PTH treatment for chronic kidney disease

Abstract

The present invention relates to PTH compounds and related embodiments for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD, or in the treatment of subjects with CKD.

Description

[Technical Field]

[0001] The present invention relates to PTH compounds and related embodiments for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD, or in the treatment of subjects with CKD. [Background technology]

[0002] Chronic hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, and the absence or insufficient production of parathyroid hormone (PTH). In the absence of PTH, the mechanisms regulating calcium transport and phosphate reabsorption in the PTH receptor-rich renal tubules become dysregulated, resulting in a breakdown of the kidney's primary role in regulating 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. Patients with chronic hypoparathyroidism have been shown to have a higher risk of associated chronic kidney disease (CKD), progression of CKD stages, progression to end-stage renal disease (ESKD), and a faster decline in estimated glomerular filtration rate (eGFR) compared to patients without hypoparathyroidism. Therefore, patients with hypoparathyroidism treated with conventional therapy require close monitoring of hypoparathyroidism symptoms and comorbidities, including the development of chronic kidney disease, the risk of kidney stones, and nephrocalcification.

[0003] Numerous studies support an increased risk of renal complications in patients with chronic hypoparathyroidism, but the underlying mechanisms of this risk in the pathophysiology of hypoparathyroidism remain unclear. Chronic hypoparathyroidism is generally managed with conventional therapies aimed at maintaining serum calcium levels in the lower end 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 found that in a study of patients with chronic hypoparathyroidism, patients not treated with recombinant human PTH 1-84 (Natpara®) had an eGFR of 8.0 ml / min / 1.73 m² over a 5-year follow-up period. 2 A decrease was reported. In contrast, patients treated with rhPTH 1-84 showed stable or minimal improvement in eGFR, suggesting that hormone replacement therapy may improve eGFR decline.

[0005] Compared to patients without hypoparathyroidism, patients with chronic hypoparathyroidism have a significantly increased risk of developing associated CKD stage 3 or higher. Patients with chronic hypoparathyroidism also have a significantly increased risk of progression to higher CKD stages and to ESKD compared to patients without hypoparathyroidism (Adv Ther (2021) 38:1876-1888 1885). [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is a need for more effective treatments for chronic kidney disease, particularly in patients with hypoparathyroidism.

[0007] The purpose of this application is to overcome these difficulties, at least partially. [Means for solving the problem]

[0008] This objective is achieved by PTH compounds for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD, or in the treatment of subjects with CKD.

[0009] Surprisingly, PTH compounds, such as PTH compounds that result in at least 10 times longer receptor signaling compared to PTH 1-84, have been shown in subjects with CKD, particularly at 60 ml / min / 1.73 m 2 In patients with hypoparathyroidism and chronic kidney disease (CKD) with an eGFR of less than 1 / 2, administration resulted in sustained improvement in eGFR, while similar patients who received conventional therapy experienced a decline in eGFR. [Modes for carrying out the invention]

[0010] In this invention, the following terms are used:

[0011] With respect to serum calcium (sCa), the terms “within normal levels” and “within normal range” as used herein refer to the calcium levels typically found in a subject of a given species, sex, and age. In humans, normal serum calcium levels typically correspond to serum calcium levels in the range of 8.3 mg / dL (albumin-corrected) to 10.6 mg / dL (albumin-corrected). With respect to serum calcium levels, the term “albumin-corrected” means that the measured serum calcium level has been corrected for calcium bound to albumin according to the following formula:

[0012] Albumin-corrected serum calcium (mg / dL) = Measured total Ca (mg / dL) + 0.8 (4.0 - serum albumin [g / dL]).

[0013] Serum calcium levels within the normal range are also called "normocalcemia."

[0014] As used herein, the term “initial dose” refers to the dose of a PTH compound administered to a subject when treatment with the PTH compound is first initiated, i.e., such a subject has not previously received any dose of a PTH compound. It is understood that the subject may continue this initial dose for a period of time, for example, several days, several weeks or several months, or for the entire duration of treatment, or that the dose may be titrated up or down in response to specific events, such as the development of hypocalcemia or hypercalcemia.

[0015] As used herein, the term “mean” refers to a simple (equally weighted) arithmetic mean, which can be obtained by summing all variables in the dataset and dividing the result by the number of variables.

[0016] If hypoparathyroidism has persisted for at least six months, the subject is said to have "chronic hypoparathyroidism." The terms "subject" and "patient" are used synonymously in this specification.

[0017] As used herein with respect to eGFR, the term "mean improvement" refers to the average improvement in eGFR measured within the population being studied.

[0018] As used herein, the term "PTH" refers to all PTH polypeptides, particularly those derived from mammalian species, especially humans and mice, characterized by increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion, as well as their variants, analogs, orthologues, homologs, and derivatives and fragments. The term "PTH" also refers to all PTHrP polypeptides that bind to and activate the common PTH / PTHrP1 receptor, such as the polypeptide of SEQ ID NO: 121. In certain embodiments, the term "PTH" refers to the PTH polypeptide of SEQ ID NO: 51, as well as its variants, homologs, and derivatives that exhibit essentially the same biological activity, namely increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion. In certain embodiments, the term "PTH" refers to the PTH polypeptide of SEQ ID NO: 51.

[0019] In certain embodiments, the term "PTH" refers to one of the following polypeptide sequences: Sequence ID 1 (PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ Sequence ID 2 (PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS Sequence ID 3 (PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK Sequence ID 4 (PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA Sequence ID 5 (PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK Sequence ID 6 (PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT Sequence ID 7 (PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL Sequence ID 8 (PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV Sequence ID 9 (PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN Sequence ID 10 (PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV

[0020] Sequence ID 11 (PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD Sequence ID 12 (PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA Sequence ID 13 (PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK Sequence ID 14 (PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD Sequence ID 15 (PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA Sequence ID 16 (PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE Sequence ID 17 (PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG Sequence ID 18 (PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL Sequence ID 19 (PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS Sequence ID 20 (PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK

[0021] Sequence ID 21 (PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE Sequence ID 22 (PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH Sequence ID 23 (PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES Sequence ID 24 (PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE Sequence ID 25 (PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV Sequence ID 26 (PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL Sequence ID 27 (PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV Sequence ID 28 (PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN Sequence ID 29 (PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED Sequence ID 30 (PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE

[0022] Sequence ID 31 (PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK Sequence ID 32 (PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK Sequence ID 33 (PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR Sequence ID 34 (PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP Sequence ID 35 (PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR Sequence ID 36 (PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ Sequence ID 37 (PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS Sequence ID 38 (PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG Sequence ID 39 (PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA Sequence ID 40 (PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD

[0023] Sequence ID 41 (PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR Sequence ID 42 (PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP Sequence ID 43 (PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA Sequence ID 44 (PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL Sequence ID 45 (PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP Sequence ID 46 (PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA Sequence ID 47 (PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG Sequence ID 48 (PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL Sequence ID 49 (PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA Sequence ID 50 (PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV

[0024] Sequence ID 51 (PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF Sequence ID 52 (PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN Sequence ID 53 (PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH Sequence ID 54 (PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV Sequence ID 55 (PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD Sequence ID 56 (PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ Sequence ID 57 (PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL Sequence ID 58 (PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK Sequence ID 59 (PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK Sequence ID 60 (PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR

[0025] Sequence ID No. 61 (amidate PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ (The C-terminus of this sequence is amidated) Sequence ID No. 62 (Amidated PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS (The C-terminus of this sequence is amidated) Sequence ID No. 63 (Amidated PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK (The C-terminus of this sequence is amidated) Sequence ID No. 64 (Amidated PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA (The C-terminus of this sequence is amidated) Sequence ID No. 65 (Amidated PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK (The C-terminus of this sequence is amidated) Sequence ID No. 66 (amidate PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT (The C-terminus of this sequence is amidated) Sequence ID No. 67 (Amidated PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL (The C-terminus of this sequence is amidated) Sequence ID No. 68 (amidate PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV (The C-terminus of this sequence is amidated) Sequence ID No. 69 (amidate PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN (The C-terminus of this sequence is amidated) Sequence ID No. 70 (amidate PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV (The C-terminus of this sequence is amidated)

[0026] Sequence ID No. 71 (amidate PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD (The C-terminus of this sequence is amidated) Sequence ID No. 72 (amidate PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA (The C-terminus of this sequence is amidated) Sequence ID No. 73 (Amidated PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK (The C-terminus of this sequence is amidated) Sequence ID No. 74 (amidate PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD (The C-terminus of this sequence is amidated) Sequence ID No. 75 (amidate PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA (The C-terminus of this sequence is amidated) Sequence ID No. 76 (amidate PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE (The C-terminus of this sequence is amidated) Sequence ID No. 77 (amidate PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG (The C-terminus of this sequence is amidated) Sequence ID No. 78 (amidate PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL (The C-terminus of this sequence is amidated) Sequence ID 79 (amidate PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS (The C-terminus of this sequence is amidated) Sequence ID No. 80 (amidate PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK (The C-terminus of this sequence is amidated)

[0027] Sequence ID No. 81 (amidate PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE (The C-terminus of this sequence is amidated) Sequence ID No. 82 (amidate PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH (The C-terminus of this sequence is amidated) Sequence ID No. 83 (Amidated PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES (The C-terminus of this sequence is amidated) Sequence ID No. 84 (Amidated PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE (The C-terminus of this sequence is amidated) Sequence ID No. 85 (Amidated PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV (The C-terminus of this sequence is amidated) Sequence ID No. 86 (Amidated PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL (The C-terminus of this sequence is amidated) Sequence ID No. 87 (Amidated PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV (The C-terminus of this sequence is amidated) Sequence ID No. 88 (Amidated PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN (The C-terminus of this sequence is amidated) Sequence ID No. 89 (Amidated PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED (The C-terminus of this sequence is amidated) Sequence ID No. 90 (amidate PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE (The C-terminus of this sequence is amidated)

[0028] Sequence ID No. 91 (amidate PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK (The C-terminus of this sequence is amidated) Sequence ID No. 92 (Amidated PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK (The C-terminus of this sequence is amidated) Sequence ID No. 93 (Amidated PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR (The C-terminus of this sequence is amidated) Sequence ID No. 94 (Amidated PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP (The C-terminus of this sequence is amidated) Sequence ID 95 (amidated PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR (The C-terminus of this sequence is amidated) Sequence ID No. 96 (Amidated PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ (The C-terminus of this sequence is amidated) Sequence ID No. 97 (Amidated PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS (The C-terminus of this sequence is amidated) Sequence ID No. 98 (Amidated PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG (The C-terminus of this sequence is amidated) Sequence ID 99 (amidate PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA (The C-terminus of this sequence is amidated) Sequence ID No. 100 (amidate PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD (The C-terminus of this sequence is amidated)

[0029] Sequence ID No. 101 (amidate PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR (The C-terminus of this sequence is amidated) Sequence ID No. 102 (amidate PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP (The C-terminus of this sequence is amidated) Sequence ID No. 103 (Amidated PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA (The C-terminus of this sequence is amidated) Sequence ID No. 104 (amidate PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL (The C-terminus of this sequence is amidated) Sequence ID No. 105 (amidate PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP (The C-terminus of this sequence is amidated) Sequence ID No. 106 (amidate PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA (The C-terminus of this sequence is amidated) Sequence ID No. 107 (Amidated PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG (The C-terminus of this sequence is amidated) Sequence ID No. 108 (amidate PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL (The C-terminus of this sequence is amidated) Sequence ID No. 109 (Amidated PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA (The C-terminus of this sequence is amidated) Sequence ID No. 110 (amidate PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV (The C-terminus of this sequence is amidated)

[0030] Sequence ID No. 111 (amidate PTH 1-34) jSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF (The C-terminus of this sequence is amidated) Sequence ID No. 112 (amidate PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN (The C-terminus of this sequence is amidated) Sequence ID No. 113 (amidate PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH (The C-terminus of this sequence is amidated) Sequence ID No. 114 (amidate PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV (The C-terminus of this sequence is amidated) Sequence ID No. 115 (Amidated PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD (The C-terminus of this sequence is amidated) Sequence ID No. 116 (amidate PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ (The C-terminus of this sequence is amidated) Sequence ID No. 117 (Amidated PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL (The C-terminus of this sequence is amidated) Sequence ID No. 118 (amidate PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK (The C-terminus of this sequence is amidated) Sequence ID No. 119 (amidate PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK (The C-terminus of this sequence is amidated) Sequence ID No. 120 (amidate PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR (The C-terminus of this sequence is amidated)

[0031] Sequence ID 121 (PTHrP) AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH and sequences having at least 90% homology to them, for example, 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%.

[0032] The terms “PTH molecule” and “PTH moiety” include poly(amino acid) conjugates having the above sequence but also having a backbone containing both amide and non-amide bonds, such as ester bonds, such as depsipeptides. A depsipeptide is a chain of amino acid residues whose backbone contains both amide (peptide) bonds and ester bonds. Therefore, as used herein, the term “side chain” refers to a portion bonded to the alpha-carbon of an amino acid moiety when the amino acid moiety is linked via an amine bond in proteins and peptides, for example, or to any carbon-carbon-containing portion bonded to the backbone of a poly(amino acid) conjugate, such as in the case of a depsipeptide. In certain embodiments, the term “PTH” refers to a sequence having a backbone formed by amide (peptide) bonds.

[0033] As used herein, the terms “release half-life” and “half-life” refer to the time required for half of each PTH molecule or PTH moiety of a sustained-release PTH compound or PTH prodrug to be released under physiological conditions (i.e., aqueous buffer, pH 7.4, 37°C).

[0034] As used herein, the term "peptide" refers to a chain of at least two and 50 or fewer amino acid monomer moieties linked by peptide (amide) bonds, and these amino acid monomer moieties may also be called "amino acid residues." Amino acid monomers may be selected from the group consisting of protein-constituent amino acids and non-protein-constituent amino acids, and may be D- or L-amino acids. The term "peptide" also includes peptide mimetics, such as peptoids, beta-peptides, cyclic peptides, and depsipeptides, and encompasses such peptide mimetic chains having 50 or fewer monomer moieties. As used herein, the term "protein" refers to a chain of more than 50 amino acid monomer moieties linked by peptide bonds, preferably containing 12,000 or fewer amino acid monomers, for example, 10,000 or fewer amino acid monomer moieties, 8,000 or fewer amino acid monomer moieties, 5,000 or fewer amino acid monomer moieties, or 2,000 or fewer amino acid monomer moieties linked by peptide bonds, and these amino acid monomer moieties may also be called "amino acid residues." For simplicity, PTH moieties and PTH molecules are generally referred to as "proteins" in this specification.

[0035] As used herein, the term "physiological conditions" refers to an aqueous buffer solution at 37°C and pH 7.4.

[0036] As used herein, the term “pharmaceutical composition” means a composition comprising one or more active ingredients, such as at least one PTH compound, and one or more excipients, and any products directly or indirectly arising from combinations, complexes, or aggregations of any two or more components of the composition, or from the dissociation of one or more of the components, or from other types of reactions or interactions of one or more of the components. Accordingly, pharmaceutical compositions for use in the present invention encompass any composition prepared by mixing one or more PTH compounds with pharmaceutically acceptable excipients.

[0037] As used herein, the term “excipient” refers to a therapeutic agent, such as a diluent, adjuvant, or vehicle on which a drug or prodrug is administered. Such pharmaceutical excipients may be sterile solutions, such as water and oils (petroleum, animal, plant, or synthetic oils, including, but not limited to, peanut oil, soybean oil, mineral oil, and sesame oil). Water is an example of an excipient when the pharmaceutical composition is administered orally. Saline solution and dextrose aqueous solution are examples of excipients when the pharmaceutical composition is administered intravenously. Saline solution, as well as dextrose aqueous solution and glycerol solution, are used as liquid excipients for injectable solutions in certain embodiments. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol. The pharmaceutical composition may also optionally contain small amounts of wetting or emulsifying agents, pH buffers such as acetates, succinates, tris, carbonates, phosphates, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-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 take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, or sustained-release formulations. The above pharmaceutical compositions may be formulated as suppositories with traditional 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 bioactive portion, along with suitable amounts of excipients to provide a suitable form for administration to the subject. The formulation should be suitable for the mode of administration.

[0038] 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.

[0039] The term "suspension composition" refers to a mixture comprising at least one water-insoluble PTH compound and one or more solvents, such as water.

[0040] As used herein, the term “dried composition” means that the pharmaceutical composition is provided in a dry form. Preferred drying methods are spray drying and freeze-drying. Such a dried composition has a residual moisture content of up to 10%, for example, less than 5% or less than 2%, as determined by Karl Fischer. In certain embodiments, such a dried pharmaceutical composition is dried by freeze-drying.

[0041] As used herein, the term “drug” refers to a substance, such as PTH, used in the treatment, cure, prevention, or diagnosis of a disease, or used in any other way to enhance physical or mental well-being. When a drug is conjugated to another part, the resulting product portion derived from that drug is called the “drug moiety.”

[0042] As used herein, the term "prodrug" refers to a covalent conjugate in which a drug moiety is reversibly and covalently bonded to a special protecting group via a reversible linker moiety, also called a "reversible prodrug linker moiety" or "reversible linker moiety," which reversibly conjugates to a biologically active moiety, thereby altering or removing undesirable properties of the parent molecule. This includes enhancing desirable properties and suppressing undesirable properties of the drug. The special non-toxic protecting group is called a "carrier." A prodrug releases the reversibly and covalently bonded drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate containing a drug moiety covalently and reversibly conjugated to a carrier moiety via a reversible linker moiety, where the covalent and reversible conjugation of the carrier to the reversible linker moiety is either direct or spacer-mediated. Such conjugates release the previously conjugated drug portion in the form of a free, unmodified drug.

[0043] A "reversible bond" is a bond that is degradable, or cleavable, under physiological conditions (pH 7.4 aqueous buffer, 37°C) in the absence of an enzyme, with a half-life of 1 hour to 3 months, 1 hour to 2 months in certain embodiments, 1 hour to 1 month in certain embodiments, 1 hour to 3 weeks in certain embodiments, 1 hour to 2 weeks in certain embodiments, 12 hours to 2 weeks in certain embodiments, and 12 hours to 1 week in certain embodiments. Therefore, a stable bond is a bond that has a half-life of more than 3 months under physiological conditions (pH 7.4 aqueous buffer, 37°C) in the absence of an enzyme.

[0044] As used herein, the terms “tracesless prodrug linker” or “tracesless linker” mean a reversible prodrug linker that, upon cleavage, releases the drug in its free form; that is, a linker portion that reversibly and covalently binds the drug portion to the carrier. As used herein, the term “free form” means the drug in its unmodified, pharmacologically active form.

[0045] As used herein, the term “reagent” means a compound containing at least one functional group for reaction with the functional group of another compound or drug. Drugs containing a functional group such as a primary or secondary amine or a hydroxyl functional group are also understood to be reagents.

[0046] As used herein, the term "moiety" refers to a portion of a molecule that lacks one or more atoms compared to the corresponding reagent. For example, when a reagent of formula "HXH" reacts with another reagent and becomes part of a reaction product, the corresponding portion of the reaction product has the structure "HX-" or "-X-", where each "-" indicates a bond to another portion. Thus, the drug portion is released as a drug from the prodrug.

[0047] Where a chemical structure is provided for an atomic group that is bonded to at least one other part or intercepted in one part, it is understood that, unless otherwise explicitly stated, such chemical structure may be bonded to at least one further part or intercepted part in any orientation. For example, part "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 )C(O)-" may be bonded to two parts, or it may be inserted into one part. Similarly, part

[0048] [ka] teeth,

[0049] [ka] as, or

[0050] [ka] It may be joined to two parts, or it may be inserted into one part.

[0051] As used herein, the term "functional group" means a group of atoms that can react with other groups of atoms. Examples of functional groups include, but are not limited to, carboxylic acids, primary or secondary amines, maleimides, thiols, sulfonic acids, carbonates, carbamates, hydroxyls, aldehydes, ketones, hydrazines, isocyanates, isothiocyanates, phosphoric acids, phosphonic acids, haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfuric acids, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziridines.

[0052] If a PTH compound contains one or more acidic or basic groups, the present invention also includes corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. Thus, PTH compounds containing acidic groups can be used in accordance with the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, etc.) or amino acids. There may be PTH compounds containing one or more basic groups, i.e., protonable groups, and such PTH compounds can be used in accordance with the present invention in the form of addition salts thereof 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, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods for converting basic groups to cations, such as alkylation of amine groups to provide suitable counterions for positively charged ammonium groups and their salts, are known to those skilled in the art. When the PTH compound contains both acidic and basic groups, the present invention also includes intramolecular salts or betaines (zwitterionic) in addition to the salt forms described above. Each salt can be obtained by conventional methods known to those skilled in the art, such as contacting these compounds with an organic acid, inorganic acid, or base in a solvent or dispersion, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the above compounds that, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates for chemical reactions or as intermediates for the production of pharmaceutically acceptable salts.

[0053] The term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a subject, and in certain embodiments, means that it is authorized for use in animals, and in particular for use in humans, by a regulatory body, such as the EMA (Europe) and / or the FDA (United States) and / or any other national regulatory body.

[0054] In this specification, the terms “about” or “approximately” in combination with numerical values ​​are used to indicate not only the numerical value itself, but also a range of plus or minus 10% or less of the numerical value, in certain embodiments a range of plus or minus 8% or less of the numerical value, in certain embodiments a range of plus or minus 5% or less of the numerical value, and in certain embodiments a range of plus or minus 2% or less of the numerical value. For example, the phrase “about 200” or “approximately 200” is used to mean a range of 200+ / -10%, i.e., a range of 180 to 220, in certain embodiments a range of 200+ / -8%, i.e., a range of 184 to 216, in certain embodiments a range of 200+ / -5%, i.e., a range of 190 to 210, and in certain embodiments a range of 200+ / -2%, i.e., a range of 196 to 204. Percentages expressed as "about 20%" or "approximately 20%" do not mean "20% + / - 10%", i.e., in the range of 10 to 30%. Rather, "about 20%" or "approximately 20%" means a range of 18 to 22%, i.e., plus or minus 10% of the number 20.

[0055] As used herein, the term "polymer" refers to a molecule comprising repeating structural units, i.e., monomers, linked by linear, cyclic, branched, crosslinked or dendrimeric chemical bonds or combinations thereof, which may be of synthetic origin, biological origin, or a combination of both. It is understood that the polymer may also comprise one or more other chemical groups and / or moieties, for example one or more functional groups. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, such as at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. Where the polymer is soluble, in certain embodiments, the polymer has a maximum molecular weight of 1000 kDa, such as up to 750 kDa, such as up to 500 kDa, such as up to 300 kDa, such as up to 200 kDa, or such as up to 100 kDa. It is understood that no meaningful molecular weight range can be provided for water-insoluble polymers, such as hydrogels. It is understood that peptides or proteins are also polymers in which amino acids are the repeating structural units, even though the side chains of each amino acid may be different.

[0056] As used herein, the term "polymeric" refers to a reagent or moiety comprising one or more polymers or polymer moieties. A polymeric reagent or moiety may optionally also comprise one or more other moieties, which in certain embodiments are selected from the group consisting of: - C 1-50 alkyl, C 2-50 alkenyl, C 2-50 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and - a bond selected from the group comprising

[0057]

Chemical Formula

[0058] Those skilled in the art will understand that polymerization products obtained from polymerization reactions do not necessarily all have the same molecular weight, but rather exhibit a molecular weight distribution. For this reason, as used herein, molecular weight range, molecular weight, range of monomer numbers in a polymer, and number of monomers in a polymer refer to the number-average molecular weight and number-average monomers, i.e., the arithmetic mean of the molecular weight of the polymer or polymer part, and the arithmetic mean of the number of monomers in the polymer or polymer part.

[0059] Therefore, in a polymer portion containing "x" monomer units, any integer represented as "x" corresponds to the arithmetic mean of the monomers. Any range of integers represented as "x" provides a range of integers in which the arithmetic mean of the monomers lies. An integer "x" represented as "about x" means that the arithmetic mean of the monomers lies within the range of integers x+ / -10%, x+ / -8% in a particular embodiment, x+ / -5% in a particular embodiment, and x+ / -2% in a particular embodiment.

[0060] As used herein, the term "number-mean molecular weight" refers to the usual arithmetic mean of the molecular weights of individual polymers.

[0061] As used herein with respect to PTH compounds, the term "water-soluble" means that at least 1 g of the PTH compound can dissolve in 1 liter of water at 20°C to form a homogeneous solution. Conversely, the term "water-insoluble" with respect to PTH compounds means that less than 1 g of the PTH compound can dissolve in 1 liter of water at 20°C to form a homogeneous solution.

[0062] As used herein with respect to a portion or reagent, the term “PEG-based” means that the portion or reagent contains PEG. In certain embodiments, a PEG-based portion or reagent contains at least 90% (w / w) PEG, such as at least 10% (w / w) PEG, e.g., at least 20% (w / w) PEG, e.g., at least 30% (w / w) PEG, e.g., at least 40% (w / w) PEG, e.g., at least 50% (w / w), e.g., at least 60% (w / w) PEG, e.g., at least 70% (w / w) PEG, e.g., at least 80% (w / w) PEG, e.g., at least 95%, etc. The remaining weight percentage of a PEG-based portion or reagent is, in certain embodiments, other portions selected from the following portions and conjugates: - C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, - A combination selected from the group including the following:

[0063] [ka] (In the formula, The dashed line indicates binding to a portion or the remainder of the reagent. -R and -R a(These are independently selected from the group consisting of -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).

[0064] As used herein, the term "substituted" means that one or more -H atoms in a molecule or part are substituted by different atoms or groups of atoms, which are called "substituents."

[0065] In certain embodiments, one or more further optional substituents may be halogen, -CN, or -COOR, independently of each other. 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 1-50 Alkyl, C2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls, where -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. x2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has -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 )- may intersect with one or more groups selected from the group consisting of, -R x1 , -R x1a , -R x1b -H, -T are independent of each other. 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls, where -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. x2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has -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 )- is optionally interrupted by one or more groups selected from the group consisting of, each T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, and each T 0 is independently optionally substituted with one or more -R, which may be the same or different, x2 optionally substituted with, each -R x2 is independently 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 Selected from the group consisting of alkyl groups, C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R x3 , -R x3a , -R x4 , -R x4a , -R x4b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0066] In certain embodiments, one or more further optional substituents may be halogen, -CN, or -COOR, independently of each other. 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 Rx1a ), -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyls, where -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is the same or different -R of one or more R's. x2 In some cases, it is replaced by C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl has -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 )- may intersect with one or more groups selected from the group consisting of, Each-R x1 , -R x1a , -R x1b , -R x3 , -R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls, where each T 0 These are independently one or more -Rs, the same or different. x2 It is sometimes replaced by, Each-R x2 These are, independently, halogen, -CN, oxo (=O), and -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 Selected from the group consisting of alkyl groups, C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R x4 , -R x4a , -R x4b These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls.

[0067] In certain embodiments, one or more further optional substituents may be halogen, -CN, or -COOR, independently of each other. 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 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, where -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is the same or different -R of one or more R's. x2 In some cases, it is replaced by C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl has -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(ORx3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- may intersect with one or more groups selected from the group consisting of, Each-R x1 , -R x1a , -R x1b , -R x2 , -R x3 , -R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls, where each T 0 These are independently one or more -Rs, the same or different. x2 It is sometimes replaced.

[0068] In certain embodiments, up to six -H atoms of the optionally substituted molecule are independently substituted by substituents, for example, five -H atoms are independently substituted by substituents, four -H atoms are independently substituted by substituents, three -H atoms are independently substituted by substituents, two -H atoms are independently substituted by substituents, or one -H atom is independently substituted by substituents.

[0069] The term “interrupted” means that a portion is inserted between two carbon atoms, or, if the insertion is at one of the ends of the portion, between a carbon or heteroatom and a hydrogen atom, or in certain embodiments, between a carbon and a hydrogen atom.

[0070] The term "C" as used herein 1-4"Alkyl" refers to a linear or branched alkyl moiety, either alone or in combination, having 1 to 4 carbon atoms. When present at the end of a molecule, it refers to a linear or branched C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Two parts of the molecule are C 1-4 When bonded by alkyl, 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 of the alkyl carbon may optionally be substituted with a substituent as defined above. Optionally, C 1-4 Alkyl may have one or more parts, as defined below, interspersed within it.

[0071] The term "C" as used herein 1-6 "Alkyl" refers to a linear or branched alkyl moiety, either alone or in combination, having 1 to 6 carbon atoms. When present at the end of a molecule, it refers to both linear and branched C atoms. 1-6 Examples 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. Two parts of the molecule are C 1-6 When bonded by an alkyl group, 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 of carbon may optionally be substituted with a substituent as defined above. 1-6 Alkyl may have one or more parts, as defined below, interspersed within it.

[0072] 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, respectively. 1-10 , C 1-20 or C 1-50 Each hydrogen atom of carbon may optionally be substituted with a substituent as defined above. 1-10 or C 1-50 Alkyl may have one or more parts, as defined below, interspersed within it.

[0073] The term "C" as used herein 2-6 An "alkenyl" refers to a straight-chain or branched hydrocarbon moiety, either alone or in combination, containing 2 to 6 carbon atoms and at least one carbon-carbon double bond. When present at the ends of a molecule, examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. Two parts of a molecule are C 2-6 When bonded with an alkenyl group, such C 2-6 An example of an alkenil is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl moiety may optionally be substituted with a substituent as defined above. Optionally, C 2-6 An alkenil may have one or more parts, as defined below, inserted into it.

[0074] Therefore, the term "C 2-10 Alkenil, "C 2-20 "Alkenil" or "C 2-50 "Alkenyl" means a linear or branched hydrocarbon moiety, either alone or in combination, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, and containing at least one carbon-carbon double bond. 2-10 Alkenil, C 2-20 Alkenyl 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 Alkenil, C 2-20 Alkenyl or C2-50 An alkenil may have one or more parts, as defined below, inserted into it.

[0075] The term "C" as used herein 2-6 "Alkynyl" refers to a linear or branched hydrocarbon moiety, either alone or in combination, containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond. When present at the end of a molecule, examples include -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of a molecule are linked by an alkynyl group, an example is -C≡C-. 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 Alkinyl may have one or more parts, as defined below, inserted into it.

[0076] Therefore, the term "C" as used herein 2-10 Alkinyl, C 2-20 "Alkinyl" and "C 2-50 "Alkynyl" means a linear or branched hydrocarbon moiety, either alone or in combination, containing at least one carbon-carbon triple bond, each having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 Alkinyl, C 2-20 Alkinyl or 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 Alkinyl, C 2-20 Alkinyl or C 2-50 Alkinyl may have one or more parts, as defined below, inserted into it.

[0077] As stated above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C2-6 Alkenil, C 2-10 Alkenil, C 2-20 Alkenil, C 2-50 Alkenil, C 2-6 Alkinyl, C 2-10 Alkinyl, C 2-20 Alkenyl or C 2-50 Alkinyl may have one or more parts interspersed in it, and in certain embodiments, these one or more parts are

[0078] [ka] (In the formula, The dashed line indicates binding to a portion or the remainder of the reagent. -R and -R a (These are independently selected from the group consisting of -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.) It is selected from the group consisting of the following.

[0079] The term "C" as used herein 3-10 "Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be substituted with a substituent as defined above. 3-10 "Cycloalkyl" also includes cross-linked birings such as norbornane or norbornene.

[0080] The term “8-30 membered carbopolycyclil” or “8-30 membered carbopolycycle” refers to a cyclic portion of two or more rings having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom and may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings). In certain embodiments, an 8-30 membered carbopolycyclil refers to a cyclic portion of 2, 3, 4, or 5 rings, and in certain embodiments, a cyclic portion of 2, 3, or 4 rings.

[0081] As used herein, the terms “3- to 10-membered heterocyclil” or “3- to 10-membered heterocycle” mean a ring (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic ring) having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms and potentially containing up to a maximum number of double bonds, wherein at least one ring atom and up to four 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 the ring is bonded to the remainder of the molecule via carbon or nitrogen atoms. Examples of heterocycles with 3 to 10 members include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxilen, thiirane, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran Examples include tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidin, isothiazolidine, thiadiazolidin, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine and homopiperazine. Each hydrogen atom of a 3-10 membered heterocyclyl or 3-10 membered heterocyclic group may be substituted with substituents defined below.

[0082] As used herein, the terms “8- to 11-membered heterobicyryl” or “8- to 11-membered heterobicyclic” mean a bicyclic heterocyclic portion having 8 to 11 ring atoms (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic ring) in which at least one ring atom is shared by both rings and may contain up to a maximum number of double bonds, wherein at least one ring atom and up to six 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 the ring is bonded to the remainder of the molecule via carbon or nitrogen atoms. Examples of 8- to 11-membered heterobicyclic compounds include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic compound also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocyclic compounds such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of the carbon atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicyclic compound may be substituted with substituents as defined below.

[0083] Similarly, the term “8-30 membered heteropolycyclil” or “8-30 membered heteropolycycle” means a heterocyclic moiety having 8 to 30 ring atoms, more than 2 rings, in particular embodiments 3, 4, or 5 rings (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings), wherein at least 1, up to 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 the rings are bonded to the remainder of the molecule via carbon or nitrogen atoms.

[0084] structure

[0085] [ka] Regarding the part, "Pair R x / R y Together with the atoms to which they are bonded, C 3-10 The phrase "forms a cycloalkyl or a 3-10 member heterocycline" is R x and R y However, it is understood that this means forming the following structure:

[0086] [ka] (In the formula, R is C 3-10 (It is a cycloalkyl or a 3- to 10-membered heterocycline.)

[0087] structure

[0088] [ka] Regarding the part, "Pair R x / R y The phrase "they, together with the atoms to which they are bonded, form ring A" is R x and R yHowever, it is also understood that this means forming the following structure:

[0089] [ka]

[0090] As used herein, "halogen" means fluoro, chloro, bromo, or iodine. In certain embodiments, the halogen is fluoro or chloro.

[0091] Generally, the terms "comprise" or "comprising" also include "consist of" or "consisting of."

[0092] In certain embodiments, PTH compounds are used in the treatment of subjects with chronic kidney disease (CKD).

[0093] In certain embodiments, PTH compounds are used in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD.

[0094] In certain embodiments, subjects at risk of developing CKD or who have CKD are mammalian subjects, e.g., human subjects, e.g., adult or pediatric subjects. In certain embodiments, subjects are male human subjects. In certain embodiments, subjects are female human subjects. In certain embodiments, subjects with CKD have hypoparathyroidism, e.g., chronic hypoparathyroidism. Chronic hypoparathyroidism may be due to surgery, genetic causes, immune system-related injury to the parathyroid gland, or the hypoparathyroidism may be idiopathic. In certain embodiments, subjects have chronic hypoparathyroidism due to surgery. In certain embodiments, subjects have chronic hypoparathyroidism due to thyroid surgery. In certain embodiments, subjects have chronic hypoparathyroidism due to parathyroid surgery. In certain embodiments, subjects have chronic hypoparathyroidism due to genetic causes. In certain embodiments, subjects have chronic hypoparathyroidism due to autosomal dominant hypocalcemia type 1. In certain embodiments, subjects have chronic hypoparathyroidism due to immune system-related injury to the parathyroid gland. In a particular embodiment, the subject has idiopathic chronic hypoparathyroidism.

[0095] In certain embodiments, the subject is managed with conventional therapy, namely active vitamin D and calcium supplement, before initiating treatment with PTH compounds. Such conventional therapy is usually administered orally.

[0096] In certain embodiments, the renal function of subjects at risk of developing CKD or who have CKD is assessed at least once by blood and / or urine tests prior to administration of a pharmaceutically effective dose of the PTH compound.

[0097] In certain embodiments, renal function in subjects at risk of or with CKD is evaluated at least twice (once as baseline before the first dose of the PTH compound, and once after the administration of one or more doses of the PTH compound). Preferably, the second evaluation is performed after multiple doses, for example, after at least two weeks, at least four weeks, or at least two months of treatment. The second evaluation may be 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.

[0098] Suitable blood and urine tests are known in the art. An exemplary blood test for evaluating CKD is a serum creatinine blood test, which measures the amount of creatinine in the blood. A suitable urine test for evaluating chronic kidney disease is, for example, the urinary albumin-creatinine ratio (UACR).

[0099] Blood and / or urine tests may also be used to determine the estimated glomerular filtration rate (eGFR). Preferred methods for determining eGFR are known in the art, such as the MDRD formula, in the form of a four-variable MDRD (Modification of Diet in Renal Disease) formula based on serum creatinine, age, ethnicity, and sex, or in the form of the original MDRD formula (which further includes serum urea nitrogen and albumin levels). Depending on the degree of renal impairment, subjects may be classified into one of the following stages based on eGFR: Stage 1 (normal), Stage 2 (mild), Stage 3 (moderate), Stage 4 (severe), or Stage 5 (end-stage renal failure):

[0100] [Table 1]

[0101] Blood and / or urine tests may include (i) determining specific parameters in the blood and / or urine samples in question, for example, determining creatinine in the blood or the albumin-creatinine ratio in the urine, and (ii) comparing these parameters to a reference. If the reference indicates that the person is at risk of developing CKD or has CKD, treatment with a PTH compound may be initiated.

[0102] In certain embodiments, eGFR serves as an indicator of CKD.

[0103] In certain embodiments, subjects have an eGFR indicating stage 3 or worse, i.e., 60 ml / min / 1.73 m². 2 It has an eGFR of less than .

[0104] In certain embodiments, subjects at risk of developing CKD have an eGFR of stage 1 or stage 2 at the start of treatment with a PTH compound, i.e., a normal eGFR or a mildly reduced eGFR, and do not progress to stage 3 for at least one year, at least two years, at least three years, at least four years, at least five years, at least ten years, at least fifteen years, or at least until the end of treatment with a PTH compound.

[0105] In certain embodiments, subjects with CKD have an eGFR showing stage 3 at the start of treatment with a PTH compound, i.e., a moderate reduction in eGFR, and do not progress to stage 4 for at least one year, at least two years, at least three years, at least four years, at least five years, at least ten years, at least fifteen years, or at least until the end of treatment with a PTH compound.

[0106] In certain embodiments, subjects with CKD have an eGFR of stage 4 at the start of treatment with a PTH compound, i.e., a significant reduction in eGFR, and do not progress to stage 5 for at least one year, at least two years, at least three years, at least four years, at least five years, at least ten years, at least fifteen years, or at least until the end of treatment with a PTH compound.

[0107] In certain embodiments, treatment with a PTH compound prevents progression to a higher CKD stage in a patient with CKD for at least two years, at least three years, at least four years, at least five years, at least ten years, at least fifteen years, or at least until the end of treatment with the PTH compound, namely, progression from stage 3 to stage 4 or from stage 4 to stage 5.

[0108] In a particular embodiment, the subject has hypoparathyroidism, for example, chronic hypoparathyroidism.

[0109] In certain embodiments, treatment with PTH compounds delays the progression of CKD stages by, for example, two, three, four, six, seven, eight, nine, or ten times compared to standard treatment, i.e., treatment with oral calcium and activated vitamin D, or treatment with PTH 1-84, particularly in subjects with hypoparathyroidism, such as chronic hypoparathyroidism. In certain embodiments, treatment with PTH compounds prevents progression to end-stage renal failure, particularly in subjects with hypoparathyroidism, such as chronic hypoparathyroidism.

[0110] Treatment with PTH compounds improves the target eGFR. In certain embodiments, treatment with PTH compounds is administered at a dose of at least 5 ml / min / 1.73m². 2 at least 6 ml / min / 1.73 m 2 at least 7 ml / min / 1.73 m 2 at least 8 ml / min / 1.73 m 2 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 2 This results in an average improvement in eGFR. In certain embodiments, such an average improvement in eGFR is achieved within 26 weeks of treatment with the PTH compound. In certain embodiments, the average improvement is achieved by 52 weeks of treatment. In certain embodiments, the average improvement can be measured after at least 110 weeks of treatment with the PTH compound. In certain embodiments, the increase in average eGFR is sustained, meaning it continues for a long period, e.g., 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, as long as treatment with the PTH compound continues, or until the end of the subject's life.

[0111] In certain embodiments, the increase in mean eGFR is greater than baseline eGFR < 60 mL / min / 1.73m². 2 In subjects with the following characteristics, ≥60 mL / min / 1.73 m 2The values ​​are numerically higher than in subjects with a baseline eGFR of <60 mL / min / 1.73 m³. Therefore, in certain embodiments, subjects with CKD have a baseline eGFR of <60 mL / min / 1.73 m³. 2 Subjects with eGFR, i.e., subjects to be treated with PTH compounds, have an eGFR of stage 3, 4, or 5.

[0112] Surprisingly, especially at 60 ml / min / 1.73 m 2 In subjects with an eGFR of less than a certain level, treatment with PTH compounds was found to be effective, as evidenced by a particularly high increase in eGFR.

[0113] In certain embodiments, treatment with PTH compounds reduces or eliminates the incidence of nephrolithiasis. In certain embodiments, treatment with PTH compounds reduces or eliminates the incidence of nephrocalcification.

[0114] In certain embodiments, patients treated with PTH compounds do not require administration of active vitamin D. In certain embodiments, patients treated with PTH compounds are independent of conventional therapy, which consists of active vitamin D and ≤600 mg / day of calcium. In certain embodiments, patients treated with PTH compounds maintain eucalcemia. In certain embodiments, patients treated with PTH compounds regain eucalcemia.

[0115] In certain embodiments, the PTH compound is administered multiple times. Treatment may begin at the time of diagnosis of CKD, or, in the case of subjects with hypoparathyroidism, at the time of diagnosis of hypoparathyroidism. The PTH compound may be administered, for example, daily or weekly. Treatment may continue for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, until medically instructed, or until the end of the subject's life.

[0116] The PTH compound may be administered to the subject daily. The PTH compound may be administered to the subject weekly.

[0117] In certain embodiments, a single dose of the PTH compound results in receptor signaling that is at least 10 times longer than a single equimolar dose of PTH 1-84, at least 15 times longer than a single equimolar dose of PTH 1-84, or at least 20 times longer than a single equimolar dose of PTH 1-84. Such a PTH compound may or may not have an extended circulating half-life. The extended circulating half-life is at least 10 times longer than the circulating half-life of PTH 1-84, and these are measured in each case after a single dose in which the dose of the PTH compound and the dose of PTH 1-84 are equimolar (with respect to PTH).

[0118] In certain embodiments, the PTH compound is a peptide. In certain embodiments, the PTH compound is the peptide of SEQ ID NO: 122, also known as AZP-3601 or enevoparatide: AVAEIQLMHQRAKWIQDARRRAFLHKLIAEIHTAEI

[0119] In certain embodiments, the PTH compound is a water-insoluble compound, which in certain embodiments is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, and microspheres. One or more PTH drugs can be non-covalently embedded in such crystals, nanoparticles, microparticles, nanospheres, and microspheres, or can be covalently conjugated to such crystals, nanoparticles, microparticles, nanospheres, and microspheres. The covalent conjugation can be a stable conjugation, i.e., conjugation via a stable bond, or a reversible conjugation, i.e., conjugation via a reversible bond to such crystals, nanoparticles, microparticles, nanospheres, and microspheres.

[0120] In certain embodiments, the PTH compound is a crystal containing at least one PTH molecule. In certain embodiments, the PTH compound is a nanoparticle containing at least one PTH molecule. In certain embodiments, the PTH compound is a microparticle containing at least one PTH molecule. In certain embodiments, the PTH compound is a nanosphere containing at least one PTH compound. In certain embodiments, the PTH compound is a microsphere containing at least one PTH compound. In certain embodiments, the compound is a vesicle, e.g., a micelle, liposome, or polymerosome containing at least one PTH compound.

[0121] In certain embodiments, the PTH compound is a water-insoluble PTH compound comprising at least one PTH molecule non-covalently embedded in a water-insoluble polymer. In certain embodiments, such water-insoluble polymers include 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), and poly(hydroxypropyl methacrylate). The polymers include poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyl oxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and polymers selected from the group consisting of these. In certain embodiments, the water-insoluble polymer is poly(lactic acid-co-glycolic acid) (PLGA).

[0122] In certain embodiments, the PTH compound is one or more partial-L 2 -L 1 -D is a conjugate containing the conjugated carrier portion Z' or a pharmaceutically acceptable salt thereof, where each -L 2 - is either independent, non-existent, or a spacer part, and each -L 1 - is an independent linker moiety to which -D is reversibly and covalently conjugated, each -D is an independent PTH moiety, and Z' is a hydrogel. Such long-acting PTH compounds are sustained-release PTH compounds. -D, -L 1 -, -L 2 Specific embodiments of - and Z' are described elsewhere in this specification.

[0123] In certain embodiments, the PTH compound is water-soluble.

[0124] In certain embodiments, the PTH compound is of formula (Ia) or (Ib)

[0125] [ka] (In the formula, Each -D is independently a PTH portion. Each-L 1 - is a linker portion that is independently and covalently and reversibly bonded to -D. Each-L 2 - is either independent, non-existent, or a spacer part. Each -Z is independently a carrier portion, such as a fatty acid derivative or polymer. x is an integer selected from the group consisting of 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. (y is an integer selected from the group consisting of 2, 3, 4, and 5.) It holds.

[0126] In certain embodiments, the PTH compound has formula (Ia). In certain embodiments, the PTH compound has formula (Ia), where x is selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, the PTH compound has formula (Ia), where x is 1.

[0127] In certain embodiments, the PTH compound has formula (Ib). In certain embodiments, the PTH compound has formula (Ib), where y is selected from the group consisting of 2, 3, and 4.

[0128] -D, -L 1 -, -L 2 Embodiments of - and -Z are described elsewhere in this specification.

[0129] In a particular embodiment, -D is sequence number 1, sequence number 2, sequence number 3, sequence number 4, sequence number 5, sequence number 6, sequence number 7, sequence number 8, sequence number 9, sequence number 10, sequence number 11, sequence number 12, sequence number 13, sequence number 14, sequence number 15, sequence number 16, sequence number 17, sequence number 18, sequence number 19, sequence number 20, sequence number 21, sequence number 22, sequence number 23, sequence number 24, sequence number 25, sequence number 26, sequence number 27, sequence number 28, sequence number 29, sequence number 30, sequence number 31, sequence number 32, sequence number 33, sequence number 34, sequence number Sequence ID 35, Sequence ID 36, Sequence ID 37, Sequence ID 38, Sequence ID 39, Sequence ID 40, Sequence ID 41, Sequence ID 42, Sequence ID 43, Sequence ID 44, Sequence ID 45, Sequence ID 46, Sequence ID 47, Sequence ID 48, Sequence ID 49, Sequence ID 50, Sequence ID 51, Sequence ID 52, Sequence ID 53, Sequence ID 54, Sequence ID 55, Sequence ID 56, Sequence ID 57, Sequence ID 58, Sequence ID 59, Sequence ID 60, Sequence ID 61, Sequence ID 62, Sequence ID 63, Sequence ID 64, Sequence ID 65, Sequence ID 66, Sequence ID 67, Sequence ID 68, Sequence ID 69, Sequence ID 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: Sequences selected from the group consisting of 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, have at least 90% homology, for example, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology,The PTH moiety contains sequences having at least 97% homology, at least 98% homology, or at least 99% homology.

[0130] In a particular embodiment, -D is sequence number 1, sequence number 2, sequence number 3, sequence number 4, sequence number 5, sequence number 6, sequence number 7, sequence number 8, sequence number 9, sequence number 10, sequence number 11, sequence number 12, sequence number 13, sequence number 14, sequence number 15, sequence number 16, sequence number 17, sequence number 18, sequence number 19, sequence number 20, sequence number 21, sequence number 22, sequence number 23, sequence number 24, sequence number 25, sequence number 26, sequence number 27, sequence number 28, sequence number 29, sequence number 30, sequence number 31, sequence number 32, Column number 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, Array Number 66, Sequence ID 67, Sequence ID 68, Sequence ID 69, Sequence ID 70, Sequence ID 71, Sequence ID 72, Sequence ID 73, Sequence ID 74, Sequence ID 75, Sequence ID 76, Sequence ID 77, Sequence ID 78, Sequence ID 79, Sequence ID 80, Sequence ID 81, Sequence ID 82, Sequence ID 83, Sequence ID 84, Sequence ID 85, Sequence ID 86, Sequence ID 87, Sequence ID 88, Sequence ID 89, Sequence ID 90, Sequence ID 91, Sequence ID 92, Sequence ID 93, Sequence ID 94, Sequence ID 95, Sequence ID 96, Sequence ID 97, Sequence ID 98, Sequence ID The PTH portion includes a sequence having at least 95% homology to a sequence selected from the group consisting of sequence 99, sequence number 100, sequence number 101, sequence number 102, sequence number 103, sequence number 104, sequence number 105, sequence number 106, sequence number 107, sequence number 108, sequence number 109, sequence number 110, sequence number 111, sequence number 112, sequence number 113, sequence number 114, sequence number 115, sequence number 116, sequence number 117, sequence number 118, sequence number 119, sequence number 120, sequence number 121, and sequence number 122.

[0131] In a particular embodiment, -D is sequence number 1, sequence number 2, sequence number 3, sequence number 4, sequence number 5, sequence number 6, sequence number 7, sequence number 8, sequence number 9, sequence number 10, sequence number 11, sequence number 12, sequence number 13, sequence number 14, sequence number 15, sequence number 16, sequence number 17, sequence number 18, sequence number 19, sequence number 20, sequence number 21, sequence number 22, sequence number 23, sequence number 24, sequence number 25, sequence number 26, sequence number 27, sequence number 28, sequence number 29, sequence number 30, sequence number 31, sequence number 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, Sequence ID 65, Sequence ID 66, Sequence ID 67, Sequence ID 68, Sequence ID 69, Sequence ID 70, Sequence ID 71, Sequence ID 72, Sequence ID 73, Sequence ID 74, Sequence ID 75, Sequence ID 76, Sequence ID 77, Sequence ID 78, Sequence ID 79, Sequence ID 80, Sequence ID 81, Sequence ID 82, Sequence ID 83, Sequence ID 84, Sequence ID 85, Sequence ID 86, Sequence ID 87, Sequence ID 88, Sequence ID 89, Sequence ID 90, Sequence ID 91, Sequence ID 92, Sequence ID 93, Sequence ID 94, Sequence ID 95, Sequence ID 96, Sequence ID The PTH portion contains sequences selected from the group consisting of sequence 97, sequence number 98, sequence number 99, sequence number 100, sequence number 101, sequence number 102, sequence number 103, sequence number 104, sequence number 105, sequence number 106, sequence number 107, sequence number 108, sequence number 109, sequence number 110, sequence number 111, sequence number 112, sequence number 113, sequence number 114, sequence number 115, sequence number 116, sequence number 117, sequence number 118, sequence number 119, sequence number 120, sequence number 121, and sequence number 122.

[0132] In a particular embodiment, -D is sequence numbers 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 1 The PTH moiety includes a sequence selected from the group consisting of 07, 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, which has at least 90% homology, for example, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology.

[0133] In a particular embodiment, -D is sequence numbers 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 96, 97, 98, 9 9. The PTH portion contains a sequence that has 95% homology to a sequence selected from the group consisting of sequence numbers 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, and 122.

[0134] In a particular embodiment, -D is selected from the group consisting of SEQ ID NOs: 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, and 122.

[0135] In a particular embodiment, -D is a PTH portion containing a sequence that has at least 90% homology, for example, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to a sequence selected from the group consisting of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114, 115, and 122.

[0136] In a particular embodiment, -D is a PTH portion that includes a sequence having 95% homology to a sequence selected from the group consisting of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114, 115, and 122.

[0137] In a particular embodiment, -D is a PTH portion containing sequences selected from the group consisting of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114, 115, and 122.

[0138] In a particular embodiment, -D is a PTH portion that includes a sequence selected from the group consisting of SEQ ID NOs. 50, SEQ ID NOs. 51, SEQ ID NOs. 52, SEQ ID NOs. 110, SEQ ID NOs. 111, SEQ ID NOs. 112, and SEQ ID NOs. 122, and having at least 90% homology, for example, 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.

[0139] In a particular embodiment, -D is a PTH moiety that includes a sequence having 95% homology to a sequence selected from the group consisting of SEQ ID NOs. 50, SEQ ID NOs. 51, SEQ ID NOs. 52, SEQ ID NOs. 110, SEQ ID NOs. 111, SEQ ID NOs. 112, and SEQ ID NOs. 122.

[0140] In a particular embodiment, -D is selected from the group consisting of SEQ ID NOs. 50, 51, 52, 110, 111, 112, and 122.

[0141] In certain embodiments, -D has sequence number 50. In certain embodiments, -D has sequence number 52. In certain embodiments, -D has sequence number 110. In certain embodiments, -D has sequence number 111. In certain embodiments, -D has sequence number 112. In certain embodiments, -D has sequence number 111. In certain embodiments, -D has sequence number 122.

[0142] In a particular embodiment, -D has sequence number 51.

[0143] In a particular embodiment, -D has sequence number 122: AVAEIQLMHQRAKWIQDARR RAFLHKLIAEIHTAEI

[0144] Part-L 1- is conjugated to a functional group on the side chain of an amino acid residue of -D, or to the N-terminal amine functional group of -D, or to the C-terminal carboxyl functional group, or to a nitrogen atom in the backbone polypeptide chain of -D. The bond to either the N-terminus or the C-terminus can be directly or indirectly via the corresponding amine or carboxyl functional group, in which case the spacer portion first conjugates to the amine or carboxyl functional group, and then -L is conjugated to this spacer portion. 1 - is conjugated.

[0145] In certain embodiments, -L 1 - is 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, hydroxyls, aldehydes, ketones, hydrazines, isocyanates, isothiocyanates, phosphoric acids, phosphonic acids, haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, sulfates, disulfides, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, guanidines, and aziridines. In certain embodiments, -L 1 - is conjugated to -D via a functional group selected from the group consisting of hydroxyl, primary amine, secondary amine, and guanidine. In certain embodiments, -L 1 - is conjugated to -D via a primary or secondary amine functional group. In certain embodiments, -L 1 - is conjugated to -D via a primary amine functional group. It is understood that not all functional groups can be present in protein constituent amino acids, and that they can be introduced by only one or more post-translational modifications, or that they may originate from non-protein constituent amino acids.

[0146] In certain embodiments, -L 1- is conjugated to the functional group of the side chain of the protein constituent amino acid residue of -D. In certain embodiments, the protein constituent amino acid is selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, and arginine. In certain embodiments, the protein constituent amino acid is selected from the group consisting of lysine, aspartic acid, arginine, and serine. In certain embodiments, the protein constituent amino acid is selected from the group consisting of lysine, arginine, and serine. In certain embodiments, -L 1 - is conjugated to the functional group of the histidine side chain of -D. In certain embodiments, -L 1 - is conjugated to the functional group of the lysine side chain of -D. In certain embodiments, -L 1 - is conjugated to the functional group of the tryptophan side chain of -D. In certain embodiments, -L 1 - is conjugated to the functional group of the serine side chain of -D. In certain embodiments, -L 1 - is conjugated to the threonine side chain functional group of -D. In certain embodiments, -L 1 - is conjugated to the tyrosine side chain functional group of -D. In certain embodiments, -L 1 - is conjugated to the functional group of the aspartic acid side chain of -D. In certain embodiments, -L 1 - is conjugated to the functional group of the glutamic acid side chain of -D. In certain embodiments, -L 1 - is conjugated to the arginine side chain functional group of -D. It should be understood that not all parts -D may contain all of these amino acid residues.

[0147] In certain embodiments, -L 1 - is either directly or indirectly conjugated to the N-terminal amine functional group of -D by the corresponding amine functional group, in which case the spacer portion first conjugates to the amine functional group, and then -L is conjugated to this spacer portion. 1- is conjugated. In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functional group of -D. In certain embodiments, -L 1 - is either directly or indirectly conjugated to the C-terminal functional group of -D by the corresponding carboxyl functional group, in which case the spacer portion first conjugates to the carboxyl functional group, and then -L is conjugated to this spacer portion. 1 - is conjugated. In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functional group of -D.

[0148] Part-L 1 - can be coupled to -D by any type of coupling, provided that it is reversible. In certain embodiments, -L 1 - is bonded to -D by a bond selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, and acylguanidine. In certain embodiments, -L 1 - is bonded to -D by a bond selected from the group consisting of amides, esters, carbamates, and acylguanidines. Some of these bonds are not reversible in themselves, however, in the present invention -L 1 It is understood that the neighboring groups contained in - make these bonds reversible. In certain embodiments, -L 1 - is bonded to -D by an ester bond. In certain embodiments, -L 1 - is bonded to -D by a carbamate bond. In certain embodiments, -L 1 - is bonded to -D by acylguanidine. In certain embodiments, -L 1 - is attached to -D by an amide bond.

[0149] Part-L 1- is a reversible prodrug linker from which the drug, namely PTH, is released in its free form, i.e., a traceless prodrug linker. Suitable prodrug linkers, such as the reversible prodrug linker portions disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1 and WO 2013 / 024053 A1, are known in the art, and these documents are incorporated herein by reference in their entirety.

[0150] In certain embodiments, -L 1 - is a reversible prodrug linker as described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1, the entirety of which these documents are incorporated herein by reference.

[0151] In certain embodiments, -L 1 - is disclosed in WO 2009 / 095479 A2. Therefore, in certain embodiments, part -L 1 - is equation (II):

[0152] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen, hydroxyl, or thiol. -X- is -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(R6 )-C(R 4 R 4a )-,-C(R 4 R 4a )-O-, -OC(R 4 R 4a )-, and -C(R 7 R 7a Selected from the group consisting of )-, X 1 It is selected from the group consisting of C and S(O), -X 2 - is -C(R 8 R 8a )- and -C(R 8 R 8a )-C(R 9 R 9a Selected from the group consisting of )-, =X 3 It is selected from the group consisting of =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 These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, -R 3 and -R 3a These are independently -H and C 1-6 Selected from the group consisting of alkyl, except -R 3 , -R 3a If one or both of them are not -H, then they are SP to the N to which they are bonded. 3 Bonded by hybrid carbon atoms, -R 7 is -N(R 10 R 10a ) and -NR 10 -(C=O)-R 11 Selected from the group consisting of, -R 7a, -R 10 , -R 10a , and -R 11 These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups, Depending on the circumstances, Pair-R 1a / -R 4a , -R 1a / -R 5a , -R 1a / -R 7a , -R 4a / -R 5a , and -R 8a / -R 9a One or more of them form a chemical bond, Depending on the circumstances, Pair-R 1 / -R 1a , -R 2 / -R 2a , -R 4 / -R 4a , -R 5 / -R 5a , -R 8 / -R 8a , and -R 9 / -R 9a One or more of them, together with the atom they are bonded to, C 3-10 Forming a cycloalkyl or 3-10 membered heterocycline, Depending on the circumstances, Pair-R 1 / -R 4 , -R 1 / -R 5 , -R 1 / -R 6 , -R 1 / -R 7a , -R 4 / -R 5 , -R 4 / -R 6 , -R 8 / -R 9 , and -R 2 / -R 3 One or more of these, together with the atoms to which they are bonded, form ring A. Depending on the case, R 3 / R 3a These, together with the nitrogen atoms to which they are bonded, form a heterocycle of 3 to 10 members. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 (Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls.) It has, Here, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (II) is -L 2 -Z or -L 2 -Z' or not substituted by substituents.

[0153] In a particular embodiment, -L of formula (II) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0154] In a particular embodiment, -L of formula (II) 1 - has not been further replaced.

[0155] -R in equation (II) 3 / -R 3a However, when they combine with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is SP 3 It is understood that only such 3- to 10-membered heterocycles, which are hybrid carbon atoms, can be formed. In other words, -R 3 / -R 3a As a result, such 3- to 10-membered heterocycles formed together with the nitrogen atoms to which they are bonded have the following structure:

[0156] [ka] (In the formula, The dashed line is -L 1 - indicates the connection to the remainder, The ring contains 3 to 10 atoms, including at least one nitrogen atom. R # and R ## is, sp 3 (Represents a hybrid of carbon atoms).

[0157] It is also understood that the above 3- to 10-member complex rings can be further permuted.

[0158] -R in equation (II) 3 / -R 3a The following are exemplary embodiments of preferred 3- to 10-membered heterocycles formed by these together with the nitrogen atoms to which they are bonded:

[0159] [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule. -R is -H and C 1-6 (Selected from the group consisting of alkyl groups).

[0160] -L in equation (II) 1 - may be further substituted depending on the case. In general, any substituent is possible as long as it does not affect the principle of cleavage, i.e., the hydrogen with the asterisk in formula (II) is not substituted, and part of formula (II)

[0161] [ka] The nitrogen remains as part of the primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a These are either -H independently of each other, or sp 3 It is bonded to -N< via hybridized carbon atoms.

[0162] In one embodiment, -R of formula (II) 1 or -R 1a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 2or -R 2a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 3 or -R 3a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 4 is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 5 or -R 5a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 6 is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 7 or -R 7a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 8 or -R 8a is, -L 2 -Z or -L 2 It is substituted with -Z'. In another embodiment, -R in formula (II) 9 or -R 9a is, -L 2 -Z or -L 2 -Z' is substituted. In another embodiment, -R 10 is, -L 2 -Z or -L 2 -Z' is substituted. In another embodiment, -R 11 is, -L 2 -Z or -L 2 It is replaced by -Z'. In certain embodiments, -R in formula (II) 3 is, -L 2 -Z or -L 2 It is replaced with -Z'.

[0163] In a particular embodiment, -X- in formula (II) is -C(R 4 R 4a )-,-N(R 4 )- and -C(R 7 R 7a Selected from the group consisting of )-. In a particular embodiment, -X- in formula (II) is -C(R 4 R 4a )-. In a particular embodiment, -X- in formula (II) is -C(R 7 R 7a )-is.

[0164] In certain embodiments, -R of formula (II) 7 -NR 10 -(C=O)-R 11 That is the case.

[0165] In certain embodiments, -R of formula (II) 7a is selected from -H, methyl and ethyl. In certain embodiments, -R of formula (II) 7a It is -H.

[0166] In certain embodiments, -R 10 is selected from -H, methyl and ethyl. In certain embodiments, -R 10 It is methyl.

[0167] In certain embodiments, -R 11 is selected from -H, methyl and ethyl. In certain embodiments, -R 11 is -H. In certain embodiments, -R 11 is, -L 2 -Z or -L 2 It is replaced with -Z'.

[0168] In a particular embodiment, -X- in formula (II) is -N(R 4 )-is.

[0169] In certain embodiments, -R 4is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R 4 It is -H.

[0170] In a particular embodiment, X of formula (II) 1 It is C.

[0171] In a particular embodiment, equation (II) = X 3 The answer is = O.

[0172] In a particular embodiment, -X of formula (II) 2 - is -C(R 8 R 8a )-is.

[0173] In certain embodiments, -R of formula (II) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (II) 8 and -R 8a Both are -H.

[0174] In certain embodiments, -R of formula (II) 1 and -R 1a This is independently selected from the group consisting of -H, methyl, and ethyl.

[0175] In certain embodiments, -R of formula (II) 1 and -R 1a At least one of them is -H. In certain embodiments, -R of formula (II) 1 and -R 1a It is -H.

[0176] In certain embodiments, -R of formula (II) 1 and -R 1a At least one of them is methyl. In certain embodiments, -R of formula (II) 1and -R 1a Both are methyl.

[0177] In certain embodiments, -R of formula (II) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (II) 2 and -R 2a Both are H.

[0178] In certain embodiments, -R of formula (II) 3 and -R 3a This is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.

[0179] In certain embodiments, -R of formula (II) 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (II) 3 It is methyl, and -R in formula (II) 3a is -H.

[0180] In certain embodiments, -R of formula (II) 3 and -R 3a Both are -H.

[0181] In certain embodiments, -D is -L of formula (II) by nitrogen by forming an amide bond. 1 It is connected to -.

[0182] In certain embodiments, part-L 1 - is equation (IIa-i)

[0183] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 3a , -R 4 and -X 2 - is used as defined in equation (II). It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - may be further substituted in some cases, except that the hydrogen with an asterisk in formula (IIa-i) is -L 2 -Z or -L 2 -Z' or not substituted by a substituent.

[0184] -R in equation (IIa-i) 3 , -R 3a If one or both of them are not -H, they are sp to the N to which they are bonded. 3 It is understood that the bonds are formed via hybridized carbon atoms.

[0185] In a particular embodiment, -L of formula (IIa-i) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0186] In a particular embodiment, part L of formula (IIa-i) 1 - has not been further replaced.

[0187] In certain embodiments, -R in formula (IIa-i) 1 and -R 1a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-i) 1 and -R 1a At least one of them is methyl. In certain embodiments, the -R of formula (IIa-i) 1 and -R1a Both are methyl.

[0188] In certain embodiments, -R in formula (IIa-i) 4 The is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-i) 4 It is -H.

[0189] In a particular embodiment, -X in formula (IIa-i) 2 - is -C(R 8 R 8a )-is.

[0190] In certain embodiments, -R in formula (IIa-i) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-i) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIa-i) 8 and -R 8a Both are -H.

[0191] In certain embodiments, -R in formula (IIa-i) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-i) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIa-i) 2 and -R 2a Both are H.

[0192] In certain embodiments, -R in formula (IIa-i) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIa-i) 3 and -R 3aAt least one of them is -H. In certain embodiments, -R of formula (IIa-i) 3 and -R 3a Both are -H.

[0193] In certain embodiments, part-L 1 - is equation (IIa-ii):

[0194] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - is used as defined in equation (II). It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further substituted, however, the hydrogen with an asterisk in formula (IIa-ii) is -L 2 -Z or -L 2 -Z' or not substituted by a substituent.

[0195] -R in equation (IIa-ii) 3 , -R 3a If one or both of them are not -H, they are sp to the N to which they are bonded. 3 It is understood that the bonds are formed via hybridized carbon atoms.

[0196] In a particular embodiment, -L of formula (IIa-ii) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0197] In a particular embodiment, part L of formula (IIa-ii)1 - has not been further replaced.

[0198] In a particular embodiment, -X in formula (IIa-ii) 2 - is -C(R 8 R 8a )-is.

[0199] In a particular embodiment, -R of formula (IIa-ii) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-ii) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIa-ii) 8 and -R 8a Both are -H.

[0200] In a particular embodiment, -R of formula (IIa-ii) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-ii) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIa-ii) 2 and -R 2a Both are H.

[0201] In a particular embodiment, -R of formula (IIa-ii) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIa-ii) 3 and -R 3a At least one of them is -H. In certain embodiments, -R of formula (IIa-ii) 3 and -R 3a Both are -H.

[0202] In certain embodiments, part-L 1- is equation (IIa-ii'):

[0203] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 2 , -R 2a , -R 3a and -X 2 - is used as defined in equation (II). It has, -L 1 - may be further substituted in some cases, however, the hydrogen atoms with an asterisk in formula (IIa-ii') are not substituted by substituents.

[0204] -R in equation (IIa-ii') 3a If it is anything other than -H, then it will be sp to the N it is bonded to. 3 It is understood that the bonds are formed via hybridized carbon atoms.

[0205] In a particular embodiment, part L of formula (IIa-ii') 1 - has not been further replaced.

[0206] In a particular embodiment, -X in formula (IIa-ii') 2 - is -C(R 8 R 8a )-is.

[0207] In a particular embodiment, -R of formula (IIa-ii') 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-ii') 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIa-ii'). 8 and -R8a Both are -H.

[0208] In a particular embodiment, -R of formula (IIa-ii') 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa-ii') 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIa-ii'). 2 and -R 2a Both are H.

[0209] In a particular embodiment, -R of formula (IIa-ii') 3a -H, methyl, ethyl, propyl, and butyl are selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In one embodiment, -R of formula (IIa-ii') 3a It is -H.

[0210] In certain embodiments, part-L 1 - is equation (IIa-iii):

[0211] [ka] (In the formula, (The dashed line indicates the bond of -D to nitrogen via an amide bond.) It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIa-iii) is -L 2 -Z or -L 2 -Z' or not substituted by a substituent.

[0212] -R in equation (IIa-iii) 3 , -R 3a If one or both of them are not -H, they are sp to the N to which they are bonded.3 It is understood that the bonds are formed via hybridized carbon atoms.

[0213] In certain embodiments, the -L of formula (IIa-iii) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0214] In a particular embodiment, part L of formula (IIa-iii) 1 - has not been further replaced.

[0215] In certain embodiments, part-L 1 - is equation (IIa-iii'):

[0216] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It has, -L 1 - indicates that the atoms may be further substituted, except that the hydrogen atoms with an asterisk in formula (IIa-iii') are not substituted by substituents.

[0217] In equation (IIa-iii'), the nitrogen adjacent to the dashed line with an asterisk is sp 3 -L via hybridized carbon atoms 2 It is understood that it is connected to -.

[0218] In a particular embodiment, part L of formula (IIa-iii') 1 - has not been further replaced.

[0219] In certain embodiments, part-L 1 - is equation (IIb-ii):

[0220] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - is used as defined in equation (II). It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIb-ii) is -L 2 -Z or -L 2 -Z' or not substituted by a substituent.

[0221] -R in equation (IIb-ii) 3 , -R 3a If one or both of them are not -H, they are sp to the N to which they are bonded. 3 It is understood that the bonds are formed via hybridized carbon atoms.

[0222] In a particular embodiment, -L of formula (IIb-ii) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0223] In a particular embodiment, part L of formula (IIb-ii) 1 - has not been further replaced.

[0224] In a particular embodiment, -X in formula (IIb-ii) 2 - is -C(R 8 R 8a )-is.

[0225] In a particular embodiment, the -R of formula (IIb-ii)8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb-ii) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb-ii) 8 and -R 8a Both are -H.

[0226] In a particular embodiment, the -R of formula (IIb-ii) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb-ii) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIb-ii) 2 and -R 2a Both are H.

[0227] In a particular embodiment, the -R of formula (IIb-ii) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIb-ii) 3 and -R 3a At least one of them is -H. In certain embodiments, -R of formula (IIb-ii) 3 and -R 3a Both are -H.

[0228] In certain embodiments, part-L 1 - is equation (IIb-iia):

[0229] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. -R 2 , -R 2a , -R 3 , -R3a and -X 2 - is used as defined in equation (II). It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further substituted, however, the hydrogen with an asterisk in formula (IIa-iia) is -L 2 -Z or -L 2 -Z' or not substituted by a substituent.

[0230] -R in equation (IIb-iia) 3 , -R 3a If one or both of them are not -H, they are sp to the N to which they are bonded. 3 It is understood that the bonds are formed via hybridized carbon atoms.

[0231] In certain embodiments, -L of formula (IIb-iia) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0232] In a particular embodiment, part L of formula (IIb-iia) 1 - has not been further replaced.

[0233] In a particular embodiment, -X in formula (IIb-iia) 2 - is -C(R 8 R 8a )-is.

[0234] In certain embodiments, the -R of formula (IIb-iia) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb-iia) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb-iia)8 and -R 8a are both -H.

[0235] In a specific embodiment, -R of formula (IIb-iia) 2 and -R 2a are each independently selected from the group consisting of -H, methyl and ethyl. In a specific embodiment, -R of formula (IIb-iia) 2 and -R 2a at least one is -H. In a specific embodiment, -R of formula (IIb-iia) 2 and -R 2a are both H.

[0236] In a specific embodiment, -R of formula (IIb-iia) 3 and -R 3a are each independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In a specific embodiment, -R of formula (IIb-iia) 3 and -R 3a at least one is -H. In a specific embodiment, -R of formula (IIb-iia) 3 and -R 3a are both -H.

[0237] In a specific embodiment, the moiety -L 1 - is of formula (IIb-ii'):

[0238]

Chemical Formula

[0239] -R in formula (IIb-ii') 3a is other than -H, it is understood that it is bonded to the N to which it is attached via an sp 3 hybridized carbon atom.

[0240] In certain embodiments, -L of formula (IIb-ii') 1 - is not further substituted.

[0241] In certain embodiments, -X of formula (IIb-ii') 2 - is -C(R 8 R 8a )-.

[0242] In certain embodiments, -R of formula (IIb-ii') 8 and -R 8a are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (IIb-ii') 8 and -R 8a at least one is -H. In certain embodiments, -R of formula (IIb-ii') 8 and -R 8a are both -H.

[0243] In certain embodiments, -R of formula (IIb-ii') 2 and -R 2a are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (IIb-ii') 2 and -R 2a at least one is -H. In certain embodiments, -R of formula (IIb-ii') 2 and -R 2a are both H.

[0244] In certain embodiments, -R of formula (IIb-ii')3a -H, methyl, ethyl, propyl, and butyl are selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In one embodiment, -R of formula (IIb-ii') 3a It is -H.

[0245] In certain embodiments, part-L 1 - is equation (IIb-iia'):

[0246] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 2 , -R 2a , -R 3a and -X 2 - is used as defined in equation (II). It has, -L 1 - may be further substituted in some cases, except that the hydrogen atoms with an asterisk in formula (IIb-iia') are not substituted by substituents.

[0247] -R in equation (IIb-iia') 3a If it is anything other than -H, then it will be sp to the N it is bonded to. 3 It is understood that the bonds are formed via hybridized carbon atoms.

[0248] In a particular embodiment, part L of formula (IIb-iia') 1 - has not been further replaced.

[0249] In a particular embodiment, -X in formula (IIb-iia') 2 - is -C(R 8 R 8a )-is.

[0250] In certain embodiments, the -R of formula (IIb-iia') 8and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb-iia') 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb-iia'). 8 and -R 8a Both are -H.

[0251] In certain embodiments, the -R of formula (IIb-iia') 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb-iia') 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIb-iia'). 2 and -R 2a Both are H.

[0252] In certain embodiments, the -R of formula (IIb-iia') 3a -H, methyl, ethyl, propyl, and butyl are selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In one embodiment, -R of formula (IIb-iia') 3a It is -H.

[0253] In certain embodiments, part-L 1 - is equation (IIb-iii):

[0254] [ka] (In the formula, (The dashed line indicates the bond of -D to nitrogen via an amide bond.) It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIb-iii) is -L2 -Z or -L 2 -Z' or an unsubstituted substituent.

[0255] -R in formula (IIb-iii) 3 , -R 3a when one or both of which are other than -H, it is understood that they are bonded to the N to which they are attached via sp 3 hybridized carbon atom.

[0256] In certain embodiments, -L in formula (IIb-iii) 1 - is substituted with one moiety -L 2 -Z or -L 2 -Z'.

[0257] In certain embodiments, the moiety -L in formula (IIb-iii) 1 - is further unsubstituted.

[0258] In certain embodiments, the moiety -L 1 - is of formula (IIb-iiia):

[0259]

Chemical Formula

[0260] -R in formula (IIb-iiia) 3 , -R 3a when one or both of which are other than -H, they are bonded to the N to which they are attached via sp3 It is understood that the bonds are formed via hybridized carbon atoms.

[0261] In certain embodiments, the -L of formula (IIb-iiia) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0262] In a particular embodiment, part L of formula (IIb-iiia) 1 - has not been further replaced.

[0263] In certain embodiments, part-L 1 - is equation (IIb-iii'):

[0264] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It has, -L 1 - indicates that the atoms may be further substituted, except that the hydrogen atoms with an asterisk in formula (IIa-iii') are not substituted by substituents.

[0265] In equation (IIa-iii'), the nitrogen adjacent to the dashed line with an asterisk is sp 3 -L via hybridized carbon atoms 2 It is understood that it is connected to -.

[0266] In a particular embodiment, part L of formula (IIa-iii') 1 - has not been further replaced.

[0267] In certain embodiments, part-L 1 - is equation (IIb-iiia'):

[0268] [ka] (In the formula, The dashed line indicates the bond of -D to nitrogen via an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It has, -L 1 - indicates that the substituent may be further substituted, except that the hydrogen atoms with an asterisk in formula (IIa-iiia') are not substituted by substituents.

[0269] In equation (IIa-iiia'), the nitrogen adjacent to the dashed line with an asterisk is sp 3 -L via hybridized carbon atoms 2 It is understood that it is connected to -.

[0270] In a particular embodiment, part L of formula (IIa-iiia') 1 - has not been further replaced.

[0271] In certain embodiments, -L 1 - is disclosed in WO2016 / 020373A1. Therefore, in certain embodiments, part -L 1 - is equation (III):

[0272] [ka] (In the formula, The dashed lines indicate bonding to a primary or secondary amine or hydroxyl group of -D via an amide bond or ester bond, respectively. -R 1 , -R 1a , -R 2 , -R 2a , -R 3 and -R 3a These are -H and -C(R) independently of each other. 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 Selected from the group consisting of and -T, -R 4 , -R 5 and -R 5a These are -H and -C(R) independently of each other. 9 R 9a R 9b Selected from the group consisting of ) and -T, a1 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 These are -H, halogen, -CN, and -COOR, which are independent of each other. 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(R10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Selected from the group consisting of alkynyl, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is the same or different -R of one or more R's. 11 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, Each-R 10 , -R 10a , and -R 10b These are independently -H, -T, and C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Selected from the group consisting of alkynyl, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is the same or different -R of one or more R's. 11 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls, each T independently has one or more identical or different -R groups. 11 It is sometimes replaced by, Each-R 11 These are, independently of each other, halogen, -CN, oxo (=O), and -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 Selected from alkyl, where C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R 12 , -R 12a , -R 13 , -R 13a , and -R 13b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Depending on the circumstances, Pair-R 1 / -R 1a , -R 2 / -R 2a , -R 3 / -R 3a , -R 6 / -R 6a , and -R 7 / -R 7a One or more of them, together with the atom they are bonded to, C 3-10 Forming a cycloalkyl or 3-10 membered heterocycline, Depending on the circumstances, Pair-R 1 / -R 2 , -R 1 / -R 3 , -R 1 / -R 4 , -R 1 / -R 5 , -R 1 / -R 6 , -R 1 / -R 7 , -R 2 / -R 3 , -R 2 / -R 4 , -R 2 / -R 5 , -R 2 / -R 6 , -R 2 / -R 7 , -R 3 / -R 4, -R 3 / -R 5 , -R 3 / -R 6 , -R 3 / -R 7 , -R 4 / -R 5 , -R 4 / -R 6 , -R 4 / -R 7 , -R 5 / -R 6 , -R 5 / -R 7 , and -R 6 / -R 7 One or more of these, together with the atoms to which they are bonded, form ring A. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 (Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls.) It has, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0273] -L in equation (III) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0274] In certain embodiments, -L of formula (III) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0275] In certain embodiments, -L of formula (III) 1 - has not been further replaced.

[0276] In certain embodiments, -L 1- is disclosed in European Patent No. 1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2, and U.S. Patent No. 8,618,124B2, all of which are incorporated herein by reference.

[0277] In certain embodiments, -L 1 - is disclosed in U.S. Patent No. 8,946,405 B2 and U.S. Patent No. 8,754,190 B2, which are incorporated herein by reference in their entirety. Thus, in certain embodiments, -L 1 - is equation (IV):

[0278] [ka] (In the formula, The dashed line indicates a bond to -D, where the bond is via a functional group of -D selected from the group consisting of -OH, -SH, and -NH2. m is either 0 or 1. -R 1 and -R 2 At least one or both of these are, independently of each other, -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 Selected from the group consisting of, -R 1 and -R 2 One or only one of these is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. -R 3-H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 Selected from the group consisting of )2, -R 4 This is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Each-R 5 These are independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. -R 9 This is selected from the group consisting of -H and optionally substituted alkyl groups, -Y- does not exist, and -X- is either -O- or -S-, or -Y- is -N(Q)CH2- and -X- is -O-, Q is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Depending on the case, -R 1 and -R 2 They may come together to form a ring of 3 to 8 members. Depending on the case, both -R 9 (These atoms, together with the nitrogen atoms they are bonded to, form a heterocyclic ring.) It has, Here, -L 1 - is at least one -L 2 -Z or -L2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0279] The term used exclusively in relation to formula (IV) has the following meanings:

[0280] As used herein, the term "alkyl" includes a linear, branched, or cyclic saturated hydrocarbon group comprising 1 to 8 carbon atoms, or in certain embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0281] The term "alkoxy" encompasses alkyl groups bonded to oxygen, including, for example, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar groups.

[0282] The term "alkenyl" encompasses non-aromatic unsaturated hydrocarbons that contain a carbon-carbon double bond.

[0283] The term "alkynyl" encompasses non-aromatic unsaturated hydrocarbons that have a carbon-carbon triple bond.

[0284] The term "aryl" encompasses aromatic hydrocarbon groups with 6 to 18 carbon atoms, for example, 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracenyl groups. The term "heteroaryl" encompasses aromatic rings with 3 to 15 carbon atoms containing at least one N, O, or S atom, for example, 3 to 7 carbon atoms containing at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl groups, and similar groups.

[0285] In some examples, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the rest of the molecule via an alkylene bond. In these circumstances, the substituent is called an alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety lies between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0286] The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0287] The term "heterocyclic ring" refers to a 4-8 membered aromatic or non-aromatic ring containing 3-7 carbon atoms and at least 1 N, O, or S atom. Examples include piperidinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term "heteroaryl" above.

[0288] If the ring system is optionally substituted, preferred substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or further rings, each optionally further substituted. Optional substituents on any of the above-mentioned groups include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, and -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atom to which they are bonded form a ring.

[0289] In certain embodiments, -L of formula (IV) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0290] In certain embodiments, -L of formula (IV) 1- has not been further replaced.

[0291] In certain embodiments, -L 1 - is disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - is equation (V):

[0292] [ka] (In the formula, The dashed line indicates the bond to -D via the amine functional group of -D. -R 1 These include optionally substituted C1-C6 linear, branched, or cyclic alkyl groups; optionally substituted aryl groups; optionally substituted heteroaryl groups; alkoxy groups; and -NR 5 Selected from a group consisting of 2, -R 2 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 3 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 4 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each-R 5 These are independently selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or together, two -R 5 (This can be a cycloalkyl or cycloheteroalkyl group.) It has, Here, -L 1- is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0293] The term used exclusively in relation to the expression (V) has the following meanings:

[0294] "Alkyl," "alkenyl," and "alkynyl" encompass a linear, branched, or cyclic hydrocarbon group of 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 carbon atoms.

[0295] "Aryl" refers to an aromatic hydrocarbon group comprising 6 to 18 carbon atoms, for example, 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracene. "Heteroaryl" refers to an aromatic ring comprising 3 to 15 carbon atoms containing at least one N, O, or S atom, for example, 3 to 7 carbon atoms containing at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar groups.

[0296] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogens (including F, Cl, Br, and I), lower alkyls (including linear, branched, and cyclic lower alkyls), lower haloalkyls (including fluoroalkyls, chloroalkyls, bromoalkyls, and iodoalkyls), OH, lower alkoxys (including linear, branched, and cyclic lower alkoxys), SH, lower alkylthios (including linear, branched, and cyclic lower alkylthios), aminos, alkylaminos, dialkylaminos, silyls (including alkylsilyls, alkoxysilyls, and arylsilyls), nitros, cyanos, carbonyls, carboxylic acids, carboxylic acid esters, carboxylic acid amides, and aminocarboxyl groups. The following can be selected: bonyl, aminoacyl, carbamate, urea, thiocarbamate, thiourea, ketone, sulfone, sulfonamide, aryl (including phenyl, naphthyl, and anthracenyl), heteroaryl (including 5-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole, 6-membered heteroaryls such as pyridine, pyrimidine, pyrazine, and condensed heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole, and benzoisothiazole).

[0297] In certain embodiments, -L of formula (V) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0298] In certain embodiments, -L of formula (V) 1 - has not been further replaced.

[0299] In certain embodiments, -L 1- is disclosed in U.S. Patent No. 7,585,837 B2, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - is equation (VI):

[0300] [ka] (In the formula, The dashed line indicates the bond to -D via the amine functional group of -D. R 1 and R 2 These are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkalyl, aralkyl, halogen, nitro, -SO3H, -SO2HH 5 Selected from the group consisting of amino, ammonium, carboxyl, PO3H2, and OPO3H2, R 3 , R 4 , and R 5 (These are independently selected from the group consisting of hydrogen, alkyl, and aryl.) It has, Here, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0301] Suitable substituents for formula (VI) are alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 Alkenyl), Alkinyl (for example, C 2-6 The moiety is an alkynyl, aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., an aromatic 4-7 membered heterocycle), or halogen moiety.

[0302] The term used exclusively in relation to formula (VI) has the following meanings:

[0303] The terms "alkyl," "alkoxy," "alkoxyalkyl," "aryl," "alkalil," and "aralkyl" refer to alkyl groups with 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl groups with 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0304] In certain embodiments, -L of formula (VI) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0305] In certain embodiments, -L of formula (VI) 1 - has not been further replaced.

[0306] -L 1 Further preferred embodiments of - are disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Therefore, preferred portion - L 1 - is equation (VII):

[0307] [ka] (In the formula, The dashed line indicates the bond to -D via the amine functional group of -D. L1 is a bifunctional bonding group, Y1 and Y2 are independently O, S, or NR 7 And, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituting alkyl, C 3-8Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy, and C 1-6 Selected from the group consisting of heteroalkoxys, When Ar is included in formula (VII), it is the part that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group. X is a chemical bond, a portion actively transported to the target cell, a hydrophobic portion, or a combination thereof. (y is either 0 or 1) It has, Here, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0308] The term used exclusively in relation to formula (VII) has the following meanings:

[0309] The term "alkyl" refers to, for example, linear, branched, or substituted C atoms. 1-12 Alkyl, for example, alkoxy, C 3-8 This is understood to include cycloalkyl or substituted cycloalkyl groups, etc.

[0310] The term "substituted" shall be understood to include adding one or more different atoms to one or more atoms contained in a functional group or compound, or replacing one or more atoms contained in a functional group or compound with one or more different atoms.

[0311] Substitutive alkyls include carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl; substituted cycloalkyls include parts such as 4-chlorocyclohexyl; aryls include parts such as naphthyl; substituted aryls include parts such as 3-bromophenyl; aralkyls include parts such as toluyl; heteroalkyls include parts such as ethylthiophene; substituted heteroalkyls include parts such as 3-methoxythiophene; alkoxys include parts such as methoxy; and phenoxys include parts such as 3-nitrophenoxy. Halos are understood to include fluoro, chloro, iodine, and bromo.

[0312] In certain embodiments, -L of formula (VII) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0313] In certain embodiments, -L of formula (VII) 1 - has not been further replaced.

[0314] In certain embodiments, -L 1 - is a substructure of equation (VIII)

[0315] [ka] (In the formula, The dashed line with an asterisk indicates the bond of -D to nitrogen via an amide bond. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Here, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0316] In certain embodiments, the -L of formula (VIII) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0317] In certain embodiments, the -L of formula (VIII) 1 - has not been further replaced.

[0318] In certain embodiments, -L 1 - is a substructure of equation (IX)

[0319] [ka] (In the formula, The dashed line with an asterisk indicates the bond of -D to nitrogen via a carbamate bond. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Here, -L 1 - is at least one -L 2 -Z or -L 2 -Z' is substituted, -L 1 - is sometimes further replaced.

[0320] In certain embodiments, -L of formula (IX) 1 - is one part -L 2 -Z or -L 2 It is replaced with -Z'.

[0321] In certain embodiments, -L of formula (IX) 1 - has not been further replaced.

[0322] In certain embodiments, -L 1 - has the structure disclosed in WO2020 / 206358 A1. Therefore, in certain embodiments, part -L 1 - is equation (X):

[0323] [ka] (In the formula, Unmarked dashed lines indicate connections to -D. The dashed line with an asterisk indicates -L 2 -Z or -L 2 Shows binding to -Z', n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. -R 1 and -R 2 These are independently electron-withdrawing groups, alkyl groups, or -H groups, and -R 1 or -R 2 At least one of them is an electron-withdrawing group, Each-R 4 These are independently C1-C3 alkyl groups or two -R groups. 4 These, together with the carbon atoms to which they are bonded, form a ring with 3 to 6 members. -Y- is absent if -D is a drug moiety bonded via an amine, or -Y- is absent if -D is a drug moiety bonded via a phenol, alcohol, thiol, thiophenol, imidazole, or non-basic amine. 6 )CH2-, where -R 6 (These are, in some cases, substituted C1-C6 alkyl groups, in some cases, substituted aryl groups, or in some cases, substituted heteroaryl groups.) It holds.

[0324] In certain embodiments, n in formula (X) is an integer selected from 1, 2, 3, 4, 5, and 6. In certain embodiments, n in formula (X) is an integer selected from 1, 2, and 3. In certain embodiments, n in formula (X) is an integer from 0, 1, 2, and 3. In certain embodiments, n in formula (X) is 1. In certain embodiments, n in formula (X) is 2. In certain embodiments, n in formula (X) is 3.

[0325] In certain embodiments, -R of formula (X) 1and -R 2 The electron-withdrawing groups are -CN;-NO2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl;-COR 3 -SOR 3 , or -SO2R 3 (In the formula, -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2, and each -R 8 These are independently -H or optionally substituted alkyl, or both -R 8 The groups, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring; or -SR 9 (In the formula, -R 9 (which is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl) is selected from the group consisting of these.

[0326] In certain embodiments, -R of formula (X) 1 and -R 2 The electron-withdrawing group is -CN. In certain embodiments, -R of formula (X) 1 and -R 2 The electron-withdrawing group is -NO2. In certain embodiments, -R of formula (X) 1 and -R 2 The electron-withdrawing group is an optionally substituted aryl group containing 6 to 10 carbon atoms. In certain embodiments, the -R of formula (X) 1 and -R 2 The electron-withdrawing group is optionally substituted phenyl, naphthyl, or anthracenyl. In certain embodiments, -R of formula (X) 1 and -R 2The electron-withdrawing group is an optionally substituted heteroaryl containing 3 to 7 carbon atoms and at least one N, O, or S atom. In certain embodiments, the -R of formula (X) 1 and -R 2 The electron-withdrawing group is optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl. In certain embodiments, -R of formula (X) 1 and -R 2 The electron-withdrawing group is an optionally substituted alkenyl containing 2 to 20 carbon atoms. In certain embodiments, the -R of formula (X) 1 and -R 2 The electron-withdrawing group is an optionally substituted alkynyl containing 2 to 20 carbon atoms. In certain embodiments, the -R of formula (X) 1 and -R 2 The electron-withdrawing group is -COR 3 -SOR 3 , or -SO2R 3 And here -R 3 -H, optionally substituted alkyl containing 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2, and each -R 8 These are either alkyl groups independently substituted with -H or containing 1 to 20 carbon atoms, or both -R groups. 8 The groups, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring. In certain embodiments, the -R of formula (X) 1 and -R 2 The electron-withdrawing group is -SR 9 And here -R 9This is an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, which contains 1 to 20 carbon atoms.

[0327] In certain embodiments, -R of formula (X) 1 or -R 2 At least one of them is -CN, -SOR 3 or -SO2R 3 In certain embodiments, -R of formula (X) 1 and -R 2 At least one of them is -CN or -SO2R 3 In certain embodiments, -R of formula (X) 1 and -R 2 At least one of them is -CN or -SO2R 3 And, -R 3 This may be a substituted alkyl, may be a substituted aryl, or -NR 8 2. In certain embodiments, -R of formula (X) 1 and -R 2 At least one of them is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted with -SO2, phenyl substituted with -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3), or -SO2N(CH2CH2OCH3)2.

[0328] In a particular embodiment, each -R of formula (X) 4 These are independently C1-C3 alkyl groups. In certain embodiments, both -R 4 It is methyl.

[0329] In certain embodiments, -Y- in formula (X) does not exist. In certain embodiments, -Y- in formula (X) is -N(R 6 It is CH2-.

[0330] In certain embodiments, -L 1 - means that n in the expression is 1, -R 1 -CN and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the formula is 1, -R 1 is -SO2N(CH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the expression is 1, -R 1 It is SO2CH3, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the expression is 1, -R 1 is -SO2N(CH2CH2)2CHCH3, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the expression is 1, -R 1 However, it is a phenyl compound substituted with -SO2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the expression is 1, -R 1 However, it is a phenyl substituted with -SO2 and -Cl, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the expression is 1, -R 1 is -SO2N(CH2CH2)2O, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the formula is 1, -R 1 is -SO2CH(CH3)2, and -R 2 is -H and -R4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the formula is 1, -R 1 is -SO2N(CH3)(CH2CH3), and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the formula is 1, -R 1 is -SO2N(CH2CH2OCH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - means that n in the formula is 1, -R 1 However, it is a phenyl substituted with -SO2 and -CH3, and -R 2 is -H and -R 4 The equation (X) is -CH3.

[0331] In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 -CN and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 is -SO2N(CH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 It is SO2CH3, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 is -SO2N(CH2CH2)2CHCH3, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1- is where n in the formula is 2, and -R 1 However, it is a phenyl compound substituted with -SO2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 However, it is a phenyl substituted with -SO2 and -Cl, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 is -SO2N(CH2CH2)2O, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 is -SO2CH(CH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 is -SO2N(CH3)(CH2CH3), and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 is -SO2N(CH2CH2OCH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 2, and -R 1 However, it is a phenyl substituted with -SO2 and -CH3, and -R 2 is -H and -R 4 The equation (X) is -CH3.

[0332] In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1-CN and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 is -SO2N(CH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 It is SO2CH3, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 is -SO2N(CH2CH2)2CHCH3, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 However, it is a phenyl compound substituted with -SO2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 However, it is a phenyl substituted with -SO2 and -Cl, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 is -SO2N(CH2CH2)2O, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 is -SO2CH(CH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1- is where n in the formula is 3, and -R 1 is -SO2N(CH3)(CH2CH3), and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 is -SO2N(CH2CH2OCH3)2, and -R 2 is -H and -R 4 The formula (X) is -CH3. In certain embodiments, -L 1 - is where n in the formula is 3, and -R 1 However, it is a phenyl substituted with -SO2 and -CH3, and -R 2 is -H and -R 4 The equation (X) is -CH3.

[0333] The term used exclusively in relation to formula (X) has the following meanings:

[0334] The term "alkyl" refers to a linear, 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 certain embodiments, alkyl groups are linear or branched. Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In certain embodiments, alkyl groups are cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0335] The term "alkoxy" refers to an alkyl group bonded to oxygen, such as methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0336] The term "alkenyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon double bond and 2-20, 2-12, 2-8, 2-6, or 2-4 carbon atoms.

[0337] The term "alkynyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon triple bond and 2-20, 2-12, 2-8, 2-6, or 2-4 carbon atoms.

[0338] The term "aryl" refers to an aromatic hydrocarbon group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracenyl groups. The term "heteroaryl" refers to an aromatic ring having 3 to 15 carbon atoms, preferably 3 to 7 carbon atoms, including at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl groups.

[0339] In certain embodiments, an alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule by an alkyl bond. Under these circumstances, the substituent is referred to as an alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety lies between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0340] The term "halogen" refers to bromo, fluoro, chloro, and iodine.

[0341] The term “heterocyclic ring” or “heterocyclyl” 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, pyrrolidine, and tetrahydrofuranyl, as well as exemplary groups provided for the term “heteroaryl” above. In certain embodiments, the heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments, the heterocyclic ring or heterocyclyl is aromatic.

[0342] The term "optionally substituted" means that the group may be unsubstituted, or may be substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5) that may be the same or different. 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 bbExamples include heterocyclyl, heteroaryl, or aryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently -R cc It is sometimes replaced by -R aa and -R bb Each of these is independently either -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -R aa and -R bb These, together with the nitrogen atom to which they are bonded, form a heterocycline, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, where each -R cc These are independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN, or -NO2.

[0343] In certain embodiments, -L 1 - has the structure disclosed in formula I of WO2021 / 242756 A1. Therefore, in certain embodiments, part -L 1 - is equation (XIIa):

[0344] [ka] (In the formula, Unmarked dashed lines indicate connections to -D-. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 2 , -R 4 and -R 8 These are independently -H or C 1-4 Selected from the group consisting of alkyl groups, -R 3 C 1-4 Alkyl or -R 3 and -R 4 These, together with the atoms to which they are bonded, form a 5- or 6-membered heterocyclic ring. -R 5 It is -NH2, However, -R 4 and -R 3 However, if they combine with the atoms to which they are bonded to form a 5- or 6-membered heterocyclic ring, -R 2 (This is not -H) It has, -L in equation (XIIa) 1 - is sometimes replaced.

[0345] In certain embodiments, -R of formula (XIIa) 4 and -R 8 Both are -H.

[0346] In certain embodiments, -R of formula (XIIa) 3 is methyl. In certain embodiments, -R of formula (XIIa) 3 It is -H.

[0347] In certain embodiments, -R of formula (XIIa) 2 It is -H.

[0348] In certain embodiments, -L 1 - is equation (XIIa-i)

[0349] [ka] (Unmarked dashed lines indicate connections to -D-, The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It holds.

[0350] In certain embodiments, -L 1 - is equation (XIIa-ii)

[0351] [ka] (Unmarked dashed lines indicate connections to -D-, The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It holds.

[0352] In certain embodiments, -L 1 - is equation (XIIa-iii)

[0353] [ka] (Unmarked dashed lines indicate connections to -D-, The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It holds.

[0354] In certain embodiments, -L 1 - has the structure disclosed in formula II of WO2022 / 096636 A1. Therefore, in certain embodiments, part -L 1 - is equation (XIIb):

[0355] [ka] (In the formula, Unmarked dashed lines indicate connections to -D-. The dashed line with an asterisk indicates -L 2 (Indicates a connection to -) It holds.

[0356] -L 1 Another embodiment of -L is disclosed in WO2024 / 100552A1, which is incorporated herein by reference in its entirety. Thus, in a particular embodiment, -L 1 - is equation (XV):

[0357] [ka] (In the formula, Unmarked dashed lines indicate the bonding of -D to nitrogen, sulfur, or oxygen by forming an amide, thioester, or ester bond. The dashed line with an asterisk indicates -L 2 - indicates binding to -R 1 This is selected from the group consisting of substituted aryl groups, unsubstituted aryl groups, and substituted carbonyl groups. -R2, -R3, -R1', -R2', -R3', and -R4' are each independently -H, substitution C1-C 50 Alkyl alkyl groups, or unsubstituted C1-C 50 (It is an alkyl group.) It has, -L 1 - may be further substituted in some cases, except that the hydrogen atoms with an asterisk in formula (XV) are not substituted by substituents.

[0358] In relation exclusively to formula (XV), the term "aryl" refers to an aryl group with 6 to 10 carbon atoms, such as phenyl, benzyl, and naphthyl.

[0359] In certain embodiments, -L 2 - is a chemical bond. In certain embodiments, -L 2 - indicates the spacer portion, for example, -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 A spacer portion selected from the group consisting of alkynyls, where -T-, C1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, -R y1 and -R y1a These are -H, -T, and C, which are independent of each other. 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynyls, -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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(Ry4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may intersect with one or more groups selected from the group consisting of, Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls, where each T is independently one or more of the same or different -R y2 It is sometimes replaced by, Each-R y2 These are, independently, halogen, -CN, oxo (=O), and -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 Selected from the group consisting of alkyl groups, where C 1-6Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0360] In certain embodiments, -L 2 - stands for -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 Selected from alkinyl, where -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, -R y1 and -R y1a These are -H, -T, and C, which are independent of each other. 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynyl, where -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls, where each T is independently one or more of the same or different -R y2 It is sometimes replaced by, -Ry2 These are halogen, -CN, oxo (=O), and -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 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0361] In certain embodiments, -L 2- stands for -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 Selected from the group consisting of alkynnyls, where -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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 )- may intersect with one or more groups selected from the group consisting of, -R y1 and -R y1a These are independently -H, -T, and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyls, Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclils, 8-11 membered heterobicyclils, 8-30 membered carbopolycyclils, and 8-30 membered heteropolycyclils, Each-R y2 These are, independently, halogen and C 1-6 Selected from the group consisting of alkyl groups, Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is sometimes substituted with one or more halogens, one or more of the same or different.

[0362] In certain embodiments, -L 2 - is -O-, -T- and -C(O)N(R y1 )- where one or more elements selected independently of C may be interspersed 1-20 It is an alkyl chain, and this C 1-20 The alkyl chain consists of -OH, -T, and -C(O)N(R) y6 R y6a ) is optionally substituted with one or more elements independently selected from, where -R y1 , -R y6 , -R y6a H and C are independent of each other. 1-4 Selected from the group consisting of alkyl groups, T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 The group is selected from cycloalkyls, 3-10 member heterocyclils, 8-11 member heterobicyclils, 8-30 member carbopolycyclils, and 8-30 member heteropolycyclils.

[0363] In certain embodiments, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0364] In certain embodiments, -L 2 - includes the portion selected from the following:

[0365] [ka] TIFF2026529721000045.tif136161 (in the formula, The dashed line is -L 2 -, -L 1 - indicates the bonding to the remainder of -Z and / or Z', respectively. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl).

[0366] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms.

[0367] Part-L 2 -The term "chain length" as used herein in relation to -L 1 -L exists at the shortest connection point between - and -Z. 2 - Refers to the number of atoms.

[0368] In certain embodiments, -L 2 - is equation (i)

[0369] [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates binding to Unmarked dashed lines indicate connections to -Z or -Z'. n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. It has, Here, part (i) of equation is sometimes further substituted.

[0370] In a particular embodiment, n in formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. In a particular embodiment, n in formula (i) is 4, 5, 6, or 7. In a particular embodiment, n in formula (i) is 4. In a particular embodiment, n in formula (i) is 5. In a particular embodiment, n in formula (i) is 6.

[0371] In certain embodiments, part-L 1 -L 2 - is selected from the following group:

[0372] [ka] (In the formula, The unmarked dashed lines indicate the bonding of -D to nitrogen by forming an amide bond. (A dashed line with an asterisk indicates a connection to -Z or Z'.)

[0373] In certain embodiments, part-L 1 -L 2 - has the formula (IIca-i). In a particular embodiment, part -L 1 -L 2 - has formula (IIca-ii). In a particular embodiment, part -L 1 -L 2 - has the equation (IIcb-iii).

[0374] In certain embodiments, part-L 1 -L 2 -teeth,

[0375] [ka] (In the formula, The unmarked dashed lines indicate the bonding of -D to nitrogen by forming an amide bond. (A dashed line with an asterisk indicates a connection to -Z or Z'.) It is selected from the group consisting of the following.

[0376] In certain embodiments, part-L 1 -L 2 - has the formula (IIcb-i). In certain embodiments, part -L 1 -L 2 - has the formula (IIcb-ii). In certain embodiments, part -L 1 -L 2 - has the equation (IIcb-iii).

[0377] Part -Z comprises fatty acid derivatives or polymers. In certain embodiments, -Z is a polymer, e.g., 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate). The polymers include polymers selected from the group consisting of poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyl oxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof. In certain embodiments, -Z comprises poly(ethylene glycol)(PEG).

[0378] In certain embodiments, -Z has a molecular weight of 5 to 200 kDa. In certain embodiments, -Z has a molecular weight of 8 to 100 kDa, for example, 10 to 80 kDa, 12 to 60 kDa, or 15 to 40 kDa. In certain embodiments, -Z has a molecular weight of about 20 kDa. In certain embodiments, -Z has a molecular weight of about 40 kDa.

[0379] In certain embodiments, -Z contains PEG and has a molecular weight of 5 to 200 kDa. In certain embodiments, -Z contains PEG and has a molecular weight of 8 to 100 kDa, for example, 10 to 80 kDa, 12 to 60 kDa, or 15 to 40 kDa. In certain embodiments, -Z contains PEG and has a molecular weight of about 20 kDa. In certain embodiments, -Z contains PEG and has a molecular weight of about 40 kDa.

[0380] In certain embodiments, -Z comprises a protein selected from the group consisting of proteins, for example, carboxyl-terminal polypeptides of chorionic gonadotropins, such as those described in U.S. Patent Application Publication No. 2012 / 0035101A1 incorporated herein by reference; albumin; XTEN sequences, such as those described in WO 2011123813 A2 incorporated herein by reference; proline / alanine random coil sequences, such as those described in WO 2011 / 144756 A1 incorporated herein by reference; proline / alanine / serine random coil sequences, such as those described in WO 2008 / 155134 A1 and WO 2013 / 024049 A1 incorporated herein by reference; and Fc fusion proteins. In certain embodiments, -Z is polysarcosine. In certain embodiments, -Z comprises poly(N-methylglycine). In certain embodiments, -Z comprises a random coil protein moiety.

[0381] In certain embodiments, -Z includes fatty acid derivatives, such as those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1, which are incorporated herein by reference in whole. In certain embodiments, -Z is a hyaluronic acid polymer. In certain embodiments, -Z is a carrier, such as those disclosed in WO 2012 / 02047 A1, which are incorporated herein by reference in whole. In certain embodiments, -Z is a carrier, such as those disclosed in WO 2013 / 024048 A1, which are incorporated herein by reference in whole. In certain embodiments, -Z is a PEG polymer, such as a linear, branched, cyclic, dendritic, or multi-armed PEG polymer. In certain embodiments, -Z is a linear PEG polymer. In certain embodiments, -Z is a multi-armed PEG polymer. In certain embodiments, -Z is a multi-armed PEG polymer having at least four PEG arms.

[0382] In certain embodiments, such a multi-armed PEG-based polymer-Z is composed of a number of parts-L 2 -L 1 -D is joined, where each part -L 2 -L 1 -D is bonded to the end of the arm in certain embodiments. In certain embodiments, such a multi-arm PEG polymer-Z is bonded to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 parts-L 2 -L 1 - is bonded to D. In certain embodiments, such a multi-armed PEG polymer-Z is bonded to 2, 3, 4, 6, or 8 parts -L. 2 -L 1 - is bonded to D. In certain embodiments, such a multi-armed PEG polymer-Z is bonded to 2, 4, or 6 parts -L 2 -L 1 - is bonded to D. In certain embodiments, such a multi-armed PEG polymer - Z is bonded to 4 or 6 parts - L 2 -L 1- is bonded to D. In certain embodiments, such a multi-armed PEG polymer - Z is bonded to four parts - L 2 -L 1 It is coupled to -D.

[0383] In certain embodiments, -Z is a cyclic PEG-based polymer. In certain embodiments, -Z is a dendritic PEG-based polymer.

[0384] In certain embodiments, -Z is a branched PEG polymer. In certain embodiments, -Z is a branched PEG polymer having 1, 2, 3, 4, 5, or 6 branch points. In certain embodiments, -Z is a branched PEG polymer having 1, 2, or 3 branch points. In certain embodiments, -Z is a branched PEG polymer having 1 branch point. In certain embodiments, -Z is a branched PEG polymer having 2 branch points. In certain embodiments, -Z is a branched PEG polymer having 3 branch points. In certain embodiments, the branch points can be selected from the group consisting of -N<, -CH<, and >C<.

[0385] In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 5 to 200 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 8 to 160 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 10 to 120 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 12 to 100 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 15 to 90 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 20 to 80 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of 25 to 60 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of approximately 20 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of approximately 40 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of approximately 60 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of approximately 80 kDa. In certain embodiments, -Z is a branched PEG polymer having one branch point and a molecular weight of approximately 40 kDa.

[0386] In certain embodiments, -Z is a branched PEG polymer having one branch point (which is -CH<) and a molecular weight of approximately 40 kDa.

[0387] In certain embodiments, -Z or Z' is a part

[0388] [ka] Includes.

[0389] In certain embodiments, -Z or Z' includes an amide bond.

[0390] In certain embodiments, -Z is part of equation (a).

[0391] [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, BP a This is a branch point selected from the group consisting of -N<, -CR<, and >C<, -R is -H and C 1-6 Selected from the group consisting of alkyl groups, a is BP a If -N < or -CR <, then it is 0, and n is BP a If >C< then it is 1, -S a -, -S a' -, -S a'' -and-S a''' - is either a chemical bond or C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyl, where C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different -R of one or more R's. 1 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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(R2 )- may intersect with one or more groups selected from the group consisting of, Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls, where each -T- is independently one or more identical or different -R 1 It is sometimes replaced by, Each-R 1 These are, independently, halogen, -CN, oxo (=O), and -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)2R 3 ,-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 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. Each-R 2 , -R2a , -R 3 , -R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more halogens, one or more of the same or different halogens. -P a' , -P a'' and -P a''' (This is independently a polymer part.) Includes.

[0392] In a particular embodiment, the BP of formula (a) a is -N <. In a particular embodiment, the BP of formula (a) a is >C<. In a particular embodiment, the BP of formula (a) a is -CR<. In certain embodiments, -R is -H. Therefore, a in equation (a) is 0.

[0393] In certain embodiments, the -S of formula (a) a - is a chemical bond. In certain embodiments, -S of formula (a) a - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -T-, -C(O)O-, -O-, -C(O)-, and -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)- and one or more chemical groups selected from the group consisting of -T- are optionally interposed, where -T- is a 3- to 10-membered heterocycline and -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a - is C 1-10 Selected from the group consisting of alkyl groups, including -T-, -C(O)N(R 4 One or more chemical groups selected from the group consisting of - and -O- are interposed.

[0394] In certain embodiments, the -S of formula (a) a' - is a chemical bond. In certain embodiments, -S of formula (a) a' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -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 )- may have one or more chemical groups selected from the group consisting of -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R4 )- may contain one or more chemical groups selected from the group consisting of ).

[0395] In certain embodiments, the -S of formula (a) a'' - is a chemical bond. In certain embodiments, -S of formula (a) a'' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -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 )- may have one or more chemical groups selected from the group consisting of -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a'' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may contain one or more chemical groups selected from the group consisting of ).

[0396] In certain embodiments, the -S of formula (a) a''' - is a chemical bond. In certain embodiments, -S of formula (a) a''' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10Selected from the group consisting of alkynnyl, this C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -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 )- may have one or more chemical groups selected from the group consisting of -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a''' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may contain one or more chemical groups selected from the group consisting of ).

[0397] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a'''These are independently 2-methacryloyloxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxy The polymers include polymers selected from the group consisting of propyl oxazoline, poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropylmethylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate polymers, xylan, and copolymers thereof.

[0398] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' It independently includes a PEG-based portion. In certain embodiments, -P of formula (a) a' , -P a'' and -P a'''It independently includes a PEG-based portion containing at least 20% PEG, for example at least 30%, for example at least 40% PEG, for example at least 50% PEG, for example at least 60% PEG, for example at least 70% PEG, for example at least 80% PEG, or for example at least 90% PEG.

[0399] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' These independently have molecular weights of 5 kDa to 50 kDa, for example 5 kDa to 40 kDa, for example 7.5 kDa to 35 kDa, for example 7.5 to 30 kDa, or for example 10 to 30 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 7.5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 10 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 12.5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 15 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 20 kDa.

[0400] In certain embodiments, -Z includes one part of formula (a). In certain embodiments, -Z includes two parts of formula (a). In certain embodiments, -Z includes three parts of formula (a). In certain embodiments, -Z is a part of formula (a).

[0401] In certain embodiments, -Z is part of equation (b).

[0402] [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, m and p are independent integers between 150 and 1000, for example between 150 and 600, for example between 200 and 550, or for example between 400 and 500. Includes.

[0403] In certain embodiments, m and p in formula (b) are the same integer. In certain embodiments, both m and p in formula (b) are between 400 and 500.

[0404] In certain embodiments, -Z is part of equation (b), and the dashed line is -L 2 This indicates a connection to -.

[0405] In certain embodiments, Z' is a hydrogel.

[0406] In certain embodiments, Z' is a PEG-based or hyaluronic acid-based hydrogel. In certain embodiments, Z' is a PEG-based hydrogel. In certain embodiments, Z' is a hyaluronic acid-based hydrogel.

[0407] In certain embodiments, Z' is a hydrogel such as those 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.

[0408] In certain embodiments, Z' is a hydrogel as disclosed in WO 2013 / 036847 A1. In particular, in certain embodiments, Z' is a hydrogel produced by a method comprising the step of reacting at least a first reactive polymer with a cleavable crosslinking compound, wherein the cleavable crosslinking compound has a first functional group -Y that reacts with the first reactive polymer. 1 The material comprises a portion which is cleaved by elimination under physiological conditions, wherein the portion comprises a second functional group -Y that reacts with a second reactive polymer. 2 Includes. In certain embodiments, the cleavable crosslinking agent compound is of formula (PL-1):

[0409] [ka] [In the formula, m is either 0 or 1. -X is a functional group that can be bonded to a reactive polymer that is detachable under physiological conditions, and the second functional group -Y 2 Includes, -R 1 , -R 2 and -R 5 At least one of the first functional group-Y can be bonded to the polymer. 1 Includes, -R 1 and -R 2 One or only one of these is selected from the group consisting of -H, alkyl, arylalkyl, and heteroarylalkyl. Depending on the case, -R 1 and -R 2 These may combine to form a 3-8 membered ring. -R 1 and -R 2 At least one or both of these are independently -CN, -NO2, aryl, heteroaryl, alkenyl, alkynyl, -COR 3 -SOR 3 , -SO2R 3 and -SR 4 Selected from the group consisting of, -R 3-H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR 9 and -NR 9 Selected from a group consisting of 2, -R 4 This is selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. Each-R 5 These are independently -H, alkyl, alkenylalkyl, alkynylalkyl, (OCH2CH2) p Selected from the group consisting of O-alkyl (wherein p is an integer from 1 to 1000), aryl, arylalkyl, heteroaryl, and heteroarylalkyl, Each-R 9 These are independently selected from the group consisting of -H and alkyl, or both -R 9 [These atoms, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring.] It has, The part of equation (PL-1) is sometimes further substituted.

[0410] The following paragraphs describe such hydrogels in more detail.

[0411] In certain embodiments, -X in formula (PL-1) is succinimidyl carbonate, sulfosuccinimidyl carbonate halide, thioether, ester, nitrophenyl carbonate, chloroformate, fluoroformate, optionally substituted phenol, and formula (PL-2):

[0412] [ka] [In the formula, The dashed line indicates the connection to the remainder of equation (PL-1). -T*- is equivalent to -O-, -S-, and -NR 6 - Selected from the group consisting of, z is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6. -X'- is either nonexistent or -OR 7 - and -SR 7 - Selected from the group consisting of, -Y 2 It is a functional group that can bond with reactive polymers, -R 6 It is selected from the group consisting of -H, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. -R 7 These are alkylene, phenylene and (OCH2CH2) p (wherein p is an integer from 1 to 1000) It is selected from the group consisting of the following.

[0413] In certain embodiments, -X in formula (PL-1) comprises an activated carbonate, e.g., succinimidyl carbonate, sulfosuccinimidyl carbonate, or nitrophenyl carbonate. In certain embodiments, -X in formula (PL-1) comprises a carbonyl halogen, e.g., O(C=O)Cl or O(C=O)F. In certain embodiments, -X in formula (PL-1) has formula (PL-2). In certain embodiments, -X in formula (PL-1) is OR 7 or SR 7 And R 7 This may be a substituted alkylene, or a substituted phenylene or (OCH2CH2) p (In the formula, p is between 1 and 1000.)

[0414] In certain embodiments, p in formula (PL-2) is an integer between 1 and 100. In certain embodiments, p in formula (PL-2) is an integer between 1 and 10.

[0415] In a particular embodiment, -Y of formula (PL-1) 1 , and -Y of equation (PL-2) 2 These are independently N3, NH2, and NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctin, acrylate, or acrylamide, wherein t Bu is tert-butyl, where -Y 1 or -Y 2 If one of them contains N3, the other does not contain alkyne or cyclooctin, and -Y 1 or -Y 2 If one of them contains SH, the other does not contain maleimide, acrylate, or acrylamide, and -Y 1 or -Y 2 If one of them contains NH2, the other does not contain CO2H, and -Y 1 or -Y 2 If one of them contains 1,3-diene or cyclopentadiene, the other does not contain furan.

[0416] In a particular embodiment, the cleavable crosslinking agent compound is of formula (PL-3):

[0417] [ka] (In the formula, m is either 0 or 1. n is an integer selected from 1 to 1000. s is 0, 1, or 2. t is selected from the group consisting of 2, 4, 8, 16, and 32. -W- stands for -O(C=O)O-, -O(C=O)NH-, -O(C=O)S-, -O(C=O)NR 6 CH2O- and -O(C=O)NR 6 Selected from the group consisting of S-, -Q is a core group having a bond value = t that connects multiple arms of a cleavable crosslinking compound, where t is an integer selected from 2, 4, 8, 16, and 32. -R 1 , -R 2 and -R 5 (This is defined as in equation (PL-1)). It holds.

[0418] In a particular embodiment, t in formula (PL-3) is 2. In a particular embodiment, t in formula (PL-3) is 4. In a particular embodiment, t in formula (PL-3) is 8. In a particular embodiment, t in formula (PL-3) is 16. In a particular embodiment, t in formula (PL-3) is 32.

[0419] In a particular embodiment, -Q in formula (PL-3) has a structure selected from the group consisting of:

[0420] [ka] TIFF2026529721000056.tif68140 (In the formula, the dashed line indicates binding to the remainder of the cleavable crosslinking agent compound).

[0421] In certain embodiments, -Q in formula (PL-3) has the structure of (PL-3-i). In certain embodiments, -Q in formula (PL-3) has the structure of (PL-3-ii). In certain embodiments, -Q in formula (PL-3) has the structure of (PL-3-iii).

[0422] In certain embodiments, the cleavageable crosslinking agent compound is of formula (PL-3) (wherein m is 0, n is approximately 100, s is 0, t is 4, -W- is -O(C=O)NH-, -Q has the structure of (PL-3i), and -R 2 H is H, while -R is H 5 is -H, and the other is -R 5 It is (CH2)5N3, and -R 1 It contains (4-chlorophenyl)SO2, a phenyl substituted with -SO2, morpholino-SO2, or -CN.

[0423] In a particular embodiment, -Y of formula (PL-3) 1 These are N3, NH2, and NH-CO2. t Bu, SH, S t Bu, maleimide, CO2H, CO2 tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctin, acrylate or acrylamide, t Bu is tert-butyl.

[0424] In certain embodiments, each -Y of formula (PL-1) or (PL-3) 1 , and -Y of equation (PL-2) 2 These are independently N3, NH2, and NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t This includes Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctin, acrylate, or acrylamide.

[0425] In a particular embodiment, -Y 1 and -Y 2 One of the components is an azide, and the other is a reactive functional group selected from the group consisting of acetylene, cyclooctin, and maleimide. In certain embodiments, -Y 1 and -Y 2 One of the components 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. In certain embodiments, -Y 1 and -Y 2 One of them is an amine, and the other is a selectively reactive functional group selected from carboxylic acids and activated carboxylic acids. In certain embodiments, -Y 1 and -Y 2 One of the components is maleimide, and the other is a selective reactive functional group selected from the group consisting of 1,3-diene, cyclopentadiene, and furan.

[0426] In certain embodiments, the first and optional second polymers contain a suitable reactive functional group or a polymer of formula [Y 3 -(CH2) s (CH2CH2O) n ] t Q(In the formula, -Y 3(where is a reactive functional group, s is 0, 1, or 2, n is an integer selected from the group in the range of 10 to 1000, and -Q is a core group having a bonding valency t, and t is an integer selected from the group consisting of 2, 4, 8, 16, and 32) Homopolymers or copolymers of polyethylene glycol, polypropylene glycol, poly(N-vinylpyrrolidone), polymethacrylate, polyphosphazene, polylactide, polyacrylamide, polyglycolate, polyethyleneimine, agarose, dextran, gelatin, collagen, polylysine, chitosan, alginate, hyaluronan, pectin, and carrageenan.

[0427] In certain embodiments, the first polymer includes a multi-arm polymer. In certain embodiments, the first polymer includes at least three arms. In certain embodiments, the first polymer includes at least four arms. In certain embodiments, the first polymer includes at least five arms. In certain embodiments, the first polymer includes at least six arms. In certain embodiments, the first polymer includes at least seven arms. In certain embodiments, the first polymer includes at least eight arms.

[0428] In certain embodiments, the second polymer includes a multi-arm polymer. In certain embodiments, the second polymer includes at least three arms. In certain embodiments, the second polymer includes at least four arms. In certain embodiments, the second polymer includes at least five arms. In certain embodiments, the second polymer includes at least six arms. In certain embodiments, the second polymer includes at least seven arms. In certain embodiments, the second polymer includes at least eight arms.

[0429] In certain embodiments, the first polymer comprises a 2-arm polyethylene glycol polymer. In certain embodiments, the first polymer comprises a 4-arm polyethylene glycol polymer. In certain embodiments, the first polymer comprises an 8-arm polyethylene glycol polymer. In certain embodiments, the first polymer comprises a 16-arm polyethylene glycol polymer. In certain embodiments, the first polymer comprises a 32-arm polyethylene glycol polymer.

[0430] In certain embodiments, the second polymer comprises a polyethylene glycol polymer with two arms. In certain embodiments, the second polymer comprises a polyethylene glycol polymer with four arms. In certain embodiments, the second polymer comprises a polyethylene glycol polymer with eight arms. In certain embodiments, the second polymer comprises a polyethylene glycol polymer with sixteen arms. In certain embodiments, the second polymer comprises a polyethylene glycol polymer with thirty-two arms.

[0431] In certain embodiments, the first and second reactive polymers are reacted with the cleavable crosslinking compound sequentially or simultaneously.

[0432] In certain embodiments, the first and second functional groups are the same.

[0433] The terms used exclusively in relation to formulas (PL-1), (PL-2), and (PL-3) have the following meanings:

[0434] The term "the part that can be cleaved by elimination under physiological conditions" refers to the group HC-(CH=CH) mThis refers to a structure containing -C-X' (wherein m is 0 or 1 and X' is a leaving group), and the elimination reaction described above for removing the HX' element may occur at a rate such that the reaction half-life is between 1 and 10,000 hours under physiological pH and temperature conditions. Preferably, the reaction half-life is between 1 and 5,000 hours, more preferably between 1 and 1,000 hours, under physiological pH and temperature conditions. Physiological pH and temperature conditions mean a pH between 7 and 8 and a temperature between 30 and 40 degrees Celsius.

[0435] The term "reactive polymers and reactive oligomers" refers to polymers or oligomers containing functional groups that are reactive to other functional groups, most preferably under mild conditions that 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, such as cycloalkynes, 1,3-dienes, such as cyclopentadiene and furan, alpha-halocarbonyls, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl esters or carbonates.

[0436] The term "functional group that can bond 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 that can bond to a reactive polymer include maleimide, thiol or protected thiol, acrylate, acrylamide, amine or protected amine, carboxylic acid or protected carboxylic acid, azide, alkyne, such as cycloalkyne, 1,3-diene, such as cyclopentadiene and furan, alpha-halocarbonyl, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl ester or carbonate.

[0437] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogens (including F, Cl, Br, and I), lower alkyls (including linear, branched, and cyclic lower alkyls), lower haloalkyls (including fluoroalkyls, chloroalkyls, bromoalkyls, and iodoalkyls), OH, lower alkoxys (including linear, branched, and cyclic lower alkoxys), SH, lower alkylthios (including linear, branched, and cyclic lower alkylthios), aminos, alkylaminos, dialkylaminos, silyls (including alkylsilyls, alkoxysilyls, and arylsilyls), nitros, cyanos, carbonyls, carboxylic acids, carboxylic acid esters, carboxylic acid amides, and aminocarboxyl groups. The following can be selected: bonyl, aminoacyl, carbamate, urea, thiocarbamate, thiourea, ketone, sulfone, sulfonamide, aryl (including phenyl, naphthyl, and anthracenyl), heteroaryl (including 5-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole, 6-membered heteroaryls such as pyridine, pyrimidine, pyrazine, and condensed heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole, and benzoisothiazole).

[0438] R 1 and R 2 The properties of may be modulated by optionally adding electron-donating substituents or electron-withdrawing substituents. The term "electron-donating group" is R 1 R 2This refers to substituents that reduce the acidity of CH, and electron-donating groups are typically associated with negative Hammett σ or Tuft σ* constants, which are well known in the field of physical organic chemistry (Hammett constants refer to aryl / heteroaryl substituents, and Tuft constants refer to substituents on non-aromatic moieties). Suitable examples of electron-donating substituents include lower alkyl, lower alkoxy, lower alkylthio, amino, alkylamino, dialkylamino, and silyl groups.

[0439] The term "electron-withdrawing group" is R 1 R 2 This refers to substituents that increase the acidity of the CH group. Electron-withdrawing groups are typically associated with positive Hammett σ or Tuft σ* constants and are well-known in the field of physical organic chemistry. Suitable examples of electron-withdrawing substituents include halogens, difluoromethyl, trifluoromethyl, nitro, cyano, and C(=O)-R x (In the formula, -R x (is H, a lower alkyl, a lower alkoxy, or an amino), or S(O) m R Y (In the formula, m is 1 or 2, -R Y Examples include lower alkyl, aryl, or heteroaryl substituents. As is well known in the art, the electronic effect of substituents can depend on the position of the substituent. For example, alkoxy substituents at the ortho or para position of an aryl ring are electron-donating and characterized by a negative Hammett σ constant, while alkoxy substituents at the meta position of an aryl ring are electron-withdrawing and characterized by a positive Hammett σ constant.

[0440] The terms "alkyl," "alkenyl," and "alkynyl" encompass linear, branched, or cyclic hydrocarbon groups of 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these groups contain 1 to 6 carbon atoms.

[0441] The term "aryl" encompasses an aromatic hydrocarbon group with 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracenyl groups. The term "heteroaryl" encompasses an aromatic ring with 3 to 15 carbon atoms, preferably 3 to 7 carbon atoms, containing at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl groups, and similar groups.

[0442] The term "halogen" includes fluoro, chloro, bromo, and iodine.

[0443] The term "maleimide" is derived from the formula

[0444] [ka] It is the basis of.

[0445] In certain embodiments, Z' is a hydrogel as disclosed in WO 2020 / 206358 A1. In particular, in certain embodiments, Z' is a hydrogel produced by a method comprising the following steps: (a) Multi-arm polymer-P 2 A step of providing a first prepolymer comprising, wherein the first prepolymer is of formula (PL-4)

[0446] [ka] [In the formula, 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 for bonding the first prepolymer to the second prepolymer, and -R 1 and -R 2 These are independently electron-withdrawing groups, alkyl groups, or -H groups, and -R1 and -R 2 At least one of them is an electron-withdrawing group, Each-R 4 These are independently either C1-C3 alkyl or two-R 4 These, together with the carbon atoms to which they are bonded, form a 3-6 membered ring. -W- does not exist, or

[0447] [ka] (In the formula, A dashed line with an asterisk indicates a bond to -NH-, while an unmarked dashed line indicates a bond to -P. 2 This shows a connection to, x, y, and z are each an integer independently selected from 0, 1, 2, 3, 4, 5, and 6. -B' is a group containing -NH2, -ONH2, ketone, aldehyde, -SH, -OH, -CO2H, carboxamide, or cyclooctin or bicyclononine. -C* is carboxamide, thioether, thiosuccinimidyl, triazole, or oxime. [is] A step having; (b) Multiarm polymer-P 1 A step of providing a second prepolymer comprising, wherein each arm has a reactive functional group -Y'' at its terminus that reacts with -Y of step (a); (c) Mixing the two prepolymers from steps (a) and (b) under conditions in which -Y and -Y'' react to form a bond -Y*-; and optionally, (d) A step to isolate the obtained hydrogel.

[0448] Therefore, Z' is a hydrogel that can be obtained by the above method. In certain embodiments, the hydrogel produced by the above method is biodegradable.

[0449] In certain embodiments, -Y and -Y'' react under step (c) to form a crosslink of formula (PL-4'):

[0450] [ka] (In the formula, n, r, -P 1 -Y*-, -R 4 , -R 1 , -R 2 , -W- and -P 2 (This is as defined above.) It forms an insoluble hydrogel matrix containing [the specified substance].

[0451] In certain embodiments, n in formula (PL-4) or (PL-4') is an integer selected from 1, 2, 3, 4, 5, and 6. In certain embodiments, n in formula (PL-4) or (PL-4') is an integer selected from 1, 2, and 3. In certain embodiments, n in formula (PL-4) or (PL-4') is an integer selected from 0, 1, 2, and 3. In certain embodiments, n in formula (PL-4) or (PL-4') is 1. In certain embodiments, n in formula (PL-4) is 2. In certain embodiments, n in formula (PL-4) or (PL-4') is 3.

[0452] In certain embodiments, the multi-arm-P of formula (PL-4) or (PL-4') 2is a polymer having r arms, where r is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a particular embodiment, r in formula (PL-4) or (PL-4') is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In a particular embodiment, r in formula (PL-4) or (PL-4') is an integer selected from 2, 4, 6, and 8. In a particular embodiment, r in formula (PL-4) or (PL-4') is 2. In a particular embodiment, r in formula (PL-4) or (PL-4') is 4. In a particular embodiment, r in formula (PL-4) or (PL-4') is 6. In a particular embodiment, r in formula (PL-4) or (PL-4') is 8.

[0453] In certain embodiments, the -P of formula (PL-4) or (PL-4') 2 It has a molecular weight of at least 1 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') 2 It has a molecular weight of 1 to 100 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of 1 to 80 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of 1 to 60 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of 1 to 40 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of 1 to 20 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of 1 to 10 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of 1 to 5 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of approximately 20 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2It has a molecular weight of approximately 40 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of approximately 60 kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') is used. 2 It has a molecular weight of approximately 80 kDa.

[0454] In a particular embodiment, the multi-arm polymer-P of step (b) 1 The polymer has r arms, where r is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a particular embodiment, the multi-arm-P of step (b) 1 The polymer has r arms, where r is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In a particular embodiment, the multi-arm-P of step (b) 1 The polymer has r arms, where r is an integer selected from 2, 4, 6, and 8. In a particular embodiment, the multi-arm-P of step (b) 1 The polymer has r arms, where r is 2. In a particular embodiment, the multi-arm-P of step (b) 1 The polymer has r arms, where r is 4. In a particular embodiment, the multi-arm-P of step (b) 1 The polymer has r arms, where r is 6. In a particular embodiment, the multi-arm-P of step (b) 1 It is a polymer having r arms, where r is 8.

[0455] In a particular embodiment, step (b) -P 1 It has a molecular weight of at least 1 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of 1 to 100 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of 1 to 80 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1It has a molecular weight of 1 to 60 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of 1 to 40 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of 1 to 20 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of 1 to 10 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of 1 to 5 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of approximately 20 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of approximately 40 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of approximately 60 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 It has a molecular weight of approximately 80 kDa.

[0456] In a particular embodiment, step (b) -P 1 , and -P of formula (PL-4) or (PL-4') 2 This includes poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), poly(ethyleneimine) (PEI), dextran, hyaluronic acid, or copolymers thereof. In certain embodiments, step (b) -P 1 , and P in formula (PL-4) or (PL-4') 2 It is a PEG-based polymer. In certain embodiments, step (b) -P 1 , and -P of formula (PL-4) or (PL-4') 2 It is a hyaluronic acid-based polymer.

[0457] In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2These are independently electron-withdrawing groups, alkyl groups, or -H groups, and -R 1 and -R 2 At least one of them is an electron-withdrawing group.

[0458] In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing groups are -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, and -COR 3 -SOR 3 , or -SO2R 3 (In the formula, -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2, and each -R 8 These are independently -H or optionally substituted alkyl, or both -R 8 The groups, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring; or -SR 9 (In the formula, -R 9 (which is optionally a substituted alkyl, optionally a substituted aryl, optionally a substituted arylalkyl, optionally a substituted heteroaryl, or optionally a substituted heteroarylalkyl).

[0459] In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is -CN. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is -NO2. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2The electron-withdrawing group is an optionally substituted aryl group containing 6 to 10 carbon atoms. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is optionally substituted phenyl, naphthyl, or anthracenyl. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is an optionally substituted heteroaryl containing 3 to 7 carbon atoms and at least one N, O, or S atom. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is an optionally substituted alkenyl containing 2 to 20 carbon atoms. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is an optionally substituted alkynyl containing 2 to 20 carbon atoms. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is -COR 3 -SOR 3 , or -SO2R 3 And R 3 -H, or optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2 (in the formula, each -R 8These are independently -H, or optionally substituted alkyl containing 1 to 20 carbon atoms, or both -R 8 The groups are those that, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring. In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron-withdrawing group is -SR 9 And, -R 9 is an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, which contains 1 to 20 carbon atoms. In certain embodiments, -R 1 and -R 2 At least one of them is -CN or -SO2R 3 That is the case.

[0460] In certain embodiments, the -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of them is -CN, -SOR 3 or -SO2R 3 In certain embodiments, the -R of formula (PL-4) or (PL-4') is used. 1 and -R 2 At least one of them is -CN or -SO2R 3 In certain embodiments, the -R of formula (PL-4) or (PL-4') is used. 1 and -R 2 At least one of them is -CN or -SO2R 3 And, -R 3 This may be a substituted alkyl, may be a substituted aryl, or -NR 8 2. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2At least one of them is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted with -SO2, phenyl substituted with -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3), or -SO2N(CH2CH2OCH3)2.

[0461] In certain embodiments, each -R of formula (PL-4) or (PL-4') 4 These can be independently C1-C3 alkyl groups or together form a 3-6 membered ring. In certain embodiments, each -R of formula (PL-4) or (PL-4') 4 These are independently C1-C3 alkyl groups. In certain embodiments, both -R groups of formula (PL-4) or (PL-4') are present. 4 It is methyl.

[0462] In certain embodiments, -Y and -Y'' are independently selected from the group consisting of amines, aminooxys, ketones, aldehydes, maleidyls, thiols, alcohols, azides, 1,2,4,6-tetradinyls, trans-cyclooctenyls, bicyclononinyls, cyclooctinyls, and their protective variants.

[0463] In certain embodiments, Y and Y'' may react with each other, for example, selectively. For example, if -Y is an amine, -Y'' is a carboxylic acid, active ester, or active carbonate to produce a residue that binds the functional group -Y*-, which is an amide or carbamate. Another example is if -Y is an azide, -Y'' is an alkynyl, bicyclononinyl, or cyclooctinyl to produce a residue that binds the functional group -Y*-, which is 1,2,3-triazole. Another example is if -Y is NH2O, -Y'' is a ketone or aldehyde to produce a residue that binds the functional group -Y*-, which is an oxime. Another example is if -Y is SH, -Y'' is a maleimide or halocarbonyl to produce a residue that binds the functional group -Y*-, which is thiosuccinimidyl or thioether. Similarly, these roles of -Y and -Y'' can be reversed to produce -Y*- with the opposite orientation.

[0464] In certain embodiments, -Y*- includes amides, oximes, 1,2,3-triazoles, thioethers, thiosuccinimides, or ethers. In certain embodiments, -Y*- is -L 2 - is

[0465] These conjugation reactions may be carried out under conditions known in the art. For example, when -Y is an azide and -Y'' is cyclooctine, the conjugation occurs in any solvent in which both components have appropriate solubility, although aqueous solutions are known to exhibit more favorable reaction rates. When mixed in an aqueous buffer in a suitable solvent, typically pH 2–7 when -Y and -Y'' are azide / cyclooctine, or pH 6–9 when -Y and -Y'' are activated esters and amines, the -Y and -Y'' groups react to form an insoluble hydrogel matrix containing the crosslink of formula (PL-4'). This process may be carried out in bulk phase or under emulsifying conditions in a mixed organic / aqueous system to form a microparticle suspension, e.g., microspheres suitable for injection.

[0466] The terms used exclusively in relation to the formulas (PL-4) and (PL-4') have the following meanings:

[0467] The term "alkyl" refers to a linear, 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 certain embodiments, alkyl groups are linear or branched. Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In certain embodiments, alkyl groups are cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0468] The term "alkoxy" refers to an alkyl group bonded to oxygen, such as methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0469] The term "alkenyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon double bond and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0470] 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.

[0471] The term "aryl" refers to an aromatic hydrocarbon group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracenyl groups. The term "heteroaryl" refers to an aromatic ring having 3 to 15 carbon atoms, preferably 3 to 7 carbon atoms, including at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl groups.

[0472] In certain embodiments, an alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule by an alkyl bond. Under these circumstances, the substituent is referred to as an alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety lies between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0473] The term "halogen" or "halo" refers to bromo, fluoro, chloro, or iodine.

[0474] The term “heterocyclic ring” or “heterocyclyl” 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, pyrrolidine, and tetrahydrofuranyl, as well as exemplary groups provided for the term “heteroaryl” above. In certain embodiments, the heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments, the heterocyclic ring or heterocyclyl is aromatic.

[0475] The term "optionally substituted" refers to a group that may be unsubstituted, or may be substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5) that may be the same or different. 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 Examples include heterocyclyl, heteroaryl, or aryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently -R cc It is sometimes replaced by -R aa and -R bb Each of these is independently either -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -R aa and -R bbThese, together with the nitrogen atom to which they are bonded, form a heterocycline, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, where each -R cc These are independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN, or -NO2.

[0476] In certain embodiments, the PTH compound is a compound of formula (XI).

[0477] [ka] [In the formula, The unmarked dashed lines indicate the bond of the N-terminal amine group of the PTH portion of sequence number 51 to the nitrogen. The dashed line with an asterisk indicates a part

[0478] [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, m and p are independent integers between 150 and 1000, for example between 150 and 600, for example between 200 and 550, for example between 400 and 500, or for example between approximately 450 and approximately 500. [Shows a connection to] That is the case.

[0479] In certain embodiments, m and p in formula (XI) are independently integers between 400 and 500. In certain embodiments, m and p in formula (XI) are independently integers between approximately 450 and 500. In certain embodiments, m and p in formula (XI) are independently integers between 450 and 500.

[0480] The compound of formula (XI) is also known as paropegteriparatide, TransCon PTH, or ACP-014.

[0481] It is understood that the nitrogen atom of the N-terminal amine group in the PTH portion of formula (XI), and the carbonyl (-(C=O)-) group to the left of the unmarked dashed line, form an amide bond.

[0482] The PTH compound of formula (XI) releases PTH 1-34, which is PTH of SEQ ID NO: 51, meaning that its active PTH is PTH 1-34.

[0483] In certain embodiments, the PTH compound is a compound of formula (XII).

[0484] [ka] (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No. 51. (Each n is an independent integer between approximately 200 and 250.) That is the case.

[0485] In certain embodiments, the PTH compound is a compound of formula (XII#).

[0486] [ka] (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No. 51. Each n is an integer between 150 and 1000, for example between 150 and 600, for example between 200 and 550, for example between 400 and 500, or for example between approximately 450 and approximately 500. That is the case.

[0487] In certain embodiments, the PTH compound is a compound of formula (XII').

[0488] [ka] (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No. 51. (Each n is an independent integer between approximately 200 and 250.) That is the case.

[0489] In certain embodiments, each n in equations (XII) and (XII') is an independent integer between 200 and 250. In certain embodiments, each n in equations (XII) and (XII') is an independent integer between approximately 210 and 240. In certain embodiments, each n in equations (XII) and (XII') is an independent integer between 210 and 240. In certain embodiments, all n are the same integer.

[0490] In certain embodiments, the PTH compound is a compound of formula (XII'#).

[0491] [ka] (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No. 51. Each n is an integer between 150 and 1000, for example between 150 and 600, for example between 200 and 550, for example between 400 and 500, or for example between approximately 450 and approximately 500. That is the case.

[0492] It is understood that the nitrogen of the N-terminal amine group in the PTH portion of formula (XII), (XII#), (XII'), or (XII'#), and the carbonyl (-(C=O)-) group to the left of the dashed line, form an amide bond.

[0493] The PTH compounds of formula (XII), (XII#), (XII'), or (XII'#) release PTH 1-34, which is the PTH of SEQ ID NO: 51, meaning that the active PTH of the PTH compounds of formula (XII), (XII#), (XII'), or (XII'#) is PTH 1-34.

[0494] In certain embodiments, each n in equations (XII) and (XII') is an integer between 200 and 250 independently. In certain embodiments, each n in equations (XIII) and (XIII') is an integer between approximately 210 and 240 independently. In certain embodiments, each n in equations (XIII) and (XIII') is an integer between 210 and 240 independently. In certain embodiments, all n in equations (XII) and (XII') are integers between 200 and 250. In certain embodiments, all n in equations (XIII) and (XIII') are integers between approximately 210 and 240. In certain embodiments, all n in equations (XIII) and (XIII') are integers between 210 and 240.

[0495] In certain embodiments, the PTH compound is a compound of formula (XIII).

[0496] [ka] (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No. 51. (Each n is an independent integer between approximately 200 and 250.) That is the case.

[0497] In formula (XIII), the chiral center marked with "#" may be in an L-configuration, a D-configuration, or a mixture of both L- and D-configurations. In a particular embodiment, the chiral center is in an L-configuration.

[0498] In certain embodiments, the second PTH compound is a compound of formula (XIII').

[0499] [ka] (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No. 51. (Each n is an independent integer between approximately 200 and 250.) That is the case.

[0500] In certain embodiments, each n in equations (XIII) and (XIII') is an integer between 200 and 250 independently. In certain embodiments, each n in equations (XIII) and (XIII') is an integer between approximately 210 and 240 independently. In certain embodiments, each n in equations (XIII) and (XIII') is an integer between 210 and 240 independently. In certain embodiments, all n in equations (XIII) and (XIII') are integers between 200 and 250. In certain embodiments, all n in equations (XIII) and (XIII') are integers between approximately 210 and 240. In certain embodiments, all n in equations (XIII) and (XIII') are integers between 210 and 240.

[0501] It is understood that the nitrogen atom of the N-terminal amine group in the PTH portion of formulas (XIII) and (XIII'), and the carbonyl (-(C=O)-) group to the left of the dashed line, form an amide bond.

[0502] The PTH compounds of formulas (XIII) and (XIII') release PTH 1-34, which is the PTH of SEQ ID NO: 51, and this means that the active PTH of the PTH compounds of formulas (II-b) and (II-b') is PTH 1-34.

[0503] In certain 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 the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, miniPEG is COCH2OCH2CH2OCH2CH2NH, COC 16 H 32 CO2H is a C18 diacid. (N-Me)G is sarcosine, K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. That is the case.

[0504] In certain 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 the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH, COC 16 H 32 CO2H is a C18 diacid. (N-Me)G is sarcosine, K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. That is the case.

[0505] The compound of formula (XIV') corresponds to Sequence ID 87 of WO2021 / 242756, and the sequence "SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK" corresponds to PTH (1-32)(Sequence ID 53)+K33 as specified herein.

[0506] The compound of formula (XIV) is the compound of formula (XIV-i). SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH (XIV-i) (In the formula, γE is the l-isomer of gamma glutamic acid, miniPEG is COCH2OCH2CH2OCH2CH2NH, COC 16 H 32 CO2H is a C18 diacid. K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. It releases.

[0507] The compound of formula (XIV-i) is the active PTH of the compound of formula (XIV).

[0508] The compound of formula (XIV') is the compound of formula (XIV-i'). SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH (XIV-i') (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH, COC 16 H 32 CO2H is a C18 diacid. K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. It releases.

[0509] The compound of formula (XIV-i') is the active PTH of the compound of formula (XIV-i').

[0510] In certain embodiments, the PTH compound of formula (XIV) or (XIV') is administered at a dose of 300 μg / week to 500 μg / week.

[0511] PTH compounds may be administered in the form of a pharmaceutical composition. Such a pharmaceutical composition comprises at least one PTH compound as described elsewhere in this specification and at least one excipient.

[0512] Such pharmaceutical compositions may have a pH of 3 to 8 or 4 to 6. In certain embodiments, such pharmaceutical compositions have a pH of 4 to 5.

[0513] In certain embodiments, such pharmaceutical compositions are liquid or suspension formulations. If the PTH compound is water-insoluble, for example, if it contains a water-insoluble carrier-Z', the pharmaceutical composition is understood to be a suspension formulation.

[0514] In certain embodiments, such a pharmaceutical composition is a dry formulation.

[0515] Such liquid, suspension, or dry pharmaceutical compositions contain at least one excipient. Excipients used in pharmaceutical compositions may be classified, for example, as buffers, isotonic modifiers, preservatives, stabilizers, anti-adsorbents, antioxidants, thickeners / viscosity enhancers, or other auxiliary agents. However, in some cases, a single excipient may have two or three functions. The at least one excipient included in the pharmaceutical composition of the present invention may be selected from the group consisting of: (i) Buffering agents: Physiologically acceptable buffering agents for maintaining pH within a desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, and pyruvate; antacids, such as Mg(OH)2 or ZnCO3, may also be used; (ii) Isotonic modifiers: for minimizing pain that may result from cell damage caused by osmotic pressure differences at injection depots; glycerin and sodium chloride are examples; effective concentrations can be determined by osmotic measurement using assumed molar osmotic concentrations of 285-315 mOsmol / kg for serum; (iii) Preservatives and / or antimicrobial agents: Parenteral formulations for multiple doses require the addition of preservatives at sufficient concentrations to minimize the risk of infection to the target at injection, and corresponding regulatory requirements have been established; typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercury nitrate, thimerosol, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride; (iv) Stabilizers: Stabilization is achieved by enhancing the protein stabilizing power, by destabilizing the denatured state, or by direct binding of the excipient to the protein; stabilizers may be amino acids, e.g., alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; sugars, e.g., glucose, sucrose, trehalose; polyols, e.g., glycerol, mannitol, sorbitol; salts, e.g., potassium phosphate, sodium sulfate; chelating agents, e.g., EDTA, hexaphosphates; ligands, e.g., divalent metal ions (zinc, calcium, etc.); other salts or organic molecules, e.g., phenolic derivatives; in addition, oligomers or polymers, e.g., cyclodextrin, dextran, dendrimers, PEG or PVP or protamine or HSA may be used; (v) Antiadsorbents: Primarily ionic or nonionic surfactants or other proteins or soluble polymers, such as poloxamer (Pluronic F-68), PEG-dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin are used to coat the inner surface of the formulation container or to competitively adsorb to the inner surface; the selected excipient concentration and type depend on the action to be avoided, but typically a single layer of surfactant is formed at the interface just above the CMC value; (vi) Antioxidant agents: Antioxidants such as ascorbic acid, ectoin, 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 are used to delay the sedimentation of particles in vials and syringes, to promote mixing and resuspending of particles, and to make the suspension easier to inject (i.e., with less force against the syringe plunger); suitable thickeners or viscosity enhancers include, for example, carbomer thickeners such as Carbopol 940 and Carbopol Ultrez 10, cellulose derivatives such as hydroxypropyl methylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (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 poly(hydroxy acids), e.g., poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and copolymers thereof (PLGA), terpolymers of D,L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks for constituting poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblocks (e.g., Pluronic®), polyether ester copolymers, e.g., polyethylene glycol terephthalate / polybutylene terephthalate copolymer, sucrose acetate isobutyrate (SAIB), dextran or its derivatives. The material is an ABA triblock or AB block copolymer, composed of a body, a combination of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and its derivatives, polyalkylimide, poly(acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAG), such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan, a hydrophobic A block, such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA), and a hydrophilic B block, such as polyethylene glycol (PEG) or polyvinylpyrrolidone;Such block copolymers and the poloxamers described above may exhibit reverse thermal gelation behavior (a fluid state at room temperature to facilitate administration, and a gel state at temperatures higher than the sol-gel transition temperature at body temperature after injection); (viii) Spreading or diffusing agents: modulate the permeability of connective tissue by hydrolysis of components of the extracellular matrix in the interstitial space (e.g., hyaluronic acid, a polysaccharide found in the intercellular space of connective tissue, for example; without limit, spreading agents, such as hyaluronidase, for example; without limit, temporarily reduce the viscosity of the extracellular matrix and promote the diffusion of injected drugs; and (ix) Other auxiliary agents: wetting agents, viscosity modifiers, antibiotics, hyaluronidase, etc.; acids and bases such as hyaluronic acid and sodium hydroxide are auxiliary agents necessary for pH adjustment during manufacturing.

[0516] PTH compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising PTH compounds or pharmaceutically acceptable salts thereof may be administered to a subject by various modes of administration, for example, by topical administration, intravenous administration or parenteral administration, or by external use, injection or infusion, for example, by intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intramedullary, intracapsular, intraorbital, intratympanic, intravesical, intracardiac, transtracheal, subepidermal, subcapsular, intraarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, by direct delivery to the brain via an implantable device (e.g., Ommaya Reservoir) that enables delivery of the present invention to brain tissue or cerebral fluid, by direct intraventricular injection or infusion, by injection or infusion into the brain or brain-related regions, by injection into the subchoroidal space, by posterior orbital injection and ophthalmic instillation. In certain embodiments, a PTH compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a PTH compound or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection.

[0517] Such subcutaneous injections are preferably carried out using a syringe and needle or a pen-type syringe. In certain embodiments, a PTH compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a PTH compound or a pharmaceutically acceptable salt thereof is administered via subcutaneous injection using a pen-type syringe.

[0518] PTH compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising PTH compounds or pharmaceutically acceptable salts thereof may be administered as required by the subject, for example, twice daily, once daily, once every two days, once a week, once every two weeks, or once a month.

[0519] In certain embodiments, the PTH compound is the PTH compound of formula (XI), which is administered once daily, for example, by subcutaneous injection. A suitable starting dose for treatment with the PTH compound of formula (XI) may be 18 μg / day, which is based on the weight of the PTH portion only, excluding the remainder of the PTH compound.

[0520] In a particular embodiment, the PTH compound is the PTH compound of SEQ ID NO: 122, which is administered once daily, for example, by subcutaneous injection.

[0521] In certain embodiments, the PTH compound is a PTH compound of formula (XII) or (XII'), which may be administered once a week, for example, by subcutaneous injection.

[0522] In certain embodiments, the PTH compound is a PTH compound of formula (XIII) or (XIII'), which may be administered once a week, for example, by subcutaneous injection.

[0523] In certain embodiments, the starting dose of the compound of formula (XI) is 12-24 μg PTH 1-34 per day. In certain embodiments, the starting dose of the compound of formula (XI) is 15-21 μg PTH 1-34 per day. In certain embodiments, the starting dose of the compound of formula (XI) is 18 ± 3 μg PTH 1-34 per day. In certain embodiments, the starting dose of the compound of formula (XI) is 18 μg PTH 1-34 per day.

[0524] In certain embodiments, the PTH compound is a compound of formula (XI) and is administered to a subject in the form of a pharmaceutical composition. In certain embodiments, 1 ml of such a pharmaceutical composition contains 3456 μg of the compound of formula (XI) (corresponding to 300 μg of PTH 1-34), 1.18 mg succinic acid, 41.7 mg mannitol, 2.5 mg metacresol, 0.13 mg sodium hydroxide, and water for injection, and has a pH of 3.7 to 4.3. In certain embodiments, 1 ml of such a pharmaceutical composition contains 3456 μg of the PTH compound of formula (XI) (corresponding to 300 μg of PTH 1-34), 1.18 mg succinic acid, 41.7 mg mannitol, 2.5 mg metacresol, 0.13 mg sodium hydroxide, and water for injection, and has a pH of 3.7 to 4.3.

[0525] In certain embodiments, the number of such pharmaceutical composition presentations is 2 to 8, each presentation containing a different dose of the PTH compound of formula (XI). In certain embodiments, the number of pharmaceutical composition presentations is 2 to 6, each presentation containing a different dose of the PTH compound of formula (XI). In certain embodiments, the number of pharmaceutical composition presentations is 2 to 4, each presentation containing a different dose of the PTH compound of formula (XI). In certain embodiments, the pharmaceutical composition is provided in 3 presentations, each presentation containing a different dose of the PTH compound of formula (XI). In certain embodiments, each presentation is a pre-filled pen.

[0526] In certain embodiments, the pharmaceutical composition is provided in three presentations, the first of which is a pre-filled pen containing 168 μg PTH 1-34 / 0.56 mL; the second of which is a pre-filled pen containing 294 μg PTH 1-34 / 0.98 mL; and the third of which is a pre-filled pen containing 420 μg PTH 1-34 / 1.4 mL, where PTH 1-34 is provided in the form of a PTH compound of formula (XI).

[0527] The first of these three suggestions may be used to administer a dose of 6, 9, or 12 μg PTH 1-34 / day; the second suggestion may be used to administer a dose of 15, 18, or 21 μg PTH 1-34 / day; and the third suggestion may be used to administer a dose of 24, 27, or 30 μg PTH 1-34 / day. Doses greater than 30 μg PTH 1-34 / day but less than or equal to 60 μg PTH 1-34 / day may be administered as two consecutive doses. For example, a dose of 33 μg PTH 1-34 / day may 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 may 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 may 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 may be administered as a combination of 21 μg PTH 1-34 / day + 21 μg PTH 1-34 / day; a dose of 45 μg PTH 1-34 / day may be administered as a combination of 21 μg PTH 1-34 / day + 24 μg PTH It may be administered as a combination of doses of 1-34 / day; the 48 μg PTH 1-34 / day dose may be administered as a combination of 24 μg PTH 1-34 / day dose + 24 μg PTH 1-34 / day dose; the 51 μg PTH 1-34 / day dose may be administered as a combination of 24 μg PTH 1-34 / day dose + 27 μg PTH 1-34 / day dose; the 54 μg PTH 1-34 / day dose may be administered as a combination of 27 μg PTH 1-34 / day dose + 27 μg PTH 1-34 / day dose; the 57 μg PTH 1-34 / day dose may be administered as a combination of 27 μg PTH 1-34 / day dose + 30 μg PTH 1-34 / day dose; the 60 μg PTH 1-34 / day dose may be administered as 30 μg PTH The dose may be administered as a combination of 1-34 / day + 30 μg PTH 1-34 / day, where PTH 1-34 is provided by the compound of formula (XI).

[0528] In patients with hypoparathyroidism accompanied by chronic kidney disease, the treatment in step (a) is: (ia) A step to confirm that the subject's serum 25(OH) vitamin D level is within the normal range within two weeks prior to administration of the first dose of compound (XI), and that serum calcium is ≥7.8 mg / dL at the start of treatment; (ib) If the subject is taking active vitamin D when treatment with the compound of formula (XI) is initiated: (ibi) If serum calcium is ≥8.3 mg / dL, on the same day that the first dose of compound (XI) is administered, maintain the same dose of calcium supplement and discontinue active vitamin D; or (ib-ii) If serum calcium is <8.3 mg / dL, reduce the dose of active vitamin D by ≥50% on the same day that the first dose of the compound of formula (XI) is administered, while maintaining the same dose of calcium supplement; or If the subject is not taking active vitamin D when treatment with the compound of formula (XI) is initiated: (ib-iii) On the same day that the first dose of the compound of formula (XI) is administered, the calcium supplement is reduced by at least 1500 mg; and (ic) If necessary, continue dietary calcium supplements at a dose of ≤600 mg / day that is shown to meet the calcium requirement. It can be initiated by...

[0529] In certain embodiments, serum 25(OH) vitamin D is within the normal range when its concentration is between 20 and 80 ng / ml.

[0530] If the subject is not taking active vitamin D and is taking a calcium supplement dose of ≤1500 mg calcium / day, the calcium supplement dose is completely discontinued in step (ib-iii).

[0531] In a particular embodiment, in a subject having hypoparathyroidism accompanied by chronic kidney disease, the treatment in step (a) is: (ia) A step to confirm that the subject's serum 25(OH) vitamin D level is within the normal range within two weeks prior to administration of the first dose of compound (XI), and that serum calcium is ≥7.8 mg / dL at the start of treatment; (ib) If the subject is taking active vitamin D when treatment with the compound of formula (XI) is initiated: (ibi) If, on the day of initiating treatment with a PTH compound, serum calcium is ≥8.3 mg / dL and current active vitamin D intake is >1 μg / day, maintain the same dose of calcium supplement and reduce the active vitamin D dose by ≥50%; or (ib-ii) If, on the day of initiating treatment with a PTH compound, serum calcium is ≥8.3 mg / dL and current active vitamin D intake is ≤1 μg / day, maintain the same dose of calcium supplement and discontinue the active vitamin D dose; or (ib-iii) If, on the day of initiating treatment with a PTH compound, serum calcium levels are between ≥7.8 mg / dL and <8.3 mg / dL with any amount of active vitamin D intake, maintain the same dose of calcium supplement and reduce the active vitamin D dose by ≥50%; or If the subject is not taking active vitamin D when treatment with the compound of formula (XI) is initiated: (ib-iii) If the current daily calcium dose is ≤1500 mg / day and serum calcium is ≥7.8 mg / dL, reduce the dose of calcium supplement by at least 1500 mg or discontinue it; and (ic) If necessary, continue dietary calcium supplements at a dose of ≤600 mg / day that is shown to meet the calcium requirement. It can be initiated by...

[0532] In a particular embodiment, step (a) is the following step in addition to steps (ia) to (ic): (id) A starting dose of 18 μg PTH 1-34 / day is administered in the form of the compound of formula (XI), followed by daily administration of the same dose; (i.e.) the step of measuring serum calcium within 7 to 14 days of the first dose of the compound of formula (XI); and (if) the step of adjusting the dosage of the compound of formula (XI), active vitamin D and / or calcium supplement. This may further include:

[0533] In certain embodiments, the compound of formula (XI) is administered as a pharmaceutical composition in step (id), each ml of this composition containing 3456 μg of the compound of formula (XI) (corresponding to 300 μg of PTH 1-34), 1.18 mg succinic acid, 41.7 mg mannitol, 2.5 mg metacresol, 0.13 mg sodium hydroxide, and water for injection. In certain embodiments, the pharmaceutical composition has a pH of 3.7 to 4.3.

[0534] In step (if), the step of adjusting the dose of the compound of formula (XI), active vitamin D and / or calcium supplement is carried out based on the serum calcium level derived in step (ie).

[0535] In a particular embodiment, the adjustment of the dosage of the compound of formula (XI), active vitamin D, and / or calcium supplement in step (if) is carried out as follows: (ifi) If serum calcium is <8.3 mg / dL: - If ≥7 days have elapsed since treatment with compound (XI) was initiated or since the dose of compound (XI) was changed, continue with the same calcium supplement dose and active vitamin D dose, and increase the dose of compound (XI) by 3 μg; or - If less than 7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, the calcium supplement and / or active vitamin D should be increased toward the previous dose, based on the physician's clinical judgment, and the same dose of compound (XI) should be continued; (if-ii) If serum calcium is 8.3-10.6 mg / dL: - If ≥7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is still taking active vitamin D, discontinue active vitamin D and increase the dose of compound (XI) by 3 μg; - If ≥7 days have elapsed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is no longer taking active vitamin D but is taking calcium supplements, and the amount of calcium supplements is ≥1500 mg / day, then reduce the amount of calcium supplements by ≥1500 mg and increase the dose of compound (XI) by 3 μg; - If ≥7 days have elapsed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is no longer taking active vitamin D but is taking calcium supplements, and the amount of calcium supplements is less than 1500 mg / day, discontinue the calcium supplements and increase the dose of compound (XI) by 3 μg; - If ≥7 days have elapsed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is no longer taking active vitamin D or calcium supplements, continue with the same dose of compound (XI); or - If less than 7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, continue with the same dose of compound (XI), the same dose of calcium supplement, and active vitamin D; (if-iii) If serum calcium is 10.7-11.9 mg / dL: - If the subject is still taking active vitamin D, discontinue the active vitamin D and continue taking the same dose of compound (XI) and calcium supplements; - If the subject is not taking active vitamin D but is taking calcium supplements at a dose of ≥1500 mg / day, reduce the calcium supplement dose by ≥1500 mg and continue with the same dose of compound (XI); - If the subject is not taking active vitamin D but is taking calcium supplements and the amount of these calcium supplements is less than 1500 mg per day, discontinue the calcium supplements and continue taking the compound of formula (XI) at the same dose; or - If the subject is not taking active vitamin D and is not taking calcium supplements, reduce the dose of compound (XI) by 3 μg; or (if-iv) If serum calcium is ≥ 12 mg / dL: - Avoid the compound of formula (XI) for 2-3 days, and retest serum calcium. - If subsequent serum calcium levels are <12 mg / dL, use the most recent serum calcium level obtained to resume titration of the compound of formula (XI), active vitamin D, and calcium supplement as described in steps (ifi) to (if-iii); - If serum calcium remains ≥12 mg / dL, withhold the compound of formula (XI) for another 2-3 days, retest serum calcium, and proceed as described in the previous step.

[0536] In certain embodiments, the dose range of the compound of formula (XI) administered to a subject is 6 to 60 μg PTH 1-34 / day, and these doses may be provided in pre-filled pens of 168 μg PTH 1-34 / 0.56 mL (delivering doses of 6, 9, or 12 μg PTH 1-34); 294 μg PTH 1-34 / 0.98 mL (delivering doses of 15, 18, or 21 μg PTH 1-34); and 420 μg PTH 1-34 / 1.4 mL (delivering doses of 24, 27, or 30 μg PTH 1-34).

[0537] In a particular embodiment, the adjustment of the dosage of the compound of formula (XI), active vitamin D, and / or calcium supplement in step (if) is carried out as follows: If serum calcium is <8.3 mg / dL: - If ≥7 days have elapsed since treatment with compound (XI) was initiated or since the dose of compound (XI) was changed, continue with the same calcium supplement dose and active vitamin D dose, and increase the dose of compound (XI) by 3 μg; or - If less than 7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, the calcium supplement and / or active vitamin D should be increased toward the previous dose, based on the physician's clinical judgment, and the same dose of compound (XI) should be continued; If serum calcium is between 8.3 and 10.6 mg / dL: - If less than 7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, continue with the same dose of compound (XI), calcium supplements, and active vitamin D; - If ≥7 days have elapsed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is still taking active vitamin D, reduce or discontinue active vitamin D and increase the dose of compound (IX) by 3 μg; - If ≥7 days have elapsed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is no longer taking active vitamin D or calcium supplements, continue with the same dose of compound (XI); - If ≥7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is no longer taking active vitamin D, and is taking calcium supplements at a dose of ≥1500 mg / day, reduce the calcium supplement dose by ≥1500 mg and increase the dose of compound (XI) by 3 μg; - If ≥7 days have passed since treatment with compound (XI) was initiated or the dose of compound (XI) was changed, and the subject is no longer taking active vitamin D, and is taking calcium supplements at a dose of ≤1500 mg / day, discontinue the calcium supplements and increase the dose of compound (XI) 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 discontinue the active vitamin D and continue with the same dose of compound (XI) and calcium supplements; - If the patient is no longer taking active vitamin D and is also not taking calcium supplements, reduce the dose of compound (XI) by 3 μg; - If the patient is no longer taking active vitamin D and is still taking calcium supplements ≥1500 mg / day, reduce the calcium supplement dose by ≥1500 mg and continue taking the same dose of compound (XI); - If the patient is no longer taking active vitamin D and is still taking calcium supplements, but at a dose of <1500 mg / day, discontinue the calcium supplements and continue taking the compound of formula (XI) at the same dose; If serum calcium is 12 mg / dL or higher, refrain from taking the compound of formula (XI) for 2-3 days, retest serum calcium, and repeat if serum calcium remains 12 mg / dL or higher. Once serum calcium falls below 12 mg / dL, resume titration of the compound of formula (XI), active vitamin D, and calcium supplements as described above.

[0538] In certain embodiments, the compound of formula (XI) or a pharmaceutical composition containing the compound of formula (XI) is visually inspected for particulate matter and discoloration before administration.

[0539] In certain embodiments, dose adjustments of the PTH compound of formula (XI), active vitamin D, and calcium supplement are made on the same day. After dose adjustments to the PTH compound of formula (XI), active vitamin D, or calcium supplement, in certain embodiments, serum calcium can be measured within 7 to 14 days to monitor the subject for clinical symptoms of hypocalcemia or hypercalcemia, and the doses of the PTH compound of formula (XI), active vitamin D, and / or calcium supplement can be adjusted as described above.

[0540] The dose of the PTH compound of formula (XI) can be increased in 3 μg increments as described above if at least 7 days have elapsed since the previous dose change of the PTH compound of formula (XI). In certain embodiments, the dose of the PTH compound of formula (XI) administered to the subject is adjusted at a frequency of no more than every 7 days. As described above, the dose of the PTH compound of formula (XI) can be decreased in 3 μg increments at a frequency of no more than every 3 days, depending on the level of hypercalcemia.

[0541] The maintenance dose should be the dose of the PTH compound of formula (XI) that achieves serum calcium within the normal range without the need for active vitamin D and calcium supplements. If necessary, sufficient calcium supplementation can be continued to meet the required levels. Once the maintenance dose is achieved, serum calcium can be measured according to standard treatment guidelines.

[0542] In a particular embodiment, step (a) is the following step in addition to steps (ia) to (if): (ig) Administration of a daily maintenance dose; and (ih) Step of measuring serum calcium according to standard treatment This may further include:

[0543] If serum calcium levels are not within the normal range, for example, 8.3–10.6 mg / dL, repeat step (if)–(ih) after step (ih).

[0544] If a single dose of the PTH compound of formula (XI) is missed by less than 12 hours, it may be taken as soon as possible. If a single dose is missed by more than 12 hours, it may be skipped, and the next dose may 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 may be resumed. In certain embodiments, administration of the PTH compound of formula (XI) is resumed at the prescribed dose as soon as possible after interruption, and this prescribed dose may or may not be a maintenance dose. When resuming treatment after interruption, serum calcium should be measured, and the doses of the PTH compound of formula (XI), active vitamin D, and calcium supplements may be adjusted as described above.

[0545] Pharmaceutical compositions and presentations for the PTH compound of formula (XI) used in steps (ia) to (ig) are as described elsewhere in this specification.

[0546] In certain embodiments, the PTH compound is the PTH compound of Sequence ID No. 122, which may be administered in doses of 20 μg to 60 μg per day.

[0547] In certain embodiments, PTH is a PTH compound of formula (XII) or (XII'), and the initial dose is 100 μg to 250 μg / week, 101.25 μg to 168.75 μg / week, 101.25 μg to 168.75 μg / week, 108 μg to 162 μg / week, 114.75 μg to 155.25 μg / week, 121.5 μg to 148.5 μg, or 128.25 μg to 141.75 μg / week. In certain embodiments, PTH is a PTH compound of formula (XII) or (XII'), and the initial dose is approximately 135 μg / week. [Examples]

[0548] Synthesis of Compound 1 Compound 1, also known as paropegteriparatide, has the following structure:

[0549] [ka] [In the formula, The unmarked dashed lines indicate the bond of the N-terminal amine group of the PTH portion of sequence number 51 to the nitrogen. The dashed line with an asterisk indicates a part

[0550] [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, (m and p are integers between approximately 450 and 500.) [Shows a connection to] It holds.

[0551] Compound 1 can be prepared as described for Compound 18 in Example 18 of WO2017 / 148883.

[0552] Example 1: TCP-304 In the Phase 3, double-blind, placebo-controlled trial TCP-304 (NCT04701203), subjects were randomized 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. Serum creatinine was measured at regular intervals, and estimated glomerular filtration rate (eGFR) was calculated using the MDRD (Modification of Diet in Renal Disease) formula [Levey et al., 2006]. The MDRD formula is as follows:

[0553] eGFR (mL / min / 1.73m 2 ) = 175 × (serum creatinine mg / dL) -1.154 × (Age) -0.203 × 0.742 [for women] × 1.212 [for Black people]

[0554] According to the eligibility criteria, eGFR < 30 mL / min / 1.73 m² 2 Subjects with [specific characteristic] were excluded. As of July 20, 2022, TCP-304 eGFR data is available from baseline to 52 weeks of follow-up. Mean eGFR at baseline was roughly similar between groups (Compound 1: 67.32, Placebo: 72.70), but consistently 90 mL / min / 1.73 m². 2 The levels were below normal (Table 1). The majority of subjects in TCP-304 demonstrated some degree of renal impairment at baseline. In total, 28.0% of randomized subjects (compound 1: 31.1%, placebo: 19.0%) had a baseline eGFR < 60 mL / min / 1.73 m². 2This defines stage 3a or worse chronic kidney disease (CKD) according to the 2012 KDIGO Guidelines for 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.].

[0555] [Table 2]

[0556] Table 2 shows the change in eGFR from baseline over the available 52-week follow-up period. Treatment with compound 1 was associated with a rapid increase (i.e., improvement) in eGFR, evident as early as week 4, which was maintained until week 52. The slope (95% CI) of the change in eGFR from baseline to week 4 was similar between the treatment groups (compound 1 / compound 1: 1.25 [0.6, 1.9] mL / min / 1.72 m²). 2 / week [P<.0001]; placebo / compound 1: 1.20 [0.3, 2.1] mL / min / 1.72 m 2 ( / week [P<.01]). From week 4 onward, subjects randomized to compound 1 showed stable eGFR, 0.20 (-0.2, 0.6) mL / min / 1.72m² from week 4 to week 12. 2 / week (P≧0.05), 0.07 (-0.1, 0.3) mL / min / 1.72m² from week 12 to week 26. 2 / week (P≧.05), and 0.05(-0.1, 0.2) mL / min / 1.72m² from week 26 to week 52. 2 The change in eGFR was accompanied by a slope (95% CI) of 0.05 / week. Conversely, subjects randomized to placebo experienced a reversal of eGFR change, returning to baseline from week 4 onward, with a change of -0.23 (-0.8, 0.3) mL / min / 1.72m² from week 4 to week 12. 2 / week (P≧0.05), and from week 12 to week 26 -0.43 (-0.8, -0.1) mL / min / 1.72m 2 The change in eGFR was accompanied by a negative slope (95% CI) at / week (P<.05). After starting compound 1 at week 26, the slope (95% CI) of the change in eGFR was 0.30 (0.1, 0.2) mL / min / 1.72m² from week 26 to week 52. 2 The number of cases increased significantly per week (P<.01).

[0557] At the end of the blinded treatment period at week 26, the eGFR in the placebo group was -1.91 mL / min / 1.73 m². 2 Compared to the reduction in (95% CI: -6.05, 2.24), subjects randomized to receive compound 1 showed a mean eGFR of 7.90 mL / min / 1.73 m². 2 An increase (95% CI: 5.20, 10.59) was observed (Table 2). Using a paired t-test, this increase from baseline was found to be significantly greater than 0 in subjects receiving compound 1 (p<0.0001, paired t-test), but not 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 change from baseline in eGFR as the dependent variable, treatment, baseline eGFR group, and sex as fixed effects, and baseline eGFR and age as covariates. Using this model, treatment with compound 1 was 8.80 (2.50) mL / min / 1.73m for compound 1 versus placebo. 2 This resulted in a least squares mean (SE) difference (p=0.0007). In the open-label extension, the significant increase in eGFR observed at week 26 in subjects initially randomized to compound 1 was maintained at week 52. Specifically, we found a mean increase of 9.28 mL / min / 1.73 m² from baseline. 2An increase (95% CI: 6.23, 12.33) was observed, which was also significantly greater than 0 by paired t-tests (p<0.0001). Participants initially randomized to placebo had a mean eGFR of 7.55 mL / min / 1.73 m² from baseline after 26 weeks of active compound 1 treatment in the open-label extension. 2 An increase was observed (95% CI: 3.35, 11.75). This increase was also significantly greater than 0 by a paired t-test (p=0.0014).

[0558] [Table 3]

[0559] To supplement the above analysis, a responder analysis using the intention-to-treat (ITT) population was also performed, and the treatment response was defined as eGFR of ≥5 mL / min / 1.73 m² from baseline. 2 This was defined as an increase in eGFR (Table 3). In subjects randomized to compound 1, 57.4% and 63.9% of subjects demonstrated an eGFR treatment response at weeks 26 and 52, respectively. In subjects randomized to placebo, the treatment response rate was 23.8% at week 26, which increased to 52.4% at week 52 after 26 weeks of treatment with open-label active compound 1. Additional responder analyses were performed to determine the treatment response as an increase in eGFR from baseline of ≥10 mL / min / 1.73 m². 2 This was defined as an increase in eGFR. In subjects randomized to compound 1, 42.6% of subjects had an eGFR of ≥10 mL / min / 1.73 m from baseline at both weeks 26 and 52. 2 At week 26, 9.5% of those randomized to placebo experienced an increase in eGFR of ≥10 mL / min / 1.73 m² from baseline. 2 There was an increase, and after 26 weeks of treatment with open-label active compound 1, it increased to 28.6% at week 52.

[0560] [Table 4]

[0561] Based on both baseline-to-responder analysis results, treatment with compound 1 in TCP-304 was >8 mL / min / 1.73 m² over 52 weeks of treatment. 2 This is demonstrated to be associated with a sustained increase in eGFR. These changes in eGFR are as follows: 1. Estimated rhPTH (1-84) level after one year of treatment: +2.13 to +3.02 mL / min / 1.73 m 2 This is significantly higher than 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. For the majority of subjects receiving compound 1 for ≥26 weeks, a change in eGFR of 5 mL / min / 1.73 m² is considered clinically significant. 2 [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].

[0562] Analysis of the change from baseline in eGFR over the available 52-week follow-up period, broken down by eGFR subgroup (i.e., <60 vs ≥60 mL / min / 1.73m²). 2 The study was also conducted on ) the 23 subjects. At baseline, eGFR < 60 mL / min / 1.73 m² 2 (Compound 1: n=19, Placebo: n=4) 59 subjects had eGFR ≥ 60 mL / min / 1.73 m 2(Compound 1: n=42, Placebo: n=17). Regardless of baseline eGFR subgroup, compound 1 treatment was again associated with a rapid increase in eGFR, evident as early as week 4, and maintained improvement until week 52. The change in eGFR from baseline to week 4 was similar for both eGFR subgroups between the treatment groups. From week 4 onward, subjects in both eGFR subgroups randomized to compound 1 demonstrated eGFR stabilization, with baseline eGFR <60 mL / min / 1.73 m². 2 The greatest numerical mean increase in eGFR was observed in subjects with the specified characteristic. Conversely, subjects randomized to placebo in both eGFR subgroups experienced a reversal of eGFR changes, with values ​​decreasing to baseline by week 26. After initiation of open-label active compound 1 at week 26, eGFR increased significantly in both eGFR subgroups, with baseline eGFR <60 mL / min / 1.73 m². 2 The greatest numerical mean increase in eGFR was observed in subjects with this characteristic.

[0563] As described above, 28% of all randomized subjects in TCP-304 had a baseline eGFR < 60 mL / min / 1.73 m². 2 These patients had stage 3a CKD or worse. Since maintaining residual renal function is clinically important for these patients, the change in eGFR from baseline was analyzed for this subset up to week 52 (Table 4a). In this eGFR subset, at the end of the blinding period at week 26, the eGFR was 0.05 mL / min / 1.73 m² compared to the placebo-treated group. 2 Compared to the increase in (95% CI: -9.46, 9.56), subjects receiving compound 1 showed an average eGFR of 11.36 mL / min / 1.73 m 2An increase (95% CI: 6.20, 16.52) was observed. A paired t-test showed that this increase from 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, baseline eGFR < 60 mL / min / 1.73 m² 2 For subjects with the following characteristics, treatment with compound 1 was administered at a rate of 12.44 (5.86) mL / min / 1.73 m³ for compound 1 versus placebo. 2 This resulted in a least squares mean (SE) difference (p=0.0479). In the open-label extension, the inventors again observed a sustained increase in eGFR at week 52 in subjects in this eGFR subset randomized to compound 1. Specifically, the inventors observed a mean increase of 11.46 mL / min / 1.73 m² from baseline. 2 An increase (95% CI: 6.03, 16.89) was observed, which was also significantly greater than 0 by a paired t-test (p=0.0003). Furthermore, subjects initially randomized to placebo showed a mean eGFR of 11.65 mL / min / 1.73 m² from baseline after 26 weeks of treatment with compound 1 in the open-label extension. 2 An increase in eGFR was observed (95% CI: 8.13, 15.17); this increase was also significantly greater than 0 by paired t-tests (p=0.0018). Importantly, the sustained increase in eGFR observed in subjects in this eGFR subset treated with compound 1 in TCP-304 corresponds to a clinically significant eGFR of 5 mL / min / 1.73 m³. 2 This surpasses the changes observed [Hirst et al., 2022, KDIGO CKD Work Group, 2013].

[0564] Baseline eGFR ≥ 60 mL / min / 1.73m² 2 Similar results were observed in subjects with the same condition (Table 4b), and at the end of the blinded treatment period at 26 weeks, the eGFR of the placebo-treated subjects was -2.43 mL / min / 1.73 m 2Compared to the reduction in (95% CI: -7.56, 2.71), subjects receiving compound 1 showed an average eGFR of 6.29 mL / min / 1.73 m². 2 An increase (95% CI: 3.13, 9.45) was observed. A paired t-test showed that this increase from baseline was significantly greater than 0 for subjects receiving compound 1 (p=0.0002), but not for subjects receiving placebo (p=0.3280). Using the ANCOVA model described above, treatment with compound 1 resulted in a 7.68 (2.68) mL / min / 1.73m² treatment compared to compound 1 versus placebo. 2 This resulted in a least squares mean (SE) difference (p=0.0060). In the open-label extension, the inventors again randomized subjects in this eGFR subset to compound 1 and found a sustained, statistically significant improvement in eGFR of 8.25 mL / min / 1.73 m² at week 52. 2 An increase (95% CI: 4.43, 12.06, p<0.0001) was observed. Furthermore, subjects initially randomized to placebo showed a mean increase of 6.45 mL / min / 1.73 m² in eGFR from baseline after 26 weeks of treatment with compound 1 in the open-label extension. 2 An increase was observed (95% CI: 1.18, 11.72); this increase was also significantly greater than 0 by a paired t-test (p=0.0199).

[0565] [Table 5]

[0566] [Table 6]

[0567] To supplement the above analysis, responder analyses using the intention-to-treat (ITT) population were also performed for each eGFR subgroup (Tables 5a and 5b). Baseline eGFR <60 mL / min / 1.73 m² were randomized to compound 1. 2In subjects with this condition, 73.7% and 68.4% of subjects had an eGFR of ≥5 mL / min / 1.73 m² from baseline at weeks 26 and 52, respectively. 2 They experienced an increase in eGFR from baseline. Furthermore, 47.4% and 42.1% of the subjects experienced an increase of ≥10 mL / min / 1.73 m² from baseline at weeks 26 and 52, respectively. 2 An increase was experienced. Baseline eGFR ≥ 60 mL / min / 1.73m² was randomized to compound 1. 2 In subjects with this condition, comparable treatment response rates (regardless of response threshold) were observed at weeks 26 and 52.

[0568] Patients randomized to placebo with baseline eGFR <60 mL / min / 1.73 m² 2 In this group, 25% had an eGFR of ≥5 mL / min / 1.73 m² from baseline at week 26. 2 An increase was observed, reaching 100% at week 52 after 26 weeks of treatment with open-label active compound 1. A response rate of 23.5% was observed in subjects with baseline eGFR ≥ 60 mL / min / 1.73 m2 at week 26, and 41.2% of subjects had an eGFR of ≥ 5 mL / min / 1.73 m2 from baseline at week 52. 2 An increase was achieved.

[0569] At week 26, patients with baseline eGFR <60 mL / min / 1.743 m² were randomized to placebo. 2 0% of subjects with this condition had an eGFR of ≥10 mL / min / 1.73 m² from baseline. 2 There was an increase in baseline eGFR ≥ 60 mL / min / 1.743 m², which rose to 75% at week 52 after 26 weeks of treatment with open-label active compound 1. The baseline eGFR ≥ 60 mL / min / 1.743 m² was randomized to placebo. 2 In subjects with this condition, 11.8% and 17.6% of subjects had an eGFR of ≥10 mL / min / 1.73 m² from baseline at weeks 26 and 52, respectively. 2 We experienced an increase in [this].

[0570] [Table 7]

[0571] [Table 8]

[0572] The improvement in eGFR observed from baseline was maintained during the 104-week follow-up period in subsequent analyses. At week 104, 93% (76 / 82) of participants remained in the study. The mean (SD) eGFR was 77.8 (14.8) mL / min / 1.73m2. Paropegteriparatide treatment resulted in a mean (SD) increase in eGFR of 8.9 (11.0) mL / min / 1.73m2 (P<.0001) from baseline to week 52, which was maintained up to week 104 with a mean (SD) change from baseline of 9.0 (10.3) mL / min / 1.73m2 (P<.0001). By week 104, 61% and 44% of participants had an increase in eGFR of ≥5 mL / min / 1.73m2 and ≥10 mL / min / 1.73m2, respectively. Among participants with baseline eGFR <60 mL / min / 1.73m2 (n=23), paropegteriparatide treatment resulted in a mean (SD) increase in eGFR of 13.8 (10.0) mL / min / 1.73m2 from baseline to week 104, with 78% and 57% having an increase in eGFR of ≥5 mL / min / 1.73m2 and ≥10 mL / min / 1.73m2, respectively.

[0573] Example 2: TCP-201 In the Phase 2, double-blind, placebo-controlled, parallel-group trial TCP-201 (NCT04009291), subjects were randomized in a 1:1:1:1 ratio to receive either compound 1, 15 μg / day; compound 1, 18 μg / day; compound 1, 21 mcg / day; or the corresponding placebo for 4 weeks. Following this 4-week placebo-controlled period, all subjects received an open-label extension to receive active compound 1. In this trial, eGFR was measured at multiple time points using the MDRD formula [Levey et al., 2006]. Eligibility criteria required eGFR ≤ 30 mL / min / 1.73 m 2 Subjects with [specific condition] were excluded. As of June 1, 2022, TCP-201 eGFR data is available from baseline to the 110-week follow-up. Given the relatively short placebo-controlled period, summary data is provided for all randomized subjects. The mean eGFR at baseline was 69.39 mL / min / 1.73 m². 2 The flow rate is 90 mL / min / 1.73 m². 2 The levels were below normal (Table 6). Consistent with TCP-304, the majority of subjects in TCP-201 demonstrated some degree of renal impairment at baseline. Similar to TCP-304, 30.5% of the subjects randomized in TCP-201 (18 out of 59 subjects) had a baseline eGFR < 60 mL / min / 1.73 m². 2 This includes defining Stage 3a or worse CKD in accordance with the 2012 KDIGO Guidelines for CKD [KDIGO CKD Work Group, 2013].

[0574] [Table 9]

[0575] Considering the significant, clinically meaningful increase in eGFR in TCP-304 for all subjects and those with significant baseline renal impairment, we then examined the change from baseline in eGFR over the available 110 weeks in TCP-201 (Table 7). At week 26, subjects treated with compound 1 showed a mean eGFR of 6.36 mL / min / 1.73m² from baseline. 2 An increase (95% CI: 3.55, 9.17) was observed, which was significantly greater than 0 (p<0.0001, paired t-test), similar to the early eGFR increase observed in TCP-304. Again, consistent with the findings from TCP-304, the increase in eGFR from baseline in TCP-201 increased further at week 58 (mean increase: 8.54 mL / min / 1.73 m²). 2 (95% CI: 5.30, 11.78), maintained at 110 weeks (8.54 mL / min / 1.73 m²). 2 (95% CI: 5.07, 11.59). The increase from baseline in eGFR was significantly greater than 0 at both week 58 (p<0.0001) and week 110 (p<0.0001).

[0576] [Table 10]

[0577] To supplement the above analysis, a responder analysis using the ITT population was also performed, and the treatment response was defined as eGFR of ≥5 mL / min / 1.73m² from baseline. 2 This was defined as an increase in eGFR (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.

[0578] [Table 11]

[0579] These eGFR changes in a similar patient population in TCP-201 complement and support the eGFR findings in TCP-304. From both baseline-to-baseline change and responder analysis results, (consistent with TCP-304) treatment with compound 1 in TCP-201 resulted in >8 mL / min / 1.73 m³ during 110 weeks of treatment. 2 This is demonstrated to be associated with a sustained increase in eGFR. These changes in eGFR are as follows: 1. Estimated rhPTH (1-84) level after one year of treatment: +2.13 to +3.02 mL / min / 1.73 m 2 This is significantly higher than the increase in [Ayodele et al., 2022, Chen et al., 2020]; and 2. For the majority of subjects receiving compound 1 for ≥26 weeks, a change in eGFR of 5 mL / min / 1.73 m² is considered clinically significant. 2 Exceeding [Hirst et al., 2022, KDIGO CKD Work Group, 2013].

[0580] As shown above, 30.5% of all randomized subjects in TCP-201 (18 out of 59 subjects) had a baseline eGFR < 60 mL / min / 1.73 m². 2 (Stage 3a CKD or worse). In this subset of patients with significant baseline renal impairment, maintaining residual renal function is clinically very important. Considering the clinically significant increase in eGFR in TCP-304 for all subjects and those with significant baseline renal impairment, we then considered the baseline eGFR <60 mL / min / 1.73 m in TCP-201. 2 For subjects with the condition, we examined the change from baseline in eGFR (Table 9).

[0581] In this subset of subjects in TCP-201 at week 26, subjects receiving compound 1 showed a mean eGFR of 7.99 mL / min / 1.73m². 2An increase (95% CI: 3.72, 12.26) was observed. Using a paired t-test, this increase from baseline at week 26 for subjects receiving compound 1 was found to be significantly greater than 0 (p=0.0011). Again, consistent with the findings from TCP-304, the increase from baseline in eGFR for this subset in TCP-201 was at week 58 (mean increase: 11.79 mL / min / 1.73 m²). 2 (95% CI: 7.76, 15.83) and at 110 weeks (8.49 mL / min / 1.73 m²) 2 (95% CI: 3.69, 13.28) was maintained. The increase from baseline in eGFR was significantly greater than 0 at both week 58 (p<0.0001) and week 110 (p=0.0018). These eGFR changes in patients with baseline renal impairment in TCP-201 again complement and support the eGFR findings in TCP-304.

[0582] [Table 12]

[0583] To the best of our knowledge, the data provided in Example 1 (TCP-304) and Example 2 (TCP-201) represent a clinically meaningful and statistically significant increase in eGFR from baseline (>8 mL / min / 1.73 m³). 2 An increase, here >5 mL / min / 1.73 m 2 This is the first report of a long-acting PTH compound causing a clinically significant change. Summarizing the data presented in Example 1 (TCP-304) and Example 2 (TCP-201), the observed increases in eGFR are as follows: 1) The effect becomes apparent during / after 26 weeks of treatment with compound 1 and is significantly elevated compared to placebo; 2) They are maintained for 104 weeks (TCP-304) and 110 weeks (TCP-201); 3) eGFR +2.13 to +3.02 mL / min / 1.73m² after 1 year of rhPTH(1-84) treatment. 2 This is significantly higher than the estimated increase [Ayodele et al., 2022, Chen et al., 2020]; 4) For the majority of subjects treated with compound 1 in TCP304 and TCP-201, ≥104 weeks, ≥5 mL / min / 1.73 m 2 Increasing; and 5) The numerical values ​​were higher in subjects with significant baseline renal impairment (stage 3a CKD or worse).

Claims

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

2. The PTH compound for use according to claim 1, wherein the PTH compound is used in the treatment of a subject having CKD.

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

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

5. A PTH compound for 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, the first assessment being before the first administration of the PTH compound and the second assessment being after the administration of one or more doses of the PTH compound.

6. The PTH compound for use according to claim 5, wherein a second evaluation is performed after administration of multiple doses.

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

8. A PTH compound for use according to any one of claims 4 to 7, wherein the amount of creatinine in the blood is measured in a blood test.

9. A PTH compound for use according to any one of claims 4 to 8, wherein the urinary albumin-creatinine ratio (UCAR) is measured in a urinalysis.

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

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

12. A PTH compound for use according to claim 10 or 11, wherein the eGFR is determined using the MDRD (Modification of Diet in Renal Disease) formula.

13. A PTH compound for use according to any one of claims 10 to 12, wherein eGFR serves as an indicator of CKD.

14. The target is <60ml / min / 1.73m 2 A PTH compound for use according to any one of claims 10 to 13, having an eGFR.

15. A PTH compound for use according to any one of claims 1 to 14, wherein the subject has hypoparathyroidism.

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

17. A PTH compound for use according to any one of claims 1, 2, or 4-16, wherein the treatment improves the target eGFR.

18. Treatment with PTH compounds is at least 5 ml / min / 1.73m 2 A PTH compound for use according to any one of claims 1, 2, or 4-17, which results in an average improvement in the eGFR of the subject.

19. Treatment with PTH compounds is at least 6 ml / min / 1.73m 2 A PTH compound for use according to any one of claims 1, 2, or 4-18, which results in an average improvement in the eGFR of the subject.

20. Treatment with PTH compounds is at least 7 ml / min / 1.73m 2 A PTH compound for use according to any one of claims 1, 2, or 4-19, which results in an average improvement in the eGFR of the subject.

21. Treatment with PTH compounds is at least 8 ml / min / 1.73m 2 A PTH compound for use according to any one of claims 1, 2, or 4-20, which results in an average improvement in the eGFR of the subject.

22. Treatment with PTH compounds is at least 9 ml / min / 1.73m 2 A PTH compound for use according to any one of claims 1, 2, or 4-21, which results in an average improvement in the eGFR of the subject.

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

24. A PTH compound for use according to any one of claims 17 to 23, wherein the mean improvement can be measured after at least 110 weeks of treatment with the PTH compound.

25. A PTH compound for use according to any one of claims 1 to 24, wherein the PTH compound is administered multiple times.

26. A PTH compound for use according to any one of claims 1, 2, or 4-25, wherein treatment begins at the time of diagnosis of CKD.

27. A PTH compound for use according to any one of claims 1, 2, or 4-26, wherein the treatment is continued for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, until medically instructed, or until the end of the subject's life.

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

29. A PTH compound for use according to any one of claims 1 to 27, wherein the PTH compound is administered weekly.

30. A PTH compound for use according to any one of claims 1 to 29, wherein a single dose of the PTH compound results in receptor signaling that is at least 10 times longer than a single equimolar dose of PTH 1-84.

31. A PTH compound for use according to any one of claims 1 to 30, wherein a single dose of the PTH compound results in receptor signaling that is at least 15 times longer than a single equimolar dose of PTH 1-84.

32. A PTH compound for use according to any one of claims 1 to 31, wherein a single dose of the PTH compound results in receptor signaling that is at least 20 times longer than a single equimolar dose of PTH 1-84.

33. PTH compounds are compounds of formula (XI). 【Chemistry 1】 [In the formula, The unmarked dashed lines indicate the bond of the N-terminal amine group of the PTH portion of sequence number 51 to the nitrogen. The dashed line with an asterisk indicates a part 【Chemistry 2】 (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, m and p are independent integers between 150 and 1000, for example between 150 and 600, for example between 200 and 550, for example between 400 and 500, or for example between approximately 450 and approximately 500. [Shows a connection to] A PTH compound for use according to any one of claims 1 to 32.

34. PTH compounds are compounds of formula (XII'). 【Transformation 3】 (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No.

51. (Each n is an independent integer between approximately 200 and 250.) A PTH compound for use according to any one of claims 1 to 32.

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

122.

36. PTH compounds are compounds of formula (XIV). k(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)-OH (XIV) (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, miniPEG is COCH 2 OCH 2 CH 2 OCH 2 CH 2 It is NH, COC 16 H 32 CO 2 H is a C18 diacid, (N-Me)G is sarcosine, K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. A PTH compound for use according to any one of claims 1 to 32.

37. PTH compounds are compounds of formula (XIV'). k(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)-OH (XIV') (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, (miniPEG) 2 COCH 2 OCH 2 CH 2 OCH 2 CH 2 It is NH, COC 16 H 32 CO 2 H is a C18 diacid, (N-Me)G is sarcosine, K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. A PTH compound for use according to any one of claims 1 to 32.

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

39. The method according to claim 38, wherein the method is a method for treating CKD in a subject having CKD.

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

41. The method according to claim 38 or 40, wherein the renal function of a subject with CKD is evaluated at least once by blood and / or urine tests before administration of 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 having CKD is evaluated at least twice by blood and / or urine tests, the first evaluation being before the first administration of the PTH compound and the second evaluation being after the administration of one or more doses of the PTH compound.

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

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

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

46. The method according to any one of claims 41 to 45, wherein the urinary albumin-creatinine ratio (UCAR) is measured in a urine test.

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

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

49. The method according to claim 47 or 48, wherein eGFR is determined using the MDRD (Modification of Diet in Renal Disease) formula.

50. The method according to any one of claims 47 to 49, wherein eGFR serves as an indicator of CKD.

51. The target is <60ml / min / 1.73m 2 The method according to any one of claims 47 to 50, having an eGFR of

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

53. The method according to any one of claims 38 to 52, wherein the subject has chronic hypoparathyroidism.

54. The method according to any one of claims 38, 39, or 41-53, wherein the treatment improves the target eGFR.

55. Treatment with PTH compounds is at least 5 ml / min / 1.73m 2 The method according to any one of claims 38, 39, or 41-54, which results in an average improvement in the eGFR of the subject.

56. Treatment with PTH compounds is at least 6 ml / min / 1.73m 2 The method according to any one of claims 38, 39, or 41-55, which results in an average improvement in the eGFR of the subject.

57. Treatment with PTH compounds is at least 7 ml / min / 1.73m 2 The method according to any one of claims 38, 39, or 41-56, which results in an average improvement in the eGFR of the subject.

58. Treatment with PTH compounds is at least 8 ml / min / 1.73m 2 The method according to any one of claims 38, 39, or 41-57, which results in an average improvement in the eGFR of the subject.

59. Treatment with PTH compounds is at least 9 ml / min / 1.73m 2 The method according to any one of claims 38, 39, or 41-58, which results in an average improvement in the eGFR of the subject.

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 mean improvement can be measured after at least 110 weeks of treatment with a PTH compound.

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

63. The method according to any one of claims 38, 39, or 41-62, wherein treatment begins at the time of diagnosis of CKD.

64. The method according to any one of claims 38, 39, or 41-63, wherein the treatment is continued for six months, one year, two years, three years, five years, ten years, until medically instructed, or until the end of the subject's life.

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 administered weekly.

67. The method according to any one of claims 38 to 66, wherein a single dose of a PTH compound results in receptor signaling that is at least 10 times longer than 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 a PTH compound results in receptor signaling that is at least 15 times longer than 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 a PTH compound results in receptor signaling that is at least 20 times longer than a single equimolar dose of PTH 1-84.

70. PTH compounds are compounds of formula (XI). 【Chemistry 4】 [In the formula, The unmarked dashed lines indicate the bond of the N-terminal amine group of the PTH portion of sequence number 51 to the nitrogen. The dashed line with an asterisk indicates a part 【Transformation 5】 (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z, m and p are independent integers between 150 and 1000, for example between 150 and 600, for example between 200 and 550, for example between 400 and 500, or for example between approximately 450 and approximately 500. [Shows a connection to] The method according to any one of claims 38 to 69.

71. PTH compounds are compounds of formula (XII'). 【Transformation 6】 (In the formula, The dashed line indicates the bond of the N-terminal amine group to nitrogen in the PTH moiety having the sequence of Sequence ID No.

51. (Each n is an independent integer between approximately 200 and 250.) The method according to any one of claims 38 to 69.

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

122.

73. PTH compounds are compounds of formula (XIV). k(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)-OH (XIV) (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, miniPEG is COCH 2 OCH 2 CH 2 OCH 2 CH 2 It is NH, COC 16 H 32 CO 2 H is a C18 diacid, (N-Me)G is sarcosine, K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. The method according to any one of claims 38 to 69.

74. PTH compounds are compounds of formula (XIV'). k(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG) 2 -γE-COC 16 H 32 CO 2 H)-OH (XIV') (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, (miniPEG) 2 COCH 2 OCH 2 CH 2 OCH 2 CH 2 It is NH, COC 16 H 32 CO 2 H is a C18 diacid, (N-Me)G is sarcosine, K is the l-isomer of lysine, -OH indicates that the C-terminal amino acid has a terminal carboxylic acid. The method according to any one of claims 38 to 69.

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