PTH treatment regimen containing two PTH compounds

Abstract

The present invention relates to a PTH compound for use in the treatment of chronic hypoparathyroidism, wherein the treatment comprises administering a weekly dose of the PTH compound to a patient having chronic hypoparathyroidism, and wherein prior to initiation of treatment, the patient is clinically determined to no longer be dependent on active vitamin D and calcium supplements to maintain serum levels within the normal range, and related aspects.

Description

[Technical Field]

[0001] The present invention relates to a PTH compound for use in the treatment of chronic hypoparathyroidism, wherein the treatment comprises administering a weekly dose of the PTH compound to a patient having chronic hypoparathyroidism, and wherein, prior to initiation of treatment, the patient is clinically determined to no longer be dependent on active vitamin D and calcium supplements to maintain serum levels within the normal range, and related aspects. [Background technology]

[0002] Hypoparathyroidism is a rare endocrine disorder characterized by low serum calcium and inappropriately low (insufficient) circulating parathyroid hormone (PTH) levels, most often secondary to thyroid surgery in adults. The standard treatment, also called conventional therapy, is active vitamin D and calcium supplements, which increase calcium and phosphorus absorption and serum levels at the expense of abnormally increased urinary calcium excretion.

[0003] The main complication of hypoparathyroidism is hypercalciuria, due to a lack of PTH-dependent calcium reabsorption in the distal renal tubules. Hypercalciuria is associated with an increased risk of nephrocalcinosis, nephrolithiasis, and renal failure. Furthermore, non-physiological levels of PTH can cause hypocalcemia if PTH levels are too low, and hypercalcemia if PTH levels are too high, such as with excessive doses of exogenously administered PTH. Hypocalcemia can cause symptoms such as numbness, muscle spasms, seizures, confusion, or cardiac arrest. Symptoms of hypercalcemia can include abdominal pain, bone pain, confusion, depression, weakness, kidney stones, or abnormal heart rhythms, such as cardiac arrest.

[0004] The physiological actions of PTH include releasing calcium and phosphorus from bone, retaining calcium but not phosphorus in the kidneys, and stimulating the renal production of active vitamin D (1,25(OH)2 vitamin D3), which in turn enhances intestinal calcium and phosphorus absorption. When PTH is delivered intermittently, such as by current daily or multiple daily injections of PTH 1-84 or PTH 1-34, PTH acts on bone as an anabolic agent by preferentially activating osteoblasts over osteoclasts. Because hypoparathyroidism is characterized by a state of low bone turnover and therefore already high bone density, this anabolic effect of intermittent PTH exposure may not be beneficial in patients with hypoparathyroidism. In contrast, continuous exposure to PTH may provide more normal bone turnover and restore a physiologically normal skeleton. Summary of the Invention [Problem to be solved by the invention]

[0005] Several PTH therapies are currently under development, aimed at once-daily (long-acting) or once-weekly (ultra-long-acting) administration at doses that effectively maintain serum calcium within normal levels. Titrating patients off conventional therapy and switching them to a long- or ultra-long-acting PTH compound risks over- or underdosing with PTH, which can result in hypercalcemia or hypocalcemia, respectively, with associated negative side effects. Therefore, to provide safe treatment, this titration process will likely need to be initiated with a low, safe dose of a long- or ultra-long-acting PTH compound in combination with conventional therapy, followed by multiple dose adjustments, ideally eliminating conventional therapy, until a safe and effective dose of the long- or ultra-long-acting PTH compound is identified. While this can be a safe process, it is time-consuming, and during the long titration period, patients will not benefit from truly effective replacement therapy.

[0006] Severe hypercalcemia has been reported with PTH products indicated for adjunctive therapy to active vitamin D and calcium. In a pivotal trial, three patients randomized to PTH therapy required the administration of IV fluids to correct hypercalcemia.

[0007] This titration process can take a significant amount of time, especially at weekly or longer dosing intervals, because overdosing with a PTH compound, for example weekly, can require significantly longer for the PTH to be cleared from the patient's body and therefore can result in adverse effects that last for an unacceptable period of time.

[0008] Thus, although therapy with ultra-long-acting PTH compounds appears attractive from the patient's perspective, it creates new and previously unidentified challenges for which there are currently no solutions. [Means for solving the problem]

[0009] In a first aspect, the present invention relates to a PTH compound for use in the treatment of chronic hypoparathyroidism, the treatment comprising administering a weekly dose of the PTH compound to a patient having chronic hypoparathyroidism, wherein prior to initiation of treatment, the patient is clinically determined to no longer be dependent on active vitamin D and calcium supplements to maintain serum within the normal range.

[0010] In a second aspect, the present invention relates to a method of treating a patient having chronic hypoparathyroidism, the method comprising administering to the patient a pharmaceutically effective weekly dose of a PTH compound, wherein prior to initiation of treatment, the patient is clinically determined to be no longer dependent on active vitamin D and calcium supplements to maintain serum calcium within the normal range.

[0011] In a third aspect, the present invention relates to a PTH compound for use in the manufacture of a medicament for the treatment of chronic hypoparathyroidism, wherein the medicament is administered once weekly to a patient having chronic hypoparathyroidism, and wherein prior to administration of the first dose of the medicament, it has been clinically determined that the patient is no longer dependent on active vitamin D and calcium supplements to maintain serum calcium within the normal range.

[0012] In a fourth aspect, the present invention relates to a first PTH compound and a second PTH compound for use in the treatment of chronic hypoparathyroidism, wherein the treatment comprises administering a pharmaceutically effective daily dose of the first PTH compound for a first treatment period, and then switching to administering a weekly dose of the second PTH compound for a second treatment period, wherein the switching of treatment periods occurs after it has been clinically determined that the patient is no longer dependent on active vitamin D and calcium supplements to maintain serum calcium within the normal range.

[0013] In a fifth aspect, the present invention relates to a method of treating a patient with chronic hypoparathyroidism, the method comprising administering a pharmaceutically effective daily dose of a first PTH compound for a first treatment period, and then switching to administering a pharmaceutically effective weekly dose of a second PTH compound for a second treatment period, the switching of treatment periods occurring after it has been clinically determined that the patient is no longer dependent on active vitamin D and calcium supplements to maintain serum calcium levels within the normal range.

[0014] In a sixth aspect, the present invention relates to a first PTH compound for use in the manufacture of a first medicament for the treatment of chronic hypoparathyroidism, and a second PTH compound for use in the manufacture of a second medicament for the treatment of chronic hypoparathyroidism, wherein the first medicament is administered daily to a patient with chronic hypoparathyroidism for a first treatment period, and then the patient is switched to weekly administration of the second medicament for a second treatment period, the switch in treatment period occurring after it has been clinically determined that the patient is no longer dependent on active vitamin D and calcium supplements to maintain serum calcium levels within the normal range.

[0015] In a seventh aspect, the present invention provides a first and a second PTH compound for use in a method of treating chronic hypoparathyroidism, the method comprising: (a) administering a first PTH compound to a patient having chronic hypoparathyroidism multiple times at a first mean inter-dosing interval, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains within a normal range in the absence of active vitamin D and calcium supplements; (b) using the dose determined in step (a) to determine an initial dose for a second PTH compound to be administered multiple times to the patient at a second average interval that is longer than the first average interval; and (c) administering the second PTH compound to the patient multiple times at a second mean inter-dosing interval, starting with the initial dose determined in step (b) and adjusting the dose if necessary, until the patient's serum calcium remains within the normal range in the absence of active vitamin D and calcium supplements. The present invention relates to a first and a second PTH compound comprising:

[0016] In an eighth aspect, the present invention provides a method of treating a patient with chronic hypoparathyroidism, comprising: (a) administering to the patient a first PTH compound multiple times at a first mean inter-dosing interval, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains within a normal range in the absence of active vitamin D and calcium supplements; (b) using the dose determined in step (a) to determine an initial dose for a second PTH compound to be administered multiple times to the patient at a second average interval that is longer than the first average interval; and (c) administering the second PTH compound to the patient multiple times at a second mean inter-dosing interval, starting with the initial dose determined in step (b) and adjusting the dose if necessary, until the patient's serum calcium remains within the normal range in the absence of active vitamin D and calcium supplements. The present invention relates to a method, comprising:

[0017] In a ninth aspect, the present invention provides a first PTH compound for use in the manufacture of a first medicament for the treatment of chronic hypoparathyroidism, and a second PTH compound for use in the manufacture of a second medicament for the treatment of chronic hypoparathyroidism, wherein the first medicament comprises: (a) to determine a dose for a patient with chronic hypoparathyroidism at a first mean interdose interval, adjusting the dose if necessary, at which the patient's serum calcium level remains within the normal range in the absence of active vitamin D and calcium supplements; (b) using the dose determined in step (a) to determine an initial dose for a second medicament to be administered multiple times to the patient at a second average interval that is longer than the first average interval; and administering the second medicament to the patient multiple times at a second mean inter-dose interval, starting with the initial dose determined in step (b) and adjusting the dose if necessary, until the patient's serum calcium remains within the normal range in the absence of active vitamin D and calcium supplements. The first PTH compound and the second PTH compound are contemplated.

[0018] In a tenth aspect, the present invention provides a method of treating a population of patients with chronic hypoparathyroidism, comprising: a) administering a first PTH compound to a population of patients multiple times with a first mean inter-dosing interval, and adjusting the dose if necessary to determine for each patient in the population a dose at which the patient's serum calcium level remains within the normal range in the absence of active vitamin D and calcium supplements; b) using the doses to determine an initial dose for a second PTH compound to be administered at a second mean interval longer than the first mean interval for a patient for whom a dose of a first PTH compound has been determined that results in the patient's serum calcium level being within the normal range in the absence of active vitamin D and calcium supplements; and c) administering the second PTH compound to the patient for whom the initial dose of the second PTH has been determined multiple times at a second mean inter-dosing interval, adjusting the dose if necessary, until the patient's serum calcium remains within the normal range in the absence of active vitamin D and calcium supplements. The present invention relates to a method, comprising: DETAILED DESCRIPTION OF THE INVENTION

[0019] Safely initiating PTH-naive patients with chronic hypoparathyroidism on ultra-long-acting PTH therapy, such as therapy with second PTH compounds, is difficult because of the need for careful titration to prevent hypocalcemia and hypercalcemia and the inability to respond rapidly if these adverse effects occur due to the prolonged PK of such compounds.

[0020] The applicant has surprisingly found that treatment with a PTH compound, such as the first PTH compound of the present invention, results in a stabilization of PTH doses, and has identified these patients as ideal candidates for switching to a PTH compound with a longer period between two doses, such as weekly PTH therapy, since the risk of calcium excursions is lower because titration of conventional therapy is not required.

[0021] Applicant has further surprisingly discovered a safe method of treating patients with an ultra-long-acting PTH compound, such as a weekly PTH compound, that provides the benefits of adequate PTH replacement therapy from the initiation of therapy: initiating treatment with a long-acting PTH compound, such as treatment with a first PTH compound, allows for titration and discontinuation of conventional therapy while maintaining the ability to intervene rapidly if serum calcium exceeds normal levels by adjusting the dose of the long-acting PTH compound or skipping doses if serum calcium becomes too high. This provides patients with a safe method for discontinuing conventional therapy and identifying individual PTH dose needs.

[0022] Accordingly, the applicant has identified that patients with chronic hypoparathyroidism who are stable, i.e., who have a dose of PTH compound, such as the first PTH compound of the present invention, administered that allows serum calcium levels within the normal range in the absence of active vitamin D and calcium supplements, are particularly suitable for initiation of treatment with an ultra-long-acting PTH compound, e.g., a PTH compound using a weekly dosing interval.

[0023] The advantage of this treatment is that it shortens the time to reach an effective dose for ultra-long-acting PTH compounds while ensuring patient safety.

[0024] In the present invention, the following terms are used:

[0025] As used herein, the terms "within normal levels" and "within the normal range" with respect to serum calcium (sCa) refer to calcium levels typically found in subjects of a given species, sex, and age. In humans, normal serum calcium levels typically correspond to serum calcium levels ranging from 8.3 mg / dL (albumin corrected) to 10.6 mg / dL (albumin corrected). The term "albumin corrected" with respect to serum calcium levels means that the measured serum calcium level has been corrected for calcium bound to albumin according to the following formula:

[0026] Albumin-corrected serum calcium (mg / dL) = measured total Ca (mg / dL) + 0.8 (4.0 - serum albumin [g / dL]).

[0027] The term "initial dose" as used herein refers to the dose of the first PTH compound administered to a patient when first starting treatment with the first PTH compound, i.e., such a patient has not previously received a dose of the first PTH compound.It is understood that a patient may continue this initial dose for a period of time, for example, for several days, weeks, or months, or for the entire duration of treatment, or may titrate the dose up or down in response to certain events, such as the occurrence of hypocalcemia or hypercalcemia.

[0028] The term "average" as used herein refers to the simple (equally weighted) arithmetic mean, which can be obtained by summing all variables in a data set and dividing the result by the number of variables.

[0029] If hypoparathyroidism persists for at least six months, the patient is said to have "chronic hypoparathyroidism."

[0030] As used herein, the term "stable patient" refers to a patient with normal serum calcium levels, taking a PTH compound such as the first or second PTH compound, and not taking conventional therapy, i.e., active vitamin D and calcium supplements.The dose of a PTH compound such as the first or second PTH compound administered to a stable patient can be adjusted from time to time.It is understood that a stable patient can still take oral calcium of <600 mg / day, which may be required for nutritional reasons and is not considered a therapeutic amount of calcium.

[0031] As used herein, the term "active vitamin D" corresponds to 1,25-dihydroxyvitamin D, also known as calcitriol.

[0032] The term "active PTH" used herein with respect to the first and second PTH compounds refers to the PTH-containing compound released from the first or second PTH compound, respectively, if the first or second PTH compound releases a PTH-containing compound, or refers to the first and / or second PTH compound itself if the first and / or second PTH compound does not release a PTH-containing moiety.For example, the conjugates of formula (I), (Ia), (I-a'), (Ib) and (I-b') release PTH 1-34, and in this case, PTH 1-34 is the active PTH of compounds (I), (Ia), (I-a'), (Ib) and (I-b').The compound of formula (II-i) releases the compound of formula (II-ii), and therefore, the compound of formula (II-ii) is the active PTH of the compound of formula (II-ii). Similarly, the compound of formula (II-i') releases the compound of formula (II-ii'), and therefore the compound of formula (II-ii') is the active PTH of the compound of formula (II-ii). In contrast, in certain embodiments, the first PTH compound is PTH 1-34, PTH 1-84, or AZP-3601, which does not release a PTH-containing compound, and therefore the active PTH of PTH 1-34, PTH 1-84, and AZP-3601 is PTH 1-34, PTH 1-84, and AZP-3601, respectively.

[0033] As used herein, the term "PTH" refers to all PTH polypeptides, e.g., from mammalian species, particularly from humans and mammalian species, more particularly from humans and mouse species, characterized by increasing serum calcium and renal phosphorus excretion and decreasing serum phosphorus and renal calcium excretion, as well as their variants, analogs, orthologs, homologs, and derivatives and fragments thereof. The term "PTH" also refers to all PTHrP polypeptides, e.g., the polypeptide of SEQ ID NO: 121, that bind to and activate the common PTH / PTHrP1 receptor. 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, i.e., 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.

[0034] In certain embodiments, the term "PTH" refers to one of the following polypeptide sequences: SEQ ID NO: 1 (PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ SEQ ID NO: 2 (PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS SEQ ID NO: 3 (PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK SEQ ID NO: 4 (PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA SEQ ID NO: 5 (PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK SEQ ID NO: 6 (PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT SEQ ID NO: 7 (PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL SEQ ID NO: 8 (PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV SEQ ID NO: 9 (PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN SEQ ID NO: 10 (PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV

[0035] SEQ ID NO: 11 (PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD SEQ ID NO: 12 (PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA SEQ ID NO: 13 (PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK SEQ ID NO: 14 (PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD SEQ ID NO: 15 (PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA SEQ ID NO: 16 (PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE SEQ ID NO: 17 (PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG SEQ ID NO: 18 (PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL SEQ ID NO: 19 (PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS SEQ ID NO: 20 (PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK

[0036] SEQ ID NO: 21 (PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE SEQ ID NO: 22 (PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH SEQ ID NO: 23 (PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES SEQ ID NO: 24 (PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE SEQ ID NO: 25 (PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV SEQ ID NO: 26 (PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL SEQ ID NO: 27 (PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV SEQ ID NO: 28 (PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN SEQ ID NO: 29 (PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED SEQ ID NO: 30 (PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE

[0037] SEQ ID NO: 31 (PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK SEQ ID NO: 32 (PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK SEQ ID NO: 33 (PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR SEQ ID NO: 34 (PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP SEQ ID NO: 35 (PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR SEQ ID NO: 36 (PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ SEQ ID NO: 37 (PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS SEQ ID NO: 38 (PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG SEQ ID NO: 39 (PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA SEQ ID NO: 40 (PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD

[0038] SEQ ID NO: 41 (PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR SEQ ID NO: 42 (PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP SEQ ID NO: 43 (PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA SEQ ID NO: 44 (PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL SEQ ID NO: 45 (PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP SEQ ID NO: 46 (PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA SEQ ID NO: 47 (PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG SEQ ID NO: 48 (PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL SEQ ID NO: 49 (PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA SEQ ID NO: 50 (PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV

[0039] SEQ ID NO: 51 (PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF SEQ ID NO: 52 (PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN SEQ ID NO: 53 (PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH SEQ ID NO: 54 (PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV SEQ ID NO: 55 (PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD SEQ ID NO: 56 (PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ SEQ ID NO: 57 (PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL SEQ ID NO: 58 (PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK SEQ ID NO: 59 (PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK SEQ ID NO: 60 (PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR

[0040] SEQ ID NO: 61 (amidated PTH 1-84) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ (the C-terminus in this sequence is amidated) SEQ ID NO: 62 (amidated PTH 1-83) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS (the C-terminus in this sequence is amidated) SEQ ID NO: 63 (amidated PTH 1-82) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK (the C-terminus in this sequence is amidated) SEQ ID NO: 64 (amidated PTH 1-81) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA (the C-terminus in this sequence is amidated) SEQ ID NO: 65 (amidated PTH 1-80) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK (the C-terminus in this sequence is amidated) SEQ ID NO: 66 (amidated PTH 1-79) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT (the C-terminus in this sequence is amidated) SEQ ID NO: 67 (amidated PTH 1-78) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL (the C-terminus in this sequence is amidated) SEQ ID NO: 68 (amidated PTH 1-77) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV (The C-terminus in this sequence is amidated) SEQ ID NO: 69 (amidated PTH 1-76) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN (the C-terminus in this sequence is amidated) SEQ ID NO: 70 (amidated PTH 1-75) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV (the C-terminus in this sequence is amidated)

[0041] SEQ ID NO: 71 (amidated PTH 1-74) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD (the C-terminus in this sequence is amidated) SEQ ID NO: 72 (amidated PTH 1-73) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA (the C-terminus in this sequence is amidated) SEQ ID NO: 73 (amidated PTH 1-72) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK (the C-terminus in this sequence is amidated) SEQ ID NO: 74 (amidated PTH 1-71) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD (the C-terminus in this sequence is amidated) SEQ ID NO: 75 (amidated PTH 1-70) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA (the C-terminus in this sequence is amidated) SEQ ID NO: 76 (amidated PTH 1-69) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE (the C-terminus in this sequence is amidated) SEQ ID NO: 77 (amidated PTH 1-68) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG (the C-terminus in this sequence is amidated) SEQ ID NO: 78 (amidated PTH 1-67) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL (the C-terminus in this sequence is amidated) SEQ ID NO: 79 (amidated PTH 1-66) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS (the C-terminus in this sequence is amidated) SEQ ID NO: 80 (amidated PTH 1-65) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK (the C-terminus in this sequence is amidated)

[0042] SEQ ID NO: 81 (amidated PTH 1-64) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE (the C-terminus in this sequence is amidated) SEQ ID NO: 82 (amidated PTH 1-63) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH (the C-terminus in this sequence is amidated) SEQ ID NO: 83 (amidated PTH 1-62) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES (the C-terminus in this sequence is amidated) SEQ ID NO: 84 (amidated PTH 1-61) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE (the C-terminus in this sequence is amidated) SEQ ID NO: 85 (amidated PTH 1-60) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV (the C-terminus in this sequence is amidated) SEQ ID NO: 86 (amidated PTH 1-59) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL (the C-terminus in this sequence is amidated) SEQ ID NO: 87 (amidated PTH 1-58) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV (The C-terminus in this sequence is amidated) SEQ ID NO: 88 (amidated PTH 1-57) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN (the C-terminus in this sequence is amidated) SEQ ID NO: 89 (amidated PTH 1-56) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED (the C-terminus in this sequence is amidated) SEQ ID NO: 90 (amidated PTH 1-55) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE (the C-terminus in this sequence is amidated)

[0043] SEQ ID NO: 91 (amidated PTH 1-54) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK (the C-terminus in this sequence is amidated) SEQ ID NO: 92 (amidated PTH 1-53) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK (the C-terminus in this sequence is amidated) SEQ ID NO: 93 (amidated PTH 1-52) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR (the C-terminus in this sequence is amidated) SEQ ID NO: 94 (amidated PTH 1-51) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP (the C-terminus in this sequence is amidated) SEQ ID NO: 95 (amidated PTH 1-50) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR (the C-terminus in this sequence is amidated) SEQ ID NO: 96 (amidated PTH 1-49) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ (the C-terminus in this sequence is amidated) SEQ ID NO: 97 (amidated PTH 1-48) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS (the C-terminus in this sequence is amidated) SEQ ID NO: 98 (amidated PTH 1-47) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG (the C-terminus in this sequence is amidated) SEQ ID NO: 99 (amidated PTH 1-46) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA (the C-terminus in this sequence is amidated) SEQ ID NO: 100 (amidated PTH 1-45) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD (the C-terminus in this sequence is amidated)

[0044] SEQ ID NO: 101 (amidated PTH 1-44) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR (the C-terminus in this sequence is amidated) SEQ ID NO: 102 (amidated PTH 1-43) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP (the C-terminus in this sequence is amidated) SEQ ID NO: 103 (amidated PTH 1-42) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA (the C-terminus in this sequence is amidated) SEQ ID NO: 104 (amidated PTH 1-41) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL (the C-terminus in this sequence is amidated) SEQ ID NO: 105 (amidated PTH 1-40) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP (the C-terminus in this sequence is amidated) SEQ ID NO: 106 (amidated PTH 1-39) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA (the C-terminus in this sequence is amidated) SEQ ID NO: 107 (amidated PTH 1-38) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG (the C-terminus in this sequence is amidated) SEQ ID NO: 108 (amidated PTH 1-37) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL (the C-terminus in this sequence is amidated) SEQ ID NO: 109 (amidated PTH 1-36) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA (the C-terminus in this sequence is amidated) SEQ ID NO: 110 (amidated PTH 1-35) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV (the C-terminus in this sequence is amidated)

[0045] SEQ ID NO: 111 (amidated PTH 1-34) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF (the C-terminus in this sequence is amidated) SEQ ID NO: 112 (amidated PTH 1-33) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN (the C-terminus in this sequence is amidated) SEQ ID NO: 113 (amidated PTH 1-32) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH (the C-terminus in this sequence is amidated) SEQ ID NO: 114 (amidated PTH 1-31) SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV (the C-terminus in this sequence is amidated) SEQ ID NO: 115 (amidated PTH 1-30) SVSEIQLMHNLGKHLNSMERVEWLRKKLQD (the C-terminus in this sequence is amidated) SEQ ID NO: 116 (amidated PTH 1-29) SVSEIQLMHNLGKHLNSMERVEWLRKKLQ (the C-terminus in this sequence is amidated) SEQ ID NO: 117 (amidated PTH 1-28) SVSEIQLMHNLGKHLNSMERVEWLRKKL (the C-terminus in this sequence is amidated) SEQ ID NO: 118 (amidated PTH 1-27) SVSEIQLMHNLGKHLNSMERVEWLRKK (the C-terminus in this sequence is amidated) SEQ ID NO: 119 (amidated PTH 1-26) SVSEIQLMHNLGKHLNSMERVEWLRK (the C-terminus in this sequence is amidated) SEQ ID NO: 120 (amidated PTH 1-25) SVSEIQLMHNLGKHLNSMERVEWLR (the C-terminus in this sequence is amidated)

[0046] SEQ ID NO: 121 (PTHrP) AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH and sequences having at least 90%, such as at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% homology thereto.

[0047] The terms "PTH molecule" and "PTH moiety" include poly(amino acid) conjugates having the above sequences but having a backbone containing both amide and non-amide bonds, e.g., ester bonds, such as depsipeptides. A depsipeptide is a chain of amino acid residues whose backbone contains both amide (peptide) and ester bonds. Thus, the term "side chain" as used herein refers to the moiety attached to the alpha-carbon of an amino acid moiety, e.g., in proteins and peptides where the amino acid moieties are attached via amine bonds, or any carbon atom-containing moiety attached to the backbone of a poly(amino acid) conjugate, e.g., as in depsipeptides. In certain embodiments, the term "PTH" refers to a sequence having a backbone formed by amide (peptide) bonds.

[0048] As used herein, the term "long-acting PTH compound" refers to a compound containing a PTH molecule or PTH moiety that can maintain a PD response, such as an increase in serum calcium levels, for at least 24 hours after administration. As used herein, the term "ultra-long-acting PTH compound" refers to a compound containing a PTH molecule or PTH moiety that can maintain a PD response, such as an increase in serum calcium levels, for at least one week after administration.

[0049] As used herein, the term "sustained-release PTH compound" or "controlled-release PTH compound" refers to any compound, conjugate, crystal, or mixture that contains at least one PTH molecule or PTH moiety from which said at least one PTH molecule or PTH moiety is released with a release half-life of at least 12 hours.

[0050] As used herein, the terms "release half-life" and "half-life" refer to the time required for half of all PTH molecules or PTH moieties, respectively, of a sustained-release PTH compound or PTH prodrug to be released under physiological conditions (i.e., aqueous buffer, pH 7.4, 37°C).

[0051] The term "peptide" as used herein refers to a chain of at least two and up to 50 amino acid monomer moieties linked by peptide (amide) bonds, which may also be referred to as "amino acid residues." The amino acid monomers may be selected from the group consisting of proteinogenic and non-proteinogenic amino acids and may be D- or L-amino acids. The term "peptide" also includes peptidomimetics, such as peptoids, beta-peptides, cyclic peptides, and depsipeptides, and encompasses such peptidomimetic chains having up to 50 monomer moieties. The term "protein" as used herein refers to a chain of more than 50 amino acid monomer moieties linked by peptide bonds, preferably having up to 12,000 amino acid monomers, e.g., up to 10,000 amino acid monomer moieties, up to 8,000 amino acid monomer moieties, up to 5,000 amino acid monomer moieties, or up to 2,000 amino acid monomer moieties linked by peptide bonds, which may also be referred to as "amino acid residues." For simplicity, PTH moieties and PTH molecules generally are referred to herein as "proteins."

[0052] As used herein, the term "physiological conditions" refers to an aqueous buffer solution at 37°C and pH 7.4.

[0053] The term "pharmaceutical composition" as used herein refers to a composition that comprises one or more active ingredients, such as at least one PTH compound, and one or more excipients, as well as any product that results directly or indirectly from the combination, complexation or aggregation of any two or more of the components of said composition, or from the dissociation of one or more of said components, or from other types of reaction or interaction of one or more of said components.Therefore, the pharmaceutical composition for use in the present invention encompasses any composition that is produced by mixing one or more PTH compounds with pharmaceutically acceptable excipients.

[0054] As used herein, the term "excipient" refers to a diluent, adjuvant, or vehicle with which a therapeutic agent, e.g., a drug or prodrug, is administered. Such pharmaceutical excipients can be sterile liquids, such as water and oils (such as those of petroleum, animal, vegetable, or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, etc.). Water is an example of an excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose solutions are examples of excipients when the pharmaceutical composition is administered intravenously. Saline solutions, as well as aqueous dextrose and glycerol solutions, are used as liquid excipients for injectable solutions in certain embodiments. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene glycol, water, ethanol, etc. The pharmaceutical compositions, if desired, may also contain minor 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 pharmaceutical compositions may be formulated as suppositories with traditional binders and excipients, such as triglycerides. Oral formulations may contain standard excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions will contain a therapeutically effective amount of the drug or biologically active moiety, together with an appropriate amount of excipient to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0055] 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.

[0056] The term "suspension composition" relates to a mixture comprising at least one water-insoluble PTH compound and one or more solvents, such as water.

[0057] As used herein, the term "dry composition" means that the pharmaceutical composition is provided in a dry form. Suitable drying methods are spray drying and lyophilization, i.e., freeze-drying. Such dry compositions have a residual moisture content of up to 10%, e.g., less than 5% or less than 2%, as determined by Karl Fischer. In certain embodiments, such dry pharmaceutical compositions are dried by lyophilization.

[0058] As used herein, the term "drug" refers to a substance, e.g., PTH, used in the treatment, cure, prevention, or diagnosis of disease or otherwise used to enhance physical or mental well-being. When a drug is conjugated to another moiety, the portion of the resulting product that is derived from the drug is called a "drug moiety."

[0059] The term "prodrug" as used herein refers to a covalent conjugate in which a drug moiety is reversibly and covalently bound 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, where the special protecting group alters or eliminates undesirable properties in the parent molecule. This includes enhancing desirable properties and suppressing undesirable properties in the drug. The special non-toxic protecting group is called a "carrier." A prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate comprising 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 direct or via a spacer. Such conjugates release the previously conjugated drug moiety in the form of free, unmodified drug.

[0060] A "reversible bond" is a bond that is degradable, i.e., cleavable, in the absence of enzymes under physiological conditions (aqueous buffer solution at pH 7.4, at 37°C) with a half-life of 1 hour to 3 months, in certain embodiments, 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, and in certain embodiments, 12 hours to 1 week. Thus, a stable bond is a bond that has a half-life of greater than 3 months in the absence of enzymes under physiological conditions (aqueous buffer solution at pH 7.4, at 37°C).

[0061] As used herein, the term "traceless prodrug linker" or "traceless linker" refers to a reversible prodrug linker, i.e., a linker moiety that reversibly and covalently attaches the drug moiety to the carrier, that is cleaved to release the drug in its free form. As used herein, the term "free form" drug refers to the drug in its unmodified, pharmacologically active form.

[0062] As used herein, the term "reagent" means a compound that contains at least one functional group for reaction with a functional group of another compound or drug. It is understood that drugs that contain functional groups such as primary or secondary amine or hydroxyl functions are also reagents.

[0063] 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 the 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 moiety. Thus, the drug moiety is released from the prodrug as the drug.

[0064] Where a chemical structure of a group of atoms is provided that is attached to or interrupted by at least one other moiety, unless expressly stated otherwise, it is understood that the chemical structure may be attached to the at least one further or interrupted moiety in either orientation. For example, the moiety "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 )C(O)-" may be attached to two moieties or may be interrupted by one moiety.

[0065] [ka] teeth,

[0066] [ka] as, or

[0067] [ka] It may be joined into two parts or may be interrupted into one part as such.

[0068] As used herein, the term "functional group" refers to an atomic group capable of reacting with another atomic group, including, but not limited to, carboxylic acids, primary or secondary amines, maleimides, thiols, sulfonic acids, carbonates, carbamates, hydroxyls, aldehydes, ketones, hydrazines, isocyanates, isothiocyanates, phosphates, phosphonates, haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfates, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziridines.

[0069] When a PTH compound contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically acceptable salts. Thus, PTH compounds containing acidic groups can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More specific 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. PTH compounds containing one or more basic groups, i.e., groups that can be protonated, may exist, and such PTH compounds can be used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, 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 are known to those skilled in the art, such as alkylation of amine groups to produce positively charged ammonium groups and suitable counterions for their salts. When PTH compounds contain both acidic and basic groups, the present invention also includes internal salts or betaines (zwitterions) in addition to the above salt forms. The respective salts can be obtained by conventional methods known to those skilled in the art, such as, for example, by contacting these compounds with organic or inorganic acids or bases in a solvent or dispersion, or by anion or cation exchange with other salts. The present invention also includes all salts of the above-mentioned compounds which are not suitable for direct use in pharmaceuticals due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0070] The term "pharmaceutically acceptable" means a substance that is not harmful when administered to a patient, and in certain embodiments, is approved for use in animals, and in particular for use in humans, by a regulatory body, e.g., the EMA (Europe) and / or the FDA (USA) and / or any other national regulatory body.

[0071] As used herein, the term "about" or "approximately" in conjunction with a numerical value refers to the numerical value itself, as well as to 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., 180 to 220, in certain embodiments, a range of 200 + / - 8%, i.e., 184 to 216, in certain embodiments, a range of 200 + / - 5%, i.e., 190 to 210, and in certain embodiments, a range of 200 + / - 2%, i.e., 196 to 204. It is understood that a percentage indicated as "about 20%" or "approximately 20%" does not mean "20% + / - 10%", i.e., a range of 10-30%, but rather "about 20%" or "approximately 20%" means 18-22%, i.e., a range of plus / minus 10% of the number 20.

[0072] As used herein, the term "polymer" refers to a molecule comprising repeating structural units, i.e., monomers, linked by linear, cyclic, branched, cross-linked, or dendrimeric chemical bonds, or a combination thereof, and may be of synthetic or biological origin, or a combination of both. It is understood that a polymer may also comprise one or more other chemical groups and / or moieties, such as, for example, one or more functional groups. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, e.g., at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, in certain embodiments, the polymer has a molecular weight of at most 1000 kDa, e.g., at most 750 kDa, e.g., at most 500 kDa, e.g., at most 300 kDa, e.g., at most 200 kDa, or e.g., at most 100 kDa. It is understood that for water-insoluble polymers, such as hydrogels, no meaningful molecular weight range can be provided. A peptide or protein is also understood to be a polymer in which amino acids are repeating structural units, even though the side chain of each amino acid may be different.

[0073] As used herein, the term "polymeric" refers to an agent or moiety that includes one or more polymers or polymeric moieties. A polymeric agent or moiety may optionally also include 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:

[0074] [ka] (In the formula, The dashed line indicates the attachment of the moiety or reagent to the remainder; -R and -R a are each 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).

[0075] Those skilled in the art will understand that the polymerization products resulting from a polymerization reaction will not all have the same molecular weight, but rather will exhibit a distribution of molecular weights. Thus, as used herein, molecular weight range, molecular weight, range of the number of monomers in a polymer, and number of monomers in a polymer refer to the number average molecular weight and number average monomer, i.e., the arithmetic mean of the molecular weight of the polymer or polymer portion, and the arithmetic mean of the number of monomers in the polymer or polymer portion.

[0076] Thus, in a polymer segment comprising "x" monomer units, any integer designated as "x" thus corresponds to the arithmetic average number of monomers. Any range of integers designated as "x" provides a range of integers within which the arithmetic average number of monomers lies. An integer "x" designated as "about x" means that the arithmetic average number of monomers lies within the integer range of x + / - 10%, in certain embodiments x + / - 8%, in certain embodiments x + / - 5%, and in certain embodiments x + / - 2%.

[0077] As used herein, the term "number average molecular weight" refers to the ordinary arithmetic mean of the molecular weights of the individual polymers.

[0078] The term "water-soluble" as used herein with respect to a PTH compound means that at least 1 g of the PTH compound can be dissolved in 1 liter of water at 20° C. to form a homogeneous solution. Accordingly, the term "water-insoluble" with respect to a PTH compound means that less than 1 g of the PTH compound can be dissolved in 1 liter of water at 20° C. to form a homogeneous solution.

[0079] The term "PEG-based" as used herein with respect to a moiety or reagent means that the moiety or reagent comprises PEG. In certain embodiments, the PEG-based moiety or reagent comprises at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, for example at least 30% (w / w) PEG, for example at least 40% (w / w) PEG, such as at least 50% (w / w), for example at least 60% (w / w) PEG, for example at least 70% (w / w) PEG, for example at least 80% (w / w) PEG, for example at least 90% (w / w), such as at least 95%. The remaining weight percentage of the PEG-based moiety or reagent is, in certain embodiments, other moieties selected from the following moieties and linkages: -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:

[0080] [ka] (In the formula, The dashed line indicates the attachment of the moiety or reagent to the remainder; -R and -R aare each 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).

[0081] As used herein, the term "substituted" means that one or more -H atoms of a molecule or moiety are replaced with a different atom or group of atoms, which are referred to as "substituents."

[0082] In certain embodiments, one or more further optional substituents are, independently of each other, halogen, —CN, —COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)R 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 alkynyl, wherein -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R x2 optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl 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 )-, optionally interrupted by one or more groups selected from the group consisting of -R x1 , -R x1a , -R x1b are independent of each other, -H, -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 alkynyl, wherein -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R x2 optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl 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 )-, optionally interrupted by one or more groups selected from the group consisting of Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; and each T 0 may independently be the same or different one or more -R x2 and optionally substituted with Each-R x2 are 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)R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4)C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 alkyl, C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R x3 , -R x3a , -R x4 , -R x4a , -R x4b are independently -H and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0083] In certain embodiments, one or more further optional substituents are, independently of each other, halogen, —CN, —COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)R 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 alkynyl, wherein -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl may be one or more -R x2 optionally substituted with C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl 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 )-, optionally interrupted by one or more groups selected from the group consisting of Each-R x1 , -R x1a , -R x1b , -R x3 , -R x3a are independently -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, wherein each T 0 may independently be the same or different one or more -R x2 and optionally substituted with Each-R x2 are 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)R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 alkyl, C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R x4 , -R x4a , -R x4b are independently -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0084] In certain embodiments, one or more further optional substituents are, independently of each other, halogen, —CN, —COOR x1 , -OR x1 , -C(O)R x1, -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)R 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 alkynyl, wherein -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl may be one or more -R x2 optionally substituted with C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl 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 )-, optionally interrupted by one or more groups selected from the group consisting of Each-R x1 , -R x1a , -R x1b , -R x2 , -R x3 , -R x3a are independently -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, Each T 0 are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, wherein each T 0 may independently be the same or different one or more -R x2 is optionally replaced by

[0085] In certain embodiments, up to six -H atoms of an optionally substituted molecule are independently substituted by substituents, e.g., 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 substituted by a substituent.

[0086] The term "interposed" means that the moiety is inserted between two carbon atoms, or, if the insertion is at one of the termini of the moiety, between a carbon or heteroatom and a hydrogen atom, in certain embodiments, between a carbon and a hydrogen atom.

[0087] As used herein, the term "C 1-4"Alkyl," alone or in combination, means a straight or branched chain alkyl moiety having 1 to 4 carbon atoms. When present at the terminal end of a molecule, it is 1-4 Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 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 of an alkyl carbon may be optionally substituted with a substituent as defined above. 1-4 The alkyl may be interrupted by one or more moieties as defined below.

[0088] As used herein, the term "C 1-6 "Alkyl," alone or in combination, means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. When present at the terminal end of a molecule, straight-chain and branched C 1-6 Examples of alkyl groups are 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. 1-6 When bonded by an alkyl group, such as 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 the carbon may be optionally substituted with a substituent as defined above. 1-6 The alkyl may be interrupted by one or more moieties as defined below.

[0089] Therefore, "C 1-10Alkyl," "C 1-20 Alkyl" or "C 1-50 "Alkyl" means 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 the carbon may be optionally substituted with a substituent as defined above. 1-10 or C 1-50 The alkyl may be interrupted by one or more moieties as defined below.

[0090] As used herein, the term "C 2-6 "Alkenyl," alone or in combination, means a straight or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having 2 to 6 carbon atoms. When present at the end of the molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. When two portions of the molecule are C 2-6 When bonded by an alkenyl group, such C 2-6 An example of an alkenyl is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl moiety may be optionally substituted with a substituent as defined above. 2-6 The alkenyl may be interrupted by one or more moieties as defined below.

[0091] Hence the term "C 2-10 alkenyl," "C 2-20 alkenyl" or "C 2-50 The term "alkenyl," alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may be optionally substituted with a substituent as defined above. 2-10 Alkenyl, C 2-20 Alkenyl or C2-50 The alkenyl may be interrupted by one or more moieties as defined below.

[0092] As used herein, the term "C 2-6 "Alkynyl," alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 6 carbon atoms. When present at the end of the molecule, examples are -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of the molecule are joined by an alkynyl group, an example is -C≡C-. C 2-6 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 The alkynyl may be interrupted by one or more moieties as defined below.

[0093] Therefore, the term "C" as used herein 2-10 alkynyl", "C 2-20 alkynyl" and "C 2-50 The term "alkynyl," alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 Alkynyl, C 2-20 Alkynyl or C 2-50 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 Alkynyl, C 2-20 Alkynyl or C 2-50 The alkynyl may be interrupted by one or more moieties as defined below.

[0094] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C2-6 Alkenyl, C 2-10 Alkenyl, C 2-20 Alkenyl, C 2-50 Alkenyl, C 2-6 Alkynyl, C 2-10 Alkynyl, C 2-20 Alkenyl or C 2-50 Alkynyl can be optionally interrupted by one or more moieties, which in certain embodiments can be

[0095] [ka] (In the formula, The dashed line indicates the attachment of the moiety or reagent to the remainder; -R and -R a are each 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. is selected from the group consisting of:

[0096] As used herein, the term "C 3-10 "Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be optionally substituted with a substituent as defined above. 3-10 "Cycloalkyl" also includes bridged bicycles such as norbornane or norbornene.

[0097] The term "8- to 30-membered carbopolycyclyl" or "8- to 30-membered carbopolycycle" refers to a cyclic moiety of two or more rings (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic) having 8 to 30 ring atoms, in which two adjacent rings share at least one ring atom and may contain up to a maximum number of double bonds. In certain embodiments, an 8- to 30-membered carbopolycyclyl refers to a cyclic moiety of 2, 3, 4, or 5 rings, and in certain embodiments, 2, 3, or 4 rings.

[0098] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" refers to a ring (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic) having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, which may contain up to a maximum number of double bonds, in which at least one ring atom, and up to four ring atoms, is replaced with a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is attached to the remainder of the molecule via a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxirene, thiylene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazol, thiazoline, thiadiazole, thiadiazoline, and tetrahydrofuran. , tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine, and homopiperazine. Each hydrogen atom of the 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be substituted with a substituent defined below.

[0099] As used herein, the term "8- to 11-membered heterobicyclyl" or "8- to 11-membered heterobicycle" refers to a bicyclic heterocyclic moiety (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings) having 8 to 11 ring atoms, in which at least one ring atom is shared by both rings and may contain up to the maximum number of double bonds, in which at least one ring atom, and up to six ring atoms, is replaced with a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule through a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicycle also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or an 8- to 11-membered heterobicycle carbon may be substituted with a substituent as defined below.

[0100] Similarly, the term "8-30 membered heteropolycyclyl" or "8-30 membered heteropolycycle" refers to a heterocyclic moiety (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings) having more than two rings, and in certain embodiments, three, four, or five rings, having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom and may contain up to a maximum of double bonds, and where at least one ring atom, and up to ten ring atoms, is replaced with a heteroatom selected from the group of sulfur (including -S(O)- and -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule via a carbon or nitrogen atom.

[0101] structure

[0102] [ka] Regarding the part, "Pair R x / R y together with the atoms to which they are attached, C 3-10 The phrase "forms a cycloalkyl or 3- to 10-membered heterocyclyl" refers to R x and R y is understood to mean forming the following structure:

[0103] [ka] (Wherein R is C 3-10 cycloalkyl or 3-10 membered heterocyclyl).

[0104] structure

[0105] [ka] Regarding the part, "Pair R x / R y together with the atoms to which they are attached form a ring A" is x and R yis also understood to mean forming the following structure:

[0106] [ka]

[0107] As used herein, "halogen" means fluoro, chloro, bromo, or iodo. In certain embodiments, halogen is fluoro or chloro.

[0108] In general, the terms "comprise" or "comprising" also encompass "consist of" or "consisting of."

[0109] The patients of the first, second, and third aspects are stable patients. Such stable patients may be treated with a first PTH compound, for example, a first PTH compound administered once every 8 hours, once every 12 hours, or once daily, before starting treatment with the weekly PTH compound, where the first PTH compound is different from the weekly-administered PTH compound, which may also be referred to as the "weekly PTH compound." Specific embodiments of the first, second, and third aspects are as described elsewhere herein. Specific embodiments of the weekly PTH compound are as described for the second PTH compound.

[0110] Unless otherwise stated, the following sections apply to all aspects of the invention.

[0111] In certain embodiments, the chronic hypoparathyroidism is due to surgery, e.g., thyroid or parathyroid surgery, genetic causes, immune system-related damage to the parathyroid glands, or is idiopathic. In certain embodiments, the chronic hypoparathyroidism is due to surgery. In certain embodiments, the chronic hypoparathyroidism is due to thyroid surgery. In certain embodiments, the chronic hypoparathyroidism is due to parathyroid surgery. In certain embodiments, the chronic hypoparathyroidism is due to genetic causes. In certain embodiments, the chronic hypoparathyroidism is due to autosomal dominant hypocalcemia type I. In certain embodiments, the chronic hypoparathyroidism is due to immune-related damage to the parathyroid glands. In certain embodiments, the chronic hypoparathyroidism is idiopathic.

[0112] In certain embodiments, the patient is a mammalian patient. In certain embodiments, the patient is a human patient, e.g., an adult or pediatric patient. In certain embodiments, the patient has chronic hypoparathyroidism due to surgery, genetic causes, immune system-related damage to the parathyroid glands, or the hypoparathyroidism is idiopathic. In certain embodiments, the patient has chronic hypoparathyroidism due to surgery. In certain embodiments, the patient has chronic hypoparathyroidism due to thyroid surgery. In certain embodiments, the patient has chronic hypoparathyroidism due to parathyroid surgery. In certain embodiments, the patient has chronic hypoparathyroidism due to genetic causes. In certain embodiments, the patient has chronic hypoparathyroidism due to autosomal dominant hypocalcemia type I. In certain embodiments, the patient has chronic hypoparathyroidism due to immune system-related damage to the parathyroid glands. In certain embodiments, the patient has idiopathic chronic hypoparathyroidism.

[0113] In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to surgery, genetic causes, immune system-related damage to the parathyroid glands, or the hypoparathyroidism is idiopathic. In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to surgery. In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to thyroid surgery. In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to parathyroid surgery. In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to genetic causes. In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to autosomal dominant hypocalcemia type I. In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to immune system-related damage to the parathyroid glands. In certain embodiments, the patient is an adult patient with idiopathic chronic hypoparathyroidism.

[0114] In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to surgery, genetic causes, immune system-related damage to the parathyroid glands, or the hypoparathyroidism is idiopathic. In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to surgery. In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to thyroid surgery. In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to parathyroid surgery. In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to genetic causes. In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to autosomal dominant hypocalcemia type I. In certain embodiments, the patient is a pediatric human patient with chronic hypoparathyroidism due to immune system-related damage to the parathyroid glands. In certain embodiments, the patient is a pediatric human patient with idiopathic chronic hypoparathyroidism.

[0115] In certain embodiments, the patient is managed with conventional therapy, ie, active vitamin D and calcium supplements, prior to initiating treatment with the first PTH compound.

[0116] In certain embodiments, the patient receives an active vitamin D and calcium supplement prior to step (a).

[0117] Once treatment with the first PTH compound is initiated, the dose of active vitamin D and calcium supplement administered to the patient is reduced until the administration of active vitamin D and calcium is completely eliminated. This reduction or elimination can be achieved by adjusting the dose of active vitamin D and / or calcium supplement one or more times. During the period when the patient titrates and stops the active vitamin D and calcium supplement, the dose of the first PTH compound may be increased or decreased one or more times. Such an increase or decrease in the dose of the first PTH compound may be performed in response to hypocalcemia or hypercalcemia, respectively.

[0118] In certain embodiments, the first PTH compound can be administered to a patient by various modes of administration, for example, via topical, enteral, or parenteral administration, or by topical, injection, or infusion methods, such as intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, or intrasternal injection and infusion, direct delivery to the brain via an implanted device (e.g., an Ommaya Reservoir) that allows delivery of the present invention or the like to brain tissue or brain fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related regions, injection into the subchoroidal space, retroorbital injection, and eye drops. In certain embodiments, the first PTH compound is administered subcutaneously, intramuscularly, or orally. In certain embodiments, the first PTH compound is administered by subcutaneous administration, for example by subcutaneous injection.

[0119] In certain embodiments, the first PTH compound is administered using a pen injector. In certain embodiments, the first PTH compound is administered using a needle and syringe. In certain embodiments, the first PTH compound is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is administered via subcutaneous injection using a needle and syringe.

[0120] In certain embodiments, the first PTH compound is the only drug containing PTH or a PTH moiety administered prior to administration of the weekly administered PTH compound of the first, second, or third embodiment, and such first PTH compound is administered using a first average interval between two consecutive administrations.

[0121] In certain embodiments, the first PTH compound is the only drug containing PTH or a PTH moiety administered to the patient during step (a).

[0122] In certain embodiments, the first average interval is between 6 hours and 1 week. In certain embodiments, the first average interval is between 6 hours and 1 day. In certain embodiments, the first average interval is approximately 8 hours. In certain embodiments, the first average interval is 8 hours. In certain embodiments, the first average interval is approximately 12 hours. In certain embodiments, the first average interval is 12 hours. In certain embodiments, the first average interval is approximately 1 day. In certain embodiments, the first average interval is 1 day. In certain embodiments, the first average interval is approximately 2 days. In certain embodiments, the first average interval is 2 days. In certain embodiments, the first average interval is approximately 3 days. In certain embodiments, the first average interval is 3 days. In certain embodiments, the first average interval is approximately 4 days. In certain embodiments, the first average interval is 4 days. In certain embodiments, the first average interval is approximately 5 days. In certain embodiments, the first average interval is 5 days. In certain embodiments, the first average interval is approximately 6 days. In certain embodiments, the first average interval is 6 days. In certain embodiments, the first average interval is approximately 1 week. In certain embodiments, the first average interval is 1 week.

[0123] In certain embodiments, the inter-dosing intervals in step (a) are of varying lengths.

[0124] In certain embodiments, all inter-dosage intervals in step (a) have the same length. When all inter-dosage intervals have the same length, the length of such interval is referred to as a "first inter-dosage interval" or, for short, "first interval."

[0125] In certain embodiments, the first interval is between 6 hours and 1 week. In certain embodiments, the first interval is between 6 hours and 1 day. In certain embodiments, the first interval is approximately 8 hours. In certain embodiments, the first interval is 8 hours. In certain embodiments, the first interval is approximately 12 hours. In certain embodiments, the first interval is 12 hours. In certain embodiments, the first interval is approximately 1 day. In certain embodiments, the first interval is 1 day. In certain embodiments, the first interval is approximately 2 days. In certain embodiments, the first interval is 2 days. In certain embodiments, the first interval is approximately 3 days. In certain embodiments, the first interval is 3 days. In certain embodiments, the first interval is approximately 4 days. In certain embodiments, the first interval is 4 days. In certain embodiments, the first interval is approximately 5 days. In certain embodiments, the first interval is 5 days. In certain embodiments, the first interval is approximately 6 days. In certain embodiments, the first interval is 6 days. In certain embodiments, the first interval is approximately 1 week. In certain embodiments, the first interval is 1 week.

[0126] The first PTH compound is administered to the patient multiple times in step (a), and the period from the first to the last administration of the first PTH compound in step (a) is referred to as the "first treatment period." In certain embodiments, such a first treatment period lasts for a period of 1 week to 20 years. In certain embodiments, the first treatment period lasts for a period of 1 week to 10 years. In certain embodiments, the first treatment period lasts for a period of 2 weeks to 5 years. In certain embodiments, the first treatment period lasts for a period of 2 weeks to 2 years. In certain embodiments, the first treatment period lasts for a period of 2 weeks to 1 year. In certain embodiments, the first treatment period lasts for a period of 2 weeks to 6 months. In certain embodiments, the first treatment period lasts for a period of 2 weeks to 4 months. In certain embodiments, such a first treatment period lasts for at least 1 week, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. It is understood that a patient may be treated with a first PTH compound and be a stable patient, but may not begin treatment with a second PTH compound for some time, which may be due, for example, to the unavailability or lack of reimbursement of a suitable second PTH compound in the patient's area. In certain embodiments, the first treatment period lasts at least until the patient has a serum calcium level within the normal range and has discontinued conventional therapy, i.e., active vitamin D and calcium supplements.

[0127] In certain embodiments, the patient is a stable patient without dose adjustment of the first PTH compound for at least the length of the interval between the penultimate and last administrations of the first PTH compound prior to administration of the first dose of the second PTH compound, i.e., no dose adjustments were made at least during the last interval of the first treatment period. In certain embodiments, the patient is a stable patient without dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mean inter-dosage intervals of the first treatment period prior to administration of the first dose of the second PTH compound. In certain embodiments, the patient is a stable patient without dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 intervals of the first treatment period prior to administration of the first dose of the second PTH compound. In certain embodiments, the patient is a stable patient without dose adjustments for at least one week prior to administration of the first dose of the second PTH compound. In certain embodiments, the patient is a stable patient who has not had a dose adjustment for at least one month prior to administration of the first dose of the second PTH compound. In certain embodiments, the patient is a stable patient who has not had a dose adjustment for at least one year prior to administration of the first dose of the second PTH compound.

[0128] In certain embodiments, the second average intervals of the seventh to tenth aspects are of varying lengths. In certain embodiments, the second average intervals of the seventh to tenth aspects have the same length. When all inter-dosage intervals have the same length, such interval length is referred to as the "second inter-dosage interval" or, for short, the "second interval." It is understood that the second interval of the first to sixth aspects is one week.

[0129] In certain embodiments, the second interval is between one week and two months. In certain embodiments, the second interval is between one week and one month. In certain embodiments, the second interval is about one week. In certain embodiments, the second interval is one week. In certain embodiments, the second interval is two weeks.

[0130] The second PTH compound is administered to the patient multiple times, and the period from the first to the last administration of the second PTH compound is referred to as the "second treatment period." In certain embodiments, such a second treatment period lasts from 1 week to 50 years, or until the patient dies or no longer requires the second PTH compound. In certain embodiments, the patient may switch to a different PTH compound or other form of treatment after the second treatment period.

[0131] In certain embodiments, the first and / or second PTH compounds are independently selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:6 8, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103 3, 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, to a sequence selected from the group consisting of SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122;A PTH or parathyroid hormone-related protein (PTHrP) molecule or a pharmaceutically acceptable salt thereof, comprising a sequence having at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology.

[0132] In certain embodiments, the first and / or second PTH compounds are independently selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO: 32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67 , SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102 2. A PTH or parathyroid hormone-related protein (PTHrP) molecule comprising a sequence having at least 95% homology to a sequence selected from the group consisting of SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122, or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, the first and / or second PTH compounds are independently selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO: No. 31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65 No. 65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO: SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121 and SEQ ID NO: 122, or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the first and / or second PTH compounds are independently selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:6 8, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103 3, 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, to a sequence selected from the group consisting of SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122;A fusion protein comprising at least one PTH or PTHrP molecule or a pharmaceutically acceptable salt thereof, comprising a sequence having at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology.

[0135] In certain embodiments, the first and / or second PTH compounds are independently selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID 2, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67 SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102 , SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122, or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the first and / or second PTH compounds are independently selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO: 66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, A fusion protein comprising at least one PTH or PTHrP molecule comprising a sequence selected from the group consisting of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122, or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the first and / or second PTH compound is a conjugate comprising a PTH moiety covalently conjugated to one or more additional moieties, which may independently be a polymer moiety or a fatty acid moiety. In certain embodiments, the bond between the PTH moiety and one additional moiety may be reversible. In certain embodiments, the bond between the PTH moiety and one additional moiety may be stable. In certain embodiments, such a PTH compound has one reversible bond between the PTH moiety and a first additional moiety and a stable bond between the PTH moiety and a second additional moiety.

[0138] In certain embodiments, such additional moieties are selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydrogen phosphate), poly(hydroxypropyl methacrylate ... and the polymeric moiety comprises one or more polymers selected from the group consisting of poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-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, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof. In certain embodiments, such further moieties are PEG-based moieties or hyaluronic acid-based moieties. In certain embodiments, such further moieties are PEG-based moieties. In certain embodiments, such further moieties are hyaluronic acid-based moieties.

[0139] In certain embodiments, such further moiety is a fatty acid moiety, such as those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1, which are incorporated herein by reference.

[0140] In certain embodiments, the first and / or second PTH compounds are independently a compound of formula (Ia) or (Ib):

[0141] [ka] (In the formula, each -D is independently a PTH moiety; Each-L 1 - is independently a linker moiety covalently and reversibly attached to -D; Each-L 2 - is independently a single chemical bond or a spacer moiety; each -Z is independently a carrier moiety, e.g., a fatty acid derivative or a 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. or a pharmaceutically acceptable salt thereof.

[0142] The compounds of formula (Ia) and (Ib) may also be referred to as "prodrugs." They release unmodified PTH in the form of DH.

[0143] In certain embodiments, x in Formula (Ia) is an integer of 1 to 8. In certain embodiments, x in Formula (Ia) is an integer of 1 to 6. In certain embodiments, x in Formula (Ia) is an integer of 1 to 4. In certain embodiments, x in Formula (Ia) is 1. In certain embodiments, x in Formula (Ia) is 2. In certain embodiments, x in Formula (Ia) is 3. In certain embodiments, x in Formula (Ia) is 4. In certain embodiments, x in Formula (Ia) is 5. In certain embodiments, x in Formula (Ia) is 6. In certain embodiments, x in Formula (Ia) is 7. In certain embodiments, x in Formula (Ia) is 8. In certain embodiments, x in Formula (Ia) is 9. In certain embodiments, x in Formula (Ia) is 10. In certain embodiments, x in Formula (Ia) is 11. In certain embodiments, x in Formula (Ia) is 12. In certain embodiments, x in Formula (Ia) is 13. In certain embodiments, x in Formula (Ia) is 14. In certain embodiments, x in Formula (Ia) is 15. In certain embodiments, x in Formula (Ia) is 16.

[0144] In certain embodiments, y in Formula (Ib) is 2. In certain embodiments, y in Formula (Ib) is 3. In certain embodiments, y in Formula (Ib) is 4. In certain embodiments, y in Formula (Ib) is 5. In certain embodiments, y in Formula (Ib) is 6. In certain embodiments, y in Formula (Ib) is 7. In certain embodiments, y in Formula (Ib) is 8. In certain embodiments, y in Formula (Ib) is 9. In certain embodiments, y in Formula (Ib) is 10. In certain embodiments, y in Formula (Ib) is 11. In certain embodiments, y in Formula (Ib) is 12. In certain embodiments, y in Formula (Ib) is 13. In certain embodiments, y in Formula (Ib) is 14. In certain embodiments, y in Formula (Ib) is 15. In certain embodiments, y in Formula (Ib) is 16. In certain embodiments, y in Formula (Ib) is 17. In certain embodiments, y in Formula (Ib) is 18. In certain embodiments, y in Formula (Ib) is 19. In certain embodiments, y in Formula (Ib) is 20.

[0145] In certain embodiments, the first PTH compound and / or the second PTH compound are independently a compound of formula (Ia). In certain embodiments, the first PTH compound and / or the second PTH compound are independently a compound of formula (Ia) with x=1.

[0146] -D, -L 1 -, -L 2 Specific embodiments for - and Z are as described elsewhere herein.

[0147] In certain embodiments, the first and / or second PTH compounds are independently water-insoluble compounds, which in certain embodiments are selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, and microspheres. In certain embodiments, the first and / or second PTH compounds can independently be crystals comprising at least one PTH molecule. In certain embodiments, the first and / or second PTH compounds can independently be nanoparticles comprising at least one PTH molecule. In certain embodiments, the first and / or second PTH compounds can independently be microparticles comprising at least one PTH molecule. In certain embodiments, the first and / or second PTH compounds can independently be nanospheres comprising at least one PTH compound. In certain embodiments, the first and / or second PTH compounds can independently be microspheres comprising at least one PTH compound. In certain embodiments, the first and / or second PTH compounds can independently be vesicles, such as micelles, liposomes, or polymersomes, comprising at least one PTH compound.

[0148] In certain embodiments, the first and / or second 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 are 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate). ), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-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, carbomethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof. In certain embodiments, the water-insoluble polymer is poly(lactic-co-glycolic acid) (PLGA).

[0149] In certain embodiments, the first PTH compound and / or the second PTH compound may each independently comprise one or more moieties -L 2 -L 1 -D is a conjugate comprising a carrier moiety Z' to which is conjugated, or a pharmaceutically acceptable salt thereof, wherein each -L 2 - is independently a chemical bond or a spacer moiety, and each -L 1 - is independently a linker moiety to which -D is reversibly and covalently conjugated, each -D is independently a PTH moiety, and Z' is a hydrogel. Such long-acting PTH compounds are sustained-release PTH compounds. -D, -L 1 -, -L 2 Specific embodiments for - and Z' are as described elsewhere herein.

[0150] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO: No. 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70 , SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO: 105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122,A PTH portion comprising a sequence having at least 97% homology, at least 98% homology, or at least 99% homology.

[0151] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID 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, SEQ ID NO: No. 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121 and SEQ ID NO: 122.

[0152] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO: No. 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO: SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122.

[0153] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO: 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.

[0154] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99 9, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120 and SEQ ID NO:122.

[0155] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120 and SEQ ID NO:122.

[0156] In certain embodiments, -D is a PTH moiety comprising a sequence having at least 90% homology, e.g., 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 NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, and SEQ ID NO:115.

[0157] In certain embodiments, -D is a PTH moiety comprising a sequence having 95% homology to a sequence selected from the group consisting of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 and SEQ ID NO:115.

[0158] In certain embodiments, -D is a PTH moiety comprising a sequence selected from the group consisting of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 and SEQ ID NO:115.

[0159] In certain embodiments, -D is a PTH moiety comprising a sequence having at least 90% homology, e.g., 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 NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111, and SEQ ID NO:112.

[0160] In certain embodiments, -D is a PTH moiety comprising a sequence having 95% homology to a sequence selected from the group consisting of SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 110, SEQ ID NO: 111 and SEQ ID NO: 112.

[0161] In certain embodiments, -D is selected from the group consisting of SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111 and SEQ ID NO:112.

[0162] In certain embodiments, -D has SEQ ID NO: 50. In certain embodiments, -D has SEQ ID NO: 52. In certain embodiments, -D has SEQ ID NO: 110. In certain embodiments, -D has SEQ ID NO: 111. In certain embodiments, -D has SEQ ID NO: 112.

[0163] In a particular embodiment, -D has SEQ ID NO:51.

[0164] In certain embodiments, -D has SEQ ID NO: 122: AVAEIQLMHQRAKWIQDARR RAFLHKLIAEIHTAEI

[0165] Part-L 1- is conjugated to a functional group in the side chain of an amino acid residue of -D, to the N-terminal amine functional group or the C-terminal carboxyl functional group of -D, or to a nitrogen atom in the backbone polypeptide chain of -D. The attachment to either the N-terminus or the C-terminus can be direct via the corresponding amine or carboxyl functional group, respectively, or indirect, in which case a spacer moiety is first conjugated to the amine or carboxyl functional group, and then -L is attached to this spacer moiety. 1 - is conjugated.

[0166] In certain embodiments, -L 1 The amino acid residue of -D to which - is conjugated comprises a functional group selected from the group consisting of carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphate, phosphonate, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, sulfate, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, guanidine, and aziridine. 1 The amino acid residue of -D to which - is conjugated contains a functional group selected from the group consisting of hydroxyl, primary amine, secondary amine, and guanidine. 1 The amino acid residue of -D to which - is conjugated contains a primary or secondary amine functional group. 1 The amino acid residue of -D to which - is conjugated contains a primary amine functionality.

[0167] Part-L 1 When - is conjugated to a functional group of the side chain of the amino acid residue of -D, said amino acid residue is selected from the group consisting of proteinogenic and non-proteinogenic amino acid residues. 1- is conjugated to a functional group in the side chain of a proteinogenic amino acid residue of -D. 1 - is conjugated to a functional group in the side chain of a non-proteinogenic amino acid residue of -D.

[0168] In certain embodiments, -L 1 - is conjugated to a functional group in the side chain of the proteinogenic amino acid residue of -D. In certain embodiments, the proteinogenic 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 proteinogenic amino acid is selected from the group consisting of lysine, aspartic acid, arginine, and serine. In certain embodiments, the proteinogenic 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 side chain of the histidine of -D. 1 - is conjugated to the functional group of the side chain of the lysine of -D. 1 - is conjugated to a functional group on the side chain of the tryptophan of -D. 1 - is conjugated to the functional group of the side chain of the serine of -D. 1 - is conjugated to the functional group of the side chain of the threonine of -D. 1 - is conjugated to the functional group of the side chain of the tyrosine of -D. 1 - is conjugated to the functional group of the side chain of the aspartic acid of -D. 1 - is conjugated to the functional group of the side chain of glutamic acid of -D. 1 - is conjugated to the functional group of the side chain of the arginine of -D. It is understood that not all -D moieties may include all of these amino acid residues.

[0169] In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functional group of -D through the corresponding amine functional group, or indirectly conjugated, in which case a spacer moiety is first conjugated to the amine functional group and then -L 1 In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functionality of -D. 1 - is directly conjugated to the C-terminal functional group of -D through the corresponding carboxyl functional group, or indirectly conjugated, in which case a spacer moiety is first conjugated to the carboxyl functional group, and -L is then conjugated to the spacer moiety. 1 In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functionality of -D.

[0170] Part-L 1 - can be attached to -D by any type of bond, provided that it is reversible. 1 - is attached to -D by a bond selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, and acylguanidine. 1 - is linked to -D by a bond selected from the group consisting of amide, ester, carbamate and acylguanidine. Some of these bonds are not reversible per se, however, in the present invention, -L 1 It is understood that the adjacent groups contained in -L make these bonds reversible. 1 - is linked to -D by an ester bond. In certain embodiments, -L 1 - is linked to -D by a carbamate bond. 1- is linked to -D by an acylguanidine. In certain embodiments, -L 1 - is attached to -D by an amide bond.

[0171] Part-L 1 is a reversible prodrug linker from which the drug, i.e., PTH, is released in its free form, i.e., a traceless prodrug linker. Suitable prodrug linkers are known in the art, such as the reversible prodrug linker moieties disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1, and WO 2013 / 024053 A1, which are incorporated herein by reference.

[0172] 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, which are incorporated herein by reference.

[0173] In certain embodiments, -L 1 - is disclosed in WO 2009 / 095479 A2. Thus, in certain embodiments, the moiety -L 1 - is a group represented by the formula (II):

[0174] [ka] (In the formula, The dashed line indicates the bond of -D to the 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(R5 R 5a )-C(R 4 R 4a )-, -C(R 4 R 4a )-N(R 6 )-, -N(R 6 )-C(R 4 R 4a )-, -C(R 4 R 4a )-O-, -OC(R 4 R 4a )- and -C(R 7 R 7a )-, X 1 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 )-, =X 3 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 are independently -H and C 1-6 is selected from the group consisting of alkyl, -R 3 and -R 3a are independently -H and C 1-6 alkyl, with the proviso that -R 3 , -R 3a If one or both of are other than -H, they may be attached to the N to which they are attached by SP 3 bonded by hybridized carbon atoms, -R7 is -N(R 10 R 10a ) and -NR 10 -(C=O)-R 11 is selected from the group consisting of -R 7a , -R 10 , -R 10a , and -R 11 are, independently of each other, -H and C 1-6 is selected from the group consisting of alkyl, In some cases, 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 the following forms a chemical bond; In some cases, 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 the following, together with the atoms to which they are attached, form a C 3-10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; In some cases, 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 3together with the atoms to which they are attached form ring A, In some cases, R 3 / R 3a together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring, A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl and where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (II) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0175] In certain embodiments, -L of formula (II) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0176] In certain embodiments, -L of formula (II) 1 - is not further substituted.

[0177] -R in formula (II) 3 / -R 3a However, when they are combined with the nitrogen atom to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is SP 3 It is understood that only such 3-10 membered heterocyclic rings can be formed that are hybridized carbon atoms. 3 / -R 3a Such 3-10 membered heterocycles formed by the following together with the nitrogen atom to which they are attached have the following structure:

[0178] [ka] (In the formula, The dashed line indicates -L 1 - indicates the bond to the remainder of the ring contains 3 to 10 atoms, including at least one nitrogen; R # and R ## sp 3 represents a hybridized carbon atom).

[0179] It is also understood that the above 3-10 membered heterocycles can be further substituted.

[0180] -R in formula (II) 3 / -R 3a Illustrative embodiments of suitable 3-10 membered heterocycles formed by, together with the nitrogen atom to which they are attached, are:

[0181] [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule; -R is -H and C 1-6 alkyl).

[0182] -L in formula (II) 1 - may be optionally further substituted. Generally, any substituent can be used as long as it does not affect the principle of cleavage, i.e., the hydrogen with an asterisk in formula (II) is not substituted, and the moiety of formula (II)

[0183] [ka] The nitrogen in remains part of a primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a are each independently -H or sp 3 It is bonded to -N< through a hybridized carbon atom.

[0184] In one embodiment, -R of formula (II) 1 or -R 1a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 2 or -R 2a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 3 or -R 3a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 4 -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 5 or -R 5a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 6 -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 7 or -R 7a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 8 or -R 8a -L 2 -Z or -L 2 In another embodiment, the -R of formula (II) is substituted with -Z'. 9 or -R 9a -L 2 -Z or -L 2 In another embodiment, -R 10 -L 2 -Z or -L 2 In another embodiment, -R 11 -L 2 -Z or -L 2In certain embodiments, -R of formula (II) is substituted with -Z'. 3 -L 2 -Z or -L 2 -Z' is substituted.

[0185] In certain embodiments, -X- in formula (II) is -C(R 4 R 4a )-, -N(R 4 )- and -C(R 7 R 7a In certain embodiments, -X- in formula (II) is selected from the group consisting of -C(R 4 R 4a In certain embodiments, -X- in formula (II) is -C(R 7 R 7a )-.

[0186] In certain embodiments, -R of formula (II) 7 is -NR 10 -(C=O)-R 11 is.

[0187] In certain embodiments, -R of formula (II) 7a is selected from -H, methyl, and ethyl. In certain embodiments, -R of formula (II) 7a is -H.

[0188] In certain embodiments, -R 10 is selected from -H, methyl, and ethyl. In certain embodiments, -R 10 is methyl.

[0189] In certain embodiments, -R 11 is selected from -H, methyl, and ethyl. In certain embodiments, -R 11 is -H. In certain embodiments, -R 11 -L 2 -Z or -L 2 -Z' is substituted.

[0190] In certain embodiments, -X- in formula (II) is -N(R 4 )-.

[0191] In certain embodiments, -R 4 is selected from the group consisting of -H, methyl, and ethyl. 4 is -H.

[0192] In certain embodiments, X in formula (II) 1 is C.

[0193] In certain embodiments, the =X group of formula (II) 3 is =O.

[0194] In certain embodiments, -X in formula (II) 2 - is -C(R 8 R 8a )-.

[0195] In certain embodiments, -R of formula (II) 8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (II) 8 and -R 8a In certain embodiments, at least one of -R in formula (II) is -H. 8 and -R 8a Both are -H.

[0196] In certain embodiments, -R of formula (II) 1 and -R 1a is independently selected from the group consisting of —H, methyl, and ethyl.

[0197] In certain embodiments, -R of formula (II) 1 and -R 1a In certain embodiments, at least one of -R in formula (II) is -H. 1 and -R 1a is -H.

[0198] In certain embodiments, -R of formula (II) 1 and -R 1a In certain embodiments, at least one of -R in formula (II) is methyl. 1 and -R 1a Both of the groups are methyl.

[0199] In certain embodiments, -R of formula (II) 2 and -R 2a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (II) 2 and -R 2a In certain embodiments, at least one of -R in formula (II) is -H. 2 and -R 2a Both are H.

[0200] In certain embodiments, -R of formula (II) 3 and -R 3a is independently selected from the group consisting of —H, methyl, ethyl, propyl, and butyl.

[0201] In certain embodiments, -R of formula (II) 3 and -R 3a In certain embodiments, at least one of -R in formula (II) is methyl. 3 is methyl, and -R in formula (II) 3a is -H.

[0202] In certain embodiments, -R of formula (II) 3 and -R 3a are both -H.

[0203] In certain embodiments, -D is linked to -L through the nitrogen by forming an amide bond. 1 - is bonded to.

[0204] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIa-i):

[0205] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 3a , -R 7 , -R 7a and -X 2 - is used as defined in formula (II) and -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (IIa-i) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0206] -R in formula (IIa-i) 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0207] In certain embodiments, -L of formula (IIa-i) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0208] In certain embodiments, the moiety -L of formula (IIa-i) 1 - is not further substituted.

[0209] In certain embodiments, -R of formula (IIa-i) 1 and -R 1ais independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-i) 1 and -R 1a In certain embodiments, at least one of -R in formula (IIa-i) is -H. 1 and -R 1a Both are -H.

[0210] In certain embodiments, -R of formula (IIa-i) 7 is -NR 10 -(C=O)-R 11 is.

[0211] In certain embodiments, -R of formula (II-i) 7a is selected from -H, methyl, and ethyl. In certain embodiments, -R in formula (II-i) 7a is -H.

[0212] In certain embodiments, -R of formula (IIa-i) 10 is selected from -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-i) 10 is methyl.

[0213] In certain embodiments, -R of formula (IIa-i) 11 is selected from -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-i) 11 is -H.

[0214] In certain embodiments, -R of formula (IIa-i) 11 -L 2 -Z or -L 2 -Z' is substituted.

[0215] In certain embodiments, -X in formula (IIa-i) 2 - is -C(R 8 R 8a )-.

[0216] In certain embodiments, -R of formula (IIa-i)8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-i) 8 and -R 8a In certain embodiments, at least one of -R in formula (IIa-i) is -H. 8 and -R 8a Both are -H.

[0217] In certain embodiments, R of formula (IIa-i) 2 and -R 2a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-i) 2 and -R 2a In certain embodiments, at least one of -R in formula (IIa-i) is -H. 2 and -R 2a Both are H.

[0218] In certain embodiments, -R of formula (IIa-i) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R of formula (IIa-i) 3 and -R 3a At least one of the groups is methyl.

[0219] In certain embodiments, -R of formula (IIa-i) 3 is —H, and —R in formula (IIa-i) 3a is methyl.

[0220] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIa-ii):

[0221] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; -R2 , -R 2a , -R 10 , -R 11 and -X 2 - is used as defined in formula (II) and -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (IIa-ii) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0222] -R in formula (IIa-ii) 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0223] In certain embodiments, -L of formula (IIa-ii) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0224] In certain embodiments, the moiety -L of formula (IIa-ii) 1 - is not further substituted.

[0225] In certain embodiments, -X in formula (IIa-ii) 2 - is -C(R 8 R 8a )-.

[0226] In certain embodiments, -R of formula (IIa-ii) 8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R 8 and -R 8aIn certain embodiments, at least one of -R in formula (IIa-ii) is -H. 8 and -R 8a Both are -H.

[0227] In certain embodiments, -R of formula (IIa-ii) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R 3 and -R 3a At least one of the groups is methyl.

[0228] In certain embodiments, -R of formula (IIa-ii) 3 is —H, and —R in formula (IIa-ii) 3a is methyl.

[0229] In certain embodiments, -R of formula (IIa-ii) 10 is selected from -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-ii) 10 is methyl.

[0230] In certain embodiments, -R of formula (IIa-ii) 11 is selected from -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-ii) 11 is -H.

[0231] In certain embodiments, -R of formula (IIa-ii) 11 -L 2 -Z or -L 2 -Z' is substituted.

[0232] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIa-ii'):

[0233] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; A dashed line with an asterisk indicates -L 2 - indicates a bond to -R 3 , -R 3a , -R 10 and -X 2 - is used as defined in formula (II) and -L 1 - is optionally further substituted, with the proviso that the hydrogen with an asterisk in formula (IIa-ii') is not replaced by a substituent.

[0234] -R in formula (IIa-ii') 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0235] In certain embodiments, -X in formula (IIa-ii') 2 - is -C(R 8 R 8a )-.

[0236] In certain embodiments, -R 8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R in formula (IIa-ii') is -H. 8 and -R 8a Both are -H.

[0237] In certain embodiments, -R 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R 3and -R 3a At least one of the groups is methyl.

[0238] In certain embodiments, -R 3 is —H, and —R in formula (IIa-ii′) 3a is methyl.

[0239] In certain embodiments, -R 10 is selected from -H, methyl, and ethyl. In certain embodiments, -R 10 is methyl.

[0240] In certain embodiments, the moiety -L 1 is a group of formula (IIa-iii):

[0241] [ka] where the dashed line indicates the bond to the nitrogen through an amide bond. and -L 1 -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (IIa-iii) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0242] -R in formula (IIa-iii) 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0243] In certain embodiments, the moiety -L of formula (IIa-iii) 1 - is not further substituted.

[0244] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIa-iii'):

[0245] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; A dashed line with an asterisk indicates -L 2 - indicates a bond to -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - is used as defined in formula (II) and -L 1 - is optionally further substituted, with the proviso that the hydrogen with an asterisk in formula (IIa-iii') is not replaced by a substituent.

[0246] -R in formula (IIa-iii') 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0247] In certain embodiments, the moiety -L of formula (IIa-iii') 1 - is not further substituted.

[0248] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIb-i):

[0249] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; -R 1 , -R 1a , -R2 , -R 2a , -R 3 , -R 3a , -R 4 and -X 2 - is used as defined in formula (II) and -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (IIb-i) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0250] -R in formula (IIb-i) 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0251] In certain embodiments, -L of formula (IIb-i) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0252] In certain embodiments, the moiety -L of formula (IIb-i) 1 - is not further substituted.

[0253] In certain embodiments, -R of formula (IIb-i) 1 and -R 1a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIb-i) 1 and -R 1a In certain embodiments, at least one of -R in formula (IIb-i) is methyl. 1 and -R 1a Both of the groups are methyl.

[0254] In certain embodiments, -R of formula (IIb-i) 4 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIb-i) 4 is -H.

[0255] In certain embodiments, -X in formula (IIb-i) 2 - is -C(R 8 R 8a )-.

[0256] In certain embodiments, -R of formula (IIb-i) 8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIb-i) 8 and -R 8a In certain embodiments, at least one of -R in formula (IIb-i) is -H. 8 and -R 8a Both are -H.

[0257] In certain embodiments, -R of formula (IIb-i) 2 and -R 2a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (IIb-i) 2 and -R 2a In certain embodiments, at least one of -R in formula (IIb-i) is -H. 2 and -R 2a Both are H.

[0258] In certain embodiments, -R of formula (IIb-i) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R of formula (IIb-i) 3 and -R 3a In certain embodiments, at least one of -R in formula (IIb-i) is -H. 3 and -R 3aBoth are -H.

[0259] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIb-ii):

[0260] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - is used as defined in formula (II) and -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (IIb-ii) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0261] -R in formula (IIb-ii) 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0262] In certain embodiments, -L of formula (IIb-ii) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0263] In certain embodiments, the moiety -L of formula (IIb-ii) 1 - is not further substituted.

[0264] In certain embodiments, -X in formula (IIb-ii) 2 - is -C(R 8 R 8a )-.

[0265] In certain embodiments, -R of formula (IIb-ii) 8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (IIb-ii) 8 and -R 8a In certain embodiments, at least one of -R in formula (IIb-ii) is -H. 8 and -R 8a Both are -H.

[0266] In certain embodiments, -R of formula (IIb-ii) 2 and -R 2a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (IIb-ii) 2 and -R 2a In certain embodiments, at least one of -R in formula (IIb-ii) is -H. 2 and -R 2a Both are H.

[0267] In certain embodiments, -R of formula (IIb-ii) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R 3 and -R 3a In certain embodiments, at least one of -R in formula (IIb-ii) is -H. 3 and -R 3a Both are -H.

[0268] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIb-ii'):

[0269] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; A dashed line with an asterisk indicates -L 2 - indicates a bond to -R 2 , -R 2a , -R 3a and -X 2 - is used as defined in formula (II) and -L 1 - is optionally further substituted, with the proviso that the hydrogen with an asterisk in formula (IIb-ii') is not substituted by a substituent.

[0270] -R in formula (IIb-ii') 3a If is other than -H, it means that the N to which it is attached has sp 3 It is understood that the bond is through a hybridized carbon atom.

[0271] In certain embodiments, the moiety -L of formula (IIb-ii') 1 - is not further substituted.

[0272] In certain embodiments, -X in formula (IIb-ii') 2 - is -C(R 8 R 8a )-.

[0273] In certain embodiments, -R 8 and -R 8a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R in formula (IIb-ii') is -H. 8 and -R 8a Both are -H.

[0274] In certain embodiments, -R 2 and -R 2a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R 2 and -R 2a In certain embodiments, at least one of -R in formula (IIb-ii') is -H. 2 and -R 2a Both are H.

[0275] In certain embodiments, -R 3a is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. 3a is -H.

[0276] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIb-iii):

[0277] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen via an amide bond. and -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted, provided that the hydrogen with an asterisk in formula (IIb-iii) is -L 2 -Z or -L 2 It is not substituted by -Z' or a substituent.

[0278] -R in formula (IIb-iii) 3 , -R 3a If one or both of are other than -H, they must not be attached to the N to which they are attached. 3 It is understood that the bond is through a hybridized carbon atom.

[0279] In certain embodiments, -L of formula (IIb-iii) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0280] In certain embodiments, the moiety -L of formula (IIb-iii) 1 - is not further substituted.

[0281] In certain embodiments, the moiety -L 1 - is a group represented by the formula (IIb-iii'):

[0282] [ka] (In the formula, The dashed line indicates the attachment of -D to the nitrogen through an amide bond; A dashed line with an asterisk indicates -L 2 - indicates a bond to and -L 1 - is optionally further substituted, with the proviso that the hydrogen with an asterisk in formula (IIb-iii') is not substituted by a substituent.

[0283] The nitrogen adjacent to the dashed line marked with an asterisk in formula (IIb-iii') is sp 3 -L through the hybridized carbon atom 2 - is understood to be bound to.

[0284] In certain embodiments, the moiety -L of formula (IIb-iii') 1 - is not further substituted.

[0285] In certain embodiments, -L 1 - is disclosed in WO2016 / 020373A1. Thus, in certain embodiments, the moiety -L 1 - is a group represented by the formula (III):

[0286] [ka] (In the formula, The dashed line indicates the attachment of -D to a primary or secondary amine or hydroxyl via an amide or ester bond, respectively; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 and -R 3a are, independently of each other, -H, -C(R 8 R 8a R 8b ), -C(=O)R 8 , -C≡N, -C(=NR 8 )R 8a , -CR 8 (=CR 8a R 8b ), -C≡CR 8 and -T, -R 4 , -R 5 and -R 5a are, independently of each other, -H, -C(R 9 R 9a R 9b ) 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 are, independently of each other, -H, halogen, -CN, -COOR 10 , -OR 10 , -C(O)R 10 , -C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)R 10 , -S(O)R10 , -N(R 10 )S(O)2N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO2, -OC(O)R 10 , -N(R 10 )C(O)R 10a , -N(R 10 )S(O)2R 10a , -N(R 10 )S(O)R 10a , -N(R 10 )C(O)OR 10a , -N(R 10 )C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 alkynyl, wherein -T, C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl may be one or more -R 11 optionally substituted with C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-, -S(O)2N(R 12 )-, -S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-, -N(R 12 )C(O)N(R 12a )- and -OC(O)N(R 12 )-, optionally interrupted by one or more groups selected from the group consisting of Each-R 10 , -R 10a , and -R10b are independently -H, -T, C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 alkynyl, wherein -T, C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl may be one or more -R 11 optionally substituted with C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-, -S(O)2N(R 12 )-, -S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-, -N(R 12 )C(O)N(R 12a )- and -OC(O)N(R 12 )-, optionally interrupted by one or more groups selected from the group consisting of Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; each T is independently selected from the group consisting of one or more —R 11 and optionally substituted with Each-R 11 are each independently a halogen, -CN, oxo (=O), -COOR 13 , -OR 13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O)2N(R 13 R 13a ), -S(O)N(R 13 R 13a ), -S(O)R 13 , -S(O)R13 , -N(R 13 )S(O)2N(R 13a R 13b ), -SR 13 , -N(R 13 R 13a ), -NO2, -OC(O)R 13 , -N(R 13 )C(O)R 13a , -N(R 13 )S(O)2R 13a , -N(R 13 )S(O)R 13a , -N(R 13 )C(O)OR 13a , -N(R 13 )C(O)N(R 13a R 13b ), -OC(O)N(R 13 R 13a ), and C 1-6 alkyl, wherein C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R 12 , -R 12a , -R 13 , -R 13a , and -R 13b are independently -H and C 1-6 alkyl, wherein C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; In some cases, 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 the following, together with the atoms to which they are attached, form a C 3-10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; In some cases, Pair-R 1 / -R 2 , -R 1 / -R 3 , -R1 / -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 together with the atoms to which they are attached form ring A, A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl and -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0287] -L in formula (III) 1 The optional further substituents of - are, in certain embodiments, as described above.

[0288] In certain embodiments, -L of formula (III) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0289] In certain embodiments, -L of formula (III) 1 - is not further substituted.

[0290] In certain embodiments, -L 1 - as disclosed in EP 1536334 B1, WO 2009 / 009712 A1, WO 2008 / 034122 A1, WO 2009 / 143412 A2, WO 2011 / 082368 A2, and U.S. Pat. No. 8,618,124 B2, which are incorporated herein by reference in their entireties.

[0291] In certain embodiments, -L 1 - is as disclosed in U.S. Pat. No. 8,946,405 B2 and U.S. Pat. No. 8,754,190 B2, which are incorporated herein by reference in their entireties. Thus, in certain embodiments, -L 1 - is a group represented by the formula (IV):

[0292] [ka] (In the formula, the dashed line indicates a bond to -D, where the bond is through a functional group of -D selected from the group consisting of -OH, -SH, and -NH; m is 0 or 1; -R 1 and -R 2 At least one or both of the following 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)2R3 , and -SR 4 is selected from the group consisting of -R 1 and -R 2 is selected from the group consisting of: -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; -R 3 is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 )2, -R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Each-R 5 is 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 is selected from the group consisting of —H and optionally substituted alkyl; -Y- is absent and -X- is -O- or -S-; or -Y- is -N(Q)CH2- and -X- is -O-; Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; In some cases, -R1 and -R 2 may be joined together to form a 3- to 8-membered ring, In some cases, both -R 9 form a heterocyclic ring together with the nitrogen to which they are attached) and where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0293] The terms used exclusively in connection with formula (IV) have the following meanings:

[0294] As used herein, the term "alkyl" includes straight-chain, branched, or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in certain embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0295] The term "alkoxy" embraces alkyl groups attached to an oxygen, such as, for example, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and the like.

[0296] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons containing a carbon-carbon double bond.

[0297] The term "alkynyl" embraces non-aromatic unsaturated hydrocarbons containing a carbon-carbon triple bond.

[0298] The term "aryl" encompasses aromatic hydrocarbon groups of 6 to 18 carbons, e.g., 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" encompasses aromatic rings containing 3 to 15 carbons, e.g., 3 to 7 carbons, containing at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0299] In some cases, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule via an alkylene bond. In these situations, the substituent is referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0300] The term "halogen" includes bromo, fluoro, chloro and iodo.

[0301] The term "heterocyclic ring" refers to a 4-8 membered aromatic or non-aromatic ring containing 3 to 7 carbon atoms and at least one N, O, or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl."

[0302] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or additional rings, each optionally further substituted. Optional substituents on any of the groups, including those listed above, include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -S2R, -SONR2, -SON2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups, together with the atoms to which they are attached, form a ring.

[0303] In certain embodiments, -L of formula (IV) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0304] In certain embodiments, -L of formula (IV) 1 - is not further substituted.

[0305] In certain embodiments, -L 1 - is as disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - is a compound of formula (V):

[0306] [ka] (In the formula, The dashed line indicates the bond of -D to -D through the amine functionality of -D; -R 1 is an optionally substituted C1-C6 linear, branched, or cyclic alkyl; an optionally substituted aryl; an optionally substituted heteroaryl; an alkoxy; and -NR 5 2, -R 2is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; -R 3 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; -R 4 is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Each-R 5 are each independently selected from the group consisting of: -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or when taken together, two -R 5 can be cycloalkyl or cycloheteroalkyl) and where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0307] The terms used exclusively in connection with formula (V) have the following meanings:

[0308] "Alkyl," "alkenyl," and "alkynyl" include straight-chain, branched, or cyclic hydrocarbon groups of 1 to 8 carbons or 1 to 6 carbons or 1 to 4 carbons, 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, they contain 1 to 6 C.

[0309] "Aryl" includes aromatic hydrocarbon groups of 6 to 18 carbons, e.g., 6 to 10 carbons, such as groups such as phenyl, naphthyl, and anthracene. "Heteroaryl" includes aromatic rings containing 3 to 15 carbons, e.g., 3 to 7 carbons, containing at least one N, O, or S atom, such as groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0310] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group containing one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogen (including F, Cl, Br, and I), lower alkyl (including straight-chain lower alkyl, branched lower alkyl, and cyclic lower alkyl), lower haloalkyl (including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl), OH, lower alkoxy (including straight-chain lower alkoxy, branched lower alkoxy, and cyclic lower alkoxy), SH, lower alkylthio (including straight-chain lower alkylthio, branched lower alkylthio, and cyclic lower alkylthio), amino, alkylamino, dialkylamino, silyl (including alkylsilyl, alkoxysilyl, and arylsilyl), nitro, cyano, carbonyl, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aminocarboxylic acid, carboxylic acid ester, carboxylic acid amide, aminocarboxylic acid ester, ... The heteroaryl may be selected from aryl, aminoacyl, carbamate, urea, thiocarbamate, thiourea, ketone, sulfone, sulfonamide, aryl (including phenyl, naphthyl, and anthracenyl), heteroaryl (including 5-membered heteroaryl such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole, 6-membered heteroaryl such as pyridine, pyrimidine, pyrazine, and fused heteroaryl such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole, and benzisothiazole).

[0311] In certain embodiments, -L in formula (V) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0312] In certain embodiments, -L in formula (V) 1 - is not further substituted.

[0313] In certain embodiments, -L 1- is as 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 a group represented by the formula (VI):

[0314] [ka] (In the formula, The dashed line indicates the bond of -D to -D through the amine functionality of -D; R 1 and R 2 are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 , amino, ammonium, carboxyl, PO3H2, and OPO3H2; R 3 , R 4 、 and R 5 are independently selected from the group consisting of hydrogen, alkyl, and aryl. and where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0315] Suitable substituents for formula (VI) are alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., aromatic 4- to 7-membered heterocycle), or halogen moiety.

[0316] The terms used exclusively in connection with formula (VI) have the following meanings:

[0317] The terms "alkyl," "alkoxy," "alkoxyalkyl," "aryl," "alkaryl," and "aralkyl" refer to alkyl groups of 1 to 8, preferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl groups of 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro, and iodo.

[0318] In certain embodiments, -L of formula (VI) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0319] In certain embodiments, -L of formula (VI) 1 - is not further substituted.

[0320] -L 1 Further preferred embodiments of - are disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Accordingly, preferred moieties -L 1 is a group represented by the formula (VII):

[0321] [ka] (In the formula, The dashed line indicates the bond of -D to -D through the amine functionality of -D; L1 is a bifunctional linking 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 are independently hydrogen, C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted 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 heteroalkoxy; Ar is a moiety that, when included in formula (VII), forms a polysubstituted aromatic hydrocarbon or polysubstituted heterocyclic group; X is a chemical bond, a moiety that is actively transported into a target cell, a hydrophobic moiety, or a combination thereof; y is 0 or 1) and where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0322] The terms used exclusively in connection with formula (VII) have the following meanings:

[0323] The term "alkyl" refers to, for example, straight-chain, branched, substituted C 1-12 Alkyl, e.g., alkoxy, C 3-8 It is understood to include cycloalkyl or substituted cycloalkyl, and the like.

[0324] The term "substituted" shall be understood to include the addition of one or more different atoms to one or more atoms contained within a functional group or compound, or the replacement of one or more atoms contained within a functional group or compound with one or more different atoms.

[0325] Substituted alkyl includes carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl; substituted cycloalkyl includes moieties such as 4-chlorocyclohexyl; aryl includes moieties such as naphthyl; substituted aryl includes moieties such as 3-bromo-phenyl; aralkyl includes moieties such as toluyl; heteroalkyl includes moieties such as ethylthiophene; substituted heteroalkyl includes moieties such as 3-methoxythiophene; alkoxy includes moieties such as methoxy; phenoxy includes moieties such as 3-nitrophenoxy. Halo- is understood to include fluoro, chloro, iodo, and bromo.

[0326] In certain embodiments, -L of formula (VII) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0327] In certain embodiments, -L of formula (VII) 1 - is not further substituted.

[0328] In certain embodiments, -L 1 - is a substructure of formula (VIII)

[0329] [ka] (In the formula, The dashed line with an asterisk indicates the attachment of -D to the nitrogen through an amide bond; Unmarked dashed lines are -L 1 - indicates the bond to the rest of Including, where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0330] In certain embodiments, -L of formula (VIII) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0331] In certain embodiments, -L of formula (VIII) 1 - is not further substituted.

[0332] In certain embodiments, -L 1 - is a substructure of formula (IX)

[0333] [ka] (In the formula, The dashed line with an asterisk indicates the attachment of -D to the nitrogen through a carbamate bond; Unmarked dashed lines are -L 1 - indicates the bond to the rest of Including, where -L 1 - At least one -L 2 -Z or -L 2 -Z' and -L 1 - is optionally further substituted.

[0334] In certain embodiments, -L of formula (IX) 1 - is one part - L 2 -Z or -L 2 -Z' is substituted.

[0335] In certain embodiments, -L of formula (IX) 1 - is not further substituted.

[0336] In certain embodiments, -L 1 - has the structure disclosed in WO2020 / 206358 A1. Thus, in certain embodiments, the moiety -L 1 - is a compound of the formula (X):

[0337] [ka] (In the formula, The unmarked dashed line indicates the bond to -D, A dashed line with an asterisk indicates -L 2 -Z or -L 2 - indicates the bond 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 are independently an electron-withdrawing group, alkyl, or -H, and -R 1 or -R 2 at least one of is an electron-withdrawing group, Each-R 4 are independently C1-C3 alkyl, or two -R 4 together with the carbon atoms to which they are attached form a 3- to 6-membered ring, -Y- is absent when -D is a drug moiety attached through an amine, or -Y- is -N(R 6 )CH2-, where -R 6 is an optionally substituted C1-C6 alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl It has.

[0338] In certain embodiments, n of formula (X) is an integer selected from 1, 2, 3, 4, 5, and 6. In certain embodiments, n of formula (X) is an integer selected from 1, 2, and 3. In certain embodiments, n of formula (X) is an integer from 0, 1, 2, and 3. In certain embodiments, n of formula (X) is 1. In certain embodiments, n of formula (X) is 2. In certain embodiments, n of formula (X) is 3.

[0339] In certain embodiments, -R of formula (X) 1and -R 2 The electron withdrawing group in the formula (I) is selected from the group consisting of -CN; -NO2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; -COR 3 , -SOR 3 , or -SO2R 3 where -R 3 is -H, 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 8 are independently —H or optionally substituted alkyl, or both —R 8 groups taken together with the nitrogen to which they are attached form a heterocyclic ring), or -SR 9 (In the formula, -R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl).

[0340] In certain embodiments, -R of formula (X) 1 and -R 2 In certain embodiments, the electron withdrawing group of formula (X) is -CN. 1 and -R 2 In certain embodiments, the electron withdrawing group of formula (X) is —NO. 1 and -R 2 is an optionally substituted aryl containing 6 to 10 carbons. 1 and -R 2 is an optionally substituted phenyl, naphthyl, or anthracenyl. 1 and -R 2is an optionally substituted heteroaryl containing 3 to 7 carbons and containing at least one N, O, or S atom. 1 and -R 2 is an optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl. 1 and -R 2 is an optionally substituted alkenyl containing 2 to 20 carbon atoms. 1 and -R 2 is an optionally substituted alkynyl containing 2 to 20 carbon atoms. 1 and -R 2 The electron-withdrawing group is -COR 3 , -SOR 3 , or -SO2R 3 where -R 3 is -H, optionally substituted alkyl containing 1 to 20 carbon atoms, or optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2, and each -R 8 are independently —H or optionally substituted alkyl containing 1 to 20 carbon atoms, or both —R 8 The groups, taken together with the nitrogen to which they are attached, form a heterocyclic ring. In certain embodiments, the -R of formula (X) 1 and -R 2 The electron-withdrawing group is -SR 9 where -R 9is an optionally substituted alkyl containing 1 to 20 carbon atoms, or is an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, or an optionally substituted heteroarylalkyl.

[0341] In certain embodiments, -R of formula (X) 1 or -R 2 At least one of the following is -CN, -SOR 3 or -SO2R 3 In certain embodiments, -R of formula (X) 1 and -R 2 At least one of the groups is -CN or -SO2R 3 In certain embodiments, -R of formula (X) 1 and -R 2 At least one of the groups is -CN or -SO2R 3 and -R 3 is optionally substituted alkyl, optionally substituted aryl, or —NR 8 2. In certain embodiments, -R of formula (X) 1 and -R 2 At least one of is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted with -SO2, phenyl substituted with -SO2 and -Cl, -SON2N(CH2CH2)2O, -SO2CH(CH3)2, -SON2N(CH3)(CH2CH3), or -SON2N(CH2CH2OCH3)2.

[0342] In certain embodiments, each —R 4 is independently C1-C3 alkyl. In certain embodiments, both -R 4 is methyl.

[0343] In certain embodiments, -Y- in formula (X) is absent. In certain embodiments, -Y- in formula (X) is -N(R 6 )CH2-.

[0344] In certain embodiments, -L 1 - is a formula in which n is 1 and -R 1 is -CN and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is -SO2N(CH3)2 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is SO2CH3 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is -SO2N(CH2CH2)2CHCH3, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is phenyl substituted with -SO2, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is phenyl substituted with -SO and -Cl, -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is -SO2N(CH2CH2)2O, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is -SO2CH(CH3)2 and -R 2 is -H and -R4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is -SO2N(CH3)(CH2CH3) and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is -SO2N(CH2CH2OCH3)2, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a formula in which n is 1 and -R 1 is phenyl substituted with -SO2 and -CH3, -R 2 is -H and -R 4 is —CH3.

[0345] In certain embodiments, -L 1 - is a group in which n is 2 and -R 1 is -CN and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is -SO2N(CH3)2 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is SO2CH3 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is -SO2N(CH2CH2)2CHCH3, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1- is a group in which n is 2 and -R 1 is phenyl substituted with -SO2, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is phenyl substituted with -SO and -Cl, -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is -SO2N(CH2CH2)2O, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is -SO2CH(CH3)2 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is -SO2N(CH3)(CH2CH3) and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is -SO2N(CH2CH2OCH3)2, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 2 and -R 1 is phenyl substituted with -SO2 and -CH3, -R 2 is -H and -R 4 is —CH3.

[0346] In certain embodiments, -L 1 - is a group in which n is 3 and -R 1is -CN and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is -SO2N(CH3)2 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is SO2CH3 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is -SO2N(CH2CH2)2CHCH3, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is phenyl substituted with -SO2, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is phenyl substituted with -SO and -Cl, -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is -SO2N(CH2CH2)2O, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is -SO2CH(CH3)2 and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1- is a group in which n is 3 and -R 1 is -SO2N(CH3)(CH2CH3) and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is -SO2N(CH2CH2OCH3)2, and -R 2 is -H and -R 4 is —CH3. In certain embodiments, —L 1 - is a group in which n is 3 and -R 1 is phenyl substituted with -SO2 and -CH3, -R 2 is -H and -R 4 is —CH3.

[0347] The terms used exclusively in connection with formula (X) have the following meanings:

[0348] The term "alkyl" refers to a linear, branched, or cyclic saturated hydrocarbon group of 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In certain embodiments, an alkyl is 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, an alkyl is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0349] The term "alkoxy" refers to an alkyl group attached to an oxygen and includes, for example, methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0350] 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.

[0351] 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.

[0352] The term "aryl" refers to an aromatic hydrocarbon group of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to an aromatic ring containing at least one N, O, or S atom and 3 to 15 carbons, preferably 3 to 7 carbons, including at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.

[0353] In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule by an alkyl bond. In these situations, the substituent is referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0354] The term "halogen" or "halo" refers to bromo, fluoro, chloro and iodo.

[0355] The term "heterocyclic ring" or "heterocyclyl" refers to a 3-15 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 the exemplary groups provided above for the term "heteroaryl." In certain embodiments, the heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments, the heterocyclic ring or heterocyclyl is aromatic.

[0356] The term "optionally substituted" refers to a group that can be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents, which can be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -OR, and the like. 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)NR aa R bb , -P(O)(OR aa )(OR bb), heterocyclyl, heteroaryl, or aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently selected from -R cc and optionally substituted by -R aa and -R bb are each independently -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -R aa and -R bb together with the nitrogen atom to which they are attached form a heterocyclyl, which is optionally substituted by alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, wherein each -R cc is independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN, or -NO2.

[0357] In certain embodiments, -L 2 - is a chemical bond. In certain embodiments, -L 2 - is a spacer moiety, e.g., -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 alkynyl, where -T-, C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50Alkynyl may be one or more -R y2 optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O)2N(R y3 )-, -S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )- and -OC(O)N(R y3 )-, optionally interrupted by one or more groups selected from the group consisting of -R y1 and -R y1a are, independently of each other, -H, -T, C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 alkynyl, -T, C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R y2 optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O)2N(R y4 )-, -S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )- and -OC(O)N(Ry4 )-, optionally interrupted by one or more groups selected from the group consisting of Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, wherein each T is independently selected from the group consisting of one or more —R y2 and optionally substituted with Each-R y2 are independently halogen, -CN, oxo(=O), -COOR y5 , -OR y5 , -C(O)R y5 , -C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)R y5 , -S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 alkyl, wherein C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R y3 , -Ry3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b are independently -H and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0358] 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 alkynyl, wherein -T-, C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl may be one or more -R y2 optionally substituted with C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O)2N(R y3 )-, -S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(Ry3 )C(O)N(R y3a )- and -OC(O)N(R y3 )-, optionally interrupted by one or more groups selected from the group consisting of -R y1 and -R y1a are, independently of each other, -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, wherein -T, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl may be one or more -R y2 optionally substituted with C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O)2N(R y4 )-, -S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )- and -OC(O)N(R y4 )-, optionally interrupted by one or more groups selected from the group consisting of Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, wherein each T is independently selected from the group consisting of one or more —R y2 and optionally substituted with -R y2 is halogen, -CN, oxo(=O), -COOR y5 , -OR y5 , -C(O)Ry5 , -C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)R y5 , -S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 alkyl, wherein C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b are, independently of each other, -H and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0359] 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(Ry1 )-, -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 alkynyl, wherein -T-, C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R y2 optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O)2N(R y3 )-, -S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )- and -OC(O)N(R y3 )-, optionally interrupted by one or more groups selected from the group consisting of -R y1 and -R y1a are independently -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, Each T is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; Each-R y2 are independently halogen and C 1-6 is selected from the group consisting of alkyl, Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b are, independently of each other, -H and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0360] In certain embodiments, -L 2 - is -O-, -T- and -C(O)N(R y1 C optionally interrupted by one or more groups independently selected from 1-20 This C is an alkyl chain. 1-20 The alkyl chains are -OH, -T and -C(O)N(R y6 R y6a Optionally substituted with one or more groups independently selected from -R y1 , -R y6 , -R y6a are independently H and C 1-4 alkyl, and T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 It is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl.

[0361] In certain embodiments, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0362] In certain embodiments, -L2 - includes a moiety selected from:

[0363] [ka] (In the formula, The dashed line indicates -L 2 -, -L 1 -, -Z and / or Z' respectively represent the bond to the remainder; -R and -R a are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0364] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms.

[0365] Part-L 2 The term "chain length" as used herein with respect to -L 1 -L at the shortest link between - and -Z 2 -Refers to the number of atoms.

[0366] In certain embodiments, -L 2 - is a group represented by the formula (i)

[0367] [ka] (In the formula, A dashed line with an asterisk indicates -L 1 - indicates a bond to An unmarked dashed line indicates a bond 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. and wherein the moiety of formula (i) is optionally further substituted.

[0368] In certain embodiments, n in formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. In certain embodiments, n in formula (i) is 4, 5, 6, or 7. In certain embodiments, n in formula (i) is 4. In certain embodiments, n in formula (i) is 5. In certain embodiments, n in formula (i) is 6.

[0369] In certain embodiments, the moiety -L 1 -L 2 is selected from the group consisting of:

[0370] [ka] TIFF2025537527000037.tif29160 (in the formula, The unmarked dashed line indicates the attachment of -D to the nitrogen by forming an amide bond; A dashed line with an asterisk indicates a bond to -Z or Z').

[0371] In certain embodiments, the moiety -L 1 -L 2 - has the formula (IIca-ii). In certain embodiments, the moiety -L 1 -L 2 has the formula (IIcb-iii).

[0372] In certain embodiments, the moiety -L 1 -L 2 is selected from the group consisting of:

[0373] [ka] (In the formula, The unmarked dashed line indicates the attachment of -D to the nitrogen by forming an amide bond; A dashed line with an asterisk indicates a bond to -Z or Z').

[0374] Carrier-Z is C8-24 In certain embodiments, -Z comprises a polymer, such as 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(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(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate). , poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-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, carbomethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof. In certain embodiments, -Z comprises poly(ethylene glycol) (PEG).

[0375] 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, e.g., 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.

[0376] In certain embodiments, -Z comprises PEG and has a molecular weight of 5 to 200 kDa. In certain embodiments, -Z comprises PEG and has a molecular weight of 8 to 100 kDa, e.g., 10 to 80 kDa, 12 to 60 kDa, or 15 to 40 kDa. In certain embodiments, -Z comprises PEG and has a molecular weight of about 20 kDa. In certain embodiments, -Z comprises PEG and has a molecular weight of about 40 kDa.

[0377] In certain embodiments, -Z comprises a protein selected from the group consisting of a protein such as a carboxyl-terminal polypeptide of chorionic gonadotropin, as described in U.S. Patent Application Publication No. 2012 / 0035101 A1, which is incorporated herein by reference; albumin; an XTEN sequence, as described in WO 2011123813 A2, which is incorporated herein by reference; a proline / alanine random coil sequence, as described in WO 2011 / 144756 A1, which is incorporated herein by reference; a proline / alanine / serine random coil sequence, as described in WO 2008 / 155134 A1 and WO 2013 / 024049 A1, which are incorporated herein by reference; and an Fc fusion protein. In certain embodiments, -Z is polysarcosine. In certain embodiments, -Z comprises poly(N-methylglycine). In certain embodiments, -Z comprises a random coil protein moiety.

[0378] In certain embodiments, -Z comprises a fatty acid derivative, such as those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1, which are incorporated herein by reference. In certain embodiments, -Z is a hyaluronic acid-based polymer. In certain embodiments, -Z is a carrier such as those disclosed in WO 2012 / 02047 A1, which is incorporated herein by reference. In certain embodiments, -Z is a carrier such as those disclosed in WO 2013 / 024048 A1, which is incorporated herein by reference. In certain embodiments, -Z is a PEG-based polymer, such as a linear, branched, or multi-arm PEG-based polymer. In certain embodiments, -Z is a linear PEG-based polymer. In certain embodiments, -Z is a multi-arm PEG-based polymer. In certain embodiments, -Z is a multi-arm PEG-based polymer having at least four PEG-based arms.

[0379] In certain embodiments, such multi-arm PEG-based polymers-Z comprise multiple moieties -L 2 -L 1 -D, where each moiety -L 2 -L 1 In certain embodiments, such multi-arm PEG-based polymers -Z comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 moieties -L. 2 -L 1 In certain embodiments, such multi-arm PEG-based polymers -Z are linked to 2, 3, 4, 6 or 8 moieties -L 2 -L 1 In certain embodiments, such multi-arm PEG-based polymers -Z are linked to 2, 4, or 6 moieties -L 2 -L 1 In certain embodiments, such multi-arm PEG-based polymers -Z are linked to four or six moieties -L 2 -L 1In certain embodiments, such multi-arm PEG-based polymers -Z are linked to four moieties -L 2 -L 1 -D is bonded.

[0380] In certain embodiments, -Z is a branched PEG-based polymer. In certain embodiments, -Z is a branched PEG-based polymer having 1, 2, 3, 4, 5, or 6 branch points. In certain embodiments, -Z is a branched PEG-based polymer having 1, 2, or 3 branch points. In certain embodiments, -Z is a branched PEG-based polymer having 1 branch point. In certain embodiments, -Z is a branched PEG-based polymer having 2 branch points. In certain embodiments, -Z is a branched PEG-based polymer having 3 branch points. In certain embodiments, the branch points can be selected from the group consisting of -N<, -CH<, and >C<.

[0381] In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of 5 to 200 kDa. In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of 8 to 100 kDa. In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of 10 to 80 kDa. In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of 12 to 60 kDa. In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of 15 to 40 kDa. In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of approximately 20 kDa. In certain embodiments, -Z is a branched PEG-based polymer having one branch point and a molecular weight of approximately 40 kDa.

[0382] In certain embodiments, -Z is a branched PEG-based polymer having one branch point (wherein the branch point is -CH<) and a molecular weight of approximately 40 kDa.

[0383] In certain embodiments, -Z or Z' is a moiety

[0384] [ka] Includes.

[0385] In certain embodiments, -Z or Z' comprises an amide bond.

[0386] In certain embodiments, -Z is a moiety of formula (a)

[0387] [ka] (In the formula, The dashed line is -L 2 represents the bond to - or to the remainder of -Z, BP a is a branch point selected from the group consisting of -N<, -CR< and >C<; -R is -H and C 1-6 is selected from the group consisting of alkyl, a is BP a is 0 when -N< or -CR<, and n is BP a is 1 if >C<, -S a -, -S a' -, -S a'' -and-S a''' - are, independently of each other, a chemical bond or C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 alkynyl, wherein C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R 1 optionally substituted with C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 2 )-, -S(O)2N(R2 )-, -S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-, -N(R 2 )C(O)N(R 2a )- and -OC(O)N(R 2 )-, optionally interrupted by one or more groups selected from the group consisting of Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, wherein each -T- is independently selected from the group consisting of one or more -R 1 and optionally substituted with Each-R 1 are independently halogen, -CN, oxo(=O), -COOR 3 , -OR 3 , -C(O)R 3 , -C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)R 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 alkyl, wherein C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R 2 , -R 2a , -R 3 , -R 3a and -R 3b are independently -H and C 1-6 alkyl, wherein C 1-6 the alkyl is optionally substituted with one or more halogens which may be the same or different; -P a' , -P a'' and -P a''' are independently polymer moieties) Includes.

[0388] In certain embodiments, BP of formula (a) a In certain embodiments, BP of formula (a) is -N<. a In certain embodiments, BP of formula (a) is >C<. a is -CR<. In certain embodiments, -R is -H. Thus, a in formula (a) is 0.

[0389] In certain embodiments, -S of formula (a) a - is a chemical bond. In certain embodiments, -S in formula (a) a -C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )- and -OC(O)N(R 4 )-, where -T- is a 3- to 10-membered heterocyclyl, and -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S in formula (a) a -C 1-10 alkyl, including -T-, -C(O)N(R 4 )- and -O-.

[0390] In certain embodiments, -S of formula (a) a' - is a chemical bond. In certain embodiments, -S in formula (a) a' -C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )- and -OC(O)N(R 4)-, where -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S in formula (a) a' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, including -O-, -C(O)-, and -C(O)N(R 4 )-.

[0391] In certain embodiments, -S of formula (a) a'' - is a chemical bond. In certain embodiments, -S in formula (a) a'' -C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )- and -OC(O)N(R 4 )-, where -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S in formula (a) a'' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, including -O-, -C(O)-, and -C(O)N(R 4)-.

[0392] In certain embodiments, -S of formula (a) a''' - is a chemical bond. In certain embodiments, -S in formula (a) a''' -C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl, wherein C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl includes -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O)2N(R 4 )-, -S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )- and -OC(O)N(R 4 )-, where -R 4 and -R 4a is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -S in formula (a) a''' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, including -O-, -C(O)-, and -C(O)N(R 4 )-.

[0393] In certain embodiments, -P of formula (a) a' , -P a'' and -P a'''are, independently, 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(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 ... and copolymers thereof. The polymers include polymers selected from the group consisting of poly(propylene glycol), poly(propyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-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, carbomethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0394] In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' In certain embodiments, -P of formula (a) independently comprises a PEG-based moiety. a' , -P a'' and -P a'''independently comprise a PEG-based moiety comprising at least 20% PEG, such as at least 30%, for example at least 40% PEG, such as at least 50% PEG, for example at least 60% PEG, such as at least 70% PEG, for example at least 80% PEG, or such as at least 90% PEG.

[0395] In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' independently have a molecular weight of 5 kDa to 50 kDa, such as 5 kDa to 40 kDa, such as 7.5 kDa to 35 kDa, such as 7.5 to 30 kDa, or such as 10 to 30 kDa. a' , -P a'' and -P a''' In certain embodiments, -P of formula (a) has a molecular weight of about 5 kDa. a' , -P a'' and -P a''' has a molecular weight of about 7.5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' has a molecular weight of about 10 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' has a molecular weight of about 12.5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' has a molecular weight of about 15 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' has a molecular weight of approximately 20 kDa.

[0396] In certain embodiments, -Z comprises one moiety of formula (a). In certain embodiments, -Z comprises two moieties of formula (a). In certain embodiments, -Z comprises three moieties of formula (a). In certain embodiments, -Z is a moiety of formula (a).

[0397] In certain embodiments, -Z is a moiety of formula (b)

[0398] [ka] (In the formula, The dashed line is -L 2 represents the bond to - or to the remainder of -Z, m and p are each independently an integer of 150 to 1000, for example, an integer of 150 to 500, for example, an integer of 200 to 500, or for example, an integer of 400 to 500. Includes.

[0399] In certain embodiments, m and p in formula (b) are the same integer. In certain embodiments, m and p in formula (b) are about 450.

[0400] In certain embodiments, -Z is a moiety of formula (b).

[0401] In certain embodiments, Z' is a hydrogel.

[0402] 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.

[0403] 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, the entireties of which are incorporated herein by reference.

[0404] 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 reacting at least a first reactive polymer with a cleavable crosslinker compound, wherein the cleavable crosslinker compound contains a first functional group, -Y, that reacts with the first reactive polymer. 1 and further comprising a moiety that is cleaved by elimination under physiological conditions, said moiety comprising a second functional group -Y that reacts with a second reactive polymer. 2 In certain embodiments, the cleavable crosslinker compound comprises the formula (PL-1):

[0405] [ka] [In the formula, m is 0 or 1; -X is a functional group capable of binding to a reactive polymer that is detachable under physiological conditions, and the second functional group -Y 2 Including, -R 1 , -R 2 and -R 5 at least one of the first functional groups -Y 1 Including, -R 1 and -R 2 is selected from the group consisting of -H, alkyl, arylalkyl, and heteroarylalkyl; In some cases, -R 1 and -R 2 may be joined together to form a 3- to 8-membered ring, -R 1 and -R 2 At least one or both of are independently -CN, -NO2, aryl, heteroaryl, alkenyl, alkynyl, -COR 3 , -SOR 3 , -SO2R 3 and -SR 4 is selected from the group consisting of -R 3is -H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR 9 and -NR 9 2, -R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Each-R 5 are independently -H, alkyl, alkenylalkyl, alkynylalkyl, (OCH2CH2) p O-alkyl (wherein p is an integer from 1 to 1000), aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Each-R 9 are independently selected from the group consisting of —H and alkyl, or both —R 9 together with the nitrogen to which they are attached form a heterocyclic ring] and The moiety of formula (PL-1) is optionally further substituted.

[0406] The following paragraphs describe such hydrogels in more detail.

[0407] In certain embodiments, -X in formula (PL-1) is selected from succinimidyl carbonate, sulfosuccinimidyl carbonate halides, thioethers, esters, nitrophenyl carbonates, chloroformates, fluoroformates, optionally substituted phenols, and compounds of formula (PL-2):

[0408] [ka] [In the formula, The dashed line indicates the bond to the remainder of formula (PL-1), -T*- is -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 absent or -OR 7 -and-SR 7 - selected from the group consisting of -Y 2 is a functional group capable of bonding with a reactive polymer, -R 6 is selected from the group consisting of -H, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; -R 7 is alkylene, phenylene and (OCH2CH2) p wherein p is an integer from 1 to 1000. is selected from the group consisting of:

[0409] In certain embodiments, -X of formula (PL-1) comprises an activated carbonate, such as succinimidyl carbonate, sulfosuccinimidyl carbonate, or nitrophenyl carbonate. In certain embodiments, -X of formula (PL-1) comprises a carbonyl halide, such as O(C=O)Cl or O(C=O)F. In certain embodiments, -X of formula (PL-1) has formula (PL-2). In certain embodiments, -X of formula (PL-1) has OR 7 or SR 7 and R 7 is optionally substituted alkylene, optionally substituted phenylene or (OCH2CH2) p (wherein p is 1 to 1000).

[0410] In certain embodiments, p in formula (PL-2) is an integer of 1 to 100. In certain embodiments, p in formula (PL-2) is an integer of 1 to 10.

[0411] In certain embodiments, -Y in formula (PL-1) 1 and -Y in formula (PL-2) 2 are independently N3, NH2, and NH-CO2 t Bu, S.H., S. t Bu, maleimide, CO2H, CO2 tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, 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 an alkyne or cyclooctyne, 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 When one of them contains a 1,3-diene or a cyclopentadiene, the other does not contain a furan.

[0412] In certain embodiments, the cleavable crosslinker compound has the formula (PL-3):

[0413] [ka] (In the formula, m is 0 or 1; n is an integer selected from 1 to 1000; s is 0, 1 or 2; t is selected from the 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 CHO- and -O(C=O)NR 6 S-, -Q is a core group having valence = t that connects the arms of the cleavable crosslinking compound; t is an integer selected from 2, 4, 8, 16, and 32; -R 1 , -R 2 and -R 5 is defined as in formula (PL-1) It has.

[0414] In certain embodiments, t in Formula (PL-3) is 2. In certain embodiments, t in Formula (PL-3) is 4. In certain embodiments, t in Formula (PL-3) is 8. In certain embodiments, t in Formula (PL-3) is 16. In certain embodiments, t in Formula (PL-3) is 32.

[0415] In certain embodiments, -Q of formula (PL-3) has a structure selected from the group consisting of:

[0416] [ka] (where the dashed line indicates the bond to the remainder of the cleavable crosslinker compound).

[0417] In certain embodiments, -Q of formula (PL-3) has the structure (PL-3-i). In certain embodiments, -Q of formula (PL-3) has the structure (PL-3-ii). In certain embodiments, -Q of formula (PL-3) has the structure (PL-3-iii).

[0418] In certain embodiments, the cleavable crosslinker compound has the structure of formula (PL-3) (wherein m is 0, n is approximately 100, s is 0, t is 4, -W- is -O(C=O)NH-, and -Q is (PL-3i) 2 is H, while -R 5 is -H and the other is -R 5 is (CH2)5N3, and -R 1 is (4-chlorophenyl)SO2, phenyl substituted with -SO2, morpholino-SO2, or -CN).

[0419] In certain embodiments, -Y in formula (PL-3) 1 are N3, NH2, and NH-CO2 t Bu, S.H., S. t Bu, maleimide, CO2H, CO2 tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide, t Bu is tert-butyl.

[0420] In certain embodiments, each -Y 1 and -Y in formula (PL-2) 2 are independently N3, NH2, and NH-CO2 t Bu, S.H., S. t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide.

[0421] In certain embodiments, -Y 1 and -Y 2 is an azide and the other is a reactive functional group selected from the group consisting of acetylene, cyclooctyne, and maleimide. 1 and -Y 2 One of -Y 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. 1 and -Y 2 One of -Y is an amine and the other is a selectively reactive functional group selected from a carboxylic acid and an activated carboxylic acid. 1 and -Y 2 One of the groups is a maleimide and the other is a selectively reactive functional group selected from the group consisting of 1,3-dienes, cyclopentadienes, and furans.

[0422] In certain embodiments, the first and optional second polymers contain suitable reactive functional groups or have the formula [Y 3 -(CH2) s (CH2CH2O) n ] t Q (wherein -Y 3is a reactive functional group, s is 0, 1 or 2, n is an integer selected from the group ranging from 10 to 1000, and -Q is a core group having a valence t, where t is an integer selected from the group consisting of 2, 4, 8, 16 and 32.

[0423] In certain embodiments, the first polymer comprises a multi-arm polymer. In certain embodiments, the first polymer comprises at least three arms. In certain embodiments, the first polymer comprises at least four arms. In certain embodiments, the first polymer comprises at least five arms. In certain embodiments, the first polymer comprises at least six arms. In certain embodiments, the first polymer comprises at least seven arms. In certain embodiments, the first polymer comprises at least eight arms.

[0424] In certain embodiments, the second polymer comprises a multi-arm polymer. In certain embodiments, the second polymer comprises at least three arms. In certain embodiments, the second polymer comprises at least four arms. In certain embodiments, the second polymer comprises at least five arms. In certain embodiments, the second polymer comprises at least six arms. In certain embodiments, the second polymer comprises at least seven arms. In certain embodiments, the second polymer comprises at least eight arms.

[0425] 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.

[0426] In certain embodiments, the second polymer comprises a 2-arm polyethylene glycol polymer. In certain embodiments, the second polymer comprises a 4-arm polyethylene glycol polymer. In certain embodiments, the second polymer comprises an 8-arm polyethylene glycol polymer. In certain embodiments, the second polymer comprises a 16-arm polyethylene glycol polymer. In certain embodiments, the second polymer comprises a 32-arm polyethylene glycol polymer.

[0427] In certain embodiments, the first and second reactive polymers are reacted sequentially or simultaneously with the cleavable crosslinker compound.

[0428] In certain embodiments, the first and second functional groups are the same.

[0429] The terms used exclusively in connection with formulae (PL-1), (PL-2) and (PL-3) have the following meanings:

[0430] The term "moiety that can be cleaved by elimination under physiological conditions" refers to the group HC-(CH=CH) m"HX'" refers to a structure containing -C-X' (where m is 0 or 1 and X' is a leaving group), and the elimination reaction as described above to remove the HX' element can occur at a rate such that the half-life of the reaction is between 1 and 10,000 hours under physiological pH and temperature conditions. Preferably, the half-life of the reaction 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 refer to a pH between 7 and 8, and a temperature between 30 and 40 degrees Celsius.

[0431] The term "reactive polymers and reactive oligomers" refers to polymers or oligomers that contain functional groups that are reactive toward other functional groups, most preferably under mild conditions compatible with 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 furans, alpha-halocarbonyls, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl esters or carbonates.

[0432] The term "functional group capable of being attached to a reactive polymer" refers to a functional group that reacts with a corresponding functional group on the reactive polymer to form a covalent bond to the polymer. Suitable functional groups that can be attached 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-dienes, such as cyclopentadiene and furan, alpha-halocarbonyl, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl ester or carbonate.

[0433] 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 halogen (including F, Cl, Br, and I), lower alkyl (including straight-chain lower alkyl, branched lower alkyl, and cyclic lower alkyl), lower haloalkyl (including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl), OH, lower alkoxy (including straight-chain lower alkoxy, branched lower alkoxy, and cyclic lower alkoxy), SH, lower alkylthio (including straight-chain lower alkylthio, branched lower alkylthio, and cyclic lower alkylthio), amino, alkylamino, dialkylamino, silyl (including alkylsilyl, alkoxysilyl, and arylsilyl), nitro, cyano, carbonyl, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aminocarboxylic acid, carboxylic acid ester, carboxylic acid amide, carboxylic acid ester ... The heteroaryl may be selected from aryl, aminoacyl, carbamate, urea, thiocarbamate, thiourea, ketone, sulfone, sulfonamide, aryl (including phenyl, naphthyl, and anthracenyl), heteroaryl (including 5-membered heteroaryl such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole, 6-membered heteroaryl such as pyridine, pyrimidine, pyrazine, and fused heteroaryl such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole, and benzisothiazole).

[0434] R 1 and R 2 The properties of R may be modulated by the optional addition of electron-donating or electron-withdrawing substituents. 1 R 2refers to a substituent that results in a decrease in the acidity of CH; electron-donating groups are typically associated with negative Hammett σ or Taft σ* constants, and are well known in the art of physical organic chemistry (Hammett constants refer to aryl / heteroaryl substituents, while Taft constants refer to substituents on non-aromatic moieties). Examples of suitable electron-donating substituents include lower alkyl, lower alkoxy, lower alkylthio, amino, alkylamino, dialkylamino, and silyl.

[0435] The term "electron-withdrawing group" refers to R 1 R 2 "C(=O)-R" refers to a substituent that increases the acidity of the C-H group. Electron-withdrawing groups are typically associated with positive Hammett σ or Taft σ* constants and are well known in the art of physical organic chemistry. Examples of suitable electron-withdrawing substituents include halogen, difluoromethyl, trifluoromethyl, nitro, cyano, C(=O)-R, and the like. x (In the formula, -R x is H, lower alkyl, lower alkoxy, or amino), or S(O) m R Y (wherein m is 1 or 2, and -R Y is lower alkyl, aryl, or heteroaryl). As is well known in the art, the electronic influence of a substituent can depend on the position of the substituent. For example, an alkoxy substituent at the ortho- or para-position of an aryl ring is electron-donating and characterized by a negative Hammett σ constant, while an alkoxy substituent at the meta-position of an aryl ring is electron-withdrawing and characterized by a positive Hammett σ constant.

[0436] The terms "alkyl," "alkenyl," and "alkynyl" include straight-chain, branched, or cyclic hydrocarbon groups of 1 to 8 carbons, or 1 to 6 carbons, or 1 to 4 carbons, 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, they contain 1 to 6 carbons.

[0437] The term "aryl" encompasses aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, such as groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" encompasses aromatic rings containing 3 to 15 carbons, preferably 3 to 7 carbons, containing at least one N, O, or S atom, such as groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0438] The term "halogen" includes fluoro, chloro, bromo and iodo.

[0439] The term "maleimide" refers to a compound of the formula

[0440] [ka] is the basis of

[0441] 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 steps of: (a) Multi-arm polymer-P 2 providing a first prepolymer comprising formula (PL-4):

[0442] [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 linking the first prepolymer to a second prepolymer; -R 1 and -R 2are independently an electron-withdrawing group, alkyl, or -H, and -R 1 and -R 2 at least one of is an electron-withdrawing group, Each-R 4 are independently C1-C3 alkyl, or two -R 4 form a 3- to 6-membered ring together with the carbon atoms to which they are attached, -W- is absent or

[0443] [ka] (In the formula, A dashed line with an asterisk indicates a bond to -NH-, and an unmarked dashed line indicates a bond to -P 2 indicates the bond to each of x, y, and z is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; -B' is -NH2, -ONH2, a ketone, an aldehyde, -SH, -OH, -CO2H, a carboxamide group, or a cyclooctyne- or bicyclononyne-containing group; -C* is a carboxamide, a thioether, a thiosuccinimidyl, a triazole, or an oxime is] having the steps; (b) Multi-arm polymer-P 1 wherein each arm is terminated with a reactive functional group -Y″ that reacts with -Y of step (a); (c) mixing the two prepolymers of steps (a) and (b) under conditions such that -Y and -Y″ react to form a bond -Y*-; and optionally, (d) Isolating the resulting hydrogel.

[0444] Thus, Z' is a hydrogel obtainable from the above method. In certain embodiments, the hydrogels produced by the aforementioned methods are degradable.

[0445] In certain embodiments, -Y and -Y'' react under step (c) to form a bridge of formula (PL-4'):

[0446] [ka] (In the formula, n, r, -P 1 , -Y*-, -R 4 , -R 1 , -R 2 , -W- and -P 2 is as defined above) The resulting mixture forms an insoluble hydrogel matrix comprising:

[0447] 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.

[0448] 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 certain embodiments, r of Formula (PL-4) or (PL-4') is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, r of Formula (PL-4) or (PL-4') is an integer selected from 2, 4, 6, and 8. In certain embodiments, r of Formula (PL-4) or (PL-4') is 2. In certain embodiments, r of Formula (PL-4) or (PL-4') is 4. In certain embodiments, r of Formula (PL-4) or (PL-4') is 6. In certain embodiments, r of Formula (PL-4) or (PL-4') is 8.

[0449] In certain embodiments, -P of formula (PL-4) or (PL-4') 2 In certain embodiments, -P of formula (PL-4) or (PL-4') has a molecular weight of at least 1 kDa. 2 In certain embodiments, -P of formula (PL-4) or (PL-4') has a molecular weight of 1 to 100 kDa. 2 In certain embodiments, -P of formula (PL-4) or (PL-4') has a molecular weight of 1 to 80 kDa. 2 In certain embodiments, -P of formula (PL-4) or (PL-4') has a molecular weight of 1 to 60 kDa. 2 has a molecular weight of 1 to 40 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 In certain embodiments, -P of formula (PL-4) or (PL-4') has a molecular weight of 1 to 20 kDa. 2 has a molecular weight of 1 to 10 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 has a molecular weight of 1 to 5 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 In certain embodiments, -P of formula (PL-4) or (PL-4') has a molecular weight of about 20 kDa. 2has a molecular weight of about 40 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 has a molecular weight of about 60 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 has a molecular weight of approximately 80 kDa.

[0450] In certain embodiments, the multi-arm polymer-P in step (b) 1 is 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 certain embodiments, the multi-arm-P of step (b) 1 is a polymer having r arms, where r is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, the multi-arm-P in step (b) 1 is a polymer having r arms, where r is an integer selected from 2, 4, 6, and 8. In certain embodiments, the multi-arm-P in step (b) 1 is a polymer having r arms, where r is 2. In certain embodiments, the multi-arm-P 1 is a polymer having r arms, where r is 4. In certain embodiments, the multi-arm-P 1 is a polymer having r arms, where r is 6. In certain embodiments, the multi-arm-P 1 is a polymer having r arms, where r is 8.

[0451] In certain embodiments, in step (b) -P 1 has a molecular weight of at least 1 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 has a molecular weight of 1 to 100 kDa. In certain embodiments, the multi-arm polymer-P in step (b) 1 In certain embodiments, the multi-arm polymer-P in step (b) has a molecular weight of 1 to 80 kDa. 1In certain embodiments, the multi-arm polymer-P in step (b) has a molecular weight of 1 to 60 kDa. 1 has a molecular weight of 1 to 40 kDa. In certain embodiments, the multi-arm polymer-P in step (b) 1 has a molecular weight of 1 to 20 kDa. In certain embodiments, the multi-arm polymer-P in step (b) 1 has a molecular weight of 1 to 10 kDa. In certain embodiments, the multi-arm polymer-P in step (b) 1 has a molecular weight of 1 to 5 kDa. In certain embodiments, the multi-arm polymer-P in step (b) 1 has a molecular weight of about 20 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 has a molecular weight of about 40 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 has a molecular weight of about 60 kDa. In certain embodiments, the multi-arm polymer-P of step (b) 1 has a molecular weight of approximately 80 kDa.

[0452] In certain embodiments, in step (b) -P 1 and -P of formula (PL-4) or (PL-4') 2 comprises poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), poly(ethyleneimine) (PEI), dextran, hyaluronic acid, or copolymers thereof. In certain embodiments, -P in step (b) 1 and P of formula (PL-4) or (PL-4') 2 is a PEG-based polymer. In certain embodiments, -P in step (b) 1 and -P of formula (PL-4) or (PL-4') 2 is a hyaluronic acid-based polymer.

[0453] In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2are independently an electron-withdrawing group, alkyl, or -H, and -R 1 and -R 2 At least one of the groups is an electron-withdrawing group.

[0454] In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron withdrawing group is -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -COR 3 , -SOR 3 , or -SO2R 3 and -R 3 is -H, 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 8 are independently —H or optionally substituted alkyl, or both —R 8 groups taken together with the nitrogen to which they are attached form a heterocyclic ring), or -SR 9 (In the formula, -R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl).

[0455] In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 In certain embodiments, the electron withdrawing group of formula (PL-4) or (PL-4') is -CN. 1 and -R 2 In certain embodiments, the electron withdrawing group of formula (PL-4) or (PL-4′) is —NO. 1 and -R 2is an optionally substituted aryl containing 6 to 10 carbons. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 is an optionally substituted phenyl, naphthyl, or anthracenyl. In certain embodiments, the -R 1 and -R 2 is an optionally substituted heteroaryl containing 3 to 7 carbons and at least one N, O, or S atom. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 is an optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl. 1 and -R 2 is an optionally substituted alkenyl containing 2 to 20 carbon atoms. 1 and -R 2 is an optionally substituted alkynyl containing 2 to 20 carbon atoms. 1 and -R 2 The electron-withdrawing group is -COR 3 , -SOR 3 , or -SO2R 3 and R 3 is -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 (in the formula, each -R 8are independently -H or optionally substituted alkyl containing 1 to 20 carbon atoms, or both -R 8 groups together with the nitrogen to which they are attached form a heterocyclic ring). In certain embodiments, -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 containing 1 to 20 carbon atoms. 1 and -R 2 At least one of the groups is -CN or -SO2R 3 is.

[0456] In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of the following is -CN, -SOR 3 or -SO2R 3 In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of the groups is -CN or -SO2R 3 In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 At least one of the groups is -CN or -SO2R 3 and -R 3 is optionally substituted alkyl, optionally substituted aryl, or —NR 8 2. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2At least one of is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted with -SO2, phenyl substituted with -SO2 and -Cl, -SON2N(CH2CH2)2O, -SO2CH(CH3)2, -SON2N(CH3)(CH2CH3), or -SON2N(CH2CH2OCH3)2.

[0457] In certain embodiments, each —R 4 are independently C1-C3 alkyl or can be taken together to form a 3- to 6-membered ring. In certain embodiments, each -R 4 is independently C1-C3 alkyl. In certain embodiments, -R in both formulas (PL-4) or (PL-4') 4 is methyl.

[0458] In certain embodiments, -Y and -Y'' are independently selected from the group consisting of amine, aminooxy, ketone, aldehyde, maleimidyl, thiol, alcohol, azide, 1,2,4,6-tetrazinyl, trans-cyclooctenyl, bicyclononynyl, cyclooctynyl, and protected variants thereof.

[0459] In certain embodiments, Y and Y" can react with each other, e.g., in a selective manner. For example, when -Y is an amine, -Y" is a carboxylic acid, an activated ester, or an activated carbonate to yield a residue that binds the functional group -Y*- that is an amide or a carbamate. As another example, when -Y is an azide, -Y" is an alkynyl, bicyclononynyl, or cyclooctynyl to yield a residue that binds the functional group -Y*- that is a 1,2,3-triazole. As another example, when -Y is NHO, -Y" is a ketone or an aldehyde to yield a residue that binds the functional group -Y*- that is an oxime. As another example, when -Y is SH, -Y" is a maleimide or a halocarbonyl to yield a residue that binds the functional group -Y*- that is a thiosuccinimidyl or a thioether. Similarly, the roles of -Y and -Y" can be reversed to yield -Y*- in the opposite orientation.

[0460] In certain embodiments, -Y*- comprises an amide, an oxime, a 1,2,3-triazole, a thioether, a thiosuccinimide, or an ether. 2 -It is.

[0461] These conjugation reactions may be carried out under conditions known in the art; for example, when -Y is an azide and -Y" is a cyclooctyne, conjugation will occur in any solvent in which both components exhibit suitable solubility, although aqueous solutions are known to exhibit more favorable reaction kinetics. When mixed in a suitable solvent, typically an aqueous buffer solution with a pH of 2-7 when -Y and -Y" are azide / cyclooctyne, or 6-9 when -Y and -Y" are activated ester and amine, the -Y and -Y" groups react to form an insoluble hydrogel matrix containing crosslinks of formula (PL-4'). This process may be carried out in bulk phase or under emulsification conditions in a mixed organic / aqueous system to form microparticle suspensions, e.g., microspheres, which are suitable for injection.

[0462] The terms used exclusively in connection with formulae (PL-4) and (PL-4') have the following meanings:

[0463] The term "alkyl" refers to a linear, branched, or cyclic saturated hydrocarbon group of 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In certain embodiments, an alkyl is 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, an alkyl is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0464] The term "alkoxy" refers to an alkyl group attached to an oxygen and includes, for example, methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0465] 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.

[0466] 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.

[0467] The term "aryl" refers to an aromatic hydrocarbon group of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to an aromatic ring containing at least one N, O, or S atom and 3 to 15 carbons, preferably 3 to 7 carbons, including at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.

[0468] In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule by an alkyl bond. In these situations, the substituent is referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0469] The term "halogen" or "halo" refers to bromo, fluoro, chloro or iodo.

[0470] The term "heterocyclic ring" or "heterocyclyl" refers to a 3-15 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 the exemplary groups provided above for the term "heteroaryl." In certain embodiments, the heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments, the heterocyclic ring or heterocyclyl is aromatic.

[0471] The term "optionally substituted" refers to a group that may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents, which may be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -OR aa , -SR aa , -NR aa R bb , -NO2, -C=NH(OR aa ), -C(O)R aa , -OC(O)R aa , -C(O)OR aa , -C(O)NR aa R bb , -OC(O)NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)OR bb , -S(O)R aa , -S(O)2R aa , -NR aa S(O)R bb , -C(O)NR aa S(O)R bb , -NR aa S(O)2R bb , -C(O)NR aa S(O)2R bb , -S(O)NR aa R bb , -S(O)NR aa R bb , -P(O)(OR aa )(OR bb ), heterocyclyl, heteroaryl, or aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently selected from -R cc and optionally substituted by -R aa and -R bb are each independently -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -R aa and -R bbtogether with the nitrogen atom to which they are attached form a heterocyclyl, which is optionally substituted by alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, wherein each -R cc is independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN, or -NO2.

[0472] In certain embodiments, the first PTH compound is a compound of formula (I)

[0473] [ka] [In the formula, The unmarked dashed line indicates the bond to the nitrogen of the N-terminal amine group of the PTH portion of SEQ ID NO: 51; Dashed lines with asterisks indicate parts

[0474] [ka] (In the formula, m and p are independently integers of approximately 400 to 500. indicates a bond to is.

[0475] In certain embodiments, m and p in formula (I) are independently an integer between 400 and 500. In certain embodiments, m and p in formula (I) are independently an integer between approximately 450 and 500. In certain embodiments, m and p in formula (I) are independently an integer between 450 and 500.

[0476] The compound of formula (I) is also known as palopegteriparatide, TransCon PTH or ACP-014.

[0477] It is understood that the nitrogen of the N-terminal amine group of the PTH moiety of formula (I) and the carbonyl (-(C=O)-) group to the left of the unmarked dashed line form an amide bond.

[0478] The PTH compound of formula (I) releases PTH 1-34, which is the PTH of SEQ ID NO: 51, meaning that the active PTH is PTH 1-34.

[0479] In certain embodiments, the first PTH compound is a compound of Formula (I), and the first average interval is about 1 day. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first average interval is about 1 day. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first average interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first average interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first average interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first average interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of Formula (I) (wherein m and p are independently integers between approximately 450 and 500), the first average interval is one day, and the administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of Formula (I) (wherein m and p are independently integers between 450 and 500), the first average interval is one day, and the administration is via subcutaneous injection using a pen injector.

[0480] In certain embodiments, the first PTH compound is a compound of Formula (I), and the first interval is about 1 day. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first interval is about 1 day. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of Formula (I), and the first interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of Formula (I) (wherein m and p are independently integers between approximately 450 and 500), the first interval is one day, and the administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of Formula (I) (wherein m and p are independently integers between 450 and 500), the first interval is one day, and the administration is via subcutaneous injection using a pen injector.

[0481] In certain embodiments, the first PTH compound is PTH 1-34 (SEQ ID NO: 51), which is also known as Forteo®. The active PTH in Forteo is PTH 1-34.

[0482] In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is approximately 8 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is 8 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is approximately 8 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is 8 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is approximately 8 hours, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is 8 hours, and administration is via subcutaneous injection using a pen injector.

[0483] In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately 8 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is 8 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately 8 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is 8 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately 8 hours, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is 8 hours, and administration is via subcutaneous injection using a pen injector.

[0484] In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is approximately 12 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is 12 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is approximately 12 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is 12 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is approximately 12 hours, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, and the first mean interval is 12 hours, and administration is via subcutaneous injection using a pen injector.

[0485] In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately 12 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is 12 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately 12 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is 12 hours, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately 12 hours, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is 12 hours, and administration is via subcutaneous injection using a pen injector.

[0486] In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 1 day. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 1 day. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 1 day, and administration is via subcutaneous injection using a pen injector.

[0487] In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately one day. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is one day. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately one day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is one day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is approximately one day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is one day, and administration is via subcutaneous injection using a pen injector.

[0488] In certain embodiments, the first PTH compound is PTH 1-84 (SEQ ID NO: 1), which is also known as Natpara® or Natpar®. The active PTH in Natpara / Natpar is PTH 1-84.

[0489] In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about 1 day. In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about 1 day. In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about 1 day, and administration is via subcutaneous injection using a pen injector.

[0490] In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about 1 day. In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about 1 day. In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about 1 day, and administration is via subcutaneous injection using a pen injector.

[0491] In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, which is also known as AZP-3601: AVAEIQLMHQRAKWIQDARRRAFLHKLIAEIHTAEI (SEQ ID NO: 122)

[0492] The active PTH of AZP-3601 is the protein of SEQ ID NO:122.

[0493] In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first average interval is approximately 1 day. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first average interval is approximately 1 day. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first average interval is approximately 1 day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first average interval is approximately 1 day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first average interval is approximately 1 day, and administration is via subcutaneous injection using a pen injector.

[0494] In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is approximately one day. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is one day. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is approximately one day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is one day, and administration is via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is approximately one day, and administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is one day, and administration is via subcutaneous injection using a pen injector.

[0495] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to a patient with chronic hypoparathyroidism for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0496] In certain embodiments, step (a) is administering to a patient with chronic hypoparathyroidism a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0497] In certain embodiments, step (a) is administering to a patient with chronic hypoparathyroidism a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection, for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0498] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0499] In certain embodiments, step (a) is administering to an adult patient with chronic hypoparathyroidism a compound of Formula (I), wherein m and p are integers between approximately 450 and 500, via subcutaneous injection, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0500] In certain embodiments, step (a) is administering to an adult patient with chronic hypoparathyroidism a compound of Formula (I), wherein m and p are integers between 450 and 500, via subcutaneous injection, for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0501] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0502] In certain embodiments, step (a) is administering to a pediatric patient with chronic hypoparathyroidism a compound of Formula (I), wherein m and p are integers between approximately 450 and 500, via subcutaneous injection, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0503] In certain embodiments, step (a) is administering to a pediatric patient with chronic hypoparathyroidism a compound of Formula (I), wherein m and p are integers between 450 and 500, via subcutaneous injection, for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0504] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to an adult patient having chronic hypoparathyroidism due to surgery, genetic causes, immune system-related damage to the parathyroid gland, or having idiopathic hypoparathyroidism, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0505] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0506] In certain embodiments, step (a) is administering to an adult patient with surgically induced chronic hypoparathyroidism a compound of Formula (I), wherein m and p are integers between approximately 450 and 500, via subcutaneous injection, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0507] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are integers between 450 and 500, via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0508] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0509] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between approximately 450 and 500, via subcutaneous injection to a pediatric patient with surgically induced chronic hypoparathyroidism for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0510] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between 450 and 500, via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0511] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0512] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between approximately 450 and 500, via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0513] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between 450 and 500, via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0514] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0515] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers from about 450 to about 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0516] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between 450 and approximately 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0517] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0518] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between approximately 450 and 500, via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0519] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently integers between 450 and 500, via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0520] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0521] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between one week and five years, with a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0522] In certain embodiments, step (a) is administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between 1 week and 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0523] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to an adult patient having chronic hypoparathyroidism due to surgery, genetic causes, immune system-related damage to the parathyroid gland, or having idiopathic hypoparathyroidism, for a first treatment period of from 1 week to 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0524] In certain embodiments, step (a) involves administering a compound of Formula (I) via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism, for a first treatment period of from 1 week to 5 years, with a first inter-dose interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0525] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of between one week and five years, using a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0526] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of between 1 week and 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0527] In certain embodiments, step (a) involves administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism, for a first treatment period of from 1 week to 5 years, with a first inter-dose interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0528] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism, for a first treatment period of between one week and five years, using a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0529] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism, for a first treatment period of between 1 week and 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0530] In certain embodiments, step (a) involves administering a compound of Formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of from 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0531] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between one week and five years, using a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0532] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between 1 week and 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0533] In certain embodiments, step (a) involves administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of from 1 week to 5 years, with a first inter-dose interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0534] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between one week and five years, using a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0535] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of between 1 week and 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0536] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of from 1 week to 5 years, with a first inter-dose interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0537] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to an adult patient having chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between one week and five years, using a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0538] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to an adult patient having chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between 1 week and 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0539] In certain embodiments, step (a) is administering a compound of Formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of from 1 week to 5 years, using a first inter-dose interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0540] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between approximately 450 and 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between one week and five years, using a first inter-dosing interval of one day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0541] In certain embodiments, step (a) comprises administering a compound of Formula (I), wherein m and p are independently an integer between 450 and 500, via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of between 1 week and 5 years, using a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dosing intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0542] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a patient with chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0543] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0544] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0545] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0546] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0547] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0548] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0549] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0550] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid glands, for a first treatment period of 1 week to 5 years, using a first inter-dosing interval of 8 hours, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0551] In certain embodiments, step (a) involves administering PTH 1-34 via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism, for a first treatment period of 1 week to 5 years, using a first inter-dose interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0552] In certain embodiments, step (a) involves administering PTH 1-34 via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism, for a first treatment period of 1 week to 5 years, using a first inter-dose interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0553] In certain embodiments, step (a) involves administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of 1 week to 5 years, using a first inter-dose interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0554] In certain embodiments, step (a) involves administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of 1 week to 5 years, using a first inter-dose interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0555] In certain embodiments, step (a) involves administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of 1 week to 5 years, using a first inter-dose interval of 8 hours, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0556] In certain embodiments, step (a) involves administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid glands, for a first treatment period of 1 week to 5 years, using a first inter-dose interval of 8 hours, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements, wherein the patient is a stable patient with no dose adjustments for the last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 inter-dose intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[0557] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to a patient with chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0558] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to an adult patient with chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0559] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0560] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0561] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to a pediatric patient with surgically-induced chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0562] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to an adult patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0563] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism of genetic origin, for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0564] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid gland, for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0565] In certain embodiments, step (a) is administering PTH 1-84 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to immune-mediated damage of the parathyroid glands, for a first treatment period of 1 week to 5 years, with a first inter-dosing interval of 1 day, adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin D and calcium supplements.

[0566] In certain embodiments, step (a) involves administering PTH 1-84 via subcutaneous injection to an adult patient with surgically induced chronic hypoparathyroidism for a first treatment period of 1 week to 5 years, with a first inter-dose interval of 1 day, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains in the normal range in the absence of active vitamin ...

Claims

1. 1. A first and second PTH compound for use in a method of treating chronic hypoparathyroidism, the method comprising: (a) administering a first PTH compound to a patient having chronic hypoparathyroidism multiple times at a first mean inter-dosing interval, and adjusting the dose if necessary to determine a dose for the patient at which the patient's serum calcium level remains within a normal range in the absence of active vitamin D and calcium supplements; (b) using the dose determined in step (a) to determine an initial dose for a second PTH compound to be administered multiple times to the patient at a second average interval that is longer than the first average interval; and (c) administering the second PTH compound to the patient multiple times at a second mean inter-dosing interval, starting with the initial dose determined in step (b) and adjusting the dose if necessary, until the patient's serum calcium remains within the normal range in the absence of active vitamin D and calcium supplements. The first and second PTH compounds comprising:

2. 2. The first and second PTH compounds for use according to claim 1, wherein the first mean inter-dosing interval is 8 hours.

3. 2. The first and second PTH compounds for use according to claim 1, wherein the first mean inter-dosing interval is 12 hours.

4. 2. The first and second PTH compounds for use according to claim 1, wherein the first mean inter-dosing interval is 1 day.

5. The first and second PTH compounds for use according to any one of claims 1 to 4, wherein the second mean inter-administration interval is one week.

6. The first and second PTH compounds for use according to any one of claims 1 to 5, wherein the patient is a mammalian patient.

7. The first and second PTH compounds for use according to any one of claims 1 to 6, wherein the patient is a human patient.

8. The first and second PTH compounds for use according to any one of claims 1 to 7, wherein the patient is an adult patient.

9. The first and second PTH compounds for use according to any one of claims 1 to 7, wherein the patient is a pediatric patient.

10. 10. The first and second PTH compounds for use according to any one of claims 1 to 9, wherein the first PTH compound is administered to a patient via topical, enteral or parenteral administration, or by external application, injection or infusion, such as intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via an implanted device allowing delivery of the invention to brain tissue or brain fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related regions, injection into the subchoroidal space, retroorbital injection or eye instillation.

11. The first and second PTH compounds for use according to any one of claims 1 to 10, wherein the first PTH compound is administered by subcutaneous administration, for example by subcutaneous injection.

12. 12. The first and second PTH compounds for use according to any one of claims 1 to 11, wherein the second PTH compound is administered to a patient via topical, enteral or parenteral administration, or by external application, injection or infusion, such as intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via an implantable device allowing delivery of the invention to brain tissue or brain fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related regions, injection into the subchoroidal space, retroorbital injection or eye instillation.

13. The first and second PTH compounds for use according to any one of claims 1 to 12, wherein the second PTH compound is administered by subcutaneous administration, for example by subcutaneous injection.

14. the first and / or second PTH compound is independently a compound of formula (Ia) or (Ib) 【Chemistry 1】 (In the formula, each -D is independently a PTH moiety; Each-L 1 - is independently a linker moiety covalently and reversibly attached to -D; Each-L 2 - is independently a single chemical bond or a spacer moiety; each -Z is independently a carrier moiety, e.g., a fatty acid derivative or a 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.

14. The first and second PTH compounds for use according to any one of claims 1 to 13, which are:

15. The first PTH compound is a compound of formula (I) 【Chemistry 2】 [In the formula, The unmarked dashed line indicates the bond to the nitrogen of the N-terminal amine group of the PTH portion of SEQ ID NO: 51; Dashed lines with asterisks indicate parts 【Transformation 3】 (In the formula, m and p are independently integers between approximately 400 and 500. indicates a bond to The first and second PTH compounds for use according to any one of claims 1 to 14, wherein

16. The first and second PTH compounds for use according to any one of claims 1 to 13, wherein the first PTH compound is PTH 1-34.

17. The first and second PTH compounds for use according to any one of claims 1 to 13, wherein the first PTH compound is PTH 1-84.

18. The first and second PTH compounds for use according to any one of claims 1 to 13, wherein the first PTH compound has the sequence of SEQ ID NO:

122.

19. The second PTH compound is a compound of formula (II-b) 【Chemistry 4】 (In the formula, The dashed line indicates the bond to the nitrogen of the N-terminal amine group of the PTH moiety having the sequence of SEQ ID NO: 51; Each n is independently an integer between approximately 200 and 250.

19. The first and second PTH compounds for use according to any one of claims 1 to 18, wherein

20. The PTH compound administered weekly is a compound of formula (II-b') 【Transformation 5】 (In the formula, The dashed line indicates the bond to the nitrogen of the N-terminal amine group of the PTH moiety having the sequence of SEQ ID NO: 51; Each n is independently an integer between approximately 200 and 250.

20. The first and second PTH compounds for use according to any one of claims 1 to 19, wherein

21. 21. The first and second PTH compounds for use according to claim 19 or 20, wherein each n is independently an integer of about 210 to 240.

22. 22. The first and second PTH compounds for use according to any one of claims 19 to 21, wherein each n is independently an integer from 210 to 240.

23. the second PTH compound is a compound of formula (II-i) 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 (II-i) (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, miniPEG is a COCH 2 OCH 2 CH 2 OCH 2 CH 2 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) 19. The first and second PTH compounds for use according to any one of claims 1 to 18, wherein

24. The second PTH compound is a compound of formula (II-i') 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 (II-i') (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, (miniPEG) 2 is COCH 2 OCH 2 CH 2 OCH 2 CH 2 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) 19. The first and second PTH compounds for use according to any one of claims 1 to 18, wherein

25. The active PTH of the first and second PTH compounds is the same, and the initial dose of the second PTH compound is D 2 ±25%, and D 2 But the equation [Equation 1] (In the formula, D 1 is the dose of the first PTH compound at which the patient's serum calcium level remains within the normal range in the absence of active vitamin D and calcium supplements; T 1 is the first inter-dose interval, T 2 is the second inter-dose interval) The first and second PTH compounds for use according to any one of claims 1 to 24, calculated using

26. The active PTH of the first and second PTH compounds is different, and the initial dose of the second PTH compound is first calculated using the following equation: [Equation 2] (In the formula, D supp1 is the dose of the first PTH compound that completely suppresses the secretion of endogenous PTH 1-84 in healthy volunteers, D supp2 is the dose of the second PTH compound that completely suppresses the secretion of endogenous PTH 1-84 in healthy volunteers, T supp1 is the length of the first inter-dosing interval of the first PTH compound for a healthy volunteer; T supp2 is the length of the second inter-dosing interval of the second PTH compound for healthy volunteers) Calculate the correction factor CF using the following equation: [Equation 3] (In the formula, D 1 is the dose of the first PTH compound at which the patient's serum calcium level remains within the normal range in the absence of active vitamin D and calcium supplements; T 1 is the first inter-dose interval, T 2 is the second inter-dose interval) Using D 2 and the initial dose of the second PTH compound is calculated by calculating D 2 The first and second PTH compounds for use according to any one of claims 1 to 24, wherein the first and second PTH compounds are ±25%.

27. 27. The first and second PTH compounds for use according to any one of claims 1 to 26, wherein the time between the last dose of the first PTH compound and the first dose of the second PTH compound corresponds to the average interval between two administrations of the first PTH compound.

28. 28. The first and second PTH compounds for use according to any one of claims 1 to 27, wherein the first PTH compound is the only drug containing PTH or a PTH moiety administered to the patient during the first treatment period.

29. 29. The first and second PTH compounds for use according to any one of claims 1 to 28, wherein the second PTH compound is the only drug containing PTH or a PTH moiety administered to the patient during treatment with the second PTH compound.

30. 30. The first and second PTH compounds for use according to any one of claims 1 to 29, wherein the period of treatment with the first PTH compound lasts from 1 week to 20 years.

31. 31. The first and second PTH compounds for use according to any one of claims 1 to 30, wherein the period of treatment with the second PTH compound lasts as long as the patient benefits from administration of the second PTH compound.

32. 32. The first and second PTH compounds for use according to any one of claims 1 to 31, wherein the chronic hypoparathyroidism is due to surgery, such as thyroid or parathyroid surgery, genetic causes, immune system-related damage to the parathyroid glands, or is idiopathic.

33. The first and second PTH compounds for use according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is due to surgery.

34. The first and second PTH compounds for use according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is of genetic origin.

35. 33. The first and second PTH compounds for use according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is due to immune system-related damage to the parathyroid glands.

36. The first and second PTH compounds for use according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is idiopathic.

37. 1. A PTH compound for use in the treatment of chronic hypoparathyroidism, the treatment comprising administering a weekly dose of the PTH compound to a patient having chronic hypoparathyroidism, wherein prior to initiation of treatment, the patient is clinically determined to no longer be dependent on active vitamin D and calcium supplements to maintain serum levels within the normal range.

38. 38. The PTH compound for use according to claim 37, wherein the patient has chronic hypoparathyroidism due to surgery, genetic causes, immune system-related damage to the parathyroid glands, or the hypoparathyroidism is idiopathic.

39. 39. The PTH compound for use according to claim 37 or 38, wherein the patient is treated with a first PTH compound prior to initiation with the weekly PTH compound.

40. 40. The PTH compound for use according to claim 39, wherein the first PTH compound and the weekly PTH compound are administered by subcutaneous injection.

41. 41. The PTH compound for use according to claim 39 or 40, wherein the first PTH compound is administered multiple times with a first mean inter-administration interval, with dose adjustments if necessary, and the first mean interval is one day.

42. 42. The PTH compound for use according to any one of claims 39 to 41, wherein the dose of the first PTH compound is increased during at least two consecutive administrations in response to hypocalcemia.

43. 43. The PTH compound for use according to any one of claims 39 to 42, wherein the dose of the first PTH compound is reduced between at least two consecutive administrations in response to hypercalcemia.

44. The first PTH compound is a compound of formula (I) 【Transformation 6】 [In the formula, The unmarked dashed line indicates the bond to the nitrogen of the N-terminal amine group of the PTH portion of SEQ ID NO: 51; Dashed lines with asterisks indicate parts 【Transformation 7】 (In the formula, m and p are independently integers from 400 to 500. indicates a bond to 44. The PTH compound for use according to any one of claims 39 to 43, having the formula:

45. 44. The PTH compound for use according to any one of claims 39 to 43, wherein the first PTH compound is AZP-3601.

46. 44. The PTH compound for use according to any one of claims 39 to 43, wherein the first PTH compound is PTH 1-84.

47. 47. The PTH compound for use according to any one of claims 39 to 46, wherein all inter-dosing intervals of the first PTH compound have the same length.

48. 48. The PTH compound for use according to any one of claims 39 to 47, wherein the first treatment period, which is the period from the first to the last administration of the first PTH compound, lasts from 1 week to 20 years.

49. 49. The PTH compound for use according to claim 48, wherein the first treatment period lasts at least until the patient has a serum calcium level that is within the normal range and has discontinued active vitamin D and calcium supplements.

50. 50. The PTH compound for use according to any one of claims 39 to 49, wherein the first PTH compound is the only drug containing PTH or a PTH moiety administered to the patient during the first treatment period.

51. 51. The PTH compound for use according to any one of claims 39 to 50, wherein no dose adjustment of the first PTH compound was made at least during the last inter-dose interval of the first treatment period prior to administration of the first weekly dose of the PTH compound.

52. The active PTH of the first PTH compound and the weekly PTH compound is the same, and the initial dose of the weekly PTH compound is 2 ±25%, and D 2 But the equation [Equation 4] (In the formula, D 1 is the dose of the first PTH compound at which the patient's serum calcium level remains within the normal range in the absence of active vitamin D and calcium supplements; T 1 is the first inter-dose interval, T 2 is the second inter-dose interval) 52. The PTH compound for use according to any one of claims 39 to 51, calculated using

53. The active PTH of the first PTH compound and the weekly PTH compound are different, and the initial dose of the weekly PTH compound is first calculated using the following equation: [Equation 5] (In the formula, D supp1 is the dose of the first PTH compound that completely suppresses the secretion of endogenous PTH 1-84 in healthy volunteers, D supp2 is the weekly PTH compound dose that completely suppresses endogenous PTH 1-84 secretion in healthy volunteers, T supp1 is the length of the first inter-dosing interval of the first PTH compound for a healthy volunteer; T supp2 is the length of the interval between the second doses of weekly PTH compounds for healthy volunteers) Calculate the correction factor CF using the following equation: [Equation 6] (In the formula, D 1 is the dose of the first PTH compound at which the patient's serum calcium level remains within the normal range in the absence of active vitamin D and calcium supplements; T 1 is the first inter-dose interval, T 2 is the second inter-dose interval) Using D 2 The initial weekly dose of PTH compound is calculated by calculating D 2 52. The PTH compound for use according to any one of claims 39 to 51, wherein the PTH compound has a saturation of 0.5%.

54. 54. The PTH compound for use according to any one of claims 39 to 53, wherein the time between the last dose of the first PTH compound and the first weekly dose of the PTH compound corresponds to the average interval between two administrations of the first PTH compound.

55. 55. The PTH compound for use according to any one of claims 37 to 54, wherein the weekly PTH compound is the only drug containing PTH or a PTH moiety administered to the patient during treatment with the weekly PTH compound.

56. The weekly PTH compound is a compound of formula (II-a) 【Transformation 8】 (In the formula, The dashed line indicates the bond to the nitrogen of the N-terminal amine group of the PTH moiety having the sequence of SEQ ID NO: 51; Each n is independently an integer from 200 to 250.

56. The PTH compound for use according to any one of claims 37 to 55, wherein

57. The weekly PTH compound is a compound of formula (II-i) 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 (II-i) (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, miniPEG is a COCH 2 OCH 2 CH 2 OCH 2 CH 2 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) 56. The PTH compound for use according to any one of claims 37 to 55, wherein

58. The weekly PTH compound is a compound of formula (II-i') 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 (II-i) (In the formula, k is d-Lys, γE is the l-isomer of gamma glutamic acid, (miniPEG) 2 is COCH 2 OCH 2 CH 2 OCH 2 CH 2 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) 56. The PTH compound for use according to any one of claims 37 to 55, wherein

59. 59. The PTH compound for use according to any one of claims 37 to 58, wherein the period of treatment with the weekly PTH compound lasts for as long as the patient benefits from the administration of the weekly PTH compound.

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