is 1. In some embodiments, n in equation (X) is 2. In some embodiments, n in equation (X) is 3.

[0267] In some implementations, -R of formula (X) 1 and -R 2The electron-withdrawing group is selected from the following group: -CN; -NO2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; COR 3 -SOR 3 、or -SO2R 3 , where -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaryl, -OR 8 or -NR 8 2, where each -R 8 Independently -H or optionally substituted alkyl, or two -R 8 The group forms a heterocycle together with the nitrogen atom it is attached to; or -SR 9 , where -R 9 It is an optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaryl.

[0268] In some implementations, -R of formula (X) 1 and -R 2 The electron-withdrawing group is -CN. In some embodiments, the -R group of formula (X) is... 1 and -R 2 The electron-withdrawing group is -NO2. In some embodiments, the -R group of formula (X) 1 and -R 2 The electron-withdrawing group is an optionally substituted aryl group containing 6 to 10 carbon atoms. In some embodiments, the -R group of formula (X) 1 and -R 2 The electron-withdrawing group is optionally substituted with phenyl, naphthyl, or anthracene. In some embodiments, the -R group of formula (X) 1 and -R 2 The electron-withdrawing group (X) is an optionally substituted heteroaryl group containing 3 to 7 carbon atoms and at least one N, O, or S atom. In some embodiments, the -R group of formula (X) 1 and -R 2 The electron-withdrawing group is optionally substituted with pyrrole, pyridinyl, pyrimidinyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl, or indenyl. In some embodiments, -R of formula (X) 1 and -R 2 The electron-withdrawing group is an optionally substituted alkenyl group containing 2 to 20 carbon atoms. In some embodiments, the -R group of formula (X) 1 and -R 2 The electron-withdrawing group is an optionally substituted alkynyl group containing 2 to 20 carbon atoms. In some embodiments, the -R group of formula (X) 1 and -R2 The electron-withdrawing group is -COR 3 -SOR 3 or -SO2R 3 , where -R 3 -H, optionally substituted alkyl (containing 1 to 20 carbon atoms), optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 8 or -NR 8 2, where each -R 8 Independently -H or optionally substituted alkyl group (containing 1 to 20 carbon atoms), or two -R 8 The group, together with the nitrogen it is attached to, forms a heterocycle. In some embodiments, the -R group of formula (X) 1 and -R 2 The electron-withdrawing group is -SR 9 , where -R 9 It is an optionally substituted alkyl group (containing 1 to 20 carbon atoms), an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaralkyl group.

[0269] In some implementations, -R of formula (X) 1 and -R 2 At least one of them is -CN or -SOR 3 or -SO2R 3 In some implementations, -R of equation (X) 1 and -R 2 At least one of them is -CN or -SO2R 3 In some implementations, -R of equation (X) 1 and -R 2 At least one of them is -CN or -SO2R 3 , where R 3 It can be an alkyl group with optional substituted alkyl group, an aryl group with optional substituted aryl group, or -NR. 8 2. In some implementations, -R of formula (X) 1 and -R 2 At least one of them is -CN, -SO2N(CH3)2, -SO2CH3, a phenyl substituted with -SO2, a phenyl substituted with -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3) or -SO2N(CH2CH2OCH3)2.

[0270] In some implementations, each -R of equation (X) 4 Independently, it is a C1-C3 alkyl group. In some embodiments, both -R 4 It is a methyl group.

[0271] In some implementations, -Y- of equation (X) is absent. In some implementations, -Y- of equation (X) is -N(R). 6 )CH2-.

[0272] In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 -CN, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 -SO2N(CH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 SO2CH3, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 For phenyl groups substituted with -SO2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 For phenyl groups substituted with -SO2 and -Cl, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 -SO2N(CH2CH2)2O, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 -SO2CH(CH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1- Possesses the formula (X), where n is 1, -R 1 For -SO2N(CH3)(CH2CH3), -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 1, -R 1 For phenyl groups substituted with -SO2 and -CH3, -R 2 -H, -R 4 It is -CH3.

[0273] In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 -CN, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 -SO2N(CH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 SO2CH3, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 For phenyl groups substituted with -SO2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 For phenyl groups substituted with -SO2 and -Cl, -R 2 -H, -R 4 -CH3. In some implementations, -L 1- Possesses the formula (X), where n is 2, -R 1 -SO2N(CH2CH2)2O, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 -SO2CH(CH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 For -SO2N(CH3)(CH2CH3), -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 2, -R 1 For phenyl groups substituted with -SO2 and -CH3, -R 2 -H, -R 4 It is -CH3.

[0274] In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 -CN, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 -SO2N(CH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 SO2CH3, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 -H, -R 4 -CH3. In some implementations, -L 1- Possesses the formula (X), where n is 3, -R 1 For phenyl groups substituted with -SO2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 For phenyl groups substituted with -SO2 and -Cl, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 -SO2N(CH2CH2)2O, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 -SO2CH(CH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 For -SO2N(CH3)(CH2CH3), -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 -H, -R 4 -CH3. In some implementations, -L 1 - Possesses the formula (X), where n is 3, -R 1 For phenyl groups substituted with -SO2 and -CH3, -R 2 -H, -R 4 It is -CH3.

[0275] Only in the context of formula (X) do the terms used have the following meanings: The term "alkyl" refers to a straight-chain, branched, or cyclic saturated hydrocarbon group having 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In some embodiments, the alkyl group is straight-chain or branched. Examples of straight-chain or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In some embodiments, the alkyl group is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0276] The term "alkoxy" refers to an alkyl group bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0277] The term "alkenyl" refers to a non-aromatic unsaturated hydrocarbon having carbon-carbon double bonds and having 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0278] The term "alkynyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon triple bond and having 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0279] The term "aryl" refers to an aromatic hydrocarbon group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracene, and similar groups. The term "heteroaryl" refers to an aromatic ring containing 3 to 15 carbon atoms and at least one N, O, or S atom (preferably containing 3 to 7 carbon atoms and at least one N, O, or S atom), including groups such as pyrrole, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indole, and indole, and similar groups.

[0280] In some embodiments, the alkenyl, ynyl, aryl, or heteroaryl moiety may be coupled to the rest of the molecule via an alkyl linker. In those cases, the substituent is referred to as alkenylalkyl, ynylalkyl, aralkyl, or heteroaryl, indicating the presence of an alkylene moiety between the alkenyl, ynyl, aryl, or heteroaryl moiety and the molecule coupled to the alkenyl, ynyl, aryl, or heteroaryl moiety.

[0281] The term "halogen" or "halogenated" refers to bromine, fluorine, chlorine, and iodine.

[0282] The term "heterocyclic" or "heterocyclic group" refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazineyl, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as exemplary groups provided by the term "heteroaryl" above. In some embodiments, the heterocyclic or heterocyclic group is non-aromatic. In some embodiments, the heterocyclic or heterocyclic group is aromatic.

[0283] The term "optionally substituted" means that the group may not be substituted, or may be substituted by one or more (e.g., 1, 2, 3, 4, or 5) identical or different substituents. Examples of substituents include: alkyl, alkenyl, alkynyl, halogen, -CN, -OR. aa -SR aa -NR aa R bb -NO2, -C=NH(OR) aa ), -C(O)R aa, -OC(O)R aa -C(O)OR aa , -C(O)NR aa R bb , -OC(O)NR aa R bb -NR aa C(O)R bb -NR aa C(O)OR bb , -S(O)R aa -S(O)2R aa -NR aa S(O)R bb , -C(O)NR aa S(O)R bb -NR aa S(O)2R bb , -C(O)NR aa S(O)2R bb , -S(O)NR aa R bb , -S(O)2NR aa R bb , -P(O)(OR aa (OR) bb ), heterocyclic, heteroaryl, or aryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, heteroaryl, and aryl groups are each independently represented by -R cc Optional substitution, where -R aa and -R bb Each can be independently -H, alkyl, alkenyl, alkynyl, heterocyclic, heteroaryl, or aryl, or -R. aa and -R bb Together with the nitrogen atoms to which they are attached, they form heterocyclic groups, which are optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, and wherein each -R cc It can be independently alkyl, alkenyl, alkynyl, halogen, heterocyclic, heteroaryl, aryl, -CN, or -NO2.

[0284] In some implementations, -L 1 - It has the structure disclosed in Formula I of WO2021 / 242756 A1.

[0285] Therefore, in some implementations, -L 1 - Partially possesses the formula (Xlla): (XIIa), in The unmarked dashed line indicates a connection to -D-; The dashed line marked with an asterisk indicates -L2 - connection; -R 2 -R 4 and -R 8 Select independently from the following group: -H or C 1-4 alkyl; -R 3 It is C 1-4 Alkyl or -R 3 and -R 4 Together with the atoms they are attached to, they form 5- or 6-membered heterocycles; -R 5 It is -NH2; The premise is that when -R 4 and -R 3 When R forms a 5- or 6-membered heterocycle together with the atoms they are attached to, 2 Not -H; and Where -L in equation (XIIa) 1 -Optionally replaced.

[0286] In some implementations, the -R of formula (XIIa) 4 and -R 8 All are -H.

[0287] In some implementations, the -R of formula (XIIa) 3 It is methyl. In some embodiments, the -R of formula (XIIa) 3 It is -H.

[0288] In some implementations, the -R of formula (XIIa) 2 It is -H.

[0289] In some implementations, -L 1 - Possesses the formula (XIIa-i) (XIIa-i), Unmarked dashed lines indicate a connection to -D-; and The dashed line marked with an asterisk indicates -L 2 - connection.

[0290] In some implementations, -L 1 - Possesses the formula (XIIa-ii) (XIIa-ii), Unmarked dashed lines indicate a connection to -D-; and The dashed line marked with an asterisk indicates -L 2 - connection.

[0291] In some implementations, -L 1- Possesses formula (XIIa-iii) (XIIa-iii), The unmarked dashed line indicates a connection with -D-; and The dashed line marked with an asterisk indicates -L 2 - connection.

[0292] In some implementations, -L 1 - It has the structure disclosed in Formula II of WO2022 / 096636 A1.

[0293] Therefore, in some implementations, -L 1 - Partially possesses the formula (XIIb): (XIIb), in The unmarked dashed line indicates a connection with -D-; and The dashed line marked with an asterisk indicates -L 2 - connection.

[0294] WO2024 / 100552A1 (which is incorporated herein by reference in its entirety) discloses -L 1 - Another implementation scheme. Therefore, in some implementation schemes, -L 1 -With formula (XV): (XV) in Unmarked dashed lines indicate linkages with nitrogen, sulfur, or oxygen of -D via amide, thioester, or ester bonds. The dashed line marked with an asterisk indicates -L 2 - connection; -R 1 Selected from the following group: substituted aryl, unsubstituted aryl, and substituted carbonyl; Each of -R2, -R3, -R1', -R2', -R3', and -R4' is independently -H, substituted C1-C. 50 Alkyl or unsubstituted C1-C 50 alkyl; And among them -L 1 -Optionally, it may be further substituted, provided that the hydrogens marked with an asterisk in formula (XV) are not substituted by substituents.

[0295] Only in the context of formula (XV) does the term "aryl" refer to an aryl group having 6-10 carbon atoms, such as phenyl, benzyl, and naphthyl.

[0296] In some implementations, -L 2- is a chemical bond. In some implementations, -L 2 - is a spacer sub-part, such as spacer sub-parts selected from the following group: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 -, -S(O)2-, -S(O)-, -N(R) y1 )S(O)2N(R y1a )-,-S-,-N(R y1 )-,-OC(OR y1 (R) y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-、C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different -R groups. y2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally punctured by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 -, -S(O)2-, -S(O)-, -N(R) y3 )S(O)2N(R y3a )-,-S-,-N(R y3 )-,-OC(OR y3 (R) y3a )-,-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-; -R y1 and -R y1a Each of the following groups can be selected independently: -H, -T, -C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50The alkynyl group is optionally surrounded by one or more identical or different -R groups. y2 Replace, and where -R y2 Optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 -, -S(O)2-, -S(O)-, -N(R) y4 )S(O)2N(R y4a )-,-S-,-N(R y4 )-,-OC(OR y4 (R) y4a )-,-N(R y4 )C(O)N(R y4a )-and-OC(O)N(R y4 )-; Each T is independently selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently and optionally surrounded by one or more identical or different -R y2 replace; Each -R y2 Independently selected from the following groups: halogen, -CN, oxo (=O), -COOR y5 -OR y5 , -C(O)R y5 , -C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 , -S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a, -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ) and C 1-6 Alkyl; wherein C 1-6 The alkyl group is optionally substituted with one or more identical or different halogens; and Each -R y3 -R y3a -R y4 -R y4a -R y5 -R y5a and -R y5b Select independently from the following groups: -H and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0297] In some implementations, -L 2 -Selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 -, -S(O)2-, -S(O)-, -N(R) y1 )S(O)2N(R y1a )-,-S-,-N(R y1 )-,-OC(OR y1 (R) y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally surrounded by one or more identical or different -R groups. y2 Replace, and where C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally cleaved by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3)-,-S(O)N(R y3 -, -S(O)2-, -S(O)-, -N(R) y3 )S(O)2N(R y3a )-,-S-,-N(R y3 )-,-OC(OR y3 (R) y3a )-,-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-; -R y1 and -R y1a Each of the following groups can be selected independently: -H, -T, -C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne group; wherein -T, C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally surrounded by one or more identical or different -R groups. y2 Replace, and where C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally cleaved by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 -, -S(O)2-, -S(O)-, -N(R) y4 )S(O)2N(R y4a )-,-S-,-N(R y4 )-,-OC(OR y4 (R) y4a )-,-N(R y4 )C(O)N(R y4a )-and-OC(O)N(R y4 )-; Each T is independently selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently and optionally surrounded by one or more identical or different -R y2 replace; -R y2 Selected from the following groups: halogens, -CN, oxo (=O), -COOR y5 -OR y5 , -C(O)Ry5 , -C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 , -S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ) and C 1-6 Alkyl; wherein C 1-6 The alkyl group is optionally substituted with one or more identical or different halogens; and Each -R y3 -R y3a -R y4 -R y4a -R y5 -R y5a and -R y5b They are selected independently from the following groups: -H and C 1-6 Alkyl; wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0298] In some implementations, -L 2 -Selected from the following group: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 -, -S(O)2-, -S(O)-, -N(R) y1 )S(O)2N(R y1a)-,-S-,-N(R y1 )-,-OC(OR y1 (R) y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different -R groups. y2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 -, -S(O)2-, -S(O)-, -N(R) y3 )S(O)2N(R y3a )-,-S-,-N(R y3 )-,-OC(OR y3 (R) y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )-; -R y1 and -R y1a Select independently from the following groups: -H, -T, C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group; Each T is independently selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic groups, 8- to 11-membered heterobicyclic groups, 8- to 30-membered carbon polycyclic groups, and 8- to 30-membered heteropolycyclic groups; Each -R y2 Independently selected from the following group: halogens and C 1-6 Alkyl; and Each -R y3 -R y3a -R y4 -R y4a -R y5 -Ry5a and -R y5b They are selected independently from the following groups: -H and C 1-6 Alkyl; wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0299] In some implementations, -L 2 - is C 1-20 An alkyl chain, optionally composed of one or more elements independently selected from -O-, -T-, and -C(O)N(R) y1 The )- group is interrupted; and C 1-20 Alkyl chains are optionally separated by one or more elements independently selected from -OH, -T, and -C(O)N(R). y6 R y6a Substitution of groups; wherein -R y1 -R y6 -R y6a Selected independently from the following groups: H and C 1-4 Alkyl, wherein T is selected from the group consisting of: phenyl, naphthyl, indenyl, indenyl, tetranaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic.

[0300] In some implementations, -L 2 - The molecular weight ranges from 14 g / mol to 750 g / mol.

[0301] In some implementations, -L 2 - Includes selections from the following , , , , , , , , , , , , , , , , , , , , and ; in The dashed lines indicate the relationship with -L. 2 -、-L 1 The connection of -, -Z and / or the rest of Z'; -R and -R a They are selected independently from the group consisting of: -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0302] In some implementations, -L 2 The chain length of - ranges from 1 to 20 atoms.

[0303] This article is about -L 2 - The term "chain length" used in some parts refers to the length of the chain that exists in -L 2 -L in the shortest connection between - and -Z 2 - The number of atoms.

[0304] In some implementations, -L 2 -Having formula (i) (i), in The dashed line marked with an asterisk indicates -L 1 - connection; An unmarked dashed line indicates a connection to -Z or -Z'; n is selected from the following group: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; and The portion of equation (i) may be further replaced.

[0305] In some embodiments, n in equation (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. In some embodiments, n in equation (i) is 4, 5, 6, or 7. In some embodiments, n in equation (i) is 4. In some embodiments, n in equation (i) is 5. In some embodiments, n in equation (i) is 6.

[0306] In some implementations, -L 1 -L 2 -Some selections are from the following group: (IIca-i) (IIca-ii) and (IIca-iii); in The unlabeled dashed lines represent the linkage with nitrogen of -D via the formation of an amide bond; and A dashed line marked with an asterisk indicates a connection to -Z or Z'.

[0307] In some implementations, -L 1 -L 2- Partially has formula (IIca-i). In some embodiments, (IIca-i) partially has formula (IIca-ii). In some embodiments, -L 1 -L 2 - Part of it has the formula (IIcb-iii).

[0308] In some implementations, -L 1 -L 2 -Some selections are from the following group: (IIcb-i) (IIcb-ii) and (IIcb-iii); in The unlabeled dashed lines represent the linkage with nitrogen of -D via the formation of an amide bond; and A dashed line marked with an asterisk indicates a connection to -Z or Z'.

[0309] In some implementations, -L 1 -L 2 - Part has formula (IIcb-i). In some implementations, -L 1 -L 2 - Partially possesses formula (IIcb-ii). In some implementations, -L 1 -L 2 - Part of it has the formula (IIcb-iii).

[0310] The -Z portion contains a fatty acid derivative or polymer. In some embodiments, -Z contains a polymer, such as polymers selected from the group consisting of: 2-methacryloyloxyethyl phosphocholine, polyacrylic acid, polyacrylate, polyacrylamide, polyalkoxy polymers, polyamides, polyamide amines, polyamino acids, polyanhydrides, polyasparagine, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactone, polycarbonate, polycyanoacrylate, polydimethacrylamide, polyester, polyethylene, polyethylene glycol, polyethylene oxide, ethyl polyphosphate, polyethyloxazoline, polyglycolic acid, polyhydroxyethyl acrylate, polyhydroxyethyloxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, polyhydroxypropyl methacrylate, polyhydroxypropyloxazoline. Polyimide carbonates, polylactic acid, polylactic acid-glycolic acid copolymers, poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), polypropylene glycol, poly(siloxane), polyurethane, polyvinyl alcohol, polyvinylamine, polyvinyl methyl ether, polyvinylpyrrolidone, silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnose-galacturonic acid polysaccharide, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof. In some embodiments, -Z comprises polyethylene glycol (PEG).

[0311] In some embodiments, the molecular weight of -Z is 5 to 200 kDa. In some embodiments, the molecular weight of -Z is 8 to 100 kDa, such as 10 to 80 kDa, 12 to 60 kDa, or 15 to 40 kDa. In some embodiments, the molecular weight of -Z is about 20 kDa. In some embodiments, the molecular weight of -Z is about 40 kDa.

[0312] In some embodiments, -Z comprises PEG and has a molecular weight of 5 to 200 kDa. In some embodiments, -Z comprises PEG and has a molecular weight of 8 to 100 kDa, such as 10 to 80 kDa, 12 to 60 kDa, or 15 to 40 kDa. In some embodiments, -Z comprises PEG and has a molecular weight of about 20 kDa. In some embodiments, -Z comprises PEG and has a molecular weight of about 40 kDa.

[0313] In some embodiments, -Z comprises a protein, such as a protein selected from the group consisting of: a C-terminal polypeptide of human chorionic gonadotropin as described in US 2012 / 0035101A1 (which is incorporated herein by reference); albumin; an XTEN sequence as described in WO2011123813 A2 (which is incorporated herein by reference); a proline / alanine random coil sequence as described in WO 2011 / 144756 A1 (which is incorporated herein by reference); a proline / alanine / serine random coil sequence as described in WO 2008 / 155134 A1 and WO 2013 / 024049 A1 (which are incorporated herein by reference); and an Fc fusion protein. In some embodiments, -Z is polysarcosine. In some embodiments, -Z comprises poly(N-methylglycine). In some embodiments, -Z comprises a random coil protein portion.

[0314] In some embodiments, -Z comprises fatty acid derivatives, such as those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1 (which are incorporated herein by reference in their entirety). In some embodiments, -Z is a hyaluronic acid-based polymer. In some embodiments, -Z is a carrier as disclosed in WO 2012 / 02047 A1 (which is incorporated herein by reference in its entirety). In some embodiments, -Z is a carrier disclosed in WO 2013 / 024048 A1 (which is incorporated herein by reference in its entirety). In some embodiments, -Z is a PEG-based polymer, such as a linear, branched, cyclic, dendritic, or multi-arm PEG-based polymer. In some embodiments, -Z is a linear PEG-based polymer. In some embodiments, -Z is a multi-arm PEG-based polymer. In some embodiments, -Z is a multi-arm PEG-based polymer having at least four PEG arms.

[0315] In some embodiments, such a multi-arm PEG-based polymer -Z is linked to multiple -L... 2 -L 1 The -D part, where each -L 2 -L 1 The -D portion is attached to the end of the arm in some embodiments. In some implementations, such a multi-arm PEG-based polymer -Z is attached to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 -L groups. 2 -L 1 -D portion. In some embodiments, such multi-arm PEG-based polymers are -Z linked to 2, 3, 4, 6, or 8 -L groups. 2 -L 1-D portion. In some embodiments, such multi-arm PEG-based polymers are -Z linked to 2, 4, or 6 -L groups. 2 -L 1 -D portion. In some embodiments, such a multi-arm PEG-based polymer -Z is linked to 4 or 6 -L... 2 -L 1 -D portion. In some embodiments, such a multi-arm PEG-based polymer -Z is linked to four -L... 2 -L 1 -D part.

[0316] In some embodiments, -Z is a cyclic PEG-based polymer. In some embodiments, -Z is a dendritic PEG-based polymer.

[0317] In some embodiments, -Z is a branched PEG-based polymer. In some embodiments, -Z is a branched PEG-based polymer having one, two, three, four, five, or six branching points. In some embodiments, -Z is a branched PEG-based polymer having one, two, or three branching points. In some embodiments, -Z is a branched PEG-based polymer having one branching point. In some embodiments, -Z is a branched PEG-based polymer having two branching points. In some embodiments, -Z is a branched PEG-based polymer having three branching points. In some embodiments, the branching points may be selected from the group consisting of -N<, -CH<, and >C<.

[0318] In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 5 to 200 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 8 to 160 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 10 to 120 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 12 to 100 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 15 to 90 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 20 to 80 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight ranging from 25 to 60 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight of about 20 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight of about 40 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight of about 60 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight of about 80 kDa. In some embodiments, -Z is a branched PEG-based polymer with one branching point and a molecular weight of about 40 kDa.

[0319] In some embodiments, -Z is a branched PEG-based polymer with a branching point of -CH< and a molecular weight of about 40 kDa.

[0320] In some implementations, -Z or Z' includes a portion .

[0321] In some implementations, -Z or Z' contains an amide bond.

[0322] In some implementations, -Z includes a portion having the following formula (a) (a), in The dashed line indicates the relationship with -L 2 - or the connection with the rest of -Z; BP a The branching points are selected from the following group: -N<, -CR<, and >C<; -R is selected from the following group: -H and C 1-6 alkyl; If BP aIf -N < or -CR <, then a is 0; if BP a If C > C < 1, then n is 1. -S a -、-S a’ -、-S a’’ -and-S a’’’ - These are chemical bonds that exist independently of each other, or are selected from the following group: C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different -R groups. 1 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally punctured by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 -, -S(O)2-, -S(O)-, -N(R) 2 )S(O)2N(R 2a )-,-S-,-N(R 2 )-,-OC(OR 2 (R) 2a )-,-N(R 2 )C(O)N(R 2a )-and-OC(O)N(R 2 )-; Each -T- is independently selected from the following group: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each -T- is independently optionally surrounded by one or more identical or different -R 1 replace; Each -R 1 Independently selected from the following groups: halogen, -CN, oxo (=O), -COOR 3 -OR 3 , -C(O)R 3 , -C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R3 , -S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each -R 2 -R 2a -R 3 -R 3a and -R 3b Select independently from the following groups: -H and C 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally substituted with one or more identical or different halogens; and -P a’ -P a’’ and -P a’’’ It is a polymer component on its own.

[0323] In some implementations, the BP of formula (a) a For -N<; in some implementations, BP of equation (a) a For >C<; in some implementations, BP of equation (a) a -CR<; in some implementations, -R is -H. Therefore, a in equation (a) is 0.

[0324] In some implementations, -S of formula (a) a - is a chemical bond. In some embodiments, -S in formula (a) a -Selected from the following group: C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group, where C1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally punctured by one or more chemical groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 -, -S(O)2-, -S(O)-, -N(R) 4 )S(O)2N(R 4a )-,-S-,-N(R 4 )-,-OC(OR 4 (R) 4a )-,-N(R 4 )C(O)N(R 4a )-and-OC(O)N(R 4 -; where -T- is a 3- to 10-membered heterocyclic group; and -R 4 and -R 4a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -S of formula (a) a -Selected from the following group: C 1-10 Alkyl group, which is interrupted by one or more chemical groups selected from the group consisting of: -T-, -C(O)N(R) 4 )- and -O-.

[0325] In some implementations, -S of formula (a) a’ - is a chemical bond. In some embodiments, -S in formula (a) a’ -Selected from the following group: C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group, where C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally cleaved by one or more chemical groups selected from the group consisting of: -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 -, -S(O)2-, -S(O)-, -N(R) 4 )S(O)2N(R 4a )-,-S-,-N(R 4 )-,-OC(OR 4 (R) 4a )-,-N(R 4 )C(O)N(R 4a)-and-OC(O)N(R 4 -; where -R 4 and -R 4a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -S of formula (a) a’ - Selected from the group consisting of methyl, ethyl, propyl, and butyl, these groups are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R). 4 )-.

[0326] In some implementations, -S of formula (a) a’’ - is a chemical bond. In some embodiments, -S in formula (a) a’’ -Selected from the following group: C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group, where C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally cleaved by one or more chemical groups selected from the group consisting of: -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 -,-S(O)2-,-S(O)-,-N(R) 4 )S(O)2N(R 4a )-,-S-,-N(R 4 )-,-OC(OR 4 (R) 4a )-,-N(R 4 )C(O)N(R 4a )-and-OC(O)N(R 4 -; where -R 4 and -R 4a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -S of formula (a) a’’ - Selected from the group consisting of methyl, ethyl, propyl, and butyl, these groups are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R). 4 )-.

[0327] In some implementations, -S of formula (a) a’’’ - is a chemical bond. In some embodiments, -S in formula (a) a’’’ -Selected from the following group: C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group, where C1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally cleaved by one or more chemical groups selected from the group consisting of: -C(O)O-, -O-, -C(O)-, -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 -,-S(O)2-,-S(O)-,-N(R) 4 )S(O)2N(R 4a )-,-S-,-N(R 4 )-,-OC(OR 4 (R) 4a )-,-N(R 4 )C(O)N(R 4a )-and-OC(O)N(R 4 -; where -R 4 and -R 4a Independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In some embodiments, -S of formula (a) a’’’ - Selected from the group consisting of methyl, ethyl, propyl, and butyl, these groups are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R). 4 )-.

[0328] In some implementations, -P of formula (a) a’ -P a’’ and -P a’’’Polymers independently comprising the group consisting of: 2-methacryloyloxyethyl phosphocholine, polyacrylic acid, polyacrylate, polyacrylamide, polyalkoxy polymers, polyamide, polyamide amine, polyamino acid, polyanhydride, polyasparagine, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactone, polycarbonate, polycyanoacrylate, polydimethacrylamide, polyester, polyethylene, polyethylene glycol, polyethylene oxide, ethyl polyphosphate, polyethyloxazoline, polyglycolic acid, polyhydroxyethyl acrylate, polyhydroxyethyloxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, polyhydroxypropyl methacrylate, polyhydroxypropyl oxazoline, polyiminocarbonate Esters, polylactic acid, polylactic acid-glycolic acid copolymers, poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), polypropylene glycol, poly(siloxane), polyurethane, polyvinyl alcohol, polyvinylamine, polyvinyl methyl ether, polyvinylpyrrolidone, silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnose-galacturonic acid polysaccharide, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0329] In some implementations, -P of formula (a) a’ -P a’’ and -P a’’’ It independently includes a PEG-based portion. In some implementations, the -P of formula (a) a’ -P a’’ and -P a’’’ It independently includes a PEG-based portion, which contains at least 20% PEG, such as at least 30% PEG, such as at least 40% PEG, such as at least 50% PEG, such as at least 60% PEG, such as at least 70% PEG, such as at least 80% PEG, or such as at least 90% PEG.

[0330] In some implementations, -P of formula (a) a’ -P a’’ and -P a’’’ The molecular weight is independently from 5 kDa to 50 kDa (inclusive of endpoints), such as 5 kDa to 40 kDa (inclusive of endpoints), such as 7.5 kDa to 35 kDa (inclusive of endpoints), such as 7.5 kDa to 30 kDa, or such as 10 kDa to 30 kDa (inclusive of endpoints). In some embodiments, the -P of formula (a) a’ -P a’’ and -P a’’’The molecular weight is approximately 5 kDa. In some embodiments, the -P of formula (a) a’ -P a’’ and -P a’’’ The molecular weight is approximately 7.5 kDa. In some embodiments, the -P of formula (a) a’ -P a’’ and -P a’’’ The molecular weight is approximately 10 kDa. In some embodiments, the -P of formula (a) a’ -P a’’ and -P a’’’ The molecular weight is approximately 12.5 kDa. In some embodiments, the -P of formula (a) a’ -P a’’ and -P a’’’ The molecular weight is approximately 15 kDa. In some embodiments, the -P of formula (a) a’ -P a’’ and -P a’’’ Its molecular weight is approximately 20 kDa.

[0331] In some embodiments, -Z includes one part of formula (a). In some embodiments, -Z includes two parts of formula (a). In some embodiments, -Z includes three parts of formula (a). In some embodiments, -Z is a part of formula (a).

[0332] In some implementations, -Z includes the portion of formula (b) below. (b), in The dashed line indicates the relationship with -L 2 - or the connection with the rest of -Z; and m and p are independent integers from 150 to 1000 (inclusive); for example, integers from 150 to 600 (inclusive); integers from 200 to 550 (inclusive); or integers from 400 to 500 (inclusive).

[0333] In some implementations, m and p in equation (b) are the same integer. In some implementations, both m and p in equation (b) range from 400 to 500.

[0334] In some implementations, -Z is part of equation (b), and the dashed line indicates the relationship with -L. 2 - connection.

[0335] In some implementations, Z' is a hydrogel.

[0336] In some embodiments, Z' is a PEG-based hydrogel or a hyaluronic acid-based hydrogel. In some embodiments, Z' is a PEG-based hydrogel. In some embodiments, Z' is a hyaluronic acid-based hydrogel.

[0337] In some embodiments, Z' is a hydrogel as described in WO 2006 / 003014 A2, WO 2011 / 012715 A1, WO 2014 / 056926 A1, WO2020 / 064846 or WO2020 / 064847 (which are incorporated herein by reference in their entirety).

[0338] In some embodiments, Z' is a hydrogel as disclosed in WO 2013 / 036847 A1. Specifically, in some embodiments, Z' is a hydrogel prepared by a method comprising the step of reacting at least one first reactive polymer with a cleavable crosslinking agent compound, wherein the cleavable crosslinking agent compound comprises a first functional group -Y that reacts with the first reactive polymer. 1 It also includes a portion that is cleaved by an elimination reaction under physiological conditions, wherein the portion contains a second functional group -γ that reacts with the second reactive polymer. 2 In some embodiments, the cleavable crosslinking agent compound has the formula (PL-1): (PL-1), in m is 0 or 1; -X contains a functional group capable of attaching to a reactive polymer that is readily eliminated under physiological conditions, and the second functional group is -Y. 2 ; -R 1 -R 2 and -R 5 At least one of them contains the first functional group -Y 1 This functional group can be attached to the polymer; -R 1 and -R 2 One and only one of them is selected from the group consisting of -H, alkyl, aralkyl and heteroaralkyl; Optional, -R 1 and -R 2 They can be connected to form 3- to 8-member rings; -R 1 and -R 2 At least one or two of them are independently selected from the group consisting of: -CN, -NO2, aryl, heteroaryl, alkenyl, alkynyl, -COR 3 -SOR 3 -SO2R 3and -SR 4 ; -R 3 Selected from the following group: -H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OR 9 and -NR 9 2; -R 4 Selected from the group consisting of: alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; Each -R 5 Independently selected from the following group: -H, alkyl, alkenylalkyl, alkynylalkyl, (OCH2CH2) p O-alkyl (p is an integer from 1 to 1000), aryl, aralkyl, heteroaryl and heteroaralkyl; Each -R 9 Independently selected from the group consisting of: -H and alkyl or both; -R 9 Together with the nitrogen to which it is attached, a heterocycle is formed; and the portion of formula (PL-1) is optionally further substituted.

[0339] The following paragraphs describe such hydrogels in more detail.

[0340] In some embodiments, -X in formula (PL-1) is selected from the group consisting of: succinimide carbonates, sulfosuccinimide carbonate halides, thioethers, esters, nitrophenyl carbonates, chloroformates, fluoroformates, optionally substituted phenols, and formula (PL-2): (PL-2), in The dashed line indicates the connection to the rest of the equation (PL-1); -T*- is selected from the following group: -O-, -S-, and -NR 6 -; z is an integer selected from the following group: 1, 2, 3, 4, 5, and 6; -X'- does not exist, or can be selected from the following group: -OR 7 -and-SR 7 -; -Y 2 It is a functional group that can connect with reactive polymers; -R 6 Selected from the following group: -H, alkyl, aryl, heteroaryl, aralkyl, and heteroarylalkyl; -R 7 Selected from the following group: alkylene, phenylene, and (OCH2CH2) p p is an integer from 1 to 1000.

[0341] In some embodiments, -X of formula (PL-1) comprises an active carbonate, such as succinimidyl carbonate, sulfosuccinimidyl carbonate, or nitrophenyl carbonate. In some embodiments, -X of formula (PL-1) comprises a carbonyl halide, such as O(C=O)Cl or O(C=O)F. In some embodiments, -X of formula (PL-1) has the form of formula (PL-2). In some embodiments, -X of formula (PL-1) is OR. 7 or SR 7 , where R 7 It can be an optionally substituted alkylene, an optionally substituted phenylene, or (OCH2CH2). p , where p is from 1 to 1000.

[0342] In some implementations, p in equation (PL-2) is an integer from 1 to 100. In some implementations, p in equation (PL-2) is an integer from 1 to 10.

[0343] In some implementations, the -Y of formula (PL-1) 1 -Y of formula (PL-2) 2 Independently contains N3, NH2, and NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide, wherein t Bu is tert-butyl, and where -Y 1 or -Y 2 When one of them contains N3, the other does not contain an alkyne or cyclooctylene; when -Y 1 or -Y 2 When one of them contains SH, the other does not contain maleimide, acrylate, or acrylamide; when -Y 1 or -Y 2 When one of them contains NH2, the other does not contain CO2H; when -Y 1 or -Y 2 When one of them contains 1,3-diene or cyclopentadiene, the other does not contain furan.

[0344] In some embodiments, the cleavable crosslinking agent compound has the formula (PL-3): (PL-3), in m is 0 or 1; n is an integer selected from 1 to 1000; s is 0, 1, or 2; t is selected from the following groups: 2, 4, 8, 16, and 32; -W- is selected from the following group: -O(C=O)O-, -O(C=O)NH-, -O(C=O)S-, -O(C=O)NR 6 CH2O- and -O(C=O)NR 6 S-; -Q is a core group with a valence of t; it connects multiple arms of a cleavable crosslinked compound; Where t is an integer selected from 2, 4, 8, 16, and 32; and Where -R 1 -R 2 and -R 5 As defined by equation (PL-1).

[0345] In some embodiments, t in equation (PL-3) is 2. In some embodiments, t in equation (PL-3) is 4. In some embodiments, t in equation (PL-3) is 8. In some embodiments, t in equation (PL-3) is 16. In some embodiments, t in equation (PL-3) is 32.

[0346] In some implementations, -Q of formula (PL-3) has a structure selected from the group consisting of: (PL-3-i) (PL-3-ii) and (PL-3-iii), The dashed lines represent connections to the rest of the cleavable crosslinking agent compound.

[0347] In some embodiments, -Q of formula (PL-3) has the structure of (PL-3-i). In some embodiments, -Q of formula (PL-3) has the structure of (PL-3-ii). In some embodiments, -Q of formula (PL-3) has the structure of (PL-3-iii).

[0348] In some embodiments, the cleavable crosslinking agent compound has the formula (PL-3), where m is 0, n is about 100, s is 0, t is 4, -W- is -O(C=O)NH-, -Q has the structure of (PL-3i), and -R 2 For H, a -R 5 One is -H, the other is -R 5 It is (CH2)5N3, -R 1 It is (4-chlorophenyl)SO2, where the phenyl group is substituted with -SO2, morpholino-SO2, or -CN.

[0349] In some implementations, the -Y of formula (PL-3) 1Includes N3, NH2, and NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide, wherein t Bu is tert-butyl.

[0350] In some implementations, each -Y of formula (PL-1) or (PL-3) 1 Each -Y of the sum (PL-2) 2 Independently contains N3, NH2, and NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide.

[0351] In some implementations, -Y 1 and -Y 2 One is an azide, and the other is a reactive functional group selected from the group consisting of acetylene, cyclooctylene, and maleimide. In some embodiments, -Y 1 and -Y 2 One is a thiol, and the other is a reactive functional group selected from the group consisting of maleimide, acrylate, acrylamide, vinyl sulfone, vinyl sulfonamide, and halocarbonyl compounds. In some embodiments, -Y 1 and -Y 2 One is an amine, and the other is a reactive functional group selected from the group consisting of carboxylic acids and activated carboxylic acids. In some embodiments, -Y 1 and -Y 2 One of them is maleimide, and the other is a reactive functional group selected from the following group: 1,3-diene, cyclopentadiene, and furan.

[0352] In some embodiments, the first polymer and any second polymer are selected from the group consisting of homopolymers or copolymers of polyethylene glycol, polypropylene glycol, poly(N-vinylpyrrolidone), polymethacrylate, polyphosphazene, polylactic acid, polyacrylamide, polyglycolate, polyethyleneimine, agarose, dextran, gelatin, collagen, polylysine, chitosan, alginate, hyaluronic acid, pectin, and carrageenan, wherein these polymers contain suitable reactive functional groups or have the formula [Y]. 3 -(CH2) s (CH2CH2O) n ] t Q, where -Y 3It is a reactive functional group, where s is 0, 1, or 2, n is an integer selected from the group consisting of 10 to 1000, and -Q is a core group with a valence t, where t is an integer selected from the group consisting of 2, 4, 8, 16, and 32.

[0353] In some embodiments, the first polymer comprises a multi-armed polymer. In some embodiments, the first polymer comprises at least three arms. In some embodiments, the first polymer comprises at least four arms. In some embodiments, the first polymer comprises at least five arms. In some embodiments, the first polymer comprises at least six arms. In some embodiments, the first polymer comprises at least seven arms. In some embodiments, the first polymer comprises at least eight arms.

[0354] In some embodiments, the second polymer comprises a multi-armed polymer. In some embodiments, the second polymer comprises at least three arms. In some embodiments, the second polymer comprises at least four arms. In some embodiments, the second polymer comprises at least five arms. In some embodiments, the second polymer comprises at least six arms. In some embodiments, the second polymer comprises at least seven arms. In some embodiments, the second polymer comprises at least eight arms.

[0355] In some embodiments, the first polymer comprises a 2-arm polyethylene glycol polymer. In some embodiments, the first polymer comprises a 4-arm polyethylene glycol polymer. In some embodiments, the first polymer comprises an 8-arm polyethylene glycol polymer. In some embodiments, the first polymer comprises a 16-arm polyethylene glycol polymer. In some embodiments, the first polymer comprises a 32-arm polyethylene glycol polymer.

[0356] In some embodiments, the second polymer comprises a 2-arm polyethylene glycol polymer. In some embodiments, the second polymer comprises a 4-arm polyethylene glycol polymer. In some embodiments, the second polymer comprises an 8-arm polyethylene glycol polymer. In some embodiments, the second polymer comprises a 16-arm polyethylene glycol polymer. In some embodiments, the second polymer comprises a 32-arm polyethylene glycol polymer.

[0357] In some embodiments, the first reactive polymer and the second reactive polymer react with the cleavable crosslinking agent compound sequentially or simultaneously.

[0358] In some implementations, the first functional group and the second functional group are the same.

[0359] Only in the context of equations (PL-1), (PL-2), and (PL-3) do the terms used have the following meanings: The term "the portion capable of being cleaved by elimination reaction under physiological conditions" refers to the portion containing HC-(CH=CH). mThe structure of the -C-X' group, where m is 0 or 1 and X' is a leaving group, wherein the elimination reaction for removing the element HX' as described above can occur at a rate of 1 to 10,000 hours with a half-life under physiological pH and temperature conditions. Under physiological pH and temperature conditions, the half-life of this reaction is preferably 1 to 5,000 hours, more preferably 1 to 1,000 hours. Physiological pH and temperature conditions refer to a pH of 7 to 8 and a temperature of 30 to 40 degrees Celsius.

[0360] The terms "reactive polymers and reactive oligomers" refer to polymers or oligomers containing functional groups that are capable of reacting with other functional groups, most preferably under mild conditions, to meet the stability requirements of peptides, proteins, and other biomolecules. Suitable functional groups found in reactive polymers include maleimides, thiols or protected thiols, alcohols, acrylates, acrylamides, amines or protected amines, carboxylic acids or protected carboxylic acids, azides, alkynes (including cycloalkynes), 1,3-dienes (including cyclopentadiene and furans), α-halocarbonyl compounds, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, or nitrobenzene esters or carbonates.

[0361] The term "functional group capable of attaching to a reactive polymer" refers to a functional group that reacts with the corresponding functional group of the reactive polymer to form a covalent bond with the polymer. Suitable functional groups capable of attaching to reactive polymers include maleimides, thiols or protected thiols, acrylates, acrylamides, amines or protected amines, carboxylic acids or protected carboxylic acids, azides, alkynes (including cycloalkynes), 1,3-dienes (including cyclopentadiene and furans), α-halocarbonyl compounds, and N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, or nitrobenzene esters or carbonates.

[0362] The term "substituted" refers to alkyl, alkenyl, alkynyl, aryl, or heteroaryl groups containing one or more substituents that replace one or more hydrogen atoms. Substituents are typically selected from halogens (including F, Cl, Br, and I); lower alkyl groups (including straight-chain, branched, and cyclic); lower haloalkyl groups (including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl); OH; lower alkoxy groups (including straight-chain, branched, and cyclic); SH; lower alkyl thio groups (including straight-chain, branched, and cyclic); amino, alkylamino, dialkylamino, silyl (including alkylsilyl, alkoxysilyl, and arylsilyl); nitro; cyano; carbonyl; carboxylic acids, carboxylic esters, carboxylic amides; aminocarbonyl; aminoacyl; carbamate; urea; thiocarbamate; thiourea; ketone; sulfone; sulfonamide; and aryl (including phenyl, naphthyl, and anthracene). Heteroaryl groups (including five-membered heteroaryl groups such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetraazole), six-membered heteroaryl groups (such as pyridine, pyrimidine, pyrazine) and fused heteroaryl groups (such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole and benzoisothiazole)).

[0363] R 1 and R 2 The properties can be tuned by optionally adding electron-donating or electron-withdrawing substituents. The term "electron-donating group" refers to a group that causes R to... 1 R 2 Substituents that reduce the acidity of CH; electron-donating groups are generally associated with negative Hammett σ or Taft σ* constants, which are well known in physical organic chemistry (Hammett constant refers to aryl / heteroaryl substituents, and Taft constant refers to substituents on non-aromatic moieties). Examples of suitable electron-donating substituents include lower alkyl, lower alkoxy, lower alkylthio, amino, alkylamino, dialkylamino, and silyl groups.

[0364] The term "electron-withdrawing group" refers to a group that causes R to... 1 R 2 Substituents that enhance the acidity of the CH group; electron-withdrawing groups are generally associated with positive Hammett σ or Taft σ* constants, which is well known in physical organic chemistry. Examples of suitable electron-withdrawing substituents include halogens, difluoromethyl, trifluoromethyl, nitro, cyano, and C(=O)-R. x , where -R x It can be H, a lower alkyl group, a lower alkoxy group, or an amino group, or S(O). m R Y Where m is 1 or 2, and -R YIt is a lower alkyl, aryl, or heteroaryl group. It is known that the electronic effect of a substituent can depend on its position. For example, an alkoxy substituent at the ortho or para position of the aromatic ring is an electron-donating group, characterized by a negative Hammett σ constant; while an alkoxy substituent at the meta position of the aromatic ring is an electron-withdrawing group, characterized by a positive Hammett σ constant.

[0365] The terms “alkyl,” “alkenyl,” and “alkynyl” include straight-chain, branched, or cyclic hydrocarbon groups with 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, wherein an alkyl group is a saturated hydrocarbon, an alkenyl group includes one or more carbon-carbon double bonds, and an alkynyl group includes one or more carbon-carbon triple bonds. Unless otherwise specified, these compounds contain 1 to 6 carbon atoms.

[0366] The term "aryl" includes an aromatic hydrocarbon group with 6 to 18 carbon atoms, preferably an aromatic hydrocarbon group with 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracene, and similar groups. The term "heteroaryl" includes an aromatic ring containing 3 to 15 carbon atoms and containing at least one N, O, or S atom, preferably an aromatic ring containing 3 to 7 carbon atoms and containing at least one N, O, or S atom, including groups such as pyrrole, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indole, indene, and similar groups.

[0367] The term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0368] The term "maleimide" is a group having the following formula. .

[0369] In some embodiments, Z' is a hydrogel as disclosed in WO 2020 / 206358 A1. Specifically, in some embodiments, Z' is a hydrogel prepared by a method comprising the following steps: (a) Providing a product containing multi-arm polymer-P 2 The first prepolymer, wherein the first prepolymer has the formula (PL-4) (PL-4), in n is an integer selected from 0, 1, 2, 3, 4, 5, and 6; r is an integer greater than 2; -Y is a reactive functional group used to link the first prepolymer to the second prepolymer; -R 1 and -R 2 It is independently an electron-withdrawing group, an alkyl group, or -H, and wherein -R 1 and -R 2 At least one of them is an electron-withdrawing group; Each -R 4 It is independently a C1-C3 alkyl group, or two -R groups. 4 Together with the carbon atoms they are attached to, they form 3 to 6-membered rings; -W- does not exist or is , The dashed line marked with an asterisk indicates a connection to -NH-, and the unmarked dashed line indicates a connection to -P. 2 The connection; Each of x, y, and z is an integer selected independently from 0, 1, 2, 3, 4, 5, and 6; -B' is a -NH2, -ONH2, ketone, aldehyde, -SH, -OH, -CO2H, carboxylic acid amide group, or a group containing cyclooctynyl or bicyclic nonyneylene; and -C* represents carboxylic acid amide, thioether, thiosuccinimide, triazole, or oxime; (b) Providing a second prepolymer comprising a multi-arm polymer-P 1 Each arm ends with a reactive functional group "-Y", which reacts with "-Y" in step (a); (c) The two prepolymers from steps (a) and (b) are mixed under conditions where -Y and -Y” react to form a linked -Y*-; and optionally (d) The hydrogel obtained by separation.

[0370] Therefore, Z' is a hydrogel obtained by the above method. In some embodiments, the hydrogel prepared by the aforementioned method is biodegradable.

[0371] In some embodiments, -Y and -Y” react in step (c) to form an insoluble hydrogel matrix comprising crosslinks of formula (PL-4'): (PL-4´), Where n, r, and -P 1 -Y*-, -R 4 -R 1 -R 2 -W- and -P 2 As defined above.

[0372] In some embodiments, n in equation (PL-4) or (PL-4') is an integer selected from 1, 2, 3, 4, 5, and 6. In some embodiments, n in equation (PL-4) or (PL-4') is an integer selected from 1, 2, and 3. In some embodiments, n in equation (PL-4) or (PL-4') is an integer selected from 0, 1, 2, and 3. In some embodiments, n in equation (PL-4) or (PL-4) is 1. In some embodiments, n in equation (PL-4) is 2. In some embodiments, n in equation (PL-4) or (PL-4) is 3.

[0373] In some implementations, the multi-arm-P of formula (PL-4) or (PL-4') 2 It is an r-arm polymer, where r is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In some embodiments, r in formula (PL-4) or (PL-4') is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In some embodiments, r in formula (PL-4) or (PL-4') is an integer selected from 2, 4, 6, and 8. In some embodiments, r in formula (PL-4) or (PL-4') is 2. In some embodiments, r in formula (PL-4) or (PL-4') is 4. In some embodiments, r in formula (PL-4) or (PL-4') is 6. In some embodiments, r in formula (PL-4) or (PL-4') is 8.

[0374] In some implementations, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is at least 1 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is from 1 to 100 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is from 1 to 80 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is from 1 to 60 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is from 1 to 40 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is from 1 to 20 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is 1 to 10 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is 1 to 5 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4')2 The molecular weight is approximately 20 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is approximately 40 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is approximately 60 kDa. In some embodiments, the -P of formula (PL-4) or (PL-4') 2 Its molecular weight is approximately 80 kDa.

[0375] In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is an integer selected from 2, 4, 6, and 8. In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is 2. In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is 4. In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is 6. In some embodiments, the multi-arm polymer-P in step (b) 1 It is an r-arm polymer, where r is 8.

[0376] In some implementations, step (b) -P 1 The molecular weight is at least 1 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is from 1 to 100 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is from 1 to 80 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is from 1 to 60 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is from 1 to 40 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is 1 to 20 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is 1 to 10 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1The molecular weight is 1 to 5 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is approximately 20 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is approximately 40 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 The molecular weight is approximately 60 kDa. In some embodiments, the multi-arm polymer-P in step (b) 1 Its molecular weight is approximately 80 kDa.

[0377] In some implementations, step (b) -P 1 -P of formula (PL-4) or (PL-4´) 2 It comprises polyethylene glycol (PEG), polyethylene oxide (PEO), polyethyleneimine (PEI), dextran, hyaluronic acid, or copolymers thereof. In some embodiments, step (b) -P 1 -P of formula (PL-4) or (PL-4´) 2 It is a PEG-based polymer. In some embodiments, the -P in step (b) 1 -P of formula (PL-4) or (PL-4´) 2 It is a hyaluronic acid-based polymer.

[0378] In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 Independently, it is an electron-withdrawing group, an alkyl group, or -H, wherein -R 1 and -R 2 At least one of them is an electron-withdrawing group.

[0379] In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 Electron-withdrawing groups include -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, and -COR. 3 -SOR 3 or -SO2R 3 , where -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaryl, -OR 8 or -NR 8 2, where each -R 8 Independently -H or optionally substituted alkyl, or two -R 8 The groups together with the nitrogen atoms to which they are attached form heterocycles; or -SR 9, where -R 9 It is an optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaryl.

[0380] In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is -CN. In some embodiments, the -R group of formula (PL-4) or (PL-4') is... 1 and -R 2 The electron-withdrawing group is -NO2. In some embodiments, the -R group of formula (PL-4) or (PL-4') is... 1 and -R 2 The electron-withdrawing group is an optionally substituted aryl group containing 6 to 10 carbon atoms. In some embodiments, the -R group of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is optionally substituted with phenyl, naphthyl, or anthracene. In some embodiments, the -R group of formula (PL-4) or (PL-4') is... 1 and -R 2 The electron-withdrawing group is an optionally substituted heteroaryl group containing 3 to 7 carbon atoms and at least one N, O, or S atom. In some embodiments, the -R group of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is optionally substituted with pyrrole, pyridinyl, pyrimidinyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl, or indenyl. In some embodiments, the -R group of formula (PL-4) or (PL-4´) is... 1 and -R 2 The electron-withdrawing group is an optionally substituted alkenyl group containing 2 to 20 carbon atoms. In some embodiments, the -R group of formula (PL-4) or (PL-4') is... 1 and -R 2 The electron-withdrawing group is an optionally substituted alkynyl group containing 2 to 20 carbon atoms. In some embodiments, the -R group of formula (PL-4) or (PL-4') is... 1 and -R 2 The electron-withdrawing group is -COR 3 -SOR 3 or -SO2R 3 , where R 3 -H, optionally substituted alkyl groups containing 1 to 20 carbon atoms, optionally substituted aryl groups, optionally substituted aralkyl groups, optionally substituted heteroaryl groups, optionally substituted heteroaralkyl groups, -OR 8 or -NR 8 2, where each -R8 Independently -H or an optionally substituted alkyl group containing 1 to 20 carbon atoms, or two -R 8 The groups, together with the nitrogen they are attached to, form a heterocycle. In some embodiments, the -R group of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is -SR 9 , where -R 9 It is an optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaryl group containing 1 to 20 carbon atoms. In some embodiments, -R 1 and -R 2 At least one of them is -CN or -SO2R 3 .

[0381] In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of them is -CN or -SOR 3 or -SO2R 3 In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of them is -CN or -SO2R 3 In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of them is -CN or -SO2R 3 , where R 3 It can be an alkyl group with optional substituted alkyl group, an aryl group with optional substituted aryl group, or -NR. 8 2. In some implementations, the -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of them is -CN, -SO2N(CH3)2, -SO2CH3, a phenyl substituted with -SO2, a phenyl substituted with -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3) or -SO2N(CH2CH2OCH3)2.

[0382] In some implementations, each -R of formula (PL-4) or (PL-4') 4 Individually, they are C1-C3 alkyl groups, or they can be combined to form 3- to 6-membered rings. In some embodiments, each -R of formula (PL-4) or (PL-4') 4It is independently a C1-C3 alkyl group. In some embodiments, the two -R groups of formula (PL-4) or (PL-4') are... 4 It is a methyl group.

[0383] In some embodiments, -Y and "-Y" are independently selected from the group consisting of: amines, aminooxy groups, ketones, aldehydes, maleimides, thiols, alcohols, azides, 1,2,4,6-tetraazines, trans-cyclooctenyl, bicyclononynyl, cyclooctynyl and their protected variants.

[0384] In some embodiments, Y and Y'' can react with each other selectively. For example, when -Y is an amine, -Y'' is a carboxylic acid, an active ester, or an active carbonate, resulting in a residual linking functional group -Y*-, which is an amide or carbamate. As another example, when -Y is an azide, -Y'' is an alkynyl, bicyclic nonynyl, or cyclooctyynyl, resulting in a residual linking functional group -Y*-, i.e., 1,2,3-triazole. As another example, when -Y is NH₂O, -Y'' is a ketone or aldehyde, resulting in a residual linking functional group -Y*-, i.e., oxime. As another example, when -Y is SH, -Y'' is a maleimide or a halocarbonyl, resulting in a residual linking functional group -Y*-, i.e., thiosuccinimide or thioether. Similarly, these effects of -Y and -Y'' can be interchanged, resulting in -Y*- with opposite directions.

[0385] In some embodiments, -Y*- includes an amide, oxime, 1,2,3-triazole, thioether, thiosuccinimide, or ether. In some embodiments, -Y*- is -L. 2 -

[0386] These conjugation reactions can be carried out under conditions known in the art. For example, when -Y is an azide and -Y” is a cyclooctylene, the conjugation reaction can be carried out in any solvent in which both components exhibit sufficient solubility, although aqueous solutions are known to show a more favorable reaction rate. When mixed in a suitable solvent, typically an aqueous buffer with a pH of 2 to 7 (when -Y and -Y” are azide / cyclooctylene) or an aqueous buffer with a pH of 6 to 9 (when -Y and -Y” are active esters and amines), the -Y and -Y” groups react to form an insoluble hydrogel matrix containing crosslinks of formula (PL-4'). This process can be carried out in the bulk phase or under emulsified conditions in a mixed organic / aqueous system to form a microparticle suspension suitable for injection, such as microspheres.

[0387] Only in the context of equations (PL-4) and (PL-4') do the terms used have the following meanings: The term "alkyl" refers to a straight-chain, branched, or cyclic saturated hydrocarbon group containing 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In some embodiments, the alkyl group is straight-chain or branched. Examples of straight-chain or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In some embodiments, the alkyl group is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0388] The term "alkoxy" refers to an alkyl group bonded to an oxygen atom, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0389] The term "alkenyl" refers to a non-aromatic unsaturated hydrocarbon having carbon-carbon double bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0390] The term "alkynyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon triple bond and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0391] The term "aryl" refers to an aromatic hydrocarbon group with 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, anthracene, and similar groups. The term "heteroaryl" refers to an aromatic ring containing 3 to 15 carbon atoms and at least one N, O, or S atom (preferably containing 3 to 7 carbon atoms and at least one N, O, or S atom), including groups such as pyrrole, pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indole, and indole.

[0392] In some embodiments, the alkenyl, ynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule via an alkyl linker. In those cases, the substituent is referred to as alkenylalkyl, ynylalkyl, aralkyl, or heteroaryl, indicating the presence of an alkylene moiety between the alkenyl, ynyl, aryl, or heteroaryl moiety and the molecule coupled to the alkenyl, ynyl, aryl, or heteroaryl group.

[0393] The term "halogen" or "halogenated" refers to bromine, fluorine, chlorine, or iodine.

[0394] The term "heterocyclic" or "heterocyclic group" refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as exemplary groups given above for the term "heteroaryl." In some embodiments, the heterocyclic or heterocyclic group is non-aromatic. In some embodiments, the heterocyclic or heterocyclic group is aromatic.

[0395] The term "optionally substituted" refers to a group that can be left unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) identical or different substituents. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, and -OR. aa -SR aa -NR aa R bb -NO2, -C=NH(OR) aa -C(O)R aa -OC(O)R aa -C(O)OR aa -C(O)NR aa R bb -OC(O)NR aa R bb -NR aa C(O)R bb -NR aa C(O)OR bb -S(O)R aa -S(O)2R aa -NR aa S(O)R bb -C(O)NR aa S(O)R bb -NR aa S(O)2R bb -C(O)NR aa S(O)2R bb -S(O)NR aa R bb -S(O)2NR aa R bb -P(O)(OR) aa (OR) bb ), heterocyclic, heteroaryl or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl and aryl groups are each independently and optionally marked with -R cc Replace, where -R aa and -R bb Each can be independently -H, alkyl, alkenyl, alkynyl, heterocyclic, heteroaryl, or aryl, or -R. aa and -R bb Together with the nitrogen atoms to which they are attached, they form a heterocyclic group, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, and wherein: each -R cc It can be alkyl, alkenyl, alkynyl, halogen, heterocyclic, heteroaryl, aryl, -CN, or -NO2 independently.

[0396] In some embodiments, the PTH compound is a compound of formula (XI). (XI), in The unlabeled dashed lines indicate the connection of the nitrogen atom to the N-terminal amine group of the PTH portion of SEQ ID NO:51; and A dashed line marked with an asterisk indicates a connection to a portion. in in The dashed line indicates the relationship with -L 2 - or the connection with the rest of -Z; m and p are independent integers from 150 to 1000; such as integers from 150 to 600; such as integers from 200 to 550; such as integers from 400 to 500; or such as integers from approximately 450 to approximately 500.

[0397] In some implementations, m and p in equation (XI) are independently integers from 400 to 500. In some implementations, m and p in equation (XI) are independently integers from approximately 450 to 500. In some implementations, m and p in equation (XI) are independently integers from 450 to 500.

[0398] The compound of formula (XI) is also known as paropeptide, TransCon PTH, or ACP-014.

[0399] It should be understood that the nitrogen of the N-terminal amine group of the PTH portion of formula (XI) forms an amide bond with the carbonyl group (-(C=O)-) to the left of the unlabeled dashed line.

[0400] The PTH compound of formula (XI) releases PTH of SEQ ID NO:51, namely PTH 1-34, which means that its active PTH is PTH 1-34.

[0401] In some embodiments, the PTH compound is a compound of formula (XII). (XII), in The dashed line represents the connection of the nitrogen atom to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer of approximately 200 to 250.

[0402] In some embodiments, the PTH compound is a compound of formula (XII#). (XII#), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer from 150 to 1000 (inclusive); such as an integer from 150 to 600 (inclusive); such as an integer from 200 to 550 (inclusive); such as an integer from 400 to 500 (inclusive); or such as an integer from approximately 450 to approximately 500 (inclusive).

[0403] In some embodiments, the PTH compound is a compound of formula (XII'). (XII'), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer of approximately 200 to 250.

[0404] In some embodiments, each n in equations (XII) and (XII') is independently an integer from 200 to 250. In some embodiments, each n in equations (XII) and (XII') is independently an integer from approximately 210 to 240. In some embodiments, each n in equations (XII) and (XII') is independently an integer from 210 to 240. In some embodiments, all n are the same integer.

[0405] In some embodiments, the PTH compound is a compound of formula (XII'#). (XII'#), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer from 150 to 1000 (inclusive); for example, an integer from 150 to 600 (inclusive); an integer from 200 to 550 (inclusive); an integer from 400 to 500 (inclusive); or an integer from approximately 450 to approximately 500.

[0406] It should be understood that the nitrogen of the N-terminal amine group of the PTH moiety forms an amide bond with the carbonyl group (-(C=O)-) to the left of the dashed line in formula (XII), (XII#), (XII'), or (XII'#).

[0407] The PTH compounds of formula (XII), (XII#), (XII') or (XII'#) release the PTH of SEQ ID NO:51, namely PTH1-34, which means that the active PTH of the PTH compounds of formula (XII), (XII#), (XII') or (XIT#) is PTH1-34.

[0408] In some embodiments, each n in equations (XII) and (XII') is independently an integer from 200 to 250. In some embodiments, each n in equations (XIII) and (XIII') is independently an integer from approximately 210 to 240. In some embodiments, all n in equations (XII) and (XII') are integers from 200 to 250. In some embodiments, all n in equations (XIII) and (XIII') are integers from approximately 210 to 240. In some embodiments, all n in equations (XIII) and (XIII') are integers from 210 to 240.

[0409] In some embodiments, the PTH compound is a compound of formula (XIII). (XIII), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer of approximately 200 to 250.

[0410] The chiral center marked with "#" in formula (XIII) can be of L or D configuration, or a mixture of L and D configurations. In some embodiments, the chiral center is of L configuration.

[0411] In some embodiments, the second PTH compound is a compound of formula (XIII').

[0412] (XIII'), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer of approximately 200 to 250.

[0413] In some embodiments, each n in equations (XIII) and (XIII') is independently an integer from 200 to 250. In some embodiments, each n in equations (XIII) and (XIII') is independently an integer from approximately 210 to 240. In some embodiments, all n in equations (XIII) and (XIII') are integers from 200 to 250. In some embodiments, all n in equations (XIII) and (XIII') are integers from approximately 210 to 240. In some embodiments, all n in equations (XIII) and (XIII') are integers from 210 to 240.

[0414] It should be understood that the nitrogen of the N-terminal amine group of the PTH moiety forms an amide bond with the carbonyl group (-(C=O)-) to the left of the dashed line in formulas (XIII) and (XIII').

[0415] The PTH compounds of formula (XIII) and (XIII') release the PTH of SEQ ID NO:51, namely PTH 1-34, which means that the active PTH of the PTH compounds of formula (II-b) and (II-b') is PTH 1-34.

[0416] In some embodiments, the PTH compound is a compound of formula (XIV). k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH (XIV), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is creatine; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

[0417] In some embodiments, the second PTH compound is a compound of formula (XIV'). k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH (XIV'), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is creatine; K is the L-isomer of lysine; -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

[0418] The compound of formula (XIV') corresponds to SEQ ID NO:87 of WO2021 / 242756, and the sequence “SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK” corresponds to PTH(1-32) (SEQ ID NO:53) + K33 therein.

[0419] Compound of formula (XIV) releases compound of formula (XIV-i). SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH(XIV-i), in γE is the l-isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

[0420] Compounds of formula (XIV-i) have the PTH activity of compounds of formula (XIV).

[0421] Compounds of formula (XIV') release compounds of formula (XIV-i') SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH(XIV-i'), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

[0422] The compound of formula (XIV-i') is the active PTH of the compound of formula (XIV-i').

[0423] In some embodiments, the PTH compound of formula (XIV) or (XIV') is administered at a dose of 300 µg / week to 500 µg / week.

[0424] PTH compounds can be administered in the form of pharmaceutical compositions. Such pharmaceutical compositions comprise at least one PTH compound as described elsewhere herein and at least one excipient.

[0425] Such pharmaceutical compositions may have a pH range of pH 3 to pH 8 (inclusive) or pH 4 to pH 6 (inclusive). In some embodiments, such pharmaceutical compositions have a pH range of pH 4 to pH 5 (inclusive).

[0426] In some embodiments, such pharmaceutical compositions are liquid or suspension formulations. It should be understood that if the PTH compound is insoluble in water, such as when it contains a water-insoluble carrier -Z', then the pharmaceutical composition is a suspension formulation.

[0427] In some embodiments, such a pharmaceutical composition is a dried preparation.

[0428] Such liquid, suspension, or dry pharmaceutical compositions contain at least one excipient. Excipients used in pharmaceutical compositions can be classified as, for example, buffers, isotonic modifiers, preservatives, stabilizers, anti-adsorption agents, antioxidants, thickeners / viscosity enhancers, or other adjuvants. However, in some cases, an excipient may have dual or triple functions. The at least one excipient included in the pharmaceutical compositions of this application may be selected from the following group: (i) Buffers: Physiologically tolerable buffers to maintain pH within the required range, such as sodium phosphate, sodium bicarbonate, sodium succinate, sodium histidine, sodium citrate and sodium acetate, sodium sulfate, sodium nitrate, sodium chloride, sodium pyruvate; antacids such as Mg(OH)2 or ZnCO3 may also be used. (ii) Isotonic modifiers: to minimize pain caused by cell damage due to differences in osmotic pressure at the injection site; glycerol and sodium chloride are examples; the effective concentration can be determined by osmometry, assuming a serum osmolarity of 285-315 mOsmol / kg; (iii) Preservatives and / or antimicrobial agents: Multi-dose parenteral preparations require the addition of sufficient concentrations of preservatives to minimize the risk of infection during injection in subjects, and corresponding regulatory requirements have been established; typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride; (iv) Stabilizers: Stabilization is achieved by enhancing protein stability, disrupting denatured states, or by excipients directly binding to proteins. Stabilizers can be amino acids, such as alanine, arginine, aspartic acid, glycine, histidine, lysine, and proline; sugars, such as glucose, sucrose, and trehalose; polyols, such as glycerol, mannitol, and sorbitol; salts, such as potassium phosphate and sodium sulfate; chelating agents, such as EDTA and hexaphosphate; ligands, such as divalent metal ions (zinc, calcium, etc.); other salts or organic molecules, such as phenolic derivatives; in addition, oligomers or polymers, such as cyclodextrin, dextran, dendritic polymers, PEG or PVP, protamine, or HSA, can also be used.

[0429] (v) Anti-adsorption agents: using a major ionic or nonionic surfactant or other protein or soluble polymer to coat or competitively adsorb onto the inner surface of the formulation container; for example, poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin; the concentration and type of excipient chosen depends on the effects to be avoided, but generally a monolayer surfactant is formed at a CMC value slightly above the interface; (vi) Antioxidant protectants: Antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate and vitamin E; chelating agents such as citric acid, EDTA, hexaphosphate and thioglycolic acid may also be used; (vii) Thickeners or viscosity enhancers: In the case of suspensions, these delay the settling of particles in vials and syringes, promote mixing and resuspension of particles, and make the suspension easier to inject (i.e., requiring less force on the syringe plunger); suitable thickeners or viscosity enhancers are, for example, carbomer thickeners (such as carbomer 940, carbomer Ultraz 10), cellulose derivatives (such as hydroxypropyl methylcellulose (HPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C)), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthan gum, carrageenan (such as Satia gum UTC) 30) Aliphatic polyhydroxy acids (such as poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), terpolymers of D,L-lactide, glycolide and caprolactone, poloxamer, hydrophilic polyoxyethylene blocks and hydrophobic polyoxypropylene blocks (forming polyoxyethylene-polyoxypropylene-polyoxyethylene triblocks) (e.g., Pluronic®), polyether ester copolymers, such as polyethylene terephthalate / polybutylene terephthalate copolymers, sucrose isobutyrate acetate (SAIB), dextran or its derivatives, combinations of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and its derivatives. Polyalkylimides, polyacrylamide-diallyldimethylammonium (DADMA) copolymers, polyvinylpyrrolidone (PVP), glycosaminoglycans (GAGs) such as dermatin sulfate, chondroitin sulfate, keratin sulfate, heparin, heparan sulfate, hyaluronic acid, ABA triblock or AB block copolymers composed of hydrophobic A blocks (such as polylactic acid (PLA) or polylactic acid-glycolic acid (PLGA) copolymers) and hydrophilic B blocks (such as polyethylene glycol (PEG) or polyvinylpyrrolidone); such block copolymers and the above-mentioned poloxamer can exhibit reverse thermogel behavior (liquid at room temperature to facilitate administration; and gel at body temperature above the sol-gel transition temperature after injection); (viii) Spreading or dispersing agents: These alter the permeability of connective tissue by hydrolyzing extracellular matrix components in the interstitial space (such as, but not limited to, hyaluronic acid, a polysaccharide present in the intercellular spaces of connective tissue); spreading agents (such as, but not limited to, hyaluronidase) can temporarily reduce the viscosity of the extracellular matrix, promoting the diffusion of injected drugs; and (ix) Other auxiliary agents: such as wetting agents, viscosity modifiers, antibiotics, hyaluronidase; acids and bases, such as hydrochloric acid and sodium hydroxide, are necessary auxiliary agents for pH adjustment in the production process.

[0430] PTH compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing PTH compounds or pharmaceutically acceptable salts thereof may be administered to subjects via a variety of administration methods, such as local, enteral, or parenteral administration, and via external application, injection, or infusion methods, including intra-articular, periarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intrasheath, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, tracheal, subepidermal, subcapsular, subarachnoid, intraspinal, intraventricular, and intrabrainstem injection and infusion; direct delivery to the brain via an implantable device; thereby delivering the application or the like directly to brain tissue or cerebrospinal fluid (e.g., Ommaya reservoir); direct intraventricular injection or infusion; injection or infusion to the brain or brain-related regions; injection into the subchoroidal space; retroorbital injection; and intraocular instillation. In some embodiments, PTH compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing PTH compounds or pharmaceutically acceptable salts thereof are administered via subcutaneous injection.

[0431] This subcutaneous injection is suitable for administration using a syringe and needle or an injection pen. In some embodiments, PTH compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing PTH compounds or pharmaceutically acceptable salts thereof are administered subcutaneously via an injection pen.

[0432] PTH compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing PTH compounds or pharmaceutically acceptable salts thereof may be administered as needed by the subject, such as twice daily, once daily, every two days, once weekly, once every two weeks, or once monthly.

[0433] In some implementations, the PTH compound is a PTH compound of formula (XI), administered, for example, once daily via subcutaneous injection. A suitable starting dose for treatment with a PTH compound of formula (XI) may be 18 µg / day, wherein this dose is based solely on the weight of the PTH portion and excludes the remainder of the PTH compound.

[0434] In some embodiments, the PTH compound is the PTH compound of SEQ ID NO: 122, for example, administered once daily via subcutaneous injection.

[0435] In some embodiments, the PTH compound is a PTH compound of formula (XII) or (XII') and can be administered, for example, once a week by subcutaneous injection.

[0436] In some embodiments, the PTH compound is a PTH compound of formula (XIII) or (XIII'), which may be administered, for example, once a week by subcutaneous injection.

[0437] In some embodiments, the starting dose range of the compound of formula (XI) is 12 to 24 µg PTH 1-34 daily. In some embodiments, the starting dose range of the compound of formula (XI) is 15 to 21 µg PTH 1-34 daily. In some embodiments, the starting dose of the compound of formula (XI) is 18 ± 3 µg PTH 1-34 daily. In some embodiments, the starting dose of the compound of formula (XI) is 18 µg PTH 1-34 daily.

[0438] In some embodiments, the PTH compound is a compound of formula (XI) and is administered to the subject in the form of a pharmaceutical composition. In some embodiments, 1 ml of such a pharmaceutical composition comprises 3456 µg of the compound of formula (XI), equivalent to 300 µg of PTH 1-34, 1.18 mg of succinic acid, 41.7 mg of mannitol, 2.5 mg of m-cresol, 0.13 mg of sodium hydroxide, and water for injection, with a pH of 3.7 to 4.3. In some embodiments, 1 ml of such a pharmaceutical composition comprises 3456 µg of the PTH compound of formula (XI), equivalent to 300 µg of PTH 1-34, namely 1.18 mg of succinic acid, 41.7 mg of mannitol, 2.5 mg of m-cresol, 0.13 mg of sodium hydroxide, and water for injection, with a pH of 3.7 to 4.3.

[0439] In some embodiments, the pharmaceutical composition is provided in 2-8 formulation strengths, each containing a different dose of the PTH compound of formula (XI). In some embodiments, the pharmaceutical composition is provided in 2-6 formulation strengths, each containing a different dose of the PTH compound of formula (XI). In some embodiments, the pharmaceutical composition is provided in 2-4 formulation strengths, each containing a different dose of the PTH compound of formula (XI). In some embodiments, the pharmaceutical composition is provided in 3 formulation strengths, each containing a different dose of the PTH compound of formula (XI). In some embodiments, each formulation strength is a pre-filled pen.

[0440] In some embodiments, the pharmaceutical composition is provided in three formulation strengths, wherein the first formulation strength is a prefilled pen containing 168 µg PTH 1-34 / 0.56 mL, the second formulation strength is a prefilled pen containing 294 µg PTH 1-34 / 0.98 mL, and the third formulation strength is a prefilled pen containing 420 µg PTH 1-34 / 1.4 mL, wherein PTH 1-34 is provided in the form of the PTH compound of formula (XI).

[0441] The first of these three formulation strengths is for administration of 6, 9, or 12 µg PTH 1-34 / day; the second is for administration of 15, 18, or 21 µg PTH 1-34 / day; and the third is for administration of 24, 27, or 30 µg PTH 1-34 / day. Doses exceeding 30 to 60 µg (inclusive) PTH 1-34 / day may be administered in two consecutive doses. For example, a dose of 33 µg PTH 1-34 / day can be administered as a combination of 15 µg PTH 1-34 / day + 18 µg PTH 1-34 / day; a dose of 36 µg PTH 1-34 / day can be administered as a combination of 18 µg PTH 1-34 / day + 18 µg PTH 1-34 / day; a dose of 39 µg PTH 1-34 / day can be administered as a combination of 18 µg PTH 1-34 / day + 21 µg PTH 1-34 / day; a dose of 42 µg PTH 1-34 / day can be administered as a combination of 21 µg PTH 1-34 / day + 21 µg PTH 1-34 / day; and a dose of 45 µg PTH 1-34 / day can be administered as a combination of 21 µg PTH 1-34 / day + 24 µg PTH The dosage can be administered in combination of 1-34 doses per day; a 48 µg PTH 1-34 day dose can be administered in combination of 24 µg PTH 1-34 day doses + 24 µg PTH 1-34 day doses; a 51 µg PTH 1-34 day dose can be administered in combination of 24 µg PTH 1-34 day doses + 27 µg PTH 1-34 day doses; a 54 µg PTH 1-34 day dose can be administered in combination of 27 µg PTH 1-34 day doses + 27 µg PTH 1-34 day doses; a 57 µg PTH 1-34 day dose can be administered in combination of 27 µg PTH 1-34 day doses + 30 µg PTH 1-34 day doses; and a 60 µg PTH 1-34 day dose can be administered in combination of 30 µg PTH 1-34 day doses + 30 µg PTH The doses are administered in combination of 1-34 per day; wherein PTH 1-34 are provided by compound of formula (XI).

[0442] For patients with chronic kidney disease and hypoparathyroidism, treatment can begin as follows (a): (ia) Confirm that the subject’s serum 25(OH) vitamin D was within the normal range and serum calcium was ≥7.8 mg / dL at the start of treatment within two weeks prior to administration of the first dose of compound (XI); (ib) If the subject was taking active vitamin D at the start of treatment with compound (XI): (ibi) If serum calcium is ≥8.3 mg / dL, maintain the calcium supplement dose unchanged and discontinue active vitamin D on the day of the first dose of compound (XI); or (ib-ii) If serum calcium < 8.3 mg / dL, reduce the dose of active vitamin D by ≥ 50% on the day of the first dose of compound (XI), while maintaining the calcium supplement dose unchanged; or If the subject did not take active vitamin D at the start of treatment with compound (XI): (ib-iii) Reduce the calcium supplement dose by at least 1500 mg on the day of the first dose of compound (XI); and (ic) Optional: Continue taking dietary calcium supplements at a dose ≤600 mg / day to meet dietary calcium requirements.

[0443] In some implementations, if the serum 25(OH) vitamin D concentration is 20 to 80 ng / ml, then the serum 25(OH) vitamin D is within the normal range.

[0444] If the subject is not taking active vitamin D and is taking a daily calcium supplement of ≤1500 mg calcium / day, then the calcium supplement should be completely discontinued in step (ib-iii).

[0445] In some implementations, for subjects with chronic kidney disease and hypoparathyroidism, the treatment in step (a) can be initiated in the following manner: (ia) Confirm that the subject’s serum 25(OH) vitamin D was within the normal range and serum calcium was ≥7.8 mg / dL at the start of treatment within two weeks prior to administration of the first dose of compound (XI); (ib) If the subject was taking active vitamin D at the start of treatment with compound (XI): (ibi) If serum calcium is ≥8.3 mg / dL and current active vitamin D intake is >1 μg / day on the day treatment with this PTH compound begins, maintain the calcium supplement dose unchanged and reduce the active vitamin D dose by ≥50%; or (ib-ii) If serum calcium is ≥8.3 mg / dL, and the current active vitamin D intake on the day the PTH compound treatment begins is ≤1 μg / day, maintain the calcium supplement dose and discontinue the active vitamin D dose; or (ib-iii) If serum calcium is ≥7.8 mg / dL and <8.3 mg / dL, regardless of the amount of active vitamin D intake on the day the PTH compound treatment begins, maintain the calcium supplement dose unchanged and reduce the active vitamin D dose by ≥50%; or If the subject did not take active vitamin D at the start of compound (XI) treatment: (ib-iii) If serum calcium is ≥7.8 mg / dL, reduce the daily dose of calcium supplement by at least 1500 mg; if the current daily dose of calcium is ≤1500 mg / day, discontinue calcium supplementation; and (ic) Optional to continue dietary calcium supplementation at a dose ≤600 mg / day to meet dietary calcium requirements.

[0446] In some implementations, step (a) may include, in addition to steps (ia) to (ic), the following steps: (id) Administer an initial dose of 18 µg PTH 1-34 / day in the form of compound of formula (XI), followed by the same dose daily. (ie) Measure serum calcium within 7 to 14 days after the first administration of compound (XI); (if) Adjust the dosage of (XI) compounds, active vitamin D and / or calcium supplements.

[0447] In some embodiments, the compound of formula (XI) is administered as a pharmaceutical composition in step (id), wherein each ml contains 3456 µg of the compound of formula (XI) (equivalent to 300 µg of PTH 1-34), 1.18 mg of succinic acid, 41.7 mg of mannitol, 2.5 mg of m-cresol, 0.13 mg of sodium hydroxide, and water for injection. In some embodiments, the pH of the pharmaceutical composition is from 3.7 to 4.3.

[0448] In step (if), the dosage of the compound of formula (XI), active vitamin D, and / or calcium supplement is adjusted based on the serum calcium level in step (ie).

[0449] In some implementations, the dosage of the compound of formula (XI), active vitamin D, and / or calcium supplement in step (if) is adjusted as follows: (ifi) If serum calcium < 8.3 mg / dL: • If ≥7 days have passed since starting treatment with compound (XI) or changing the dosage of compound (XI), continue taking the same dosage of calcium supplement and active vitamin D, and increase the dosage of compound (XI) by 3 µg; or • If less than 7 days have passed since starting treatment with compound (XI) or adjusting the dose of compound (XI), the calcium supplement and / or active vitamin D may be increased to the previous dose based on the doctor's clinical judgment, and the same dose of compound (XI) may continue to be used. (if-ii) If serum calcium ranges from 8.3 to 10.6 mg / dL: • If ≥7 days have passed since the start of treatment with the compound of formula (XI) or since the dose of the compound of formula (XI) was changed, and the subject is still taking active vitamin D, then the active vitamin D should be discontinued and the dose of the compound of formula (XI) should be increased by 3 µg. • If ≥7 days have passed since the start of treatment with the compound of formula (XI) or since the change of the dose of the compound of formula (XI), and the subject is no longer taking active vitamin D but is taking calcium supplements of ≥1500 mg / day, then the calcium supplement dose shall be reduced by ≥1500 mg and the dose of the compound of formula (XI) shall be increased by 3 µg. • If ≥7 days have passed since the start of treatment with the compound of formula (XI) or since the change of the dose of the compound of formula (XI), and the subject is no longer taking active vitamin D but is taking calcium supplements of less than 1500 mg / day, then the calcium supplements should be discontinued and the dose of the compound of formula (XI) should be increased by 3 µg. • If ≥7 days have passed since the start of treatment with a compound of formula (XI) or since the dose of a compound of formula (XI) was changed, and the subject has stopped taking active vitamin D and calcium supplements, continue using the same dose of the compound of formula (XI); or • If less than 7 days have passed since the start of treatment with the compound of formula (XI) or since the change of the dose of the compound of formula (XI), continue to use the same dose of the compound of formula (XI), calcium supplement and active vitamin D; (if-iii) If serum calcium ranges from 10.7 to 11.9 mg / dL: • If the subject is still taking active vitamin D, discontinue taking active vitamin D and continue taking the same dose of the compound of formula (XI) and calcium supplement; • If the subject is not taking active vitamin D but is taking calcium supplements at a dose of ≥1500 mg / day, the dose of calcium supplements shall be reduced by ≥1500 mg and the same dose of compound (XI) shall continue to be taken. • If the subject is not taking active vitamin D but is taking calcium supplements, where the calcium supplement is less than 1500 mg / day, then the calcium supplement should be discontinued and the same dose of the compound of formula (XI) should be continued; or • If the subject is not taking active vitamin D and is not taking calcium supplements, reduce the dose of the compound of formula (XI) by 3 µg; or (if-iv) If serum calcium ≥ 12 mg / dL: • Discontinue use of compound (XI) for 2 to 3 days, and recheck serum calcium and... • If subsequent serum calcium is <12 mg / dL, titrate using the most recently obtained serum calcium, the restorative (XI) compound, active vitamin D, and calcium supplement, as described in steps (ifi) to (if-iii); • If serum calcium remains ≥ 12 mg / dL, discontinue use of compound (XI) for 2 to 3 days, recheck serum calcium, and proceed as described in the previous step.

[0450] In some embodiments, the dosage of the compound of formula (XI) administered to the subject ranges from 6 to 60 µg PTH1-34 / day (inclusive), and these dosages can be delivered via pre-filled syringes in the following specifications: 168 µg PTH1-34 / 0.56 mL (delivering a dose of 6, 9, or 12 µg PTH1-34); 294 µg PTH1-34 / 0.98 mL (delivering a dose of 15, 18, or 21 µg PTH1-34); and 420 µg PTH1-34 / 1.4 mL (delivering a dose of 24, 27, or 30 µg PTH1-34).

[0451] In some implementations, the dosage of the compound of formula (XI) in step (if), active vitamin D, and / or calcium supplement is adjusted as follows: If serum calcium is <8.3 mg / dL: • If ≥7 days have passed since starting treatment with a compound of formula (XI) or changing the dose of a compound of formula (XI), continue taking the same dose of calcium supplement and active vitamin D, and increase the dose of the compound of formula (XI) by 3 µg; or • If less than 7 days have passed since the start of treatment with compound (XI) or the change of the dosage of compound (XI), the calcium supplement and / or active vitamin D may be increased to the previous dosage based on the doctor’s clinical judgment, and the same dosage of compound (XI) may continue to be used. If serum calcium is between 8.3 and 10.6 mg / dL: • If less than 7 days have passed since starting treatment with a compound of formula (XI) or changing the dose of a compound of formula (XI), continue using the same dose of the compound of formula (XI), calcium supplement, and active vitamin D. • If ≥7 days have passed since the start of treatment with the compound of formula (XI) or the dose of the compound of formula (XI) has been changed, and the subject is still taking active vitamin D, reduce or stop taking active vitamin D and increase the dose of the compound of formula (XI) by 3 µg. • If ≥7 days have passed since the start of treatment with compound (XI) or the dose of compound (XI) has been changed, and the subject has stopped taking active vitamin D and calcium supplements, then continue taking the same dose of compound (XI). • If ≥7 days have passed since the start of treatment with the compound of formula (XI) or the dose of the compound of formula (XI) has been changed, and the subject is no longer taking active vitamin D and is taking a calcium supplement at a dose of ≥1500 mg / day, then the calcium supplement should be reduced by ≥1500 mg and the dose of the compound of formula (XI) should be increased by 3 µg. • If ≥7 days have passed since the start of treatment with the compound of formula (XI) or the dose of the compound of formula (XI) has been changed, and the subject is no longer taking active vitamin D and is taking a calcium supplement at a dose ≤ 1500 mg / day, then the calcium supplement should be discontinued and the dose of the compound of formula (XI) should be increased by 3 µg. If serum calcium is between 10.7 and 11.9 mg / dL: • If the patient is still taking active vitamin D, reduce or stop taking active vitamin D and continue taking the same dose of the compound of formula (XI) and calcium supplements; • If the patient no longer takes active vitamin D and calcium supplements, reduce the dose of the compound of formula (XI) by 3 µg; • If the patient no longer takes active vitamin D but is still taking calcium supplements of ≥ 1500 mg / day, reduce the calcium supplements by ≥ 1500 mg and continue taking the same dose of the compound of formula (XI); • If the patient stops taking active vitamin D but continues to take calcium supplements at a dose <1500 mg / day, then stop taking calcium supplements and continue taking the same dose of the compound of formula (XI); If serum calcium is 12 mg / dL or higher, discontinue the use of compound (XI) for 2 to 3 days, recheck serum calcium and repeat. If serum calcium is still 12 mg / dL or higher, and once serum calcium is <12 mg / dL, resume the titration of compound (XI), active vitamin D and calcium supplement as described above.

[0452] In some embodiments, prior to application, the particulate matter and discoloration of the compound of formula (XI) or the pharmaceutical composition containing the compound of formula (XI) are visually inspected.

[0453] In some embodiments, the dosage adjustments of the PTH compound of formula (XI), active vitamin D, and calcium supplement are performed on the same day. Following a change in the dosage of the PTH compound of formula (XI), active vitamin D, or calcium supplement, serum calcium is measured within 7 to 14 days in some embodiments, and the clinical signs of hypocalcemia or hypercalcemia in the subject can be monitored, and the dosages of the PTH compound of formula (XI), active vitamin D, and / or calcium supplement can be adjusted as described above.

[0454] If at least 7 days have passed since the last dose change of the PTH compound of formula (XI), the dose of the PTH compound of formula (XI) may be increased in increments of 3 µg as described above. In some embodiments, the dose adjustment frequency of the PTH compound of formula (XI) administered to the subject may not exceed once every 7 days. For the above-mentioned hypercalcemia, the frequency of dose reduction of the PTH compound of formula (XI) may not exceed 3 µg every 3 days.

[0455] The maintenance dose should be the dose of the PTH compound of formula (XI) to achieve serum calcium within the normal range without the need for active vitamin D and calcium supplements. Optionally, sufficient calcium supplementation to meet dietary requirements may be continued. Once the maintenance dose is achieved, serum calcium can be measured according to standards of care.

[0456] In some implementations, in addition to steps (ia) to (if), step (a) further includes the following steps: (ig) Administer the daily maintenance dose; and (ih) Measure serum calcium according to standard nursing care.

[0457] Optionally, if serum calcium levels are not within the normal range (e.g., 8.3 to 10.6 mg / dL), repeat steps (if) to (ih) after step (ih).

[0458] If a dose of the PTH compound of formula (XI) is missed within 12 hours, it can be taken as soon as possible. If a dose is missed more than 12 hours, it can be skipped, and the next dose can be taken as scheduled. If three or more consecutive doses are missed, it is recommended to monitor for signs and symptoms of hypocalcemia and consider measuring serum calcium. If necessary, treatment with active vitamin D and calcium supplements can be resumed. In some implementations, after interruption, administration of the PTH compound of formula (XI) can be resumed as soon as possible at a prescribed dose, which may or may not be a maintenance dose. When resuming treatment after an interruption, serum calcium should be measured, and the doses of the PTH compound of formula (XI), active vitamin D, and calcium supplements can be adjusted as described above.

[0459] Pharmaceutical compositions and formulations of the PTH compounds of formula (XI) used in steps (ia) to (ig) are as described elsewhere herein.

[0460] In some embodiments, the PTH compound is the PTH compound of SEQ ID NO: 122, which is administered at a dose range of 20 µg / day to 60 µg / day.

[0461] In some embodiments, the PTH is a PTH compound of formula (XII) or (XII'), with an initial dose range of 100 µg / week to 250 µg / week, 101.25 µg / week to 168.75 µg / week, 108 µg / week to 162 µg / week, 114.75 µg / week to 155.25 µg / week, 121.5 µg / week to 148.5 µg / week, or 128.25 µg / week to 141.75 µg / week. In some embodiments, the PTH is a PTH compound of formula (XII) or (XII'), with an initial dose of about 135 µg / week.

[0462] Example Synthesis of Compound 1 Compound 1, also known as pallopegteriparatide, has the following structure: (XI), in Unmarked dashed lines indicate the connection of nitrogen to the N-terminal amine group of the PTH portion of SEQ ID NO:51; The dashed line marked with an asterisk indicates a connection to the following section. in in The dashed line indicates the relationship with -L 2- or the connection with the rest of -Z; m and p are integers ranging from approximately 450 to approximately 500.

[0463] Compound 1 can be prepared according to the description of compound 18 in Example 18 of WO2017 / 148883.

[0464] Example 1: TCP-304 In TCP-304 (NCT04701203), a phase III, double-blind, placebo-controlled trial, subjects were randomly assigned in a 3:1 ratio to receive either compound 1 or placebo for 26 weeks, followed by an open-label extension period in which all subjects received compound 1. In this trial, serum creatinine levels were measured at standard intervals, and the estimated glomerular filtration rate (eGFR) was calculated using the Modified Diet for Kidney Disease (MDRD) formula [Levey et al., 2006]. The MDRD formula is as follows: eGFR (mL / min / 1.73 m 2 = 175 × (serum creatinine mg / dL) -1.154 × (age) -0.203 ×0.742 [if female] × 1.212 [if black].

[0465] Inclusion criteria excluded individuals with eGFR < 30 mL / min / 1.73m 2 Subjects were included. eGFR data for TCP-304 were available from baseline to a 52-week follow-up period as of July 20, 2022. Mean eGFR at baseline was broadly similar across groups (compound 1: 67.32; placebo: 72.70), but remained consistently below 90 mL / min / 1.73 mcg. 2 Normal levels (Table 1). Most subjects in the TCP-304 group showed some degree of renal impairment at baseline. A total of 28.0% of the randomized subjects (compound 1 group: 31.1%; placebo group: 19.0%) had a baseline eGFR <60 mL / min / 1.73 mcg. 2 According to the 2012 KDIGO CKD guidelines, it is defined as stage 3a or more severe chronic kidney disease (CKD) [KDIGO CKD Work Group, 2013; KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1-150.].

[0466] Table 1: Baseline Renal Function – TCP-304

[0467] Abbreviations: eGFR = Estimated glomerular filtration rate; MDRD = Dietary modification for kidney disease; N = Number of participants; SD = Standard deviation Table 2 shows the change in eGFR from baseline during the available 52-week follow-up period. Treatment with compound 1 was associated with a rapid increase (i.e., improvement) in eGFR, which was first observed at week 4 and persisted until week 52. The slope (95% CI) of the change in eGFR from baseline to week 4 was similar across all treatment groups (compound 1 / compound 1: 1.25 [0.6, 1.9] mL / min / 1.72 m 2 / week [P<.0001]; placebo / compound 1: 1.20 [0.3, 2.1]mL / min / 1.72m 2 / week [P<.01]). After week 4, subjects randomly assigned to compound 1 showed stable eGFR, with the slope of eGFR change (95% CI) being 0.20 (-0.2, 0.6) mL / min / 1.72m from week 4 to week 12. 2 / week (P ≥ 0.05), from week 12 to week 26: 0.07 (-0.1, 0.3) mL / min / 1.72m 2 / week (P ≥ 0.05), and from week 26 to week 52, 0.05 (-0.1, 0.2) mL / min / 1.72m 2 / week (P ≥ .05). Conversely, in subjects randomly assigned to the placebo group, eGFR changes reversed back to baseline after week 4, with a negative slope (95% CI) of -0.23 (-0.8, 0.3) mL / min / 1.72m from week 4 to week 12. 2 / week (P ≥ 0.05), from week 12 to week 26: -0.43 (-0.8, -0.1) mL / min / 1.72m 2 / week (P<.05). After starting compound 1 at week 26, the slope (95% CI) of the eGFR change significantly increased from week 26 to week 52 to 0.30 (0.1, 0.2) mL / min / 1.72m 2 / week (P<.01).

[0468] At the end of the blinded treatment period at week 26, an increase in mean eGFR of 7.90 mL / min / 1.73 m was observed in subjects randomized to receive compound 1. 2(95% CI: 5.20, 10.59), while the eGFR of the placebo-treated subjects decreased by -1.91 mL / min / 1.73 m 2 (95% CI: -6.05, 2.24) (Table 2). Paired t-tests revealed that the increase in eGFR from baseline was significantly greater than 0 in subjects receiving compound 1 (p < 0.0001, paired t-test), while this was not the case in subjects receiving placebo (p = 0.3468). To determine the treatment difference between compound 1 and placebo at week 26, an ANCOVA model was used with the change in eGFR from baseline as the dependent variable, treatment regimen, baseline eGFR group, and sex as fixed effects, and baseline eGFR and age as covariates. Using this model, the least squares mean (SE) difference in compound 1 treatment compared to placebo was 8.80 (2.50) mL / min / 1.73 m 2 During the open-label extension period, subjects initially randomized to compound 1 showed a significant increase in eGFR at week 26, which was maintained at week 52. Specifically, we observed a mean increase of 9.28 mL / min / 1.73 m from baseline. 2 (95% CI: 6.23, 12.33), and this value was again significantly greater than 0 by paired t-test (p<0.0001). During the open-label extension period, subjects initially randomized to the placebo group showed a mean increase in eGFR of 7.55 mL / min / 1.73 m from baseline after 26 weeks of treatment with active compound 1. 2 (95% CI: 3.35, 11.75). The increase was also significantly greater than 0 by paired t-test (p = 0.0014).

[0469] Table 2: Changes in eGFR from baseline at week 26 (end of blinding period) and week 52 (open-label extension period) - TCP-304

[0470] *Derived from a paired t-test, testing whether the change is >0. †Calculated using an ANCOVA model with the change in eGFR relative to baseline as the dependent variable, treatment, baseline eGFR group, and sex as fixed effects, and baseline eGFR and age as covariates.

[0471] Abbreviations: CI = Confidence Interval; eGFR = Estimated Glomerular Filtration Rate; MDRD = Dietary Modification for Kidney Disease; N = Number of Participants; SD = Standard Deviation; SE = Standard Error To supplement the above analysis, a response analysis was also conducted in the intention-to-treat (ITT) population, where a treatment response was defined as an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline. 2 (Table 3). For subjects randomly assigned to compound 1, 57.4% and 63.9% of subjects, respectively, demonstrated an eGFR response at weeks 26 and 52. The response rate for subjects randomly assigned to placebo was 23.8% at week 26, increasing to 52.4% at week 52 after 26 weeks of treatment with the open-label active compound 1. Additional responder analyses were performed, defining a response as an increase in eGFR ≥ 10 mL / min / 1.73 m from baseline. 2 For subjects randomly assigned to compound 1, 42.6% experienced an increase in eGFR ≥ 10 mL / min / 1.73 m from baseline at both weeks 26 and 52. 2 At week 26, 9.5% of subjects randomly assigned to placebo had an increase in eGFR ≥ 10 mL / min / 1.73 m from baseline. 2 After 26 weeks of treatment with open-label active compound 1, the increase rose to 28.6% at week 52.

[0472] Table 3: eGFR increase compared to baseline ≥ 5 mL / min / 1.73m 2 and ≥10 mL / min / 1.73m 2 Proportion of patients (ITT population, all subjects) - TCP-304

[0473] Treatment response was defined as an increase in eGFR of ≥5 mL / min / 1.73 m from baseline. 2 Or an increase in eGFR of ≥10 mL / min / 1.73 m from baseline. 2 .

[0474] Abbreviations: eGFR = Estimated glomerular filtration rate; ITT = Intention-to-treat; MDRD = Dietary modification for kidney disease; N = Number of subjects in the ITT population; n = Number of subjects who responded to treatment. Both baseline changes and responder analysis results indicated that, in TCP-304, treatment with compound 1 resulted in a sustained increase in eGFR >8 mL / min / 1.73 mcg over a 52-week treatment period. 2 Related. These changes in the eGFR include: 1. Significantly higher than the estimated +2.13 to 3.02 mL / min / 1.73 mcg for rhPTH(l-84) after 1 year of treatment. 2 The increase in [Ayodele et al., Adv Ther. 2022 Nov; 39(11):5013-5024; Chen et al., J Clin Endocrinol Metab. 2020 Oct 1; 105(10):e3557-65]; and 2. In most subjects who received compound 1 for ≥ 26 weeks, the change in eGFR was greater than 5 mL / min / 1.73m 2 It is considered to have clinical significance [Hirst et al., Br J Gen Pract. 2022 Mar 31; 72(717):e261-e268, KDIGO CKD Work Group, 2013, Kidney inter., Suppl. 2013; 3: 1-150].

[0475] Analysis of changes in eGFR from baseline during the 52-week follow-up period was also performed according to the eGFR subgroup (i.e., <60 mL / min / 1.73 m). 2 Comparison ≥ 60 mL / min / 1.73 m 2 The study was conducted. At baseline, the eGFR of 23 subjects was <60 mL / min / 1.73 m. 2 (Compound 1 group: n = 19; placebo group: n = 4), 59 subjects had eGFR ≥ 60 mL / min / 1.73 m 2 (Compound 1 group: n = 42; Placebo group: n = 17). Regardless of baseline eGFR subgroup, compound 1 treatment was again associated with a rapid increase in eGFR, which was first observed at week 4 and continued to improve until week 52. In all treatment groups, the change in eGFR from baseline to week 4 was similar in both eGFR subgroups. After week 4, subjects randomly assigned to either eGFR subgroup of compound 1 showed stable eGFR, with baseline eGFR < 60 mL / min / 1.73 m 2 The subjects in the placebo group showed the greatest mean increase in eGFR values. Conversely, subjects randomly assigned to the placebo group in both eGFR subgroups experienced a reversal of eGFR changes, with values ​​returning to baseline levels by week 26. Following the introduction of open-label active compound 1 at week 26, significant increases in eGFR were observed in both eGFR subgroups, with baseline eGFR < 60 mL / min / 1.73 m 2 The subjects showed the greatest average increase in eGFR values.

[0476] As mentioned above, 28% of all randomly assigned subjects in TCP-304 had a baseline eGFR <60 mL / min / 1.73 m 2 (Stage 3a CKD or more severe). Given the critical clinical significance of maintaining residual renal function in such patients, baseline changes in eGFR were analyzed in this subgroup up to week 52 (Table 4a). For this eGFR subgroup, at the end of the blinded treatment period at week 26, subjects treated with compound 1 showed a mean increase in eGFR of 11.36 mL / min / 1.73 mL. 2 (95% CL 6.20, 16.52), while the mean increase in eGFR in subjects receiving placebo was 0.05 mL / min / 1.73m 2 (95% CI: -9.46, 9.56). Paired t-tests showed that the increase relative to baseline was significantly greater than 0 in subjects receiving compound 1 (p = 0.0002), but not in subjects receiving placebo (p = 0.9877). Using the ANCOVA model described above, treatment with compound 1 resulted in eGFR < 60 mL / min / 1.73 mcg at baseline. 2 For the subjects, the least squares mean (SE) difference between compound 1 and placebo was 12.44 (5.86) mL / min / 1.73m 2 (p = 0.0479). During the open-label extension period, we again observed a sustained increase in eGFR in subjects randomly assigned to the compound 1 eGFR subgroup at week 52. Specifically, we observed a mean increase of 11.46 mL / min / 1.73 m from baseline. 2 (95% CI: 6.03, 16.89), again confirmed by paired t-test to be significantly greater than 0 (p = 0.0003). Furthermore, in subjects initially randomized to placebo who received compound 1 for 26 weeks during the open-label extension period, the mean increase in eGFR compared to baseline was 11.65 mL / min / 1.73 m 2 (95% CI: 8.13, 15.17); this increase was also significantly greater than 0 by paired t-test (p = 0.0018). Importantly, the sustained increase in eGFR observed in the eGFR subgroup treated with compound 1 in TCP-304 was higher than the clinically significant eGFR change of 5 mL / min / 1.73 m 2 [Hirst et al., 2022, KDIGO CKD Work Group, 2013].

[0477] For baseline eGFR ≥ 60 mL / min / 1.73 m 2 Similar results were observed in subjects receiving compound 1 (Table 4b), with a mean increase in eGFR of 6.29 mL / min / 1.73 m at the end of the blinded treatment period at week 26. 2 (95% CI: 3.13, 9.45), while the eGFR of subjects treated with placebo decreased by -2.43 mL / min / 1.73 m 2 (95% CI: -7.56, 2.71). Paired t-tests showed that the increase from baseline was significantly greater than 0 in subjects receiving compound 1 (p = 0.0002), but not in subjects receiving placebo (p = 0.3280). Using the ANCOVA model described above, treatment with compound 1 resulted in a least-squares mean (SE) difference of 7.68 (2.68) mL / min / 1.73 m 2 (p = 0.0060). During the open-label extension period, we again observed that at week 52, subjects randomly assigned to the eGFR subgroup of compound 1 showed a sustained and statistically significant increase in eGFR of 8.25 mL / min / 1.73 m 2 (95% CI: 4.43, 12.06, p < 0.0001). Furthermore, subjects initially randomized to placebo experienced a mean increase in eGFR of 6.45 mL / min / 1.73 m³ / min compared to baseline after 26 weeks of treatment with compound 1 during the open-label extension period. 2 (95% CI: 1.18, 11.72); this increase was also significantly greater than 0 by paired t-test (p = 0.0199).

[0478] Table 4a: Baseline eGFR < 60 mL / min / 1.73 m 2 The subjects' eGFR - TCP-304 was measured at week 26 (end of blinding) and week 52 (open-label extension).

[0479] *Derived from a paired t-test, testing whether the change is >0. †Calculated using an ANCOVA model with the change in eGFR relative to baseline as the dependent variable, treatment, baseline eGFR group, and sex as fixed effects, and baseline eGFR and age as covariates.

[0480] Abbreviations: CI = Confidence Interval; eGFR = Estimated Glomerular Filtration Rate; MDRD = Dietary Modification for Kidney Disease; LSMean = Least Squares Mean; N = Number of Subjects; SD = Standard Deviation; SE = Standard Error Table 4b: Baseline eGFR ≥ 60 mL / min / 1.73 m 2 The subjects' eGFR - TCP-304 was measured at week 26 (end of blinding) and week 52 (open-label extension).

[0481] *Derived from a paired t-test, testing whether the change is >0. †Calculated using an ANCOVA model with the change in eGFR relative to baseline as the dependent variable, treatment, baseline eGFR group, and sex as fixed effects, and baseline eGFR and age as covariates.

[0482] Abbreviations: CI = Confidence Interval; eGFR = Estimated Glomerular Filtration Rate; MDRD = Dietary Modification for Kidney Disease; LSMean = Least Squares Mean; N = Number of Subjects; SD = Standard Deviation; SE = Standard Error To supplement the above analyses, responder analyses were also performed for each eGFR subgroup in the intention-to-treat (ITT) population (Tables 5a and 5b). For those randomly assigned to compound 1, baseline response was <60 mL / min / 1.73 m 2 Of the participants, 73.7% and 68.4% experienced an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline at weeks 26 and 52, respectively. 2 Furthermore, 47.4% and 42.1% of subjects, respectively, experienced an increase in eGFR of ≥ 10 mL / min / 1.73 m from baseline at weeks 26 and 52. 2 At weeks 26 and 52, the baseline eGFR for randomized individuals to compound 1 was ≥60 mL / min / 1.73 m. 2 A considerable treatment response rate was observed in the subjects (regardless of the response threshold).

[0483] For individuals randomly assigned to placebo, baseline eGFR < 60 mL / min / 1.73 m 2 Of the participants, 25% experienced an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline at week 26. 2After 26 weeks of treatment with open-label active compound 1, this increase reached 100% at week 52. At week 26, for baseline ≥ 60 mL / min / 1.73m 2 Among the subjects, a response rate of 23.5% was observed, and at week 52, 41.2% of subjects achieved an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline. 2 .

[0484] At week 26, baseline eGFR < 60 mL / min / 1.743 mJ / min was observed in individuals randomly assigned to placebo. 2 In 0% of the subjects, the increase in eGFR compared to baseline was ≥ 10 mL / min / 1.73m 2 However, after 26 weeks of treatment with open-label active compound 1, this increase rose to 75% at week 52. For baseline eGFR ≥ 60 mL / min / 1.743 m... 2 Of the participants, 11.8% and 17.6% experienced an increase in eGFR of ≥ 10 mL / min / 1.73 m from baseline at weeks 26 and 52, respectively. 2 .

[0485] Table 5a: In subjects with baseline eGFR < 60, an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline was considered significant. 2 and an increase in eGFR of ≥10 mL / min / 1.73m from baseline. 2 Proportion of patients (ITT population) - TCP-304

[0486] Treatment response was defined as an increase in eGFR of ≥5 mL / min / 1.73 m from baseline. 2 Or an increase in eGFR of ≥10 mL / min / 1.73 m from baseline. 2 .

[0487] Abbreviations: eGFR = Estimated glomerular filtration rate; ITT = Intention-to-treat; MDRD = Dietary modification for kidney disease; N = Number of subjects in the ITT population; n = Number of subjects who responded to treatment. Table 5b: In subjects with baseline eGFR ≥ 60, an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline was considered significant. 2 An increase in eGFR compared to baseline of ≥10 mL / min / 1.73m 2 Proportion of patients (ITT population) - TCP-304

[0488] Treatment response was defined as an increase in eGFR of ≥5 mL / min / 1.73 m from baseline. 2 Or an increase in eGFR of ≥10 mL / min / 1.73 m from baseline. 2 .

[0489] Abbreviations: eGFR = Estimated glomerular filtration rate; ITT = Intention-to-treat; MDRD = Dietary modification for kidney disease; N = Number of subjects in the ITT population; n = Number of subjects who responded to treatment. In subsequent analyses, the observed improvement in eGFR compared to baseline was maintained throughout the 104-week follow-up period. At week 104, 93% (76 / 82) of the participants remained in the trial. The mean (SD) eGFR was 77.8 (14.8) mL / min / 1.73 m 2 Paroperitone treatment increased eGFR by an average of 8.9 (11.0) mL / min / 1.73 m from baseline to week 52 (SD). 2 (P<.0001), this continued until week 104, with a mean (SD) change of 9.0 (10.3) mL / min / 1.73m compared to baseline. 2 (P<.0001). By week 104, 61% and 44% of participants had an increase in eGFR of ≥5 mL / min / 1.73 m, respectively. 2 and ≥10 mL / min / 1.73m 2 At baseline, eGFR < 60 mL / min / 1.73m 2 Among the participants (n=23), paroperitone treatment increased eGFR from baseline to week 104 by a mean (SD) of 13.8 (10.0) mL / min / 1.73 m 2 Furthermore, 78% and 57% of participants showed an increase in eGFR of ≥5 mL / min / 1.73 m, respectively. 2 and ≥10 mL / min / 1.73m 2 .

[0490] Example 2: TCP-201 In TCP-201 (NCT04009291), a phase II, double-blind, placebo-controlled, parallel-group trial, subjects were randomized in a 1:1:1:1 ratio to receive the following treatments for 4 weeks: compound 1, 15 µg / day; compound 1, 18 µg / day; compound 1, 21 mcg / day; or the corresponding placebo. Following this 4-week placebo-controlled period was an open-label extension period in which all subjects received the active compound 1. In this trial, eGFR was measured at multiple time points using the MDRD formula [Levey et al., 2006]. Inclusion criteria excluded subjects with eGFR ≤ 30 mL / min / 1.73 mcg / day. 2 Subjects were included. As of June 1, 2022, eGFR data for TCP-201 were available from baseline to week 110 follow-up. Given the relatively short placebo-controlled period, pooled data were provided for all randomly assigned subjects. The mean eGFR at baseline was 69.39 mL / min / 1.73 m 2 Below 90 mL / min / 1.73 m 2 Normal levels (Table 6). Consistent with TCP-304, most subjects in TCP-201 showed some degree of renal impairment at baseline. Similar to TCP-304, 30.5% of the randomly assigned subjects in TCP-201 (18 out of 59 subjects) had a baseline eGFR <60 mL / min / 1.73 m 2 According to the 2012 KDIGO CKD Guidelines [KDIGO CKDWork Group, 2013], it is defined as stage 3a or more severe CKD.

[0491] Table 6: Baseline Renal Function - TCP-201

[0492] Abbreviations: eGFR = Estimated glomerular filtration rate; MDRD = Dietary modification for kidney disease; N = Number of subjects; SD = Standard deviation Given the substantial and clinically significant increase in eGFR observed in all subjects in TCP-304, as well as those with significantly impaired baseline renal function, we next examined the changes in eGFR from baseline over the available 110 weeks in TCP-201 (Table 7). At week 26, for subjects treated with compound 1, a mean increase in eGFR from baseline of 6.36 mL / min / 1.73 m 2(95% CI: 3.55, 9.17), significantly greater than 0 (p < 0.0001, paired t-test), similar to the early eGFR increase noted in TCP-304. Again consistent with the findings of TCP-304, the increase in eGFR relative to baseline in TCP-201 further increased at week 58 (mean increase: 8.54 mL / min / 1.73 m). 2 (95% CI: 5.30, 11.78), remained stable at week 110 (8.54 mL / min / 1.73 m). 2 (95% CI: 5.07, 11.59). At week 58 (p<0.0001) and week 110 (p<0.0001), the increase in eGFR from baseline was significantly greater than 0.

[0493] Table 7: Changes in eGFR from baseline at weeks 26, 58, and 110 for all subjects (open-label extension period) - TCP-201

[0494] *Derived from a paired t-test, testing whether the change is >0. Abbreviations: CI = Confidence Interval; eGFR = Estimated Glomerular Filtration Rate; MDRD = Dietary Modification for Kidney Disease; N = Number of Subjects; SD = Standard Deviation To supplement the above analysis, a responder analysis was also conducted using the ITT population, where a treatment response was defined as an increase in eGFR of ≥ 5 mL / min / 1.73 m from baseline. 2 (Table 8). Among subjects receiving compound 1, 52.5%, 66.1%, and 55.9% experienced an eGFR treatment response at weeks 26, 58, and 110, respectively.

[0495] Table 8: eGFR increase compared to baseline ≥5 mL / min / 1.73 m 2 The proportion of patients (ITT population) -TCP-201

[0496] Treatment response was defined as an increase in eGFR of ≥5 mL / min / 1.73 m from baseline. 2 .

[0497] Abbreviations: eGFR = Estimated glomerular filtration rate; ITT = Intention-to-treat; MDRD = Dietary modification for kidney disease; N = Number of subjects in the ITT population; n = Number of subjects who responded to treatment. These eGFR changes in a similar patient population in TCP-201 complement and corroborate the eGFR results in TCP-304. Both the changes compared to baseline and the responder analysis results indicate that in TCP-201, treatment with compound 1 (consistent with TCP-304) resulted in eGFR > 8 mL / min / 1.73 mcg / min over 110 weeks of treatment. 2 The correlation continues to increase. These changes in the eGFR are: 1. Significantly higher than the estimated +2.13 to 3.02 mL / min / 1.73 mcg for rhPTH(l-84) after 1 year of treatment. 2 The increase in magnitude [Ayodele et al., 2022; Chen et al., 2020]; and 2. In most subjects who received compound 1 for ≥ 26 weeks, the change in eGFR was greater than 5 mL / min / 1.73m 2 It is considered to have clinical significance [Hirst et al., 2022, KDIGO CKD Work Group, 2013].

[0498] As shown above, 30.5% (18 out of 59 subjects) of all randomly assigned subjects in TCP-201 had a baseline eGFR < 60 mL / min / 1.73 m 2 (Stage 3a CKD or more severe). Maintaining residual renal function is of significant clinical importance for patients in this subgroup with significantly impaired baseline renal function. Given that all subjects in TCP-304, as well as those with significantly impaired baseline renal function, had clinically significant increases in eGFR, we next examined baseline eGFR <60 mL / min / 1.73 mcg in TCP-201. 2 The change in eGFR of the subjects compared to baseline (Table 9).

[0499] For this subgroup of subjects receiving TCP-201 at week 26, an average increase in eGFR of 7.99 mL / min / 1.73 m was observed in subjects receiving compound 1. 2 (95% CI: 3.72, 12.26). Using a paired t-test, the increase in eGFR from baseline in subjects receiving compound 1 at week 26 was significantly greater than 0 (p = 0.0011). Consistent with findings from TCP-304, the increase in eGFR from baseline in this subgroup of TCP-201 was observed at week 58 (mean increase: 11.79 mL / min / 1.73 m). 2 (95% CI: 7.76, 15.83) and at week 110 (8.49 mL / min / 1.73 m 2(95% CI: 3.69, 13.28) This was maintained. At week 58 (p<0.0001) and week 110 (p = 0.0018), the increase in eGFR from baseline was significantly greater than 0. These changes in eGFR in patients with baseline renal impairment in TCP-201 further complement and confirm the eGFR results in TCP-304.

[0500] Table 9: Baseline eGFR < 60 mL / min / 1.73 m 2 Changes in eGFR from baseline at weeks 26, 58, and 110 (open-label extension period) - TCP-201

[0501] *Derived from a paired t-test, testing whether the change is >0. Abbreviations: CI = Confidence Interval; eGFR = Estimated Glomerular Filtration Rate; MDRD = Dietary Modification for Kidney Disease; N = Number of Subjects To the best of our knowledge, the data provided in Example 1 (TCP-304) and Example 2 (TCP-201) represent the first report of long-acting PTH compounds that resulted in clinically and statistically significant increases in eGFR compared to baseline (an increase of >8 mL / min / 1.73 mcg). 2 Among them, >5 mL / min / 1.73m 2 The changes were clinically significant. Combining the data presented in Example 1 (TCP-304) and Example 2 (TCP-201), an increase in eGFR was observed: 1) Symptoms appeared at / after 26 weeks of treatment with compound 1, and were significantly higher compared to placebo; 2) This continues until week 104 (TCP-304) and week 110 (TCP-201); 3) Significantly higher than the estimated eGFR of +2.13 to 3.02 mL / min / 1.73 m after 1 year of rhPTH (l-84) treatment. 2 The increase in magnitude [Ayodele et al., 2022; Chen et al., 2020]; 4) In TCP-304 and TCP-201, most subjects treated with compound 1 for ≥104 weeks showed an increase in eGFR ≥ 5 mL / min / 1.73m 2 ; 5) The value was higher in subjects with significantly impaired baseline renal function (stage 3a CKD or more).

Claims

1. A PTH compound for the prevention of CKD in a subject at risk of developing chronic kidney disease (CKD) or for the treatment of a subject with CKD.

2. The PTH compound for the purpose of claim 1, wherein the PTH compound is used to treat a subject with CKD.

3. The PTH compound for the purpose of claim 1, wherein the PTH compound is used to prevent CKD in subjects at risk of developing CKD.

4. The PTH compound for the stated purpose according to claim 1 or 3, wherein the renal function of the subject with CKD is assessed at least once by blood and / or urine tests before administration of a pharmaceutically effective dose of the PTH compound.

5. The PTH compound for the stated use according to any one of claims 1 to 4, wherein the renal function of a subject at risk of or with CKD is assessed at least twice by blood and / or urine tests, wherein the first assessment is prior to the first administration of the PTH compound and the second assessment is after administration of one or more doses of the PTH compound.

6. The PTH compound for the stated purpose according to claim 5, wherein the second evaluation is performed after multiple doses have been administered.

7. The PTH compound for the stated purpose according to claim 5 or 6, wherein the second evaluation is performed after at least two weeks of treatment, at least four weeks of treatment, at least two months of treatment, or at least six months of treatment.

8. The PTH compound for the purpose according to any one of claims 4 to 7, wherein a blood test measures the amount of creatinine in the blood.

9. The PTH compound for the said use according to any one of claims 4 to 8, wherein a urine test measures the urine albumin / creatinine ratio (UCAR).

10. The PTH compound for the said use according to any one of claims 4 to 9, wherein renal function is measured in the form of an estimated glomerular filtration rate (eGFR).

11. The PTH compound for the stated use according to claim 10, wherein eGFR is measured at least once before administration of a pharmaceutically effective dose of the PTH compound.

12. The PTH compound for the stated purpose according to claim 10 or 11, wherein the eGFR is determined using the modified diet for kidney disease (MDRD) formula.

13. The PTH compound for the said use according to any one of claims 10 to 12, wherein eGFR is an indication of CKD.

14. The PTH compound for the said use according to any one of claims 10 to 13, wherein the subject's eGFR < 60 ml / min / 1.73 m 2 .

15. The PTH compound for the use according to any one of claims 1 to 14, wherein the subject suffers from hypoparathyroidism.

16. The PTH compound for the use according to any one of claims 1 to 15, wherein the subject suffers from chronic hypoparathyroidism.

17. The PTH compound for the purpose according to any one of claims 1, 2, 4 to 16, wherein the treatment improves the eGFR of the subject.

18. The PTH compound for the stated purpose according to any one of claims 1, 2, 4 to 17, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 5 ml / min / 1.73 m 2 .

19. The PTH compound for the stated purpose according to any one of claims 1, 2, 4 to 18, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 6 ml / min / 1.73 m 2 .

20. The PTH compound for the stated purpose according to any one of claims 1, 2, 4 to 19, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 7 ml / min / 1.73 m 2 .

21. The PTH compound for the stated purpose according to any one of claims 1, 2, 4 to 20, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 8 ml / min / 1.73 m 2 .

22. The PTH compound for the stated purpose according to any one of claims 1, 2, 4 to 21, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 9 ml / min / 1.73 m 2 .

23. The PTH compound for the said use according to any one of claims 17 to 22, wherein the improvement is achieved within 52 weeks of treatment.

24. The PTH compound for the said use according to any one of claims 17 to 23, wherein the average improvement is measured after treatment with the PTH compound for at least 110 weeks.

25. The PTH compound for the purpose according to any one of claims 1 to 24, wherein the PTH compound is applied multiple times.

26. The PTH compound for the purpose according to any one of claims 1, 2, or 4 to 25, wherein treatment is initiated after a diagnosis of CKD.

27. The PTH compound for the purpose according to any one of claims 1, 2 or 4 to 26, wherein treatment is performed for six months, one year, two years, three years, five years, or ten years, until medically indicated or until the death of the subject.

28. The PTH compound for the purpose according to any one of claims 1 to 27, wherein the PTH compound is administered daily.

29. The PTH compound for the purpose according to any one of claims 1 to 27, wherein the PTH compound is applied weekly.

30. The PTH compound for the purpose according to any one of claims 1 to 29, wherein a single dose of the PTH compound prolongs receptor signal transduction time by at least 10 times compared to a single equimolar dose of PTH 1-84.

31. The PTH compound for the said use according to any one of claims 1 to 30, wherein a single dose of the PTH compound prolongs the receptor signal transduction time by at least 15 times compared to a single equimolar dose of PTH 1-84.

32. The PTH compound for the said use according to any one of claims 1 to 31, wherein a single dose of the PTH compound prolongs the receptor signal transduction time by at least 20 times compared to a single equimolar dose of PTH 1-84.

33. The PTH compound for the said use according to any one of claims 1 to 32, wherein the compound is a compound of formula (XI). (XI), in Unmarked dashed lines indicate nitrogen linkage to the N-terminal amine group of the PTH portion of SEQ ID NO:51; and The dashed line marked with an asterisk indicates a connection to the following section. in The dashed line indicates the relationship with -L 2 - or the connection with the rest of -Z; and m and p are independent integers from 150 to 1000 including the endpoints; such as integers from 150 to 600 including the endpoints; such as integers from 200 to 550 including the endpoints; such as integers from 400 to 500 including the endpoints, or such as integers from about 450 to about 500.

34. The PTH compound for the said use according to any one of claims 1 to 32, wherein said compound is a compound of formula (XII'). (XII'), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer of approximately 200 to 250.

35. The PTH compound for the purpose according to any one of claims 1 to 32, wherein the PTH compound has the sequence SEQ ID NO:

122.

36. The PTH compound for the said use according to any one of claims 1 to 32, wherein the compound is a compound of formula (XIV). k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH(XIV), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2N; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is creatine; K is the L-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

37. The PTH compound for the said use according to any one of claims 1 to 32, wherein the compound is a compound of formula (XIV'). k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)–OH(XIV′), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is creatine; K is the L-isomer of lysine; -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

38. A method for preventing CKD in a subject at risk of developing chronic kidney disease (CKD) or for treating a subject with CKD, wherein the method comprises administering to the subject a pharmaceutically effective dose of a PTH compound.

39. The method of claim 38, wherein the method is a method of treating CKD in a subject suffering from CKD.

40. The method of claim 38, wherein the method is a method for preventing CKD in a subject at risk of developing CKD.

41. The method according to claim 38 or 40, wherein the renal function of the subject with CKD is assessed at least once by blood and / or urine tests before administering a pharmaceutically effective dose of the PTH compound.

42. The method according to any one of claims 38 to 41, wherein the renal function of a subject at risk of or with CKD is assessed at least twice by blood and / or urine tests, wherein the first assessment is prior to the first administration of the PTH compound and the second assessment is after administration of one or more doses of the PTH compound.

43. The method of claim 42, wherein the second evaluation is performed after the administration of multiple doses.

44. The method according to claim 42 or 43, wherein the second assessment is performed after at least two weeks of treatment, at least four weeks of treatment, at least two months of treatment, or at least six months of treatment.

45. The method according to any one of claims 41 to 44, wherein the blood test measures the amount of creatinine in the blood.

46. ​​The method according to any one of claims 41 to 45, wherein the urine test measures the urine albumin / creatinine ratio (UCAR).

47. The method according to any one of claims 41 to 46, wherein renal function is measured in the form of an estimated glomerular filtration rate (eGFR).

48. The method of claim 47, wherein eGFR is measured at least once before administering a pharmaceutically effective dose of the PTH compound.

49. The method of claim 47 or 48, wherein the eGFR is determined using the modified diet for kidney disease (MDRD) formula.

50. The method according to any one of claims 47 to 49, wherein eGFR is an indication of CKD.

51. The method according to any one of claims 47 to 50, wherein the subject's eGFR is < 60 ml / min / 1.73 m 2 .

52. The method according to any one of claims 38 to 51, wherein the subject suffers from hypoparathyroidism.

53. The method according to claims 38 to 52, wherein the subject suffers from chronic hypoparathyroidism.

54. The method according to any one of claims 38, 39, or 41 to 53, wherein, The treatment improved the subject's eGFR.

55. The method according to any one of claims 38, 39, or 41 to 54, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 5 ml / min / 1.73 m 2 .

56. The method according to any one of claims 38, 39, or 41 to 55, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 6 ml / min / 1.73 m 2 .

57. The method according to any one of claims 38, 39, or 41 to 56, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 7 ml / min / 1.73 m 2 .

58. The method according to any one of claims 38, 39, or 41 to 57, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 8 ml / min / 1.73 m 2 .

59. The method according to any one of claims 38, 39, or 41 to 58, wherein treatment with the PTH compound resulted in a mean improvement in the subject's eGFR of at least 9 ml / min / 1.73 m 2 .

60. The method according to any one of claims 54 to 59, wherein the average improvement is achieved within 52 weeks of treatment.

61. The method according to any one of claims 54 to 60, wherein the average improvement can be measured after at least 110 weeks of treatment with the PTH compound.

62. The method according to any one of claims 1 to 24, wherein the PTH compound is applied multiple times.

63. The method according to any one of claims 38, 39 or 41 to 62, wherein treatment begins after a diagnosis of CKD.

64. The method according to any one of claims 38, 39 or 41 to 63, wherein the treatment is performed for six months, one year, two years, three years, five years, or ten years, until there is a medical indication or until the subject's life ends.

65. The method according to any one of claims 38 to 64, wherein the PTH compound is administered daily.

66. The method according to any one of claims 38 to 64, wherein the PTH compound is applied weekly.

67. The method according to any one of claims 38 to 66, wherein a single dose of the PTH compound prolongs the receptor signal transduction time by at least 10 times compared to a single equimolar dose of PTH 1-84.

68. The method according to any one of claims 38 to 67, wherein a single dose of the PTH compound prolongs the receptor signal transduction time by at least 15 times compared to a single equimolar dose of PTH 1-84.

69. The method according to any one of claims 38 to 68, wherein a single dose of the PTH compound prolongs the receptor signal transduction time by at least 20 times compared to a single equimolar dose of PTH 1-84.

70. The method according to any one of claims 38 to 69, wherein the compound is a compound of formula (XI). (XI), in The unlabeled dashed lines indicate the connection of nitrogen to the N-terminal amine group of the PTH portion of SEQ ID NO:51; and The dashed line marked with an asterisk indicates a connection to the following section. in The dashed line indicates the relationship with -L 2 - or the connection with the rest of -Z; and m and p are independent integers from 150 to 1000 including the endpoints; such as integers from 150 to 600 including the endpoints; such as integers from 200 to 550 including the endpoints; such as integers from 400 to 500 including the endpoints, or such as integers from about 450 to about 500.

71. The method according to any one of claims 38 to 69, wherein the compound is a compound of formula (XII'). (XII'), in The dashed line represents the connection of nitrogen to the N-terminal amine group of the PTH portion having the sequence SEQ ID NO:51; and Each n is an integer of approximately 200 to 250.

72. The method according to any one of claims 38 to 69, wherein the PTH compound has the sequence SEQ ID NO:

122.

73. The method according to any one of claims 38 to 69, wherein the compound is a compound of formula (XIV). k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH(XIV), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2N; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is creatine; K is the L-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

74. The method according to any one of claims 38 to 69, wherein the compound is a compound of formula (XIV'). k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)–OH(XIV′), in k is d-Lys; γE is the l-isomer of γ-glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is creatine; K is the L-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

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