PTH therapeutic regimen comprising two PTH compounds

Abstract

The present application relates to the use of a PTH compound for the treatment of chronic parathyroidism wherein said treatment comprises the step of administering a weekly dose of a PTH compound per week to a patient suffering from chronic parathyroidism, and wherein before the start of the treatment, the PTH compound is added to the patient. Patients are clinically determined to no longer rely on active vitamin D and calcium supplements to maintain serum within a normal range; and related aspects.

Description

Technical Field

[0001] The present application relates to the use of a PTH compound in treating chronic hypoparathyroidism, wherein the treatment comprises the step of administering a weekly dose of a PTH compound to a patient suffering from chronic hypoparathyroidism, and 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 levels within a normal range; and related aspects. Background Art

[0002] Hypoparathyroidism is a rare endocrine disorder characterized by low serum calcium and inappropriately low (deficient) circulating parathyroid hormone (PTH) levels, most commonly seen in adults following thyroid surgery. Standard treatment, also known as conventional therapy, is the use of active vitamin D and calcium supplements, which increase calcium and phosphate absorption and serum levels at the expense of abnormally increased urinary calcium excretion.

[0003] The major complication of hypoparathyroidism is hypercalciuria, which is due to a lack of PTH-dependent calcium reabsorption in the distal renal tubules. Hypercalciuria is associated with an increased risk of nephrocalcinosis, kidney stones, and renal failure. In addition, nonphysiological levels of PTH may lead to hypocalcemia (if PTH levels are too low) or hypercalcemia (if PTH levels are too high, such as due to an overdose of externally administered PTH). Hypocalcemia may cause symptoms such as numbness, muscle spasms, seizures, confusion, or cardiac arrest. Symptoms of hypercalcemia may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones, or cardiac arrhythmias (including cardiac arrest).

[0004] The physiological actions of PTH include releasing calcium and phosphate from bone, retaining calcium but not phosphate in the kidneys, and stimulating renal production of active vitamin D (1,25(OH)2 vitamin D3), which in turn enhances intestinal absorption of calcium and phosphate. When PTH is delivered intermittently (as currently provided as one or more daily injections of PTH 1-84 or PTH 1-34), it acts on bone as an anabolic agent by preferentially activating osteoblasts rather than osteoclasts. The anabolic effects of intermittent PTH exposure may not be beneficial in patients with hypoparathyroidism, who already have high bone mineral density because this disease is characterized by a low bone turnover state. In contrast, continuous exposure to PTH may provide more normal bone turnover and restore physiologically normal bone.

[0005] Several PTH therapies are currently under development and are intended to be administered once daily (long-acting) or once weekly (ultra-long-acting) at doses that effectively maintain serum calcium at normal levels. Gradually stopping a patient's conventional therapy and switching to a long-acting or ultra-long-acting PTH compound carries the risk of overdosing or underdosing PTH, which may lead to hypercalcemia or hypocalcemia, respectively, and associated negative side effects. Therefore, to provide safe treatment, this titration process must begin with a low, safe dose of a long-acting or ultra-long-acting PTH compound in combination with conventional therapy, followed by multiple dose adjustments, ideally eliminating the administration of conventional therapy, to ultimately determine a safe and effective dose of the long-acting or ultra-long-acting PTH compound. While this can be a safe process, it is slow and patients do not benefit from a true and effective alternative therapy during the long-term titration period.

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

[0007] Especially with weekly or longer dosing intervals, this titration process can be time consuming because, for example, if a PTH compound is overdosed once weekly, it will take significantly longer to clear the PTH from the patient's body, potentially leading to side effects that may persist for an unacceptable period of time.

[0008] Therefore, although treatment with ultra-long-acting PTH compounds appears attractive from the patient's perspective, it raises new, as yet unidentified challenges for which no solutions currently exist. Summary of the Invention

[0009] In a first aspect, the present application relates to the use of a PTH compound in the treatment of chronic hypoparathyroidism, wherein the treatment comprises the step of administering a dose of a PTH compound once a week to a patient suffering from chronic hypoparathyroidism, 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 levels within a normal range.

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

[0011] In a third aspect, the present application relates to the use of a PTH compound in the preparation of a medicament for treating chronic hypoparathyroidism, wherein the medicament is administered once a week to a patient suffering from chronic hypoparathyroidism, and wherein, prior to administration of the first dose of the medicament, the patient has been clinically determined to be no longer dependent on active vitamin D and calcium supplements to maintain serum calcium within a normal range.

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

[0013] In a fifth aspect, the present application relates to a method for treating a patient suffering from chronic hypoparathyroidism, the method comprising the following steps: administering a pharmaceutically effective dose of a first PTH compound daily during a first treatment period, and then switching to weekly administration of a pharmaceutically effective dose of a second PTH compound during a second treatment period, wherein before the treatment period is switched, it is clinically determined that the patient is no longer dependent on active vitamin D and calcium supplements to maintain serum calcium levels within a normal range.

[0014] In a sixth aspect, the present application relates to the use of a first PTH compound in the preparation of a first medicament for treating chronic hypoparathyroidism, and the use of a second PTH compound in the preparation of a second medicament for treating chronic hypoparathyroidism; wherein, during a first treatment period, the first medicament is administered daily to a patient suffering from chronic hypoparathyroidism, and then the patient is switched to weekly administration of the second medicament during a second treatment period, wherein, before the treatment period is switched, it is clinically determined that the patient is no longer dependent on active vitamin D and calcium supplements to maintain serum calcium levels within a normal range.

[0015] In a seventh aspect, the present application relates to a method for treating chronic hypoparathyroidism using a first PTH compound and a second PTH compound, the method comprising:

[0016] (a) administering a first PTH compound to a patient with chronic hypoparathyroidism a plurality of times at a first average administration interval, adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within a normal range without the use of active vitamin D and calcium supplements;

[0017] (b) using the dose determined in step (a), determining an initial dose of a second PTH compound to be administered to the patient multiple times at a second average interval that is longer than the first average interval; and

[0018] (c) administering the second PTH compound to the patient a plurality of times at a second average administration interval, starting from the initial dose determined in step (b), and adjusting the dose as needed, until the patient's serum calcium remains within the normal range without the use of active vitamin D and calcium supplements.

[0019] In an eighth aspect, the present application relates to a method for treating a patient suffering from chronic hypoparathyroidism, comprising:

[0020] (a) administering a first PTH compound to the patient a plurality of times at a first average administration interval, adjusting the dose as needed, to determine a dose that maintains the patient's serum calcium level within a normal range without the use of active vitamin D and calcium supplements;

[0021] (b) using the dose determined in step (a), determining an initial dose of a second PTH compound to be administered to the patient multiple times at a second average interval that is longer than the first average interval; and

[0022] (c) administering the second PTH compound to the patient a plurality of times at a second average administration interval, starting from the initial dose determined in step (b), and adjusting the dose as needed, until the patient's serum calcium remains within the normal range without the use of active vitamin D and calcium supplements.

[0023] In a ninth aspect, the present application relates to the use of a first PTH compound in the preparation of a first medicament for treating chronic hypoparathyroidism, and the use of a second PTH compound in the preparation of a second medicament for treating chronic hypoparathyroidism, wherein the first medicament is intended for:

[0024] (a) administering to a patient with chronic hypoparathyroidism multiple times at a first average administration interval, adjusting the dose as needed, to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements;

[0025] (b) using the dose determined in step (a), determining an initial dose of a second PTH compound to be administered to the patient multiple times at a second average interval longer than the first average interval; and

[0026] The second agent is administered to the patient a plurality of times at second even intervals, beginning with the initial dose determined in step (b), and the dose is adjusted as needed until the patient's serum calcium remains within the normal range without the use of active vitamin D and calcium supplements.

[0027] In a tenth aspect, the present application relates to a method for treating a patient population with chronic hypoparathyroidism, comprising:

[0028] a) administering a first PTH compound to a patient population a plurality of times at a first average administration interval, and adjusting the dosage as needed, to determine a dosage for individual patients in the patient population that maintains the patient's serum calcium level within a normal range without the use of active vitamin D and calcium supplements;

[0029] b) determining an initial dose of a second PTH compound to be administered to the patients using the dose administered at a second average interval that is longer than the first average interval, wherein the dose of the first PTH compound has been determined to result in serum calcium levels in the patients within a normal range without the use of active vitamin D and calcium supplements; and

[0030] c) administering the second PTH compound to patients for whom the starting dose of the second PTH has been determined multiple times at the second average administration interval, adjusting the dose as needed, until the patient's serum calcium remains within the normal range without the use of active vitamin D and calcium supplements.

[0031] Safely initiating ultra-long-acting PTH therapy (eg, a second PTH compound) in patients with chronic hypoparathyroidism who have not received PTH therapy is challenging because of the need for careful titration to prevent hypocalcemia and hypercalcemia and the inability to rapidly respond to such adverse effects if they occur due to the long PK of these compounds.

[0032] Applicants have surprisingly discovered that treatment with a PTH compound (e.g., the first PTH compound of the present application) can stabilize PTH dosages and have identified these patients as ideal candidates for switching to a PTH compound administered with a longer interval between doses (e.g., once-weekly PTH therapy) because titration of conventional therapy is not required and the risk of calcium excursion is low.

[0033] Furthermore, Applicants have surprisingly discovered a safe method for treating patients with an ultra-long-acting PTH compound (e.g., a once-weekly PTH compound) that provides the benefits of appropriate PTH replacement therapy from the outset of treatment: by initiating treatment with a long-acting PTH compound (e.g., with a first PTH compound), conventional therapy can be gradually discontinued while maintaining the ability to intervene rapidly if serum calcium exceeds normal levels by adjusting the dose or skipping a dose of the long-acting PTH compound if serum calcium is too high. This provides a safe way for patients to discontinue conventional therapy and determine their individual PTH dosage requirements.

[0034] Thus, Applicants have discovered that stable chronic hypoparathyroidism patients, those who are administered a dose of a PTH compound (such as the first PTH compound of the present application) that allows serum calcium levels to be within the normal range without taking active vitamin D and calcium supplements, are particularly suitable for initiating treatment with an ultra-long-acting PTH compound (such as a PTH compound having, for example, a weekly dosing interval).

[0035] The advantage of this treatment is that it shortens the time to reach an effective dose of the ultra-long-acting PTH compound while ensuring the safety of the patient. Detailed Description of the Invention

[0037] In this application, the terms used have the following meanings.

[0038] 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 in the range of 8.3 mg / dL (corrected for albumin) to 10.6 mg / dL (corrected for albumin). The term "albumin-corrected" with respect to serum calcium levels means that the measured serum calcium levels are corrected for calcium bound to albumin according to the formula: albumin-corrected serum calcium (mg / dL) = measured total calcium Ca (mg / dL) + 0.8 (4.0-serum albumin [g / dL]).

[0039] As used herein, the term "starting dose" refers to the dose of the first PTH compound administered to a patient when treatment with the first PTH compound is first initiated, i.e., the patient has not previously received a dose of the first PTH compound. It should be understood that the patient can continue to use this starting dose for a period of time, such as several days, weeks, or months, or throughout the treatment period, or the dose can be increased or decreased in response to certain events (e.g., the occurrence of hypocalcemia or hypercalcemia).

[0040] As used herein, the term "mean" refers to the simple (equally weighted) arithmetic mean, which can be obtained by adding all variables in a data set and dividing the result by the number of variables.

[0041] If hypoparathyroidism persists for at least six months, the patient is said to have "chronic hypoparathyroidism."

[0042] As used herein, the term "stable patient" refers to a patient with normal serum calcium levels who is taking a PTH compound (e.g., a first or second PTH compound) and who is not receiving conventional therapy (i.e., not using active vitamin D and calcium supplements). The dose of the PTH compound (e.g., a first or second PTH compound) administered to a stable patient may be adjusted from time to time. It should be understood that a stable patient may still take <600 mg / day of oral calcium, which may be required for nutritional reasons and is not considered a therapeutic amount of calcium.

[0043] As used herein, the term "active vitamin D" corresponds to 1,25-dihydroxyvitamin D, also known as calcitriol.

[0044] As used herein, the term "active PTH" in relation to a first or second PTH compound refers to the PTH-containing compound released from the first or second PTH compound, respectively, provided that the first or second PTH compound is capable of releasing such a PTH-containing compound; however, if the first and / or second PTH compound is not capable of releasing a PTH-containing moiety, the term refers to the first and / or second PTH compound itself. For example, a conjugate of formula (I), (Ia), (I-a'), (Ib), and (I-b') releases PTH 1-34, in which case PTH 1-34 is the active PTH of compounds (I), (Ia), (I-a'), (Ib), and (I-b'). A compound of formula (II-i) releases a compound of formula (II-ii), and thus, the compound of formula (II-ii) is the active PTH of the compound of formula (II-i). Similarly, a compound of formula (II-i') releases a compound of formula (II-ii'), and thus, the compound of formula (II-ii') is the active PTH of the compound of formula (II-i'). 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 thus the active PTHs of PTH 1-34, PTH 1-84, and AZP-3601 are PTH 1-34, PTH 1-84, and AZP-3601, respectively.

[0045] As used herein, the term "PTH" refers to all PTH polypeptides, such as those from mammalian species, particularly humans and mammalian species, more particularly humans and murine species, and variants, analogs, orthologs, homologs, derivatives, and fragments thereof, characterized by increasing serum calcium and renal phosphate excretion and decreasing serum phosphorus and renal calcium excretion. The term "PTH" also refers to all PTHrP polypeptides, such as the polypeptide of SEQ ID NO:121, which 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 and variants, homologs, and derivatives thereof, which exhibit substantially the same biological activity, namely, increasing serum calcium and renal phosphate 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.

[0046] In certain embodiments, the term "PTH" refers to one of the following polypeptide sequences:

[0047] SEQ ID NO: 1 (PTH 1-84)

[0048] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ

[0049] SEQ ID NO:2 (PTH 1-83)

[0050] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS

[0051] SEQ ID NO: 3 (PTH 1-82)

[0052] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK

[0053] SEQ ID NO:4 (PTH 1-81)

[0054] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA

[0055] SEQ ID NO:5(PTH 1-80)

[0056] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK

[0057] SEQ ID NO:6(PTH 1-79)

[0058] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

[0059] NVLVESHEKSLGEADKADVNVLT

[0060] SEQ ID NO:7(PTH 1-78)

[0061] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

[0062] NVLVESHEKSLGEADKADVNVL

[0063] SEQ ID NO:8(PTH 1-77)

[0064] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

[0065] NVLVESHEKSLGEADKADVNV

[0066] SEQ ID NO:9(PTH 1-76)

[0067] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

[0068] NVLVESHEKSLGEADKADVN

[0069] SEQ ID NO:10(PTH 1-75)

[0070] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED

[0071] <h2 style=";text-align:left;direction:ltr">NVLVESHEKSLGEADKADV<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0072] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:11(PTH 1-74)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0073] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0074] <h2 style=";text-align:left;direction:ltr"> NVLVESHEKSLGEADKAD<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0075] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:12(PTH 1-73)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0076] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0077] <h2 style=";text-align:left;direction:ltr"> NVLVESHEKSLGEADKA<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0078] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:13(PTH 1-72)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0079] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0080] <h2 style=";text-align:left;direction:ltr"> NVLVESHEKSLGEADK<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0081] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:14(PTH 1-71)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0082] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0083] <h2 style=";text-align:left;direction:ltr"> NVLVESHEKSLGEAD<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0084] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:15(PTH 1-70)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0085] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0086] <h2 style=";text-align:left;direction:ltr"> NVLVESHEKSLGEA<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0087] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:16(PTH 1-69)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0088] <h2 style=";text-align:left;direction:ltr">SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0089] <h2 style=";text-align:left;direction:ltr"> NVLVESHEKSLGE<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0090] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:17(PTH 1-68)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0091] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0092] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:18(PTH 1-67)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0093] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0094] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:19(PTH 1-66)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0095] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0096] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:20(PTH 1-65)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0097] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0098] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:21(PTH 1-64)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0099] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0100] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:22(PTH 1-63)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0101] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0102] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:23(PTH 1-62)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0103] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0104] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:24(PTH 1-61)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0105] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0106] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:25(PTH 1-60)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0107] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0108] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:26(PTH 1-59)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0109] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0110] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:27(PTH 1-58)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0111] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0112] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:28(PTH 1-57)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0113] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0114] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:29(PTH 1-56)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0115] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0116] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:30(PTH 1-55)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0117] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0118] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:31(PTH 1-54)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0119] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0120] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:32(PTH 1-53)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0121] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0122] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:33(PTH 1-52)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0123] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0124] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:34(PTH 1-51)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0125] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0126] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:35(PTH 1-50)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0127] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0128] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:36(PTH 1-49)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0129] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0130] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:37(PTH 1-48)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0131] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0132] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:38(PTH 1-47)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0133] <h2 style=";text-align:left;direction:ltr"> SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG

[0134] SEQ ID NO:39(PTH 1-46)

[0135] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA

[0136] SEQ ID NO:40(PTH 1-45)

[0137] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD

[0138] SEQ ID NO:41(PTH 1-44)

[0139] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR

[0140] SEQ ID NO:42(PTH 1-43)

[0141] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP

[0142] SEQ ID NO:43(PTH 1-42)

[0143] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA

[0144] SEQ ID NO:44(PTH 1-41)

[0145] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL

[0146] SEQ ID NO:45(PTH 1-40)

[0147] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP

[0148] SEQ ID NO:46(PTH 1-39)

[0149] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA

[0150] SEQ ID NO:47(PTH 1-38)

[0151] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG

[0152] SEQ ID NO:48(PTH 1-37)

[0153] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL

[0154] SEQ ID NO:49(PTH 1-36)

[0155] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA

[0156] SEQ ID NO:50(PTH 1-35)

[0157] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV

[0158] SEQ ID NO:51(PTH 1-34)

[0159] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF

[0160] SEQ ID NO:52(PTH 1-33)

[0161] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN

[0162] SEQ ID NO:53(PTH 1-32)

[0163] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH

[0164] SEQ ID NO:54(PTH 1-31)

[0165] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV

[0166] SEQ ID NO:55(PTH 1-30)

[0167] SVSEIQLMHNLGKHLNSMERVEWLRKKLQD

[0168] SEQ ID NO:56(PTH 1-29)

[0169] SVSEIQLMHNLGKHLNSMERVEWLRKKLQ

[0170] SEQ ID NO:57 (PTH 1-28)

[0171] SVSEIQLMHNLGKHLNSMERVEWLRKKL

[0172] SEQ ID NO:58 (PTH 1-27)

[0173] SVSEIQLMHNLGKHLNSMERVEWLRKK

[0174] SEQ ID NO:59 (PTH 1-26)

[0175] SVSEIQLMHNLGKHLNSMERVEWLRK

[0176] SEQ ID NO:60 (PTH 1-25)

[0177] SVSEIQLMHNLGKHLNSMERVEWLR

[0178] SEQ ID NO:61 (amidated PTH 1-84)

[0179] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ; wherein the C-terminus is amidated

[0180] SEQ ID NO:62 (amidated PTH 1-83)

[0181] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKS; wherein the C-terminus is amidated

[0182] SEQ ID NO:63 (amidated PTH 1-82)

[0183] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAK; wherein the C-terminus is amidated

[0184] SEQ ID NO: 64 (amidated PTH 1-81)

[0185] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKA; wherein the C-terminus is amidated

[0186] SEQ ID NO:65 (amidated PTH 1-80)

[0187] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTK; wherein the C-terminus is amidated

[0188] SEQ ID NO: 66 (amidated PTH 1-79)

[0189] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLT; wherein the C-terminus is amidated

[0190] SEQ ID NO:67 (amidated PTH 1-78)

[0191] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVL; wherein the C-terminus is amidated

[0192] SEQ ID NO: 68 (amidated PTH 1-77)

[0193] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNV; wherein the C-terminus is amidated

[0194] SEQ ID NO: 69 (amidated PTH 1-76)

[0195] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN; wherein the C-terminus is amidated

[0196] SEQ ID NO:70 (amidated PTH 1-75)

[0197] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADV; wherein the C-terminus is amidated

[0198] SEQ ID NO:71 (amidated PTH 1-74)

[0199] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKAD; wherein the C-terminus is amidated

[0200] SEQ ID NO:72 (amidated PTH 1-73)

[0201] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKA; wherein the C-terminus is amidated

[0202] SEQ ID NO:73 (amidated PTH 1-72)

[0203] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADK; wherein the C-terminus is amidated

[0204] SEQ ID NO:74 (amidated PTH 1-71)

[0205] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEAD; wherein the C-terminus is amidated

[0206] SEQ ID NO:75 (amidated PTH 1-70)

[0207] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEA; wherein the C-terminus is amidated

[0208] SEQ ID NO:76 (amidated PTH 1-69)

[0209] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGE; wherein the C-terminus is amidated

[0210] SEQ ID NO:77 (amidated PTH 1-68)

[0211] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLG; wherein the C-terminus is amidated

[0212] SEQ ID NO:78 (amidated PTH 1-67)

[0213] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSL; wherein the C-terminus is amidated

[0214] SEQ ID NO:79 (amidated PTH 1-66)

[0215] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKS; wherein the C-terminus is amidated

[0216] SEQ ID NO:80 (amidated PTH 1-65)

[0217] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEK; wherein the C-terminus is amidated

[0218] SEQ ID NO:81 (amidated PTH 1-64)

[0219] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHE; wherein the C-terminus is amidated

[0220] SEQ ID NO:82 (amidated PTH 1-63)

[0221] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESH; wherein the C-terminus is amidated

[0222] SEQ ID NO:83 (amidated PTH 1-62)

[0223] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVES; wherein the C-terminus is amidated

[0224] SEQ ID NO:84 (amidated PTH 1-61)

[0225] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLVE; wherein the C-terminus is amidated

[0226] SEQ ID NO:85 (amidated PTH 1-60)

[0227] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV; wherein the C-terminus is amidated

[0228] SEQ ID NO:86 (amidated PTH 1-59)

[0229] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVL; wherein the C-terminus is amidated

[0230] SEQ ID NO:87 (amidated PTH 1-58)

[0231] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNV; wherein the C-terminus is amidated

[0232] SEQ ID NO:88 (amidated PTH 1-57)

[0233] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDN; wherein the C-terminus is amidated

[0234] SEQ ID NO:89 (amidated PTH 1-56)

[0235] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKED; the C-terminus is amidated

[0236] SEQ ID NO:90 (amidated PTH 1-55)

[0237] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKE; wherein the C-terminus is amidated

[0238] SEQ ID NO:91 (amidated PTH 1-54)

[0239] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKK; the C-terminus is amidated

[0240] SEQ ID NO:92 (amidated PTH 1-53)

[0241] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRK; the C-terminus is amidated

[0242] SEQ ID NO:93 (amidated PTH 1-52)

[0243] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPR; wherein the C-terminus is amidated

[0244] SEQ ID NO:94 (amidated PTH 1-51)

[0245] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRP; wherein the C-terminus is amidated

[0246] SEQ ID NO:95 (amidated PTH 1-50)

[0247] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQR; wherein the C-terminus is amidated

[0248] SEQ ID NO:96 (amidated PTH 1-49)

[0249] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQ; wherein the C-terminus is amidated

[0250] SEQ ID NO:97 (amidated PTH 1-48)

[0251] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS; the C-terminus is amidated

[0252] SEQ ID NO:98 (amidated PTH 1-47)

[0253] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAG; the C-terminus is amidated

[0254] SEQ ID NO:99 (amidated PTH 1-46)

[0255] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDA; wherein the C-terminus is amidated

[0256] SEQ ID NO: 100 (amidated PTH 1-45)

[0257] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRD; wherein the C-terminus is amidated

[0258] SEQ ID NO: 101 (amidated PTH 1-44)

[0259] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPR; wherein the C-terminus is amidated

[0260] SEQ ID NO: 102 (amidated PTH 1-43)

[0261] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAP; wherein the C-terminus is amidated

[0262] SEQ ID NO: 103 (amidated PTH 1-42)

[0263] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLA; wherein the C-terminus is amidated

[0264] SEQ ID NO: 104 (amidated PTH 1-41)

[0265] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPL; wherein the C-terminus is amidated

[0266] SEQ ID NO: 105 (amidated PTH 1-40)

[0267] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAP; the C-terminus is amidated

[0268] SEQ ID NO: 106 (amidated PTH 1-39)

[0269] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGA; wherein the C-terminus is amidated

[0270] SEQ ID NO: 107 (amidated PTH 1-38)

[0271] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALG; the C-terminus is amidated

[0272] SEQ ID NO: 108 (amidated PTH 1-37)

[0273] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL; wherein the C-terminus is amidated

[0274] SEQ ID NO: 109 (amidated PTH 1-36)

[0275] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVA; wherein the C-terminus is amidated

[0276] SEQ ID NO: 110 (amidated PTH 1-35)

[0277] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFV; wherein the C-terminus is amidated

[0278] SEQ ID NO: 111 (amidated PTH 1-34)

[0279] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF; the C-terminus is amidated

[0280] SEQ ID NO: 112 (amidated PTH 1-33)

[0281] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN; wherein the C-terminus is amidated

[0282] SEQ ID NO: 113 (amidated PTH 1-32)

[0283] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVH; wherein the C-terminus is amidated

[0284] SEQ ID NO: 114 (amidated PTH 1-31)

[0285] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDV; wherein the C-terminus is amidated

[0286] SEQ ID NO: 115 (amidated PTH 1-30)

[0287] SVSEIQLMHNLGKHLNSMERVEWLRKKLQD; wherein the C-terminus is amidated

[0288] SEQ ID NO: 116 (amidated PTH 1-29)

[0289] SVSEIQLMHNLGKHLNSMERVEWLRKKLQ; wherein the C-terminus is amidated

[0290] SEQ ID NO: 117 (amidated PTH 1-28)

[0291] SVSEIQLMHNLGKHLNSMERVEWLRKKL; wherein the C-terminus is amidated

[0292] SEQ ID NO: 118 (amidated PTH 1-27)

[0293] SVSEIQLMHNLGKHLNSMERVEWLRKK; the C-terminus is amidated

[0294] SEQ ID NO: 119 (amidated PTH 1-26)

[0295] SVSEIQLMHNLGKHLNSMERVEWLRK; wherein the C-terminus is amidated

[0296] SEQ ID NO: 120 (amidated PTH 1-25)

[0297] SVSEIQLMHNLGKHLNSMERVEWLR; the C-terminus is amidated

[0298] SEQ ID NO:121 (PTHrP)

[0299] AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATSEVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVETYKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDSGVTGSGLEGDHLSDTSTTSLELDSRRH

[0300] 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.

[0301] The terms "PTH molecule" and "PTH portion" also include poly (amino acid) conjugates having a sequence as described above but having a backbone comprising amide and non-amide bonds (e.g., ester bonds), such as depsipeptides. Depsipeptides are chains of amino acid residues wherein the backbone comprises amide (peptide) and ester bonds. Thus, as used herein, the term "side chain" refers to a moiety attached to the alpha carbon of an amino acid moiety if the amino acid moiety is attached via an amine bond (e.g., in proteins and peptides), or to any moiety comprising a carbon atom attached to the backbone of a poly (amino acid) conjugate, such as in the case of depsipeptides. In certain embodiments, the term "PTH" refers to a sequence having a backbone formed by an amide (peptide) bond.

[0302] As used herein, the term "long-acting PTH compound" refers to a compound comprising a PTH molecule or a PTH portion that is capable of maintaining a PD response (e.g., increasing serum calcium levels) for at least 24 hours after administration. As used herein, the term "ultra-long-acting PTH compound" refers to a compound comprising a PTH molecule or a PTH portion that is capable of maintaining a PD response (e.g., increasing serum calcium levels) for at least one week after administration.

[0303] 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 portion and from which at least one PTH molecule or PTH portion is released with a release half-life of at least 12 hours.

[0304] 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 in a sustained-release PTH compound or PTH prodrug, respectively, to be released under physiological conditions (i.e., aqueous buffer, pH 7.4, 37°C).

[0305] As used herein, the term "peptide" refers to a chain of at least two and up to 50 amino acid monomer moieties (also referred to as "amino acid residues") connected by peptide (amide) bonds. The amino acid monomers can be selected from proteinogenic amino acids and non-proteinogenic amino acids, and can be D-amino acids or L-amino acids. The term "peptide" also includes peptidomimetics, such as peptoids, beta peptides, cyclic peptides, and depsipeptides, and encompasses peptidomimetics having up to 50 monomer moieties. As used herein, the term "protein" refers to a chain of more than 50 amino acid monomer moieties (also referred to as "amino acid residues") connected by peptide bonds, wherein preferably no more than 12,000 amino acid monomers are connected by peptide bonds, for example no more than 10,000 amino acid monomer moieties, no more than 8,000 amino acid monomer moieties, no more than 5,000 amino acid monomer moieties, or no more than 2,000 amino acid monomer moieties. For simplicity, PTH moieties and PTH molecules are collectively referred to herein as "proteins."

[0306] As used herein, the term "physiological conditions" refers to an aqueous buffer having a pH of 7.4 and a temperature of 37°C.

[0307] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more active ingredients (e.g., at least one PTH compound) and one or more excipients, as well as any product produced directly or indirectly by the combination, complexation, or polymerization of any two or more components of the composition, or by the dissociation of one or more components, or by other types of reactions or interactions of one or more components. Therefore, the pharmaceutical composition used in the present application encompasses any composition made by mixing one or more PTH compounds and a pharmaceutically acceptable excipient.

[0308] As used herein, the term "excipient" refers to a diluent, adjuvant or carrier used together with a therapeutic agent (such as a drug or prodrug). Such pharmaceutical excipients can be sterile liquids, such as water and oil (including oils from petroleum, animal, plant or synthetic sources), including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered orally, water is an example of an excipient. When the pharmaceutical composition is administered intravenously, normal saline and aqueous glucose solution are examples of excipients. In certain embodiments, normal saline solution, aqueous glucose solution and aqueous glycerol solution are used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. If desired, the pharmaceutical composition may also contain a small amount of a wetting agent or emulsifier, a pH buffer such as acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or a detergent such as Tween, poloxamer, poloxamines, CHAPS, Igepal, or an amino acid (e.g., glycine, lysine, or histidine). These pharmaceutical compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, or sustained-release formulations. The pharmaceutical composition may be formulated into a suppository with conventional binders and excipients such as triglycerides. Oral formulations may contain standard excipients such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions will contain a therapeutically effective amount of the drug or biologically active moiety, and an appropriate amount of excipients to provide a form suitable for administration to a patient. The formulation should suit the mode of administration.

[0309] As used herein, the term "liquid composition" refers to a mixture comprising a water-soluble PTH compound and one or more solvents (eg, water).

[0310] The term "suspension composition" refers to a mixture comprising at least one water-insoluble PTH compound and one or more solvents (eg, water).

[0311] As used herein, the term "dry composition" refers to a pharmaceutical composition provided in a dried form. Suitable drying methods include spray drying and lyophilization, i.e., freeze drying. Such dry compositions may have a residual water content of at most 10%, such as less than 5% or less than 2%, as determined by Karl Fischer. In certain embodiments, such dry pharmaceutical compositions are dried by lyophilization.

[0312] As used herein, the term "drug" refers to a substance, such as PTH, that is used to treat, cure, prevent, or diagnose disease or to otherwise enhance physical or mental health. If a drug is conjugated to another moiety, the portion of the resulting product derived from the drug is referred to as the "drug moiety."

[0313] As used herein, the term "prodrug" refers to a covalent conjugate in which the drug moiety is reversibly covalently linked to a specialized protecting group via a reversible linker moiety, also referred to as a "reversible prodrug linker moiety" or "reversible linker moiety," which is reversibly linked to the biologically active moiety, and in which the specialized protecting group alters or eliminates undesirable properties in the parent molecule. This also includes enhancing the beneficial properties of the drug and inhibiting undesirable properties. The specialized non-toxic protecting group is referred to as a "carrier." The prodrug releases the reversibly covalently bound drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate comprising a drug moiety that is covalently reversibly conjugated to a carrier moiety via a reversible linker moiety, wherein the covalent reversible conjugation of the carrier to the reversible linker moiety is direct or carried out via a spacer. This conjugate releases the pre-conjugated drug moiety in the form of a free, unmodified drug.

[0314] A "reversible linkage" is a linkage that is degradable (i.e., cleavable) under physiological conditions (pH 7.4, 37°C aqueous buffer) in the absence of enzymes with a half-life ranging from one hour to three months, in certain embodiments, from one hour to two months, in certain embodiments, from one hour to one month, in certain embodiments, from one hour to three weeks, in certain embodiments, from one hour to two weeks, in certain embodiments, from 12 hours to two weeks, in certain embodiments, from 12 hours to one week. Thus, a stable linkage is a linkage that has a half-life of more than three months under physiological conditions (pH 7.4, 37°C aqueous buffer) in the absence of enzymes.

[0315] 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 links a drug moiety to a carrier, which upon cleavage releases the drug in free form. As used herein, the term "free form" of a drug refers to its unmodified, pharmacologically active form.

[0316] As used herein, the term "agent" refers to a compound comprising at least one functional group for reacting with a functional group of another compound or drug. It should be understood that drugs comprising functional groups (such as primary or secondary amine or hydroxyl functional groups) are also reagents.

[0317] As used herein, the term "moiety" refers to a portion of a molecule that lacks one or more atoms compared to the corresponding agent. For example, if a reagent of the formula "HXH" reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure "HX-" or "-X-", where each "-" represents a connection to another moiety. Thus, the drug moiety is released from the prodrug as a drug.

[0318] It is understood that if a chemical structure of a group of atoms is provided where the group of atoms is connected to at least one other moiety or interrupts a moiety, the chemical structure may be connected to the at least one other moiety or interrupted moiety in either orientation unless expressly stated otherwise. For example, the moiety "-C(O)N(R 1 )-” can be used as “-C(O)N(R 1 )-" or "-N(R 1 )C(O)-" connects two parts, or interrupts one part. Similarly, part

[0319]

[0320] As the following can be connected to two parts or can interrupt one part:

[0321]

[0322] As used herein, the term "functional group" refers to a group of atoms that can react with another group of atoms. Functional groups include, but are not limited to, the following groups: carboxylic acid, primary or secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamide, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine.

[0323] When the PTH compound contains one or more acidic or basic groups, the present application also includes its corresponding pharmaceutically or toxicologically acceptable salts, in particular its pharmaceutically usable salts. Therefore, according to the present application, PTH compounds containing acidic groups can be used, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts formed with ammonia or organic amines (such as ethylamine, ethanolamine, triethanolamine or amino acids). According to the present application, PTH compounds containing one or more basic groups (i.e., groups that can be protonated) can be present and used in the form of addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic 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 into cations are known to those skilled in the art, such as alkylation of amine groups to produce positively charged ammonium groups and suitable counterions of salts. If the PTH compound contains both acidic and basic groups, in addition to the above-mentioned salt forms, the application also includes inner salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these compounds with organic or inorganic acids or bases in a solvent or dispersant, or by obtaining by anion exchange or cation exchange with other salts. The present application also includes all salts of compounds which are unsuitable for direct use in medicine due to low physiological compatibility but which can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0324] The term "pharmaceutically acceptable" refers to a substance that does not cause harm when administered to a patient, and in certain embodiments refers to a substance approved for use in animals, and particularly in humans, by a regulatory agency, such as the EMA (Europe) and / or the FDA (USA) and / or any other national regulatory agency.

[0325] As used herein, the term "about" or "approximately" is used in conjunction with a numerical value to indicate a range that includes the numerical value plus and minus no more than 10% of the numerical value, in certain embodiments no more than 8% of the numerical value, in certain embodiments no more than 5% of the numerical value, and in certain embodiments no more than 2% of the numerical value. For example, the phrase "about 200" or "approximately 200" is used to indicate a range of 200 + / - 10%, i.e., a range of 180 to 220, inclusive; in certain embodiments, 200 + / - 8%, i.e., a range of 184 to 216, inclusive; in certain embodiments, 200 + / - 5%, i.e., a range of 190 to 210, inclusive; and in certain embodiments, 200 + / - 2%, i.e., a range of 196 to 204, inclusive. It should be understood that a percentage given as “about 20%” or “approximately 20%” does not mean “20% + / - 10%”, i.e., a range of 10 to 30% inclusive, but rather “about 20%” or “approximately 20%” means a range of 18 to 22% inclusive, i.e., plus or minus 10% of the value 20.

[0326] As used herein, the term "polymer" refers to a molecule comprising a repeating structural unit, wherein the repeating structural unit (i.e., monomer) is connected by a chemical bond in a linear, cyclic, branched, cross-linked or dendritic form or a combination thereof, which can be synthetic or biologically derived or a combination of the two. It should be understood that polymers can also include one or more other chemical groups and / or moieties, such as one or more functional groups. In certain embodiments, the molecular weight of a soluble polymer is at least 0.5 kDa, for example, a molecular weight of at least 1 kDa, a molecular weight of at least 2 kDa, a molecular weight of at least 3 kDa, or a molecular weight of at least 5 kDa. If a polymer is soluble, its molecular weight in certain embodiments is at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, or at most 100 kDa. It should be understood that for water-insoluble polymers (such as hydrogels), a meaningful molecular weight range can not be provided. It will be understood that a peptide or protein is also a polymer in which amino acids are repeating structural units, although the side chains of each amino acid may be different.

[0327] As used herein, the term "polymer" refers to an agent or moiety that comprises one or more polymers or polymer moieties. A polymeric agent or moiety may also optionally comprise one or more other moieties, which in certain embodiments are selected from:

[0328] ·C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetrahydronaphthyl; and

[0329] A linker selected from the group consisting of:

[0330]

[0331] in:

[0332] Dashed lines indicate connections to other moieties or reagents, and

[0333] -R and -R a are independently selected from the group consisting of: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

[0334] It is understood by those skilled in the art that the polymer products obtained from a polymerization reaction do not all have the same molecular weight, but rather exhibit a distribution of molecular weights. Therefore, as used herein, molecular weight ranges, molecular weights, ranges for the number of monomers in a polymer, and the number of monomers in a polymer refer to the number average molecular weight and the number average monomers, i.e., the arithmetic mean of the molecular weight of a polymer or polymer portion, and the arithmetic mean of the number of monomers in a polymer or polymer portion.

[0335] Thus, in a polymer portion comprising "x" monomer units, any integer for a given "x" therefore corresponds to the arithmetic mean number of monomers. Any integer range for a given "x" provides an integer range within which the arithmetic mean number of monomers lies. An integer for "x" given as "about x" means that the arithmetic mean number of monomers is within an integer range of x + / - 10%, in certain embodiments x + / - 8%, in certain embodiments x + / - 5%, and in certain embodiments x + / - 2%.

[0336] As used herein, the term "number average molecular weight" refers to the common arithmetic mean of the molecular weights of the individual polymers.

[0337] As used herein, the term "water-soluble" 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. Thus, 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.

[0338] As used herein, the term "PEG-based" in relation to a moiety or agent means that the moiety or agent comprises PEG. In certain embodiments, the moiety or agent based on PEG comprises at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w) PEG, such as at least 60% (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as at least 90% (w / w) PEG, such as at least 95%. The remaining weight percentage of the PEG-based moiety or agent is other moieties, which in certain embodiments are selected from the following moieties and linkages:

[0339] ·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 tetrahydronaphthyl; and

[0340] A linker selected from the group consisting of:

[0341]

[0342] in

[0343] Dashed lines indicate connections to other moieties or reagents, and

[0344] -R and -R a are independently selected from the group consisting of: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

[0345] As used herein, the term "substituted" refers to the replacement of one or more -H atoms of a molecule or moiety with a different atom or group of atoms, termed a "substituent."

[0346] In certain embodiments, one or more additional optional substituents are independently selected from the group consisting of halogen, -CN, -COOR x1 、-OR x1 、-C(O)R x1 、-C(O)N(R x1 R x1a )、-S(O)2N(R x1 R x1a )、-S(O)N(R x1 R x1a)、-S(O)2R x1 、-S(O)R x1 、-N(R x1 )S(O)2N(R x1a R x1b ),-SR x1 、-N(R x1 R x1a )、-NO2、-OC(O)R x1 、-N(R x1 )C(O)R x1a 、-N(R x1 )S(O)2R x1a 、-N(R x1 )S(O)R x1a 、-N(R x1 )C(O)OR x1a 、-N(R x1 )C(O)N(R x1a R x1b )、-OC(O)N(R x1 R x1a ),-T 0 、C 1-50 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 The alkynyl group may be optionally substituted with one or more identical or different -R x2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group may be optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-、-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0347] -R x1 、-Rx1a 、-R x1b are independently selected from the following groups: -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 The alkynyl group may be optionally substituted with one or more identical or different -R x2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group may be optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-、-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0348] Each T 0 Independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; wherein each T 0 are independently optionally replaced by one or more identical or different -R x2 replace;

[0349] Each -R x2 Independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR x4 、-OR x4 、-C(O)R x4 、-C(O)N(R x4 R x4a )、-S(O)2N(R x4 R x4a )、-S(O)N(R x4 R x4a )、-S(O)2R x4 、-S(O)Rx4 、-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; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different;

[0350] Each -R x3 、-R x3a 、-R x4 、-R x4a 、-R x4b are independently selected from the group consisting of: -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more same or different halogens.

[0351] In certain embodiments, one or more additional optional substituents are independently selected from the group consisting of halogen, -CN, -COOR x1 、-OR x1 、-C(O)R x1 、-C(O)N(R x1 R x1a )、-S(O)2N(R x1 R x1a )、-S(O)N(R x1 R x1a )、-S(O)2R x1 、-S(O)R x1 、-N(R x1 )S(O)2N(R x1a R x1b ),-SR x1 、-N(R x1 R x1a)、-NO2、-OC(O)R x1 、-N(R x1 )C(O)R x1a 、-N(R x1 )S(O)2R x1a 、-N(R x1 )S(O)R x1a 、-N(R x1 )C(O)OR x1a 、-N(R x1 )C(O)N(R x1a R x1b )、-OC(O)N(R x1 R x1a ),-T 0 、C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl; wherein -T 0 、C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group may be optionally substituted with one or more identical or different -R x2 substituted, and wherein C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group may be optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-、-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0352] Each -R x1 、-R x1a 、-R x1b 、-R x3 、-R x3a Each independently selected from the group consisting of: -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0353] Each T 0 Independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; wherein each T 0 are independently optionally replaced by one or more identical or different -R x2 replace;

[0354] Each -R x2 Independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR x4 、-OR x4 、-C(O)R x4 、-C(O)N(R x4 R x4a )、-S(O)2N(R x4 R x4a )、-S(O)N(R x4 R x4a )、-S(O)2R x4 、-S(O)R x4 、-N(R x4 )S(O)2N(R x4a R x4b ),-SR x4 、-N(R x4 R x4a )、-NO2、-OC(O)R x4 、-N(R x4 )C(O)R x4a 、-N(R x4 )S(O)2R x4a 、-N(R x4 )S(O)R x4a 、-N(R x4 )C(O)OR x4a 、-N(R x4 )C(O)N(R x4a R x4b )、-OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different;

[0355] Each -R x4 、-R x4a 、-R x4b Independently selected from the group consisting of: -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0356] In certain embodiments, one or more additional optional substituents are independently selected from the group consisting of halogen, -CN, -COOR x1 、-OR x1 、-C(O)R x1 、-C(O)N(R x1 R x1a )、-S(O)2N(R x1 R x1a )、-S(O)N(R x1 R x1a )、-S(O)2R x1 、-S(O)R x1 、-N(R x1 )S(O)2N(R x1a R x1b ),-SR x1 、-N(R x1 R x1a )、-NO2、-OC(O)R x1 、-N(R x1 )C(O)R x1a 、-N(R x1 )S(O)2R x1a 、-N(R x1 )S(O)R x1a 、-N(R x1 )C(O)OR x1a 、-N(R x1 )C(O)N(R x1a R x1b )、-OC(O)N(R x1 R x1a ),-T 0 、C 1-6 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 is optionally substituted by one or more identical or different -R x2 substituted, and wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-、-S(O)2-、-S(O)-、-N(Rx3 )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 )-;

[0357] Each -R x1 、-R x1a 、-R x1b 、-R x2 、-R x3 、-R x3a Independently selected from the group consisting of: -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0358] Each T 0 Independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; wherein each T 0 are optionally replaced by one or more identical or different -R x2 replace.

[0359] In certain embodiments, up to 6 -H atoms in the optionally substituted molecule are independently substituted with substituents, e.g., 5 -H atoms are independently substituted with substituents, 4 -H atoms are independently substituted with substituents, 3 -H atoms are independently substituted with substituents, 2 -H atoms are independently substituted with substituents, or 1 -H atom is substituted with a substituent.

[0360] The term "interruption" refers to the insertion of a moiety between two carbon atoms, or (if the insertion is at one end of the moiety) between a carbon or heteroatom and a hydrogen atom, in certain embodiments between a carbon and a hydrogen atom.

[0361] As used herein, the term "C 1-4 "Alkyl" alone or in combination means a straight chain or branched chain alkyl moiety having 1 to 4 carbon atoms. If present at the end of a molecule, the straight chain or branched chain C 1-4 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 1-4 When alkyl is connected, this type of C 1-4Examples of alkyl groups are: -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-4 Each hydrogen on the alkyl carbon may be optionally replaced by a substituent as defined above. 1-4 An alkyl group may be interrupted by one or more moieties as defined below.

[0362] 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. If the group is located at the end of a molecule, the 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 alkyl is connected, this type of 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 a carbon may optionally be replaced by a substituent as defined above. 1-6 An alkyl group may be interrupted by one or more moieties as defined below.

[0363] Therefore, “C 1-10 Alkyl", "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, wherein C 1-10 、C 1-20 or C 1-50 Each hydrogen atom of a carbon may be optionally substituted with a substituent as defined above. 1-10 or C 1-50 An alkyl group may be interrupted by one or more moieties as defined below.

[0364] As used herein, the term "C 2-6 "Alkenyl" alone or in combination means a straight or branched hydrocarbon moiety having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. If present at the end of a molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3 and -CH=CH-CH=CH2. When the two parts of the molecule are separated by C 2-6 When alkenyl is connected, this type of C2-6 An example of an alkenyl group is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl moiety may be optionally substituted with a substituent as defined above. 2-6 An alkenyl group may be interrupted by one or more moieties as defined below.

[0365] Therefore, the term "C 2-10 Alkenyl", "C 2-20 Alkenyl" or "C 2-50 "Alkenyl" alone or in combination means a straight or branched chain hydrocarbon moiety having 2 to 10, 2 to 20 or 2 to 50 carbon atoms and containing at least one carbon-carbon double bond. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may be optionally substituted by a substituent as defined above. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 An alkenyl group may be interrupted by one or more moieties as defined below.

[0366] As used herein, the term "C 2-6 "Alkynyl" alone or in combination means a straight or branched hydrocarbon moiety having 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. If present at the end of a molecule, examples are -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH and CH2-C≡C-CH3. When two parts of a molecule are linked through an alkynyl group, an example is -C≡C-. C 2-6 Each hydrogen atom of the alkynyl group may be optionally substituted by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 An alkynyl group may be interrupted by one or more moieties as defined below.

[0367] Therefore, as used herein, the term "C 2-10 Alkynyl", "C 2-20 Alkynyl" and "C 2-50 "Alkynyl" alone or in combination means a straight or branched chain hydrocarbon moiety having 2 to 10, 2 to 20 or 2 to 50 carbon atoms, respectively, and having at least one carbon-carbon triple bond. 2-10 Alkynyl, C 2-20 Alkynyl or C 2-50 Each hydrogen atom of the alkynyl group may be optionally substituted 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 An alkynyl group may be interrupted by one or more moieties as defined below.

[0368] As mentioned above, C1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 Alkenyl, C 2-10 Alkenyl, C 2-20 Alkenyl, C 2-50 Alkenyl, C 2-6 Alkynyl, C 2-10 Alkynyl, C 2-20 Alkenyl or C 2-50 Alkynyl groups may be optionally interrupted by one or more moieties which, in certain embodiments, are selected from the group consisting of:

[0369]

[0370] in

[0371] Dashed lines indicate connections to other moieties or reagents; and

[0372] -R and -R a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.

[0373] As used herein, the term "C 3-10 "Cycloalkyl" refers to 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 substituted with a substituent as defined above. 3-10 "Cycloalkyl" also includes bridged bicyclic rings such as norbornane or norbornene.

[0374] The term "8- to 30-membered carbon polycyclyl" or "8- to 30-membered carbon polycyclic ring" refers to a cyclic moiety of two or more rings having 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and may contain up to the maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings). In certain embodiments, the 8- to 30-membered carbon polycyclyl refers to a cyclic moiety of two, three, four or five rings, and in certain embodiments, a cyclic moiety of two, three or four rings.

[0375] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" refers to a ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, which may contain up to the maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom, up to 4 ring atoms, are substituted with a heteroatom selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiol, aziridine, oxirane, thipropylene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolin, thiadiazole, thiadiazoline, 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 heterocyclic group or the 3- to 10-membered heterocyclic group may be substituted with a substituent as defined below.

[0376] As used herein, the term "8- to 11-membered heterobicyclyl" or "8- to 11-membered heterobicycle" refers to a heterocyclic moiety having two rings of 8 to 11 ring atoms, wherein at least one ring atom is shared by both rings and may contain up to the maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom up to 6 ring atoms are substituted with heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule via a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicyclic rings are: indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazolinone, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine. The term "8- to 11-membered heterobicyclic ring" also includes spirocyclic structures of two rings, such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridged heterocycles, such as 8-azabicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclic ring or an 8- to 11-membered heterobicyclic ring carbon may be substituted with a substituent as defined below.

[0377] Similarly, the term "8- to 30-membered heteropolycyclyl" or "8- to 30-membered heteropolycycle" refers to a heterocyclic moiety having from 8 to 30 ring atoms and having two or more rings, and in certain embodiments three, four, or five rings, wherein two adjacent rings share at least one ring atom and may contain up to the maximum number of double bonds (fully, partially, or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom up to ten ring atoms are substituted with heteroatoms selected from sulfur (including -S(O)- and -S(O)2-), oxygen, and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom.

[0378] It should be understood that the structure Some of the related phrases "R x / R y The pairs are linked together with the atoms to which they are attached to form C 3-10 Cycloalkyl or 3 to 10 membered heterocyclic group" refers to R x and R y The following structure is formed:

[0379]

[0380] Where R is C 3-10 cycloalkyl or 3- to 10-membered heterocyclic group.

[0381] It should also be understood that Some of the related phrases "R x / R y The pairs of atoms to which they are attached are joined together to form a ring A" and are referred to as R x and R y The following structure is formed:

[0382]

[0383] As used herein, "halogen" refers to fluorine, chlorine, bromine, or iodine. In certain embodiments, halogen is fluorine or chlorine.

[0384] In general, the term "comprises / comprising" also covers "consisting of".

[0385] The patients of the first, second, and third aspects are stable patients. Such stable patients may be treated with a first PTH compound prior to starting weekly PTH compound therapy, for example, a first PTH compound administered once every 8 hours, once every 12 hours, or once daily, and this first PTH compound is different from the PTH compound administered once weekly, which may also be referred to as a "weekly PTH compound." Specific embodiments of the first, second, and third aspects are described elsewhere herein. Specific embodiments of the weekly PTH compound are as described for the second PTH compound.

[0386] Unless otherwise indicated, the following sections apply to all aspects of this application.

[0387] In certain embodiments, chronic hypoparathyroidism is due to surgery (such as thyroid or parathyroid surgery), genetic causes, immune system-related parathyroid damage, or is congenital. In certain embodiments, chronic hypoparathyroidism is due to surgery. In certain embodiments, chronic hypoparathyroidism is due to thyroid surgery. In certain embodiments, chronic hypoparathyroidism is due to parathyroid surgery. In certain embodiments, chronic hypoparathyroidism is due to genetic causes. In certain embodiments, chronic hypoparathyroidism is due to autosomal dominant hypocalcemia type I. In certain embodiments, chronic hypoparathyroidism is due to immune-related parathyroid damage. In certain embodiments, chronic hypoparathyroidism is congenital.

[0388] In certain embodiments, the patient is a mammalian patient. In certain embodiments, the patient is a human patient, such as an adult or pediatric patient. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to surgery, genetic causes, parathyroid gland damage related to the immune system, or the hypoparathyroidism is congenital. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to surgery. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to thyroid surgery. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to parathyroid surgery. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to genetic causes. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to autosomal dominant hypocalcemia type I. In certain embodiments, the patient suffers from chronic hypoparathyroidism due to immune-related parathyroid gland damage. In certain embodiments, the patient suffers from congenital chronic hypoparathyroidism.

[0389] In certain embodiments, the patient is an adult patient with chronic hypoparathyroidism due to surgery, genetic causes, immune system-related parathyroid damage, or the hypoparathyroidism is congenital. In certain embodiments, the patient is an adult human patient with chronic hypoparathyroidism due to surgery. In certain embodiments, the patient is an adult human patient with chronic hypoparathyroidism due to thyroid surgery. In certain embodiments, the patient is an adult human patient with chronic hypoparathyroidism due to parathyroid surgery. In certain embodiments, the patient is an adult human patient with chronic hypoparathyroidism due to genetic causes. In certain embodiments, the patient is an adult human patient with chronic hypoparathyroidism due to autosomal dominant hypocalcemia type I. In certain embodiments, the patient is an adult human patient with chronic hypoparathyroidism due to immune-related parathyroid damage. In certain embodiments, the patient is an adult human patient with congenital chronic hypoparathyroidism.

[0390] In certain embodiments, the patient is a pediatric patient who has chronic hypoparathyroidism due to surgery, genetic causes, parathyroid-related damage to the immune system, or the hypoparathyroidism is congenital. 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-related parathyroid damage. In certain embodiments, the patient is a pediatric human patient with congenital chronic hypoparathyroidism.

[0391] In certain embodiments, prior to initiating treatment with the first PTH compound, the patient is controlled with conventional therapy, ie, active vitamin D and calcium supplements.

[0392] In certain embodiments, the patient receives active vitamin D and calcium supplements prior to step (a).

[0393] Upon initiation of treatment with the first PTH compound, the dosage of active vitamin D and calcium supplements administered to the patient is reduced until administration of active vitamin D and calcium is completely discontinued. This reduction or discontinuation can be achieved by adjusting the dosage of active vitamin D and / or calcium supplements one or more times. The dosage of the first PTH compound may be increased or decreased one or more times during the period during which the patient gradually discontinues active vitamin D and calcium supplements. This increase or decrease in the dosage of the first PTH compound can be performed in response to hypocalcemia or hypercalcemia, respectively.

[0394] In certain embodiments, the first PTH compound can be administered to a patient by various modes of administration, such as topical, enteral or parenteral administration or by topical, injection or infusion methods, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcutaneous, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via an implantable device (e.g., Ommaya reservoir) that allows the application to be delivered to brain tissue or cerebral fluid, direct intracerebroventricular injection or infusion, injection or infusion into the brain or brain-related areas, injection into the subchoroidal space, retro-orbital 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 (e.g., by subcutaneous injection).

[0395] 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.

[0396] In certain embodiments, the first PTH compound is the only drug comprising PTH or a PTH portion that is administered prior to the weekly administration of the PTH compound of the first, second, or third embodiment. Such first PTH compound is administered at a first average interval between two consecutive administrations.

[0397] In certain embodiments, the first PTH compound is the only drug comprising PTH or a PTH portion administered to the patient during step (a).

[0398] In certain embodiments, the first average interval ranges from 6 hours to one week. In certain embodiments, the first average interval ranges from 6 hours to one day. In certain embodiments, the first average interval is about 8 hours. In certain embodiments, the first average interval is 8 hours. In certain embodiments, the first average interval is about 12 hours. In certain embodiments, the first average interval is 12 hours. In certain embodiments, the first average interval is about one day. In certain embodiments, the first average interval is one day. In certain embodiments, the first average interval is about two days. In certain embodiments, the first average interval is two days. In certain embodiments, the first average interval is about three days. In certain embodiments, the first average interval is three days. In certain embodiments, the first average interval is about four days. In certain embodiments, the first average interval is four days. In certain embodiments, the first average interval is about five days. In certain embodiments, the first average interval is five days. In certain embodiments, the first average interval is about six days. In certain embodiments, the first average interval is six days. In certain embodiments, the first average interval is about one week. In certain embodiments, the first average interval is one week.

[0399] In certain embodiments, the administration intervals in step (a) vary in length.

[0400] In certain embodiments, all administration intervals in step (a) have the same length. If the length of all administration intervals is the same, the length of that interval is referred to as the "first administration interval" or simply "first interval."

[0401] In certain embodiments, the first interval ranges from 6 hours to one week. In certain embodiments, the first interval ranges from 6 hours to one day. In certain embodiments, the first interval is about 8 hours. In certain embodiments, the first interval is 8 hours. In certain embodiments, the first interval is about 12 hours. In certain embodiments, the first interval is 12 hours. In certain embodiments, the first interval is about one day. In certain embodiments, the first interval is one day. In certain embodiments, the first interval is about two days. In certain embodiments, the first interval is two days. In certain embodiments, the first interval is about three days. In certain embodiments, the first interval is three days. In certain embodiments, the first interval is about four days. In certain embodiments, the first interval is four days. In certain embodiments, the first interval is about five days. In certain embodiments, the first interval is five days. In certain embodiments, the first interval is about six days. In certain embodiments, the first interval is six days. In certain embodiments, the first interval is about one week. In certain embodiments, the first interval is one week.

[0402] In step (a), the first PTH compound is administered to the patient multiple times, and the period from the first administration of the first PTH compound 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 one week to 20 years. In certain embodiments, the first treatment period lasts for a period of one week to 10 years. In certain embodiments, the first treatment period lasts for a period of two weeks to five years. In certain embodiments, the first treatment period lasts for a period of two weeks to two years. In certain embodiments, the first treatment period lasts for a period of two weeks to one year. In certain embodiments, the first treatment period lasts for a period of two weeks to six months. In certain embodiments, the first treatment period lasts for a period of two weeks to four months. In certain embodiments, such a first treatment period lasts for at least one week, such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, or ten years. It is understood that a patient may be treated with a first PTH compound and be a stable patient, but may not be started on a second PTH compound for a period of time, which may be due to, for example, a lack of a suitable second PTH compound in the patient's area or a lack of reimbursement. In certain embodiments, the first treatment period continues at least until the patient's serum calcium level is within the normal range and conventional therapy, i.e., active vitamin D and calcium supplements, is discontinued.

[0403] In certain embodiments, the patient is a patient with stable disease and, prior to the administration of the first dose of the second PTH compound, there were no dose adjustments to the first PTH compound for at least the length of the interval between the second-to-last and last administrations of the first PTH compound, i.e., at least for the last interval of the first treatment period. In certain embodiments, the patient is a patient with stable disease and, prior to the administration of the first dose of the second PTH compound, there were no dose adjustments to the first PTH compound for an average of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administrations of the first treatment period. In certain embodiments, the patient is a patient with stable disease and, prior to the administration of the first dose of the second PTH compound, there were no dose adjustments to the first PTH compound for an average of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administrations of the first treatment period. In certain embodiments, the patient has been a patient with stable disease and had no dose adjustments for at least one week prior to the administration of the first dose of the second PTH compound. In certain embodiments, the patient has been a patient with stable disease and had no dose adjustments for at least one month prior to the administration of the first dose of the second PTH compound. In certain embodiments, the patient has been a disease-stable patient for at least one year prior to administration of the first dose of the second PTH compound without dose adjustment.

[0404] In certain embodiments, the second average intervals of aspects 7 to 10 are of different lengths. In certain embodiments, the second average intervals of aspects 7 to 10 are of the same length. If all administration intervals are of the same length, the length of that interval is referred to as the "second administration interval" or simply "second interval." It should be understood that the second interval of aspects 1 to 6 is one week.

[0405] In certain embodiments, the second interval ranges from one week to two months. In certain embodiments, the second interval ranges from one week to 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.

[0406] The second PTH compound is administered to the patient in multiple doses, and the period from the first administration of the second PTH compound to the last administration of the second PTH compound is referred to as the "second treatment period." In certain embodiments, this second treatment period ranges from one week to 50 years, or until the patient dies or until the patient no longer requires the second PTH compound. In certain embodiments, the patient can be switched to a different PTH compound or other form of treatment after the second treatment period.

[0407] In certain embodiments, the first and / or second PTH compound is independently a PTH or parathyroid hormone-related protein (PTHrP) molecule or a pharmaceutically acceptable salt thereof 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: 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 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 IDNO: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 IDNO: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:11l, 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.

[0408] In certain embodiments, the first and / or second PTH compound is independently a PTH or parathyroid hormone-related protein (PTHrP) molecule or a pharmaceutically acceptable salt thereof comprising a sequence having at least 95% homology to a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30 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 IDNO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ IDNO: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, SEQID 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. <0003In certain embodiments, the first and / or second PTH compound is independently a PTH or PTHrP molecule or a pharmaceutically acceptable salt thereof comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 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 IDNO: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.

[0410] In certain embodiments, the first and / or second PTH compound is independently a fusion protein comprising at least one PTH or PTHrP molecule, or a pharmaceutically acceptable salt thereof, 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: 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 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 IDNO: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 IDNO: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.

[0411] In certain embodiments, the first and / or second PTH compound is independently a fusion protein comprising at least one PTH or PTHrP molecule, or a pharmaceutically acceptable salt thereof, the fusion protein comprising a sequence having at least 95% homology to a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30 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 IDNO: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, SEQID 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.

[0412] In certain embodiments, the first and / or second PTH compound is independently a fusion protein comprising at least one PTH or PTHrP molecule or a pharmaceutically acceptable salt thereof, the fusion protein comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 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 IDNO: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, SEQID NO:120, SEQ ID NO:121 and SEQ ID NO:122.

[0413] In certain embodiments, the first and / or second PTH compounds are independently conjugates comprising a PTH moiety covalently conjugated to one or more other moieties, which may be a polymer moiety or a fatty acid moiety. In certain embodiments, the connection between the PTH moiety and the other moiety may be reversible. In certain embodiments, the connection between the PTH moiety and the other moiety may be stable. In certain embodiments, such PTH compounds have a reversible connection between the PTH moiety and the first other moiety and a stable connection between the PTH moiety and the second other moiety.

[0414] In certain embodiments, such other moieties are polymeric moieties comprising one or more polymers selected from the group consisting of 2-methacryloyloxyethylphosphoylcholines, polyacrylic acids, polyacrylates, polyacrylamides, polyalkoxy polymers, polyamides, polyamidoamines, polyamino acids, polyanhydrides, polyaspartamides, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactones, polycarbonates, polycyanoacrylates, polydimethylacrylamide, polyesters, polyethylene, polyethylene glycol, polyethylene oxide, polyethyl phosphate, polyethyl oxazoline, polyglycolic acid, polyhydroxyethyl acrylate, polyhydroxyethyl oxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, polyhydroxypropyl methacrylate, polyhydroxypropyl oxazoline, polyiminocarbonates, polylactic acid In certain embodiments, the present invention relates to a hyaluronic acid-glycolic acid copolymer (HAC), a poly(vinyl alcohol), a poly(vinylamine), a poly(vinyl methyl ether), a polyvinylpyrrolidone, a silicone, a cellulose, a carboxymethyl cellulose, a hydroxypropyl methyl cellulose, a chitin, a chitosan, a dextran, a dextrin, a gelatin, a hyaluronic acid and a derivative, a functionalized hyaluronic acid, a mannan, a pectin, a rhamnogalacturonic acid, a starch, a hydroxyalkyl starch, a hydroxyethyl starch and other carbohydrate-based polymers, a xylan and a copolymer thereof. In certain embodiments, the present invention relates to a hyaluronic acid-glycolic acid copolymer (HAC), a poly(vinyl alcohol), a poly(vinylamine), a poly(vinyl methyl ether), a poly(vinylpyrrolidone), a silicone, a cellulose, a carboxymethyl cellulose, a hydroxypropyl methyl cellulose, a chitin, a chitosan, a dextran, a dextrin, a gelatin, a hyaluronic acid and a derivative, a functionalized hyaluronic acid, a mannan, a pectin, a rhamnogalacturonic acid, a starch, a hydroxyalkyl starch, a hydroxyethyl starch and other carbohydrate-based polymers, a xylan and a copolymer thereof. In certain embodiments, the present invention relates to a hyaluronic acid-glycolic acid copolymer (HAC). ...

[0415] In certain embodiments, such other moieties are fatty acid moieties, such as those disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512 A1, which are incorporated herein by reference.

[0416] In certain embodiments, the first and / or second PTH compound is independently a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof:

[0417]

[0418] in

[0419] Each -D is independently a PTH moiety;

[0420] Each -L 1 - is independently a linker moiety that is covalently and reversibly attached to -D;

[0421] Each -L 2 - is independently a single chemical bond or a spacer moiety;

[0422] Each -Z is independently a carrier moiety, such as a fatty acid derivative or a polymer;

[0423] x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25; and

[0424] y is an integer selected from 2, 3, 4 and 5.

[0425] The compounds of formula (Ia) and (Ib) may also be referred to as "prodrugs." They release unmodified PTH in the form of DH.

[0426] In certain embodiments, x in Formula (Ia) is an integer from 1 to 8. In certain embodiments, x in Formula (Ia) is an integer from 1 to 6. In certain embodiments, x in Formula (Ia) is an integer from 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.

[0427] 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 of Formula (Ib) is 18. In certain embodiments, y of Formula (Ib) is 19. In certain embodiments, y of Formula (Ib) is 20.

[0428] In certain embodiments, the first PTH compound and / or the second PTH compound are independently compounds of formula (Ia).In certain embodiments, the first PTH compound and / or the second PTH compound are independently compounds of formula (Ia), wherein x=1.

[0429] -D, -L 1 -、-L 2 Specific embodiments of - and Z are described elsewhere herein.

[0430] 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 are independently crystals comprising at least one PTH molecule. In certain embodiments, the first and / or second PTH compounds are independently nanoparticles comprising at least one PTH molecule. In certain embodiments, the first and / or second PTH compounds are independently microparticles comprising at least one PTH molecule. In certain embodiments, the first and / or second PTH compounds are independently nanospheres comprising at least one PTH compound. In certain embodiments, the first and / or second PTH compounds are independently microspheres comprising at least one PTH compound. In certain embodiments, the first and / or second PTH compounds are independently vesicles comprising at least one PTH compound, such as micelles, liposomes, or polymersomes.

[0431] 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, the water-insoluble polymer comprises a polymer selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholine, polyacrylic acid, polyacrylate, polyacrylamide, polyalkoxy polymer, polyamide, polyamidoamine, polyamino acid, polyanhydride, polyaspartamide, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactone, polycarbonate, polycyanoacrylate, polydimethylacrylamide, polyester, polyethylene, polyethylene glycol, polyethylene oxide, polyethyl phosphate, polyethyl oxazoline, polyglycolic acid, polyhydroxyethyl acrylate, polyhydroxyethyl oxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, polyhydroxypropyl methacrylate. , polyhydroxypropyl oxazoline, polyiminocarbonate, polylactic acid, lactic acid-glycolic acid copolymer, polymethacrylamide, polymethacrylate, polymethyl oxazoline, polyorganophosphazene, polyorthoester, polyoxazoline, polypropylene glycol, polysiloxane, polyurethane, polyvinyl alcohol, polyvinylamine, polyvinyl methyl ether, polyvinyl pyrrolidone, silicone, cellulose, carboxymethyl cellulose, 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, the water-insoluble polymer is lactic acid-glycolic acid copolymer (PLGA).

[0432] In certain embodiments, the first PTH compound and / or the second PTH compound are each independently a conjugate comprising a carrier moiety Z', or a pharmaceutically acceptable salt thereof, one or more moieties -L 2 -L 1 -D is conjugated to a carrier moiety Z', wherein each -L 2 - is independently a chemical bond or a spacer moiety; each -L 1 - is a linker moiety that is independently reversibly and covalently conjugated to -D; each -D is independently a PTH moiety; and Z' is a hydrogel. This long-acting PTH compound is a sustained-release PTH compound. -D, -L 1 -、-L 2 Specific embodiments of - and Z' are described elsewhere herein.

[0433] In certain embodiments, -D is a PTH portion 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: 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 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, SEQID 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.

[0434] In certain embodiments, -D is a PTH moiety that comprises a sequence having at least 95% homology to a sequence selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:, 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 IDNO: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.

[0435] In certain embodiments, -D is a PTH moiety that comprises a sequence selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQID 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.

[0436] In certain embodiments, -D is a PTH moiety comprising a sequence that is at least 90% homologous (e.g., at least 91% homologous, at least 92% homologous, at least 93% homologous, at least 94% homologous, at least 95% homologous, at least 96% homologous, at least 97% homologous, at least 98% homologous, or at least 99% homologous) to a sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, 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.

[0437] In certain embodiments, -D is a PTH moiety comprising a sequence at least 95% homologous to a sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105 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.

[0438] 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.

[0439] In certain embodiments, -D is a PTH moiety comprising a sequence that is at least 90% homologous (e.g., at least 91% homologous, at least 92% homologous, at least 93% homologous, at least 94% homologous, at least 95% homologous, at least 96% homologous, at least 97% homologous, at least 98% homologous, or at least 99% homologous) 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.

[0440] In certain embodiments, -D is a PTH moiety comprising a sequence at least 95% homologous 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.

[0441] 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.

[0442] In certain embodiments, -D is a PTH moiety comprising a sequence that is at least 90% homologous (e.g., at least 91% homologous, at least 92% homologous, at least 93% homologous, at least 94% homologous, at least 95% homologous, at least 96% homologous, at least 97% homologous, at least 98% homologous, or at least 99% homologous) 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.

[0443] In certain embodiments, -D is a PTH moiety comprising a sequence at least 95% homologous 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.

[0444] 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.

[0445] In certain embodiments, -D is SEQ ID NO: 50. In certain embodiments, -D is SEQ ID NO: 52. In certain embodiments, -D is SEQ ID NO: 110. In certain embodiments, -D is SEQ ID NO: 111. In certain embodiments, -D is SEQ ID NO: 112.

[0446] In certain embodiments, -D is SEQ ID NO:51.

[0447] In certain embodiments, -D is SEQ ID NO: 122:

[0448] AVAEIQLMHQRAKWIQDARR RAFLHKLIAEIHTAEI.

[0449] Part-L 1 - can be conjugated to a functional group of 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 main chain polypeptide of -D. The connection to the N-terminus or C-terminus can be directly connected or indirectly connected through the corresponding amine or carboxyl functional group, respectively, wherein the spacer part is first conjugated to the spacer part -L 1 - Conjugated amine or carboxyl functional groups.

[0450] In certain embodiments, -L 1 - The conjugated -D amino acid residue comprises a functional group selected from the group consisting of carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, keto, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, sulfate, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, ethylene oxide, guanidine, and aziridine. In certain embodiments, -L 1 -The conjugated -D amino acid residue comprises a functional group selected from the group consisting of hydroxyl, primary amine, secondary amine, and guanidine. 1 -D amino acid residues to be conjugated contain primary or secondary amine functional groups. In certain embodiments, -L 1 The -D amino acid residue to be conjugated contains a primary amine functionality.

[0451] If part-L 1 - is conjugated to a functional group on the side chain of a -D amino acid residue, the amino acid residue being selected from a proteinogenic amino acid residue and a non-proteinogenic amino acid residue. 1 - a functional group conjugated to the side chain of a proteinogenic amino acid residue of -D. In certain embodiments, -L 1 -A functional group conjugated to the side chain of a non-proteinogenic amino acid residue of -D.

[0452] In certain embodiments, -L 1 - a functional group conjugated to the side chain of a 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, -L 1 - a functional group conjugated to the histidine side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the lysine side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the tryptophan side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the serine side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the threonine side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the tyrosine side chain of -D. In certain embodiments, -L1 - a functional group conjugated to the aspartic acid side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the glutamic acid side chain of -D. In certain embodiments, -L 1 - a functional group conjugated to the arginine side chain of -D. It will be appreciated that not every -D moiety may comprise all of these amino acid residues.

[0453] In certain embodiments, -L 1 - is conjugated directly or indirectly to the N-terminal amine function of -D via the corresponding amine function, wherein the spacer moiety is first conjugated to the spacer moiety -L 1 - conjugated amine functional group. In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functionality of -D. In certain embodiments, -L 1 - is conjugated directly or indirectly to the C-terminal functional group of -D via the corresponding carboxyl functional group, wherein the spacer moiety is first conjugated to the spacer moiety -L 1 -conjugated carboxyl functional group. In certain embodiments, -L 1 - is directly conjugated to the N-terminal amine functionality of -D.

[0454] Part-L 1 - can be connected to -D via any type of reversible linkage. In certain embodiments, -L 1 - is connected to -D via a linkage selected from the group consisting of an amide bond, an ester bond, a carbamate bond, an acetal bond, an aminal bond, an imine bond, an oxime bond, a hydrazone bond, a disulfide bond, and an acylguanidine bond. In certain embodiments, -L 1 - is connected to -D via a linker selected from the group consisting of an amide bond, an ester bond, a carbamate bond, and an acylguanidine bond. It should be understood that some of these links are irreversible per se, but in this application, -L 1 -The adjacent groups contained in the -L make these linkages reversible. In certain embodiments, -L 1 - is linked to -D through an ester bond. In certain embodiments, -L 1 - is linked to -D via a carbamate bond. In certain embodiments, -L 1 - is linked to -D through an acylguanidine. In certain embodiments, -L 1 - is linked to -D via an amide bond.

[0455] Part-L 1- is a reversible prodrug linker from which the drug, i.e., PTH, is released in free form, i.e., it is a traceless prodrug linker. Suitable prodrug linkers are known in the art, for example, 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.

[0456] 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.

[0457] In certain embodiments, -L 1 - disclosed in WO 2009 / 095479 A2. Thus, in certain embodiments, the moiety -L 1 - having formula (II):

[0458]

[0459] Wherein the dotted line represents the nitrogen, hydroxyl group or thiol group attached to -D;

[0460] -X- is selected from the group consisting of: -C(R 4 R 4a )-、-N(R 4 )-、-O-、-C(R 4 R 4a )-C(R 5 R 5a )-、-C(R 5 R 5a )-C(R 4 R 4a )-、-C(R 4 R 4a )-N(R 6 )-、-N(R 6 )-C(R 4 R 4a )-、C(R 4 R 4a )-O-、-OC(R 4 R 4a )- and -C(R 7 R 7a )-.

[0461] X 1 Selected from: C and S(O);

[0462] -X 2 -Selected from: -C(R 8 R 8a )- and -C(R 8 R 8a )-C(R 9 R 9a )-;

[0463] =X 3 Selected from: =O, =S, and =N-CN;

[0464] -R 1 、-R 1a 、-R 2 、-R 2a 、-R 4 、-R 4a 、-R 5 、-R 5a 、-R 6 、-R 8 、-R 8a 、-R 9 and -R 9a Independently selected from: -H and C 1-6 alkyl;

[0465] -R 3 and -R 3a Independently selected from: -H and C 1-6 Alkyl, provided that if -R 3 、-R 3a If one or both of them are not -H, then they are passed to SP 3 - Hybridized carbon atoms are connected to nitrogen;

[0466] -R 7 Selected from: -N(R 10 R 10a ) and -NR 10 -(C=O)-R 11 ;

[0467] -R 7a 、-R 10 、-R 10a and -R 11 Independently selected from: -H and C 1-6 alkyl;

[0468] Optionally, -R 1a / -R 4a 、-R 1a / -R 5a 、-R 1a / -R 7a 、-R 4a / -R5a and -R 8a / -R 9a One or more of the pairs form a chemical bond;

[0469] Optionally, -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 pairs join together with the atoms to which they are attached to form C 3-10 Cycloalkyl; or 3 to 10-membered heterocyclic group;

[0470] Optionally, -R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 、-R 1 / -R 7a 、-R 4 / -R 5 、-R 4 / -R 6 、-R 8 / -R 9 and -R 2 / -R 3 One or more of the pairs are linked together with the atoms to which they are attached to form ring A;

[0471] Optionally, R 3 / R 3a Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic ring;

[0472] A is selected from the group consisting of: phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; and

[0473] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (II) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0474] In certain embodiments, -L in formula (II) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0475] In certain embodiments, -L of formula (II) 1 - has not been further replaced.

[0476] It should be understood that if -R 3 / -R 3a Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic ring, only those in which the atom directly attached to the nitrogen is SP 3 -3 to 10 membered heterocyclic ring of carbon atoms. 3 / -R 3a Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic ring having the following structure:

[0477]

[0478] in

[0479] The dotted line indicates the connection to -L 1 - the rest of

[0480] The ring contains 3 to 10 atoms including at least one nitrogen; and

[0481] R # and R ## Represents sp 3 -Hybridized carbon atoms.

[0482] It is also to be understood that the 3- to 10-membered heterocyclic ring may be further substituted.

[0483] -R of formula (II) 3 / -R 3a Illustrative embodiments of suitable 3- to 10-membered heterocyclic rings formed together with the nitrogen atom to which they are attached are as follows:

[0484]

[0485] in

[0486] Dashed lines indicate connections to the rest of the molecule; and

[0487] -R is selected from: -H and C 1-6 alkyl.

[0488] -L in formula (II) 1- may be optionally further substituted. Generally speaking, any substituent may be used as long as it does not affect the cleavage principle, i.e., the hydrogens marked with an asterisk in formula (II) are not replaced, and Part of the nitrogen is still part of the primary, secondary or tertiary amine, i.e. -R 3 and -R 3a Independently of each other -H or through sp 3 The -hybridized carbon atom is connected to -N<.

[0489] In one embodiment, -R 1 or -R 1a L 2 -Z or -L 2 In another embodiment, -R 2 or -R 2a L 2 -Z or -L 2 In another embodiment, -R 3 or -R 3a L 2 -Z or -L 2 In another embodiment, -R 4 L 2 -Z or -L 2 In another embodiment, -R 5 or -R 5a L 2 -Z or -L 2 In another embodiment, -R 6 L 2 -Z or -L 2 In another embodiment, -R 7 or -R 7a L 2 -Z or -L 2 In another embodiment, -R 8 or -R 8a L 2 -Z or -L 2 In another embodiment, -R 9 or -R 9a L 2 -Z or -L 2 In another embodiment, -R 10 L 2 -Z or -L 2In another embodiment, -R 11 L 2 -Z or -L 2 In certain embodiments, -R 3 L 2 -Z or -L 2 -Z' instead.

[0490] In certain embodiments, -X- of formula (II) is selected from: -C(R 4 R 4a )-、-N(R 4 )- and -C(R 7 R 7a In certain embodiments, -X- of formula (II) is -C(R 4 R 4a In certain embodiments, -X- of formula (II) is -C(R 7 R 7a )-.

[0491] In certain embodiments, -R 7 -NR 10 -(C=O)-R 11 .

[0492] In certain embodiments, -R 7a In certain embodiments, -R 7a is -H.

[0493] In certain embodiments, -R 10 In certain embodiments, -R 10 It is a methyl group.

[0494] In certain embodiments, -R 11 In certain embodiments, -R 11 In certain embodiments, -R 11 L 2 -Z or -L 2 -Z' instead.

[0495] In certain embodiments, -X- of formula (II) is -N(R 4 )-.

[0496] In certain embodiments, -R 4 In certain embodiments, -R 4 is -H.

[0497] In certain embodiments, X of formula (II) 1 For C.

[0498] In certain embodiments, =X of formula (II) 3 =O.

[0499] In certain embodiments, -X in formula (II) 2 -for-C(R 8 R 8a )-.

[0500] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R 8 and -R 8a All are -H.

[0501] In certain embodiments, -R 1 and -R 1a Independently selected from: -H, methyl and ethyl.

[0502] In certain embodiments, -R 1 and -R 1a In certain embodiments, at least one of -R 1 and -R 1a is -H.

[0503] In certain embodiments, -R 1 and -R 1a In certain embodiments, -R 1 and -R 1a All are methyl.

[0504] In certain embodiments, -R 2 and -R 2a In certain embodiments, -R 2 and -R 2a In certain embodiments, at least one of -R 2 and -R 2a Both are H.

[0505] In certain embodiments, -R 3 and -R3a Independently selected from: -H, methyl, ethyl, propyl and butyl.

[0506] In certain embodiments, -R 3 and -R 3a In certain embodiments, -R 3 is methyl and -R in formula (II) 3a is -H.

[0507] In certain embodiments, -R 3 and -R 3a All are -H.

[0508] In certain embodiments, -D is linked to -L through the nitrogen by forming an amide bond. 1 -.

[0509] In certain embodiments, the moiety -L 1 - having the formula (IIa-i):

[0510]

[0511] in

[0512] The dashed line indicates the nitrogen connected to -D via an amide bond;

[0513] -R 1 、-R 1a 、-R 2 、-R 2a 、-R 3 、-R 3a 、-R 7 、-R 7a and -X 2 As defined in formula (II); and

[0514] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-i) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0515] It should be understood that if -R 3 、-R 3a If one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0516] In certain embodiments, -L of formula (IIa-i) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0517] In certain embodiments, the moiety -L of formula (IIa-i) 1 - has not been further replaced.

[0518] In certain embodiments, -R 1 and -R 1a In certain embodiments, -R 1 and -R 1a In certain embodiments, at least one of -R 1 and -R 1a All are -H.

[0519] In certain embodiments, -R 7 -NR 10 -(C=O)-R 11 .

[0520] In certain embodiments, -R 7a In certain embodiments, -R of formula (II-i) is selected from the group consisting of: -H, methyl, and ethyl. 7a is -H.

[0521] In certain embodiments, -R 10 In certain embodiments, -R of formula (IIa-i) is selected from the group consisting of: -H, methyl, and ethyl. 10 It is a methyl group.

[0522] In certain embodiments, -R 11 In certain embodiments, -R of formula (IIa-i) is selected from the group consisting of: -H, methyl, and ethyl. 11 is -H.

[0523] In certain embodiments, -R 11 L 2 -Z or -L 2 -Z' instead.

[0524] In certain embodiments, -X of Formula (IIa-i) 2 -for-C(R 8 R 8a )-.

[0525] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R 8 and -R 8a All are -H.

[0526] In certain embodiments, R of Formula (IIa-i) 2 and -R 2a In certain embodiments, R of formula (IIa-i) is independently selected from: -H, methyl and ethyl. 2 and -R 2a In certain embodiments, R in formula (IIa-i) is 2 and -R 2a Both are H.

[0527] In certain embodiments, -R 3 and -R 3a In certain embodiments, -R 3 and -R 3a At least one of them is a methyl group.

[0528] In certain embodiments, -R 3 is -H and -R of formula (IIa-i) 3a It is a methyl group.

[0529] In certain embodiments, the moiety -L 1 - having the formula (IIa-ii):

[0530]

[0531] Wherein the dotted line represents the nitrogen connected to -D via an amide bond;

[0532] -R 2 、-R 2a 、-R 10 、-R 11 and -X 2 - used as defined in formula (II); and

[0533] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1- is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-ii) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0534] It should be understood that if -R 3 、-R 3a If one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0535] In certain embodiments, -L of formula (IIa-ii) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0536] In certain embodiments, the moiety -L of formula (IIa-ii) 1 - has not been further replaced.

[0537] In certain embodiments, -X of Formula (IIa-ii) 2 -for-C(R 8 R 8a )-.

[0538] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R 8 and -R 8a All are -H.

[0539] In certain embodiments, -R 3 and -R 3a In certain embodiments, -R 3 and -R 3a At least one of them is a methyl group.

[0540] In certain embodiments, -R 3 is -H and -R of formula (IIa-ii) 3a It is a methyl group.

[0541] In certain embodiments, -R 10In certain embodiments, -R of formula (IIa-ii) is selected from the group consisting of: -H, methyl, and ethyl. 10 It is a methyl group.

[0542] In certain embodiments, -R 11 In certain embodiments, -R of formula (IIa-ii) is selected from the group consisting of: -H, methyl, and ethyl. 11 is -H.

[0543] In certain embodiments, -R 11 L 2 -Z or -L 2 -Z' instead.

[0544] In certain embodiments, the moiety -L 1 - having the formula (IIa-ii'):

[0545]

[0546] in

[0547] The dashed line indicates the nitrogen connected to -D via an amide bond;

[0548] The dashed line marked with an asterisk indicates the connection to -L 2 -;

[0549] -R 3 、-R 3a 、-R 10 and -X 2 - used as defined in formula (II); and

[0550] Where -L 1 - is optionally further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIa-ii') are not replaced by a substituent.

[0551] It should be understood that if -R 3 、-R 3a If one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0552] In certain embodiments, -X of Formula (IIa-ii') 2 -for-C(R 8 R 8a )-.

[0553] In certain embodiments, -R 8 and -R 8aIndependently selected from: -H, methyl, and ethyl. In certain embodiments, -R of formula (IIa-ii') 8 and -R 8a at least one of which is -H. In certain embodiments, -R of formula (IIa-ii') 8 and -R 8a are both -H.

[0554] In certain embodiments, -R of formula (IIa-ii') 3 and -R 3a are independently selected from: -H, methyl, ethyl, propyl, and butyl. In certain embodiments, -R of formula (IIa-ii') 3 and -R 3a at least one of which is methyl.

[0555] [[ID=II]]In certain embodiments, -R of formula (IIa-ii') 3 is -H and -R of formula (IIa-ii') 3a is methyl.

[0556] 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.

[0557] In certain embodiments, part -L 1 - has formula (IIa-iii):

[0558]

[0559] where the dashed line represents connection to nitrogen through an amide bond; and where -L / 1 - is replaced by -L 2 -Z or -L 2 -Z', and where -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIa-iii) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0560] It should be understood that if -R 3 and / or -R 3a of formula (IIa-iii) is / are not -H, they are connected to the N to which they are attached through sp 3 -hybridized carbon atoms.

[0561] In certain embodiments, part -L 1 - of formula (IIa-iii) is not further substituted.

[0562] In certain embodiments, the moiety -L 1 - having the formula (IIa-iii'):

[0563]

[0564] in

[0565] The dashed line indicates the nitrogen connected to -D via an amide bond;

[0566] The dashed line marked with an asterisk indicates the connection to -L 2 -;

[0567] -R 2 、-R 2a 、-R 3 、-R 3a and -X 2 - use as defined in formula (II); and

[0568] Where -L 1 - is optionally further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIa-iii') are not replaced by a substituent.

[0569] It should be understood that if -R 3 、-R 3a If one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0570] In certain embodiments, the moiety -L of formula (IIa-iii') 1 - has not been further replaced.

[0571] In certain embodiments, the moiety -L 1 -having the formula (IIb-i):

[0572]

[0573] in

[0574] The dashed line indicates the nitrogen connected to -D via an amide bond;

[0575] -R 1 、-R 1a 、-R 2 、-R 2a 、-R 3 、-R 3a 、-R 4 and -X 2 - as defined in formula (II); and wherein -L 1-Being at least one -L 2 -Z or -L 2 -Z' substituted, and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIb-i) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0576] It should be understood that if -R 3 、-R 3a If one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0577] In certain embodiments, -L of formula (IIb-i) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0578] In certain embodiments, the moiety -L of formula (IIb-i) 1 - has not been further replaced.

[0579] In certain embodiments, -R 1 and -R 1a In certain embodiments, -R 1 and -R 1a In certain embodiments, -R 1 and -R 1a All are methyl.

[0580] In certain embodiments, -R 4 In certain embodiments, -R of formula (IIb-i) is selected from the group consisting of: -H, methyl, and ethyl. 4 is -H.

[0581] In certain embodiments, -X of formula (IIb-i) 2 -for-C(R 8 R 8a )-.

[0582] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R 8 and -R 8aIn certain embodiments, at least one of -R 8 and -R 8a All are -H.

[0583] In certain embodiments, -R 2 and -R 2a In certain embodiments, -R 2 and -R 2a In certain embodiments, at least one of -R 2 and -R 2a Both are H.

[0584] In certain embodiments, -R 3 and -R 3a In certain embodiments, -R 3 and -R 3a In certain embodiments, at least one of -R 3 and -R 3a All are -H.

[0585] In certain embodiments, the moiety -L 1 - having the formula (IIb-ii):

[0586]

[0587] Wherein the dotted line represents the nitrogen connected to -D via an amide bond;

[0588] -R 2 、-R 2a 、-R 3 、-R 3a and -X 2 - used as defined in formula (II); and

[0589] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIb-ii) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0590] It should be understood that if -R 3 、-R 3aIf one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0591] In certain embodiments, -L of formula (IIb-ii) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0592] In certain embodiments, the moiety -L of formula (IIb-ii) 1 - has not been further replaced.

[0593] In certain embodiments, -X of formula (IIb-ii) 2 -for-C(R 8 R 8a )-.

[0594] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R in formula (IIb-ii) is independently selected from: -H, methyl and ethyl. 8 and -R 8a In certain embodiments, at least one of -R in formula (IIb-ii) is -H. 8 and -R 8a All are -H.

[0595] In certain embodiments, -R 2 and -R 2a In certain embodiments, -R 2 and -R 2a In certain embodiments, at least one of -R 2 and -R 2a Both are H.

[0596] In certain embodiments, -R 3 and -R 3a 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 All are -H.

[0597] In certain embodiments, the moiety -L 1- having the formula (IIb-ii'):

[0598]

[0599] in

[0600] The dashed line indicates the nitrogen connected to -D via an amide bond;

[0601] The dashed line marked with an asterisk indicates the connection to -L 2 -;

[0602] -R 2 、-R 2a 、-R 3a and -X 2 - used as defined in formula (II); and

[0603] Where -L 1 - is optionally further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIb-ii') are not replaced by substituents.

[0604] It should be understood that if -R 3a If not -H, it passes sp 3 The -hybridized carbon atom is connected to the nitrogen to which it is attached.

[0605] In certain embodiments, the moiety -L of formula (IIb-ii') 1 - has not been further replaced.

[0606] In certain embodiments, -X of Formula (IIb-ii') 2 -for-C(R 8 R 8a )-.

[0607] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R 8 and -R 8a All are -H.

[0608] In certain embodiments, -R 2 and -R 2a In certain embodiments, -R 2 and -R 2aIn certain embodiments, at least one of -R 2 and -R 2a Both are H.

[0609] In certain embodiments, -R 3a is selected from the group consisting of: -H, methyl, ethyl, propyl and butyl. In one embodiment, -R 3a is -H.

[0610] In certain embodiments, the moiety -L 1 - having the formula (IIb-iii):

[0611]

[0612] in

[0613] The dashed line represents the nitrogen connected to -D via an amide bond; and

[0614] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIb-iii) is not replaced by -L 2 -Z or -L 2 -Z' or a substituent.

[0615] It should be understood that if -R 3 、-R 3a If one or both are not -H, they are sp 3 -hybridized carbon atoms are linked to the N to which they are attached.

[0616] In certain embodiments, -L of formula (IIb-iii) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0617] In certain embodiments, the moiety -L of formula (IIb-iii) 1 - has not been further replaced.

[0618] In certain embodiments, the moiety -L 1 - having the formula (IIb-iii'):

[0619]

[0620] in

[0621] The dashed line indicates the nitrogen connected to -D via an amide bond;

[0622] The dashed line marked with an asterisk indicates the connection to -L 2 -;and

[0623] Where -L 1 - is optionally further substituted, provided that the hydrogen atoms marked with an asterisk in formula (IIb-iii') are not replaced by a substituent.

[0624] It is understood that the nitrogen adjacent to the dashed line marked with an asterisk in formula (IIb-iii') is sp 3 -hybridized carbon atom connected to -L 2 -.

[0625] In certain embodiments, the moiety -L of formula (IIb-iii') 1 - has not been further replaced.

[0626] In certain embodiments, -L 1 - disclosed in WO2016 / 020373A1. Thus, in certain embodiments, the moiety -L 1 - having formula (III):

[0627]

[0628] in

[0629] Dashed lines represent primary or secondary amines or hydroxyl groups linked to -D via amide or ester bonds, respectively;

[0630] -R 1 、-R 1a 、-R 2 、-R 2a 、-R 3 and -R 3a are independently selected from the group consisting of: -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;

[0631] -R 4 、-R 5 and -R 5a independently selected from -H, -C(R 9 R 9a R9b ) and -T;

[0632] a1 and a2 are independently 0 or 1;

[0633] Each -R 6 、-R 6a 、-R 7 、-R 7a 、-R 8 、-R 8a 、-R 8b 、-R 9 、-R 9a and -R 9b are independently selected from the group consisting of: -H, halogen, -CN, -COOR 10 、-OR 10 、-C(O)R 10 、-C(O)N(R 10 R 10a )、-S(O)2N(R 10 R 10a )、-S(O)N(R 10 R 10a )、-S(O)2R 10 、-S(O)R 10 、-N(R 10 )S(O)2N(R 10a R 10b ),-SR 10 、-N(R 10 R 10a )、-NO2、-OC(O)R 10 、-N(R 10 )C(O)R 10a 、-N(R 10 )S(O)2R 10a 、-N(R 10 )S(O)R 10a 、-N(R 10 )C(O)OR 10a 、-N(R 10 )C(O)N(R 10a R 10b )、-OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl; wherein -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl is optionally substituted by one or more identical or different -R 11 substituted, and wherein C1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-、-S(O)2N(R 12 )-、-S(O)N(R 12 )-、-S(O)2-、-S(O)-、-N(R 12 )S(O)2N(R 12a )-、-S-、-N(R 12 )-、-OC(OR 12 )(R 12a )-、-N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-;

[0634] Each -R 10 、-R 10a and -R 10b Independently selected from the group consisting of -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 is optionally substituted by one or more identical or different -R 11 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-、-S(O)2N(R 12 )-、-S(O)N(R 12 )-、-S(O)2-、-S(O)-、-N(R 12 )S(O)2N(R 12a )-、-S-、-N(R 12 )-、-OC(OR 12 )(R 12a )-、-N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-;

[0635] Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10The group consisting of cycloalkyl, 3 to 10 membered heterocyclyl and 8 to 11 membered heterobicyclyl; wherein each T is independently optionally replaced by one or more identical or different -R 11 replace;

[0636] Each -R 11 are independently selected from halogen, -CN, oxo (=O), -COOR 13 、-OR 13 、-C(O)R 13 、-C(O)N(R 13 R 13a )、-S(O)2N(R 13 R 13a )、-S(O)N(R 13 R 13a )、-S(O)2R 13 、-S(O)R 13 、-N(R 13 )S(O)2N(R 13a R 13b ),-SR 13 、-N(R 13 R 13a )、-NO2、-OC(O)R 13 、-N(R 13 )C(O)R 13a 、-N(R 13 )S(O)2R 13a 、-N(R 13 )S(O)R 13a 、-N(R 13 )C(O)OR 13a 、-N(R 13 )C(O)N(R 13a R 13b )、-OC(O)N(R 13 R 13a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different;

[0637] Each -R 12 、-R 12a 、-R 13 、-R 13a and -R 13b Independently selected from: -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different;

[0638] Optionally, -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 pairs join together with the atoms to which they are attached to form C 3-10 cycloalkyl or 3- to 10-membered heterocyclic group;

[0639] Optionally, -R 1 / -R 2 、-R 1 / -R 3 、-R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 、-R 1 / -R 7 、-R 2 / -R 3 、-R 2 / -R 4 、-R 2 / -R 5 、-R 2 / -R 6 、-R 2 / -R 7 、-R 3 / -R 4 、-R 3 / -R 5 、-R 3 / -R 6 、-R 3 / -R 7 、-R 4 / -R 5 、-R 4 / -R 6 、-R 4 / -R 7 、-R 5 / -R 6 、-R 5 / -R 7 and -R 6 / -R 7 One or more of the pairs are linked together with the atoms to which they are attached to form ring A;

[0640] A is selected from the group consisting of: phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl;

[0641] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted.

[0642] In certain embodiments, -L of formula (III) 1 The optional further substituents of - are as defined above.

[0643] In certain embodiments, -L of formula (III) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0644] In certain embodiments, -L of formula (III) 1 - has not been further replaced.

[0645] In certain embodiments, -L 1 - as disclosed in EP1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2 and US8618124B2, which are incorporated herein by reference in their entirety.

[0646] In certain embodiments, -L 1 - as disclosed in US8946405B2 and US8754190B2, which are incorporated herein by reference in their entirety. Thus, in certain embodiments, -L 1 - having formula (IV):

[0647]

[0648] in

[0649] The dotted line represents the connection to -D, and wherein the connection is through a functional group of -D selected from the group consisting of: -OH, -SH, and -NH2; m is 0 or 1;

[0650] -R 1 and -R 2 At least one or two of them are independently selected from the following groups: -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 、-S(O)R 3 、-S(O)2R 3 and-SR 4 ,

[0651] -R 1 and -R 2 Only one of them is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aralkyl, and optionally substituted heteroaralkyl;

[0652] -R 3 Selected from: -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 9 and -N(R 9 )2;

[0653] -R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;

[0654] Each -R 5 independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;

[0655] -R 9 is selected from: -H and optionally substituted alkyl;

[0656] -Y- is absent and -X- is -O- or -S-; or

[0657] -Y- is -N(Q)CH2- and -X- is -O-;

[0658] Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;

[0659] Optionally, -R 1 and -R 2 can be linked to form a 3- to 8-membered ring; and

[0660] Optionally, -R 9 Together with the nitrogen to which they are attached, they form a heterocyclic ring;

[0661] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted.

[0662] In the context of formula (IV) only, the terms used have the following meanings:

[0663] As used herein, the term "alkyl" includes straight chain, branched chain, or cyclic saturated hydrocarbon groups of 1 to 8 carbon atoms, or in certain embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0664] The term "alkoxy" includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0665] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons having carbon-carbon double bonds.

[0666] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon triple bond.

[0667] The term "aryl" includes aromatic hydrocarbon groups of 6 to 18 carbon atoms (e.g., 6 to 10 carbon atoms), including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings comprising 3 to 15 carbon atoms containing at least one N, O, or S atom, such as 3 to 7 carbon atoms containing at least one N, O, or S atom, including pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0668] In some cases, the alkenyl, alkynyl, aryl, or heteroaryl moiety can be coupled to the rest of the molecule through an alkylene linkage. In these cases, the substituent will be referred to as an alkenylalkyl, alkynylalkyl, aralkyl, or heteroaralkyl group, indicating that an alkylene moiety is present between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which it is attached.

[0669] The term "halogen" includes bromine, fluorine, chlorine and iodine.

[0670] The term "heterocycle" refers to a 4- to 8-membered aromatic or non-aromatic ring containing 3 to 7 carbon atoms and at least one atom of N, O, or S. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl".

[0671] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or another ring, each of which is optionally further substituted. Optional substituents on any group (including the above groups) include halogen, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, wherein each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atoms to which they are attached form a ring.

[0672] In certain embodiments, -L in formula (IV) 1 -Being a part-L2 -Z or -L 2 -Z' instead.

[0673] In certain embodiments, -L of formula (IV) 1 - has not been further replaced.

[0674] In certain embodiments, -L 1 - as disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - having formula (V):

[0675]

[0676] in

[0677] The dashed line indicates the connection to -D through the amine functionality of -D;

[0678] -R 1 Selected from the group consisting of: optionally substituted C1-C6 linear, branched or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR 5 2;

[0679] -R 2 is selected from: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0680] -R 3 is selected from: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0681] -R 4 is selected from: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0682] Each -R 5 are independently selected from the following groups: -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or when two -R 5 When taken together, they may be cycloalkyl or cycloheteroalkyl;

[0683] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted.

[0684] In the context of formula (V) only, the terms used have the following meanings:

[0685] "Alkyl," "alkenyl," and "alkynyl" include linear, branched, or cyclic hydrocarbon groups of 1-8 carbons, 1-6 carbons, or 1-4 carbons, wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds, and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1-6 C.

[0686] "Aryl" includes aromatic hydrocarbon groups of 6-18 carbon atoms (e.g., 6-10 carbon atoms), including phenyl, naphthyl, anthracene, and the like. "Heteroaryl" includes aromatic rings of 3-15 carbon atoms (e.g., 3-7 carbon atoms containing at least one N, O, or S atom) containing at least one N, O, or S atom, including pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0687] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl or heteroaryl group containing one or more substituents replacing one or more hydrogen atoms. The substituents can generally be selected from the following groups: halogen, including F, Cl, Br and I; lower alkyl, including linear, branched and cyclic alkyl; lower haloalkyl, including fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl; OH; lower alkoxy, including linear, branched and cyclic alkoxy; SH; lower alkylthio, including linear, branched and cyclic alkylthio; amino; alkylamino; dialkylamino; silyl, including alkylsilyl, alkoxysilyl and arylsilyl; nitro; cyano; carbonyl; carboxylic acid; carboxylic ester; carboxylic acid amide; amino carbonyl; 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).

[0688] In certain embodiments, -L of formula (V) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0689] In certain embodiments, -L of formula (V) 1 - has not been further replaced.

[0690] In certain embodiments, -L 1 - as disclosed in US7585837B2, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - having formula (VI):

[0691]

[0692] in

[0693] The dashed line indicates the connection to -D through the amine functionality of -D;

[0694] R 1 and R 2 independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 , amino, ammonium, carboxyl, PO3H2 and OPO3H2;

[0695] R 3 、R 4 and R 5 independently selected from: hydrogen, alkyl, and aryl;

[0696] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted.

[0697] Suitable substituents for formula (VI) are alkyl groups (such as C 1-6 Alkyl), alkenyl (such as C 2-6 alkenyl), alkynyl (e.g. C 2-6 alkynyl), aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., 4- to 7-membered heterocyclic aromatic), or halogen moiety.

[0698] In the context of formula (VI) only, the terms used have the following meanings:

[0699] The terms "alkyl", "alkoxy", "alkoxyalkyl", "aryl", "alkaryl" and "aralkyl" refer to alkyl groups having 1 to 8 carbon atoms (e.g., 1 to 4 carbon atoms), such as methyl, ethyl, propyl, isopropyl and butyl, and aryl groups having 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromine, fluorine, chlorine and iodine.

[0700] In certain embodiments, -L of formula (VI) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0701] In certain embodiments, -L of formula (VI) 1 - has not been further replaced.

[0702] -L 1Another preferred embodiment of - is disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. 1 - having formula (VII):

[0703]

[0704] in

[0705] The dashed line indicates the connection to -D through the amine functionality of -D;

[0706] L1 is a bifunctional linker group,

[0707] Y1 and Y2 are independently O, S or NR 7 ;

[0708] R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6 heteroalkoxy;

[0709] Ar is a moiety that, when included in formula (VII), forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group;

[0710] X is a chemical bond or a moiety that is actively transported to target cells, a hydrophobic moiety, or a combination thereof,

[0711] y is 0 or 1;

[0712] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and wherein -L 1 - is optionally further substituted.

[0713] In the context of formula (VII) only, the terms used have the following meanings:

[0714] The term "alkyl" is understood to include, for example, straight chain, branched, substituted C 1-12 Alkyl, including alkoxy, C 3-8Cycloalkyl or substituted cycloalkyl, etc.

[0715] The term "substituted" should be understood to include adding or replacing one or more atoms contained in a functional group or compound with one or more different atoms.

[0716] Substituted alkyl groups include carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl; substituted cycloalkyl groups include structural units such as 4-chlorocyclohexyl; aryl groups include structural units such as naphthyl; substituted aryl groups include structural units such as 3-bromophenyl; aralkyl groups include structural units such as tolyl; heteroalkyl groups include structural units such as ethylthiophene; substituted heteroalkyl groups include structural units such as 3-methoxythiophene; alkoxy groups include structural units such as methoxy; and phenoxy groups include structural units such as 3-nitrophenoxy. Halogen is understood to include fluorine, chlorine, iodine, and bromine.

[0717] In certain embodiments, -L of formula (VII) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0718] In certain embodiments, -L of formula (VII) 1 - has not been further replaced.

[0719] In certain embodiments, -L 1 - comprising a substructure of formula (VIII):

[0720]

[0721] in

[0722] The dashed line marked with an asterisk indicates the nitrogen connected to -D via an amide bond;

[0723] The unmarked dashed line indicates the connection to -L 1 -the rest of; and

[0724] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substituted, and where -L 1 - is optionally further substituted.

[0725] In certain embodiments, -L of formula (VIII) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0726] In certain embodiments, -L of formula (VIII) 1 - has not been further replaced.

[0727] In certain embodiments, -L 1 - comprising a substructure of formula (IX):

[0728]

[0729] in

[0730] The dashed line marked with an asterisk indicates the nitrogen connected to -D via a carbamate bond;

[0731] Unlabeled dashed lines indicate connections to -L 1 -the rest of; and

[0732] Where -L 1 -Being at least one -L 2 -Z or -L 2 -Z' substitution, where -L 1 - is optionally further substituted.

[0733] In certain embodiments, -L of formula (IX) 1 -Being a part-L 2 -Z or -L 2 -Z' instead.

[0734] In certain embodiments, -L of formula (IX) 1 - has not been further replaced.

[0735] In certain embodiments, -L 1 - has a structure as disclosed in WO2020 / 206358A1. Therefore, in certain embodiments, the moiety -L 1 -having the formula (X):

[0736]

[0737] in

[0738] Unlabeled dashed lines indicate connections to -D;

[0739] The dashed line marked with an asterisk indicates the connection to -L 2 -Z or -L 2 -Z';

[0740] n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;

[0741] -R 1 and -R 2 are independently electron-withdrawing groups, alkyl groups or -H, and wherein -R 1 and -R 2 At least one of them is an electron-withdrawing group;

[0742] Each -R 4 are independently C1-C3 alkyl, or two -R 4 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring; and

[0743] When -D is a drug molecule linked via an amine group, -Y- is absent; or when -D is a drug molecule linked via a phenol group, an alcohol group, a thiol group, a thiophenol group, an imidazole group, or a non-basic amine group, -Y- is -N(R 6 )CH2-; wherein -R 6 is an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0744] In certain embodiments, n in Formula (X) is an integer selected from 1, 2, 3, 4, 5, and 6. In certain embodiments, n in Formula (X) is an integer selected from 1, 2, and 3. In certain embodiments, n in Formula (X) is an integer selected from 0, 1, 2, and 3. In certain embodiments, n in Formula (X) is 1. In certain embodiments, n in Formula (X) is 2. In certain embodiments, n in Formula (X) is 3.

[0745] In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group 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 aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 8 or -NR 8 2, where each -R 8 are independently -H or optionally substituted alkyl, or two -R 8 The groups, together with the nitrogen to which they are attached, form a heterocyclic ring; or -SR 9 , where -R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl.

[0746] In certain embodiments, -R in Formula (X) 1 and -R 2 The electron withdrawing group is -CN. In certain embodiments, -R 1 and -R 2 The electron withdrawing group of formula (X) is -NO2.1 and -R 2 The electron withdrawing group of is an optionally substituted aryl group containing 6 to 10 carbons. In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group of is an optionally substituted phenyl, naphthyl or anthracenyl. In certain embodiments, -R 1 and -R 2 The electron withdrawing group of is an optionally substituted heteroaryl group containing 3 to 7 carbon atoms and containing at least one N, O or S atom. In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group of is an optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl or indenyl. In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group of is an optionally substituted alkenyl group containing 2 to 20 carbon atoms. In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group of is an optionally substituted alkynyl group containing 2 to 20 carbon atoms. In certain embodiments, -R of formula (X) 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, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 8 or NR 8 2, where each -R 8 are independently -H or an optionally substituted alkyl group containing 1 to 20 carbon atoms, or two -R 8 The groups together with the nitrogen to which they are attached form a heterocyclic ring. In certain embodiments, -R 1 and -R 2 The electron-withdrawing group is -SR 9 , where -SR 9 is an optionally substituted alkyl group containing 1 to 20 carbon atoms, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group or an optionally substituted heteroaralkyl group.

[0747] In certain embodiments, -R in Formula (X) 1 or -R 2 At least one of them is -CN, -SOR 3 or-SO2R3 In certain embodiments, -R 1 and -R 2 At least one of them is -CN or -SO2R 3 In certain embodiments, -R in Formula (X) 1 and -R 2 At least one of them is -CN or -SO2R 3 , where -R 3 is optionally substituted alkyl, optionally substituted aryl or -NR 8 2. In certain embodiments, -R in formula (X) 1 and -R 2 At least one of them is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted by -SO2, phenyl substituted by -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3) or -SO2N(CH2CH2OCH3)2.

[0748] In certain embodiments, each -R in Formula (X) 4 In certain embodiments, two -R 4 All are methyl.

[0749] In certain embodiments, -Y- in formula (X) is absent. In certain embodiments, -Y- in formula (X) is -N(R 6 )CH2-.

[0750] In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -CN, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 SO2CH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is a phenyl group substituted by -SO2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is a phenyl group substituted by -SO2 and -Cl, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH2CH2)2O, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2CH(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is -SO2N(CH3)(CH2CH3), -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is a phenyl group substituted by -SO2 and -CH3, -R 2 is -H, and -R 4 is -CH3.

[0751] In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -CN, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 SO2N(CH3)2, -R2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 SO2CH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 is a phenyl group substituted by -SO2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 is a phenyl group substituted by -SO2 and -Cl, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH2CH2)2O, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2CH(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 is -SO2N(CH3)(CH2CH3), -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 is a phenyl group substituted by -SO2 and -CH3, -R 2is -H, and -R 4 is -CH3.

[0752] In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -CN, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 SO2CH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is a phenyl group substituted by -SO2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is a phenyl group substituted by -SO2 and -Cl, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH2CH2)2O, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2CH(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is -SO2N(CH3)(CH2CH3), -R 2is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is a phenyl group substituted by -SO2 and -CH3, -R 2 is -H, and -R 4 is -CH3.

[0753] In the context of formula (X) only, the terms used have the following meanings:

[0754] The term "alkyl" refers to a straight chain, branched chain, 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, the alkyl group is straight chain or branched chain. Examples of straight chain alkyl groups or branched chain alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In certain embodiments, the alkyl group is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0755] The term "alkoxy" refers to an alkyl group bound to oxygen and includes methoxy, ethoxy, isopropoxy, cyclopropyloxy, and cyclobutyloxy.

[0756] 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.

[0757] 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.

[0758] The term "aryl" refers to an aromatic hydrocarbon group of 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl and anthracenyl. The term "heteroaryl" refers to an aromatic ring containing 3 to 15 carbon atoms and containing at least one nitrogen, oxygen or sulfur atom, preferably an aromatic ring containing 3 to 7 carbon atoms and containing at least one nitrogen, oxygen or sulfur atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl and indenyl.

[0759] In certain embodiments, the alkenyl, alkynyl, aryl or heteroaryl moiety can be coupled to the remainder of the molecule through an alkyl linkage. In these cases, the substituent will be referred to as alkenylalkyl, alkynylalkyl, aralkyl or heteroaralkyl, indicating that there is an alkylene moiety between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which it is coupled.

[0760] The term "halogen" or "halo" refers to bromine, fluorine, chlorine and iodine.

[0761] The term "heterocycle" or "heterocyclyl" refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl." In certain embodiments, the heterocycle or heterocyclyl is non-aromatic. In certain embodiments, the heterocycle or heterocyclyl is aromatic.

[0762] The term "optionally substituted" means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) identical or different substituents. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -OR aa 、-SR aa 、-NR aa R bb 、-NO2、-C=NH(OR aa ),-C(O)R aa 、-OC(O)R aa 、-C(O)OR aa 、-C(O)NR aa R bb 、-OC(O)NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)OR bb 、-S(O)R aa 、-S(O)2R aa 、-NR aa S(O)R bb 、-C(O)NR aa S(O)R bb 、-NR aa S(O)2R bb 、-C(O)NR aa S(O)2R bb 、-S(O)NR aa R bb 、-S(O)2NR aa R bb 、-P(O)(ORaa )(OR bb ), heterocyclyl, heteroaryl or aryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are each independently optionally replaced by -R cc Substitution, where -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, they form a heterocyclic group, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy or -CN, wherein: each -R cc are independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN or -NO2.

[0763] In certain embodiments, -L 2 - is a chemical bond. In certain embodiments, -L 2 - is a spacer moiety, for example a spacer moiety selected from the group consisting of: -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 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl is optionally substituted by one or more identical or different -R y2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S(O)2N(R y3 )-、-S(O)N(R y3 )-、-S(O)2、-S(O)-、-N(Ry3 )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 )-;

[0764] -R y1 and -R y1a are independently selected from the following groups: -H, -T, 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 is optionally substituted by one or more identical or different -R y2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 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 )-;

[0765] Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, 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 optionally replaced by one or more identical or different -R y2 replace;

[0766] Each -R y2 Independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR y5 、-OR y5 、-C(O)R y5、-C(O)N(R y5 R y5a )、-S(O)2N(R y5 R y5a )、-S(O)N(R y5 R y5a )、-S(O)2R y5 、-S(O)R y5 、-N(R y5 )S(O)2N(R y5a R y5b ),-SR y5 、-N(R y5 R y5a )、-NO2、-OC(O)R y5 、-N(R y5 )C(O)R y5a 、-N(R y5 )S(O)2R y5a 、-N(R y5 )S(O)R y5a 、-N(R y5 )C(O)OR y5a 、-N(R y5 )C(O)N(R y5a R y5b )、-OC(O)N(R y5 R y5a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[0767] Each -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Independently selected from: -H and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more same or different halogens.

[0768] In certain embodiments, -L 2 - is selected from: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-、-S(O)2N(R y1 )-、-S(O)N(R y1 )-、-S(O)2、-S(O)-、-N(R y1 )S(O)2N(R y1a )-、-S-、-N(Ry1 )-、-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 is optionally substituted by one or more identical or different -R y2 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 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 )-;

[0769] -R y1 and -R y1a are independently selected from the following groups: -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 is optionally substituted by one or more identical or different -R y2 substituted, and wherein C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -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 )-;

[0770] Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, 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 optionally replaced by one or more identical or different -R y2 replace;

[0771] -R y2 Selected from the group consisting of halogen, -CN, oxo (=O), -COOR y5 、-OR y5 、-C(O)R y5 、-C(O)N(R y5 R y5a )、-S(O)2N(R y5 R y5a )、-S(O)N(R y5 R y5a )、-S(O)2R y5 、-S(O)R y5 、-N(R y5 )S(O)2N(R y5a R y5b ),-SR y5 、-N(R y5 R y5a )、-NO2、-OC(O)R y5 、-N(R y5 )C(O)R y5a 、-N(R y5 )S(O)2R y5a 、-N(R y5 )S(O)R y5a 、-N(R y5 )C(O)OR y5a 、-N(R y5 )C(O)N(R y5a R y5b )、-OC(O)N(R y5 R y5a ) and C 1-6Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[0772] Each -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Independently selected from: -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more same or different halogens.

[0773] In certain embodiments, -L 2 - is selected from the group consisting of -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 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl is optionally substituted by one or more identical or different -R y2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S(O)2N(R y3 )-、-S(O)N(R y3 )-、-S(O)2-、-S(O)-、-N(R y3 )S(O)2N(R y3a )-、-S-、-N(R y3 )-、-OC(OR y3 )(Ry3a )-、-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[0774] -R y1 and -R y1a Independently selected from the group consisting of -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl;

[0775] Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, 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;

[0776] Each -R y2 Independently selected from the group consisting of halogen and C 1-6 alkyl; and each -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Independently selected from: -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more same or different halogens.

[0777] In certain embodiments, -L 2 - for C 1-20 The alkyl chain is optionally interrupted by one or more groups independently selected from the group consisting of -O-, -T- and -C(O)N(R y1 )-; and the C 1-20 The alkyl chain is optionally substituted with one or more groups independently selected from the group consisting of: -OH, -T, and -C(O)N(R y6 R y6a )-; among them, -R y1 、-R y6 、-R y6a Independently selected from: H and C 1-4 Alkyl, and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, 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.

[0778] In certain embodiments, -L 2- has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0779] In certain embodiments, -L 2 - comprising a portion selected from the following:

[0780]

[0781] in

[0782] The dotted lines indicate connections to -L 2 -、-L 1 -, -Z and / or the rest of Z'; and -R and -R a are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0783] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms.

[0784] As used herein, with respect to part-L 2 The term "chain length" refers to the length of the chain present in -L 1 -L in the shortest connection between - and -Z 2 -The atomic number of .

[0785] In certain embodiments, -L 2 - having formula (i):

[0786]

[0787] in

[0788] The dashed line marked with an asterisk indicates the connection to -L 1 -;

[0789] Unlabeled dashed lines indicate connections to -Z or -Z';

[0790] 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

[0791] wherein the moiety of formula (i) is optionally further substituted.

[0792] In certain embodiments, n in formula (i) is selected from 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.

[0793] In certain embodiments, the moiety -L1 -L 2 -Selected from the group consisting of:

[0794]

[0795] in

[0796] The unlabeled dashed line represents the nitrogen connected to -D by forming an amide bond; and

[0797] Dashed lines marked with an asterisk indicate connections to -Z or Z'.

[0798] In certain embodiments, the moiety -L 1 -L 2 - has formula (IIca-ii). In certain embodiments, the moiety -L 1 -L 2 - having the formula (IIcb-iii).

[0799] In certain embodiments, the moiety -L 1 -L 2 -Selected from the group consisting of:

[0800]

[0801] in

[0802] The unlabeled dashed line represents the nitrogen connected to -D by forming an amide bond; and

[0803] Dashed lines marked with an asterisk indicate connections to -Z or Z'.

[0804] Vector-Z includes C 8-24In certain embodiments, -Z comprises a polymer, such as a polymer selected from the group consisting of 2-methacryloyloxyethylphosphorylcholine, polyacrylic acid, polyacrylate, polyacrylamide, polyalkoxy polymer, polyamide, polyamidoamine, polyamino acid, polyanhydride, polyaspartamide, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactone, polycarbonate, polycyanoacrylate, polydimethylacrylamide, polyester, polyethylene, polyethylene glycol, polyethylene oxide, polyethyl phosphate, polyethyl oxazoline, polyglycolic acid, polyhydroxyethyl acrylate, polyhydroxyethyl oxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, polyhydroxypropyl methacrylate, poly Hydroxypropyl oxazoline, polyiminocarbonate, polylactic acid, lactic acid-glycolic acid copolymer, polymethacrylamide, polymethacrylate, polymethyl oxazoline, polyorganophosphazene, polyorthoester, polyoxazoline, polypropylene glycol, polysiloxane, polyurethane, polyvinyl alcohol, polyvinylamine, polyvinyl methyl ether, polyvinyl pyrrolidone, silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and its copolymers. In certain embodiments, -Z comprises polyethylene glycol (PEG).

[0805] In certain embodiments, the molecular weight of -Z ranges from 5 to 200 kDa. In certain embodiments, the molecular weight of -Z ranges from 8 to 100 kDa, such as from 10 to 80 kDa, 12 to 60 kDa, or 15 to 40 kDa. In certain embodiments, the molecular weight of -Z is about 20 kDa. In certain embodiments, the molecular weight of -Z is about 40 kDa.

[0806] In certain embodiments, -Z comprises PEG and has a molecular weight range of 5 to 200 kDa. In certain embodiments, -Z comprises PEG and has a molecular weight range of 8 to 100 kDa, such as 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 approximately 20 kDa. In certain embodiments, -Z comprises PEG and has a molecular weight of approximately 40 kDa.

[0807] In certain embodiments, -Z comprises a protein, such as a protein selected from the group consisting of: a carboxy-terminal polypeptide of chorionic gonadotropin, as described in US2012 / 0035101 A1, which is incorporated herein by reference; an 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 portion.

[0808] In certain embodiments,-Z comprises fatty acid derivatives, such as the derivatives disclosed in WO 2005 / 027978 A2 and WO 2014 / 060512A1, which are incorporated herein by reference. In certain embodiments,-Z is a hyaluronic acid-based polymer. In certain embodiments,-Z is a carrier as disclosed in WO 2012 / 02047A1, which is incorporated herein by reference. In certain embodiments,-Z is a carrier as disclosed in WO 2013 / 024048 A1, which is incorporated herein by reference. In certain embodiments,-Z is a PEG-based polymer, such as 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 with at least 4 PEG-based arms.

[0809] In certain embodiments, this multi-arm PEG-based polymer-Z is attached to multiple moieties-L 2 -L 1 -D, where each part -L 2 -L 1 -D is in some embodiments attached to the end of the arm. In some embodiments, this multi-arm PEG-based polymer -Z is attached to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 moieties -L 2 -L 1 In certain embodiments, this multi-arm PEG-based polymer -Z is linked to 2, 3, 4, 6, or 8 moieties -L 2 -L 1 In certain embodiments, this multi-arm PEG-based polymer -Z is linked to 2, 4, or 6 moieties -L 2 -L1 -D. In certain embodiments, this multi-arm PEG-based polymer -Z is linked to 4 or 6 moieties -L 2 -L 1 -D. In certain embodiments, this multi-arm PEG-based polymer -Z is linked to four moieties -L 2 -L 1 -D.

[0810] In certain embodiments, -Z is a branched PEG-based polymer. In certain embodiments, -Z is a branched PEG-based polymer with one, two, three, four, five or six branch points. In certain embodiments, -Z is a branched PEG-based polymer with one, two or three branch points. In certain embodiments, -Z is a branched PEG-based polymer with one branch point. In certain embodiments, -Z is a branched PEG-based polymer with two branch points. In certain embodiments, -Z is a branched PEG-based polymer with three branch points. In certain embodiments, the branch points may be selected from -N<, -CH< and >C<.

[0811] In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight range of 5 to 200kDa. In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight range of 8 to 100kDa. In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight range of 10 to 80kDa. In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight range of 12 to 60kDa. In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight range of 15 to 40kDa. In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight range of about 20kDa. In certain embodiments, -Z is a branched PEG-based polymer with a branch point and a molecular weight of about 40kDa.

[0812] In certain embodiments, -Z is a branched PEG-based polymer having one branch point (branch point is -CH<) and a molecular weight of about 40 kDa.

[0813] In certain embodiments, -Z or Z" comprises the moiety:

[0814]

[0815] In certain embodiments, -Z or Z' comprises an amide bond.

[0816] In certain embodiments, -Z comprises a moiety of formula (a)

[0817]

[0818] The dotted line indicates the connection to the rest of -Z or -L 2 -;

[0819] BP a is a branch point selected from the group consisting of: -N<, -CR<, and >C<;

[0820] -R is selected from: -H and C 1-6 alkyl;

[0821] If BP a If -N< or -CR< then a is 0, and if BP a If >C<, then n is 1;

[0822] -S a -、-S a’ -、-S a” -and-S a”’ - are independently a chemical bond or selected from the group consisting of: 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 is optionally substituted by one or more identical or different -R 1 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 2 )-、-S(O)2N(R 2 )-、-S(O)N(R 2 )-、-S(O)2-、-S(O)-、-N(R 2 )S(O)2N(R 2a )-、-S-、-N(R 2 )-、-OC(OR 2 )(R 2a )、-N(R 2 )C(O)N(R 2a )-and-OC(O)N(R 2 )-;

[0823] Each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, C 3-10Cycloalkyl, 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 optionally replaced by one or more identical or different -R 1 replace;

[0824] Each -R 1 Independently selected from the group consisting of 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)2R 3 、-S(O)R 3 、-N(R 3 )S(O)2N(R 3a R 3b ),-SR 3 、-N(R 3 R 3a )、-NO2、-OC(O)R 3 、-N(R 3 )C(O)R 3a 、-N(R 3 )S(O)2R 3a 、-N(R 3 )S(O)R 3a 、-N(R 3 )C(O)OR 3a 、-N(R 3 )C(O)N(R 3a R 3b )、-OC(O)N(R 3 R 3a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different;

[0825] Each -R 2 、-R 2a 、-R 3 、-R 3a and -R 3b Independently selected from: -H and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[0826] -P a’、-P a” and -P a”’ are independently polymer moieties.

[0827] In certain embodiments, BP of formula (a) a In certain embodiments, BP of formula (a) a In certain embodiments, BP of formula (a) a In certain embodiments, -R is -H. Thus, a of formula (a) is 0.

[0828] In certain embodiments, -S of formula (a) a - is a chemical bond. In certain embodiments, -S of formula (a) a -Selected from the following group: C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, where C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more chemical groups selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-、-S(O)2N(R 4 )-、-S(O)N(R 4 )-、-S(O)2-、-S(O)-、-N(R 4 )S(O)2N(R 4a )-、-S-、-N(R 4 )-、-OC(OR 4 )(R 4a )-、-N(R 4 )C(O)N(R 4a )-and-OC(O)N(R 4 )-; wherein -T- is a 3- to 10-membered heterocyclic group; and -R 4 and -R 4a In certain embodiments, -S of formula (a) is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. a -Selected from C 1-10 Alkyl groups interrupted by one or more chemical groups selected from the group consisting of: -T-, -C(O)N(R 4 )- and -O-.

[0829] In certain embodiments, -S of formula (a) a’ - is a chemical bond. In certain embodiments, -S of formula (a) a’ -Selected from the following group: C 1-10 Alkyl, C 2-10 Alkenyl and C2-10 Alkynyl, where C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more chemical groups selected from the group consisting of: -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-、-S(O)2N(R 4 )-、-S(O)N(R 4 )-、-S(O)2-、-S(O)-、-N(R 4 )S(O)2N(R 4a )-、-S-、-N(R 4 )-、-OC(OR 4 )(R 4a )-、-N(R 4 )C(O)N(R 4a )-and-OC(O)N(R 4 )-; where -R 4 and -R 4a In certain embodiments, -S of formula (a) is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. a’ - is selected from the group consisting of methyl, ethyl, propyl, butyl, optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 )-.

[0830] In certain embodiments, -S of formula (a) a” - is a chemical bond. In certain embodiments, -S of formula (a) a” -Selected from the following group: C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, where C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more chemical groups selected from the group consisting of: -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-、-S(O)2N(R 4 )-、-S(O)N(R 4 )-、-S(O)2-、-S(O)-、-N(R 4 )S(O)2N(R 4a )-、-S-、-N(R 4 )-、-OC(OR 4 )(R 4a )-、-N(R 4 )C(O)N(R 4a)-and-OC(O)N(R 4 )-; where -R 4 and -R 4a In certain embodiments, -S of formula (a) is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. a” - is selected from the group consisting of methyl, ethyl, propyl, and butyl, optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R 4 )-.

[0831] In certain embodiments, -S of formula (a) a”’ - is a chemical bond. In certain embodiments, -S of formula (a) a”’ -Selected from: C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, where C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more chemical groups selected from the group consisting of: -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-、-S(O)2N(R 4 )-、-S(O)N(R 4 )-、-S(O)2-、-S(O)-、-N(R 4 )S(O)2N(R 4a )-、-S-、-N(R 4 )-、-OC(OR 4 )(R 4a )-、-N(R 4 )C(O)N(R 4a )-and-OC(O)N(R 4 )-; where -R 4 and -R 4a In certain embodiments, -S in formula (a) is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. a”’ - is selected from the group consisting of methyl, ethyl, propyl, and butyl, optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)-, and -C(O)N(R 4 )-.

[0832] In certain embodiments, -P of formula (a) a’ 、-P a” and -P a”’independently comprising a polymer selected from the group consisting of 2-methacryloyloxyethyl phosphorylcholine, polyacrylic acid, polyacrylate, polyacrylamide, polyalkoxy polymer, polyamide, polyamidoamine, polyamino acid, polyanhydride, polyaspartamide, polybutyric acid, polyglycolic acid, polybutylene terephthalate, polycaprolactone, polycarbonate, polycyanoacrylate, polydimethylacrylamide, polyester, polyethylene, polyethylene glycol, polyethylene oxide, polyethyl phosphate, polyethyl oxazoline, polyglycolic acid, polyhydroxyethyl acrylate, polyhydroxyethyl oxazoline, polyhydroxymethyl acrylate, polyhydroxypropyl methacrylamide, polyhydroxypropyl methacrylate, polyhydroxypropyl oxazoline, Polyiminocarbonate, polylactic acid, lactic acid-glycolic acid copolymer, polymethacrylamide, polymethacrylate, polymethyloxazoline, polyorganophosphazene, polyorthoester, polyoxazoline, polypropylene glycol, polysiloxane, polyurethane, polyvinyl alcohol, polyvinylamine, polyvinyl methyl ether, polyvinyl pyrrolidone, silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and its copolymers.

[0833] In certain embodiments, -P of formula (a) a’ 、-P a” and -P a”’ In certain embodiments, -P of formula (a) a’ 、-P a” and -P a”’ Independently comprising a PEG-based portion, the portion comprises at least 20% PEG, such as at least 30%, such as at least 40% PEG, such as at least 50% PEG, such as at least 60% PEG, such as at least 70% PEG, such as at least 80% PEG or such as at least 90% PEG.

[0834] In certain embodiments, -P of formula (a) a’ 、-P a” and -P a”’ The molecular weight range of is independently 5kDa to 50kDa and inclusive, such as 5kDa to 40kDa and inclusive, such as 7.5kDa to 35kDa and inclusive, or such as 10 to 30kDa and inclusive. In certain embodiments, -P in formula (a) a’ 、-P a” and -P a”’ The molecular weight of is about 5kDa. In certain embodiments, -P in formula (a) a’ 、-P a” and -Pa”’ The molecular weight of is about 7.5kDa. In certain embodiments, -P in formula (a) a’ 、-P a” and -P a”’ The molecular weight of is about 10kDa. In certain embodiments, -P in formula (a) a’ 、-P a” and -P a”’ The molecular weight of is about 12.5kDa. In certain embodiments, -P in formula (a) a’ 、-P a” and -P a”’ The molecular weight of is about 15kDa. In certain embodiments, -P in formula (a) a’ 、-P a” and -P a”’ The molecular weight is approximately 20 kDa.

[0835] 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).

[0836] In certain embodiments, -Z comprises a moiety of formula (b)

[0837]

[0838] in

[0839] The dotted line indicates the connection to the rest of the -Z or -L 2 -;and

[0840] m and p are each independently an integer from 150 to 1000, inclusive; such as an integer from 150 to 500, inclusive; such as an integer from 200 to 500, inclusive; or such as an integer from 400 to 500, inclusive.

[0841] 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.

[0842] In certain embodiments, -Z is a moiety of formula (b).

[0843] In certain embodiments, Z' is a hydrogel.

[0844] In certain embodiments, Z' is a PEG-based hydrogel or a hyaluronic acid-based hydrogel. In certain embodiments, Z' is a PEG-based hydrogel. In certain embodiments, Z' is a hyaluronic acid-based hydrogel.

[0845] In certain embodiments, Z' is a hydrogel as described in WO 2006 / 003014 A2, WO 2011 / 012715 A1, WO 2014 / 056926 A1, WO 2020 / 064846, or WO 2020 / 064847, which are herein incorporated by reference in their entireties.

[0846] In certain embodiments, Z' is a hydrogel as disclosed in WO 2013 / 036847 A1. Specifically, in certain embodiments, Z' is a hydrogel prepared by a method comprising the steps of: reacting at least a first reactive polymer with a cleavable cross-linker compound, wherein the cleavable cross-linker compound comprises a first functional group -Y that reacts with the first reactive polymer. 1 , and further comprising a portion that cleaves by elimination under physiological conditions, wherein the portion comprises a second functional group -Y that reacts with a second reactive polymer 2 .

[0847] In certain embodiments, the cleavable cross-linker compound has Formula (PL-1):

[0848]

[0849] in

[0850] m is 0 or 1;

[0851] -X comprises a functional group capable of being linked to a reactive polymer that is readily eliminated under physiological conditions and the second functional group -Y 2 ;

[0852] -R 1 、-R 2 and -R 5 At least one of the above-mentioned functional groups comprises the first functional group -Y capable of being attached to a polymer 1 ;

[0853] -R 1 and -R 2 There is one and only one selected from: -H, alkyl, aralkyl and heteroaralkyl;

[0854] Optionally, -R 1 and -R 2 Can be linked to form 3- to 8-membered rings;

[0855] -R 1 and -R 2 At least one or two of them are independently selected from the following groups: -CN, -NO2, aryl, heteroaryl, alkenyl, alkynyl, -COR 3 、-SOR3 、-SO2R 3 and-SR 4 ;

[0856] -R 3 Selected from: -H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OR 9 and -NR 9 2;

[0857] -R 4 Selected from: alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;

[0858] Each -R 5 Independently selected from the group consisting of: -H, alkyl, alkenylalkyl, alkynylalkyl, (OCH2CH2) p O-alkyl (p is an integer from 1 to 1000), aryl, aralkyl, heteroaryl, and heteroaralkyl;

[0859] Each -R 9 Independently selected from: -H and alkyl, or two -R 9 Together with the nitrogen to which they are attached, they form a heterocyclic ring;

[0860] And wherein the moiety of formula (PL-1) is optionally further substituted.

[0861] The following paragraphs describe this hydrogel in more detail.

[0862] In certain embodiments, -X in formula (PL-1) is selected from the group consisting of succinimidyl carbonate, sulfosuccinimidyl carbonate halides, thioethers, esters, nitrobenzene carbonate, chloroformates, fluoroformates, optionally substituted phenols, and formula (PL-2):

[0863] in

[0864] The dashed line indicates the connection to the rest of formula (PL-1);

[0865] -T*- is selected from: -O-, -S- and -NR 6 -;

[0866] z is an integer selected from 1, 2, 3, 4, 5 and 6;

[0867] -X'- is absent or selected from: -OR 7 -and-SR 7 -;

[0868] -Y 2 is a functional group capable of linking to a reactive polymer;

[0869] -R 6is selected from: -H, alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; and

[0870] -R 7 Selected from: alkylene, phenylene and (OCH2CH2) p , where p is an integer from 1 to 1000.

[0871] In certain embodiments, -X of formula (PL-1) comprises an activated carbonate, such as succinimidyl carbonate, sulfosuccinimidyl carbonate, or nitrobenzene 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) is OR 7 or SR 7 , where R 7 is optionally substituted alkylene, optionally substituted phenylene or (OCH2CH2) p , where p is from 1 to 1000.

[0872] In certain embodiments, p of Formula (PL-2) is an integer from 1 to 100. In certain embodiments, p of Formula (PL-2) is an integer from 1 to 10.

[0873] In certain embodiments, -Y of formula (PL-1) 1 -Y of the Japanese formula (PL-2) 2 Independently contains N3, NH2, NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide, wherein t Bu is tert-butyl, and wherein when -Y 1 or -Y 2 When one of them contains N3, the other does not contain an alkyne or cyclooctyne; when -Y 1 or -Y 2 When one of the contains SH, the other does not contain maleimide, acrylate or acrylamide; when -Y 1 or -Y 2 When one of them contains NH2, the other does not contain CO2H; and when -Y 1 or -Y 2 When one of the compounds contains 1,3-diene or cyclopentadiene, the other compound does not contain furan.

[0874] In certain embodiments, the cleavable cross-linker compound has Formula (PL-3):

[0875]

[0876] in

[0877] m is 0 or 1;

[0878] n is an integer selected from 1 to 1000;

[0879] s is 0, 1, or 2;

[0880] t is selected from: 2, 4, 8, 16 and 32;

[0881] -W- is selected from the group consisting of: -O(C=O)O-, -O(C=O)NH-, -O(C=O)S-, -O(C=O)NR 6 CH2O- and -O(C=O)NR 6 S-;

[0882] -Q is a core group with a valence = t that connects the multiple arms of the cleavable cross-linking compound;

[0883] wherein t is an integer selected from 2, 4, 8, 16 and 32; and

[0884] Where -R 1 、-R 2 and -R 5 As defined in formula (PL-1).

[0885] In certain embodiments, t of Formula (PL-3) is 2. In certain embodiments, t of Formula (PL-3) is 4. In certain embodiments, t of Formula (PL-3) is 8. In certain embodiments, t of Formula (PL-3) is 16. In certain embodiments, t of Formula (PL-3) is 32.

[0886] In certain embodiments, -Q of Formula (PL-3) has a structure selected from the group consisting of:

[0887]

[0888] The dashed line represents the remaining portion that is attached to the cleavable cross-linker compound.

[0889] In certain embodiments, -Q of formula (PL-3) has the structure of (PL-3-i). In certain embodiments, -Q of formula (PL-3) has the structure of (PL-3-ii). In certain embodiments, -Q of formula (PL-3) has the structure of (PL-3-iii).

[0890] In certain embodiments, the cleavable cross-linker compound has the formula (PL-3), wherein m is 0, n is about 100, s is 0, t is 4, -W- is -O(C=O)NH-, -Q has the structure of (PL-3i), and -R 2 for H, A-R 5 for -H, another -R 5 is (CH2)5N3, and -R 1 is (4-chlorophenyl)SO2, phenyl substituted by -SO2, morpholino-SO2 or -CN.

[0891] In certain embodiments, -Y of formula (PL-3) 1 Contains N3, NH2, NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkynyl, cyclooctyne, acrylate or acrylamide, wherein t Bu is tert-butyl.

[0892] In certain embodiments, each -Y of Formula (PL-1) or (PL-3) 1 -Y of the Japanese formula (PL-2) 2 Independently contains N3, NH2, NH-CO2 t Bu, SH, S t Bu, maleimide, CO2H, CO2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide.

[0893] In certain embodiments, -Y 1 and -Y 2 In certain embodiments, -Y 1 and -Y 2 One of the -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 In certain embodiments, -Y 1 and -Y 2 One of the groups is maleimide and the other is a selectively reactive functional group selected from 1,3-diene, cyclopentadiene and furan.

[0894] In certain embodiments, the first polymer and any second polymer are selected from the group consisting of homopolymeric or copolymeric polyethylene glycol, polypropylene glycol, poly(N-vinyl pyrrolidone), polymethacrylate, polyphosphazene, polylactide, polyacrylamide, polyglycolate, polyethyleneimine, agarose, dextran, gelatin, collagen, polylysine, chitosan, alginate, hyaluronic acid, pectin, and carrageenan, wherein the polymers meet one of the following conditions: 1) contain a suitable reactive functional group; 2) have the formula [Y 3 -(CH2) s (CH2CH2O) n ] t Q, where -Y 3 is a reactive functional group, s is 0, 1 or 2, n is an integer selected from 10 to 1000, -Q is a core group having a valence of t, and t is an integer selected from 2, 4, 8, 16 and 32.

[0895] 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.

[0896] 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.

[0897] 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.

[0898] 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.

[0899] In certain embodiments, the first and second reactive polymers are reacted with the cleavable cross-linker compound sequentially or simultaneously.

[0900] In certain embodiments, the first functional group and the second functional group are the same.

[0901] In the context of formulae (PL-1), (PL-2) and (PL-3) only, the terms used have the following meanings:

[0902] The term "a moiety capable of being cleaved by elimination under physiological conditions" refers to a moiety comprising the group HC-(CH=CH) m -C-X' structure, wherein m is 0 or 1, and X' is a leaving group, wherein the elimination reaction to remove the element HX' as described above 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 pH between 7 and 8 and temperature between 30 and 40 degrees Celsius.

[0903] The terms "reactive polymers and reactive oligomers" refer to polymers or oligomers that contain functional groups that can react with other functional groups, and these reactions are most preferably carried out under mild conditions to ensure the stability requirements of peptides, proteins and other biomolecules. Suitable functional groups in reactive polymers include: maleimide, thiol or protected thiol, alcohol, acrylate, acrylamide, amine or protected amine, carboxylic acid or protected carboxylic acid, azide, alkyne (including cycloalkyne), 1,3-dienes (including cyclopentadiene and furan), α-halocarbonyl, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide ester, or nitrophenyl ester or carbonate.

[0904] The term "functional group that can be attached to a reactive polymer" refers to a functional group that reacts with a corresponding functional group of the reactive polymer to form a covalent bond with the polymer. Suitable functional groups that can be attached to the reactive polymer include: maleimide, thiol or protected thiol, acrylate, acrylamide, amine or protected amine, carboxylic acid or protected carboxylic acid, azide, alkyne (including cycloalkyne), 1,3-dienes (including cyclopentadiene and furan), α-halocarbonyl, and N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide ester, or nitrophenyl ester or carbonate.

[0905] The term "substituted" means that one or more hydrogen atoms in an alkyl, alkenyl, alkynyl, aryl or heteroaryl group are replaced by one or more substituents. The substituents can generally be selected from: halogen (including F, Cl, Br and I); lower alkyl (including linear, branched and cyclic alkyl); lower haloalkyl (including fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl); OH; lower alkoxy (including linear, branched and cyclic alkoxy); SH; lower alkylthio (including linear, branched and cyclic alkylthio); amino; alkylamino; dialkylamino; silyl (including alkylsilyl, alkoxysilyl and arylsilyl); nitro; cyano; carbonyl; carboxylic acid; carboxylate; carboxylic acid ester; Acid amide; aminocarbonyl; aminoacyl; carbamate; urea; thiocarbamate; thiourea; ketone; sulfone; sulfonamide; aryl, including phenyl, naphthyl and anthracenyl; heteroaryl (including 5-membered heteroaryl, including pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole, 6-membered heteroaryl, including pyridine, pyrimidine, pyrazine, and fused heteroaryl, including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole and benzisothiazole).

[0906] R 1 and R 2 The properties of the can be adjusted by optionally adding electron donating or electron withdrawing substituents. The term "electron donating group" refers to a group that causes R 1 R 2 Substituents that reduce the acidity of the CH group; electron-donating groups generally have negative Hammett σ or Taft σ* constants and are well known in the field of physical organic chemistry (the Hammett constant refers to aryl / heteroaryl substituents, and the Taft constant refers to substituents on non-aromatic moieties). Examples of suitable electron-donating substituents include lower alkyl, lower alkoxy, lower alkylthio, amino, alkylamino, dialkylamino, and silicon.

[0907] The term "electron withdrawing group" refers to a group that can enhance the 1 R 2The CH group is an acidic substituent; electron withdrawing groups generally have a positive Hammett σ or Taft σ* constant 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 x , where -R x is H, lower alkyl, lower alkoxy or amino, or S(O) m R Y , where m is 1 or 2 and -R Y is a lower alkyl, aryl, or heteroaryl group. As is well known in the art, the electronic influence of a substituent may depend on the position of the substituent. For example, an alkoxy substituent in the ortho or para position of an aromatic ring is electron donating and has a negative Hammett σ constant, while an alkoxy substituent in the meta position of an aromatic ring is electron withdrawing and has a positive Hammett σ constant.

[0908] The terms "alkyl," "alkenyl," and "alkynyl" include straight, branched, or cyclic hydrocarbon groups of 1 to 8 carbons, or 1 to 6 carbons, or 1 to 4 carbons, wherein 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.

[0909] The term "aryl" includes aromatic hydrocarbon groups of 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings containing 3 to 15 carbon atoms (preferably 3 to 7 carbon atoms) and containing at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.

[0910] The term "halogen" includes fluorine, chlorine, bromine and iodine.

[0911] The term "maleimide" is a group of the formula:

[0912]

[0913] In certain embodiments, Z' is a hydrogel as disclosed in WO 2020 / 206358 A1. Specifically, in certain embodiments, Z' is a hydrogel prepared by a method comprising the following steps:

[0914] (a) providing a multi-arm polymer-P 2 A first prepolymer of wherein the first prepolymer has formula (PL-4)

[0915]

[0916] in

[0917] n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;

[0918] r is an integer greater than 2;

[0919] -Y is a reactive functional group for connecting the first prepolymer and the second prepolymer;

[0920] -R 1 and -R 2 are independently electron-withdrawing groups, alkyl groups or -H, and wherein -R 1 and -R 2 At least one of them is an electron-withdrawing group;

[0921] Each -R 4 are independently C1-C3 alkyl or two -R 4 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring;

[0922] -W- does not exist or is

[0923]

[0924] The dashed line marked with an asterisk indicates the connection to -NH-, and the unmarked dashed line indicates the connection to -P 2 ;

[0925] Each of x, y, and z is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0926] -B' is -NH2, -ONH2, a ketone, an aldehyde, -SH, -OH, -CO2H, a carboxamide group, or a group containing a cyclooctyne or a bicyclononyne; and

[0927] -C* is carboxamide, thioether, thiosuccinimide, triazole or oxime;

[0928] (b) providing a multi-arm polymer-P 1 a second prepolymer of wherein each arm is terminated by a reactive functional group -Y" that reacts with -Y of step (a);

[0929] (c) mixing the two prepolymers of steps (a) and (b) under conditions wherein -Y and -Y" react to form a bond -Y*-; and optionally

[0930] (d) Isolating the resulting hydrogel.

[0931] Thus, Z' is the hydrogel obtained by the above method. In certain embodiments, the hydrogel produced by the above method is degradable.

[0932] In certain embodiments, -Y and -Y" react under step (c) to form an insoluble hydrogel matrix comprising crosslinks of formula (PL-4'):

[0933]

[0934] Among them, n, r, -P 1 、-Y*-、-R 4 、-R 1 、-R 2 , -W-, and -P 2 As defined above.

[0935] In certain embodiments, n of Formula (PL-4) or (PL-4') is an integer selected from 1, 2, 3, 4, 5, and 6. In certain embodiments, n of Formula (PL-4) or (PL-4') is an integer selected from 1, 2, and 3. In certain embodiments, n of Formula (PL-4) or (PL-4') is an integer selected from 0, 1, 2, and 3. In certain embodiments, n of Formula (PL-4) or (PL-4') is 1. In certain embodiments, n of Formula (PL-4) is 2. In certain embodiments, n of Formula (PL-4) or (PL-4') is 3.

[0936] In certain embodiments, the multi-arm-P of formula (PL-4) or (PL-4') 2 is an r-arm polymer, wherein 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.

[0937] In certain embodiments, -P of formula (PL-4) or (PL-4') 2 The molecular weight of the compound is at least 1 kDa. In certain embodiments, the compound of formula (PL-4) or (PL-4') -P 2 The molecular weight of -P is 1 to 100 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 The molecular weight of the compound is 1 to 80 kDa. In certain embodiments, the compound of formula (PL-4) or (PL-4') 2The molecular weight of the compound is 1 to 60 kDa. In certain embodiments, the compound of formula (PL-4) or (PL-4') 2 The molecular weight of the compound is 1 to 40 kDa. In certain embodiments, the compound of formula (PL-4) or (PL-4') 2 The molecular weight of -P is 1 to 20 kDa. In certain embodiments, -P of formula (PL-4) or (PL-4') 2 The molecular weight of the compound is 1 to 10 kDa. In certain embodiments, the compound of formula (PL-4) or (PL-4') 2 The molecular weight of the compound is 1 to 5 kDa. In certain embodiments, the compound of formula (PL-4) or (PL-4') 2 The molecular weight of is about 20kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight of is about 40kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight of is about 60kDa. In certain embodiments, the -P of formula (PL-4) or (PL-4') 2 The molecular weight is approximately 80 kDa.

[0938] In certain embodiments, the multi-arm polymer-P of step (b) 1 is an r-arm polymer, wherein 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 an r-arm polymer, wherein r is an integer selected from 2, 3, 4, 5, 6, 7 and 8. In certain embodiments, the multi-arm-P of step (b) 1 is an r-arm polymer, wherein r is an integer selected from 2, 4, 6 and 8. In certain embodiments, the multi-arm-P of step (b) 1 is an r-arm polymer, wherein r is 2. In certain embodiments, the multi-arm-P 1 is an r-arm polymer, wherein r is 4. In certain embodiments, the multi-arm-P 1 is an r-arm polymer, wherein r is 6. In certain embodiments, the multi-arm-P 1 It is an r-arm polymer, wherein r is 8.

[0939] In certain embodiments, the -P in step (b) 1 The molecular weight of the multi-arm polymer-P in step (b) is at least 1 kDa. 1 The molecular weight of the multi-arm polymer-P in step (b) is 1 to 100 kDa. 1The molecular weight of the multi-arm polymer-P in step (b) is 1 to 80 kDa. 1 The molecular weight of the multi-arm polymer-P in step (b) is 1 to 60 kDa. 1 The molecular weight of the multi-arm polymer-P in step (b) is 1 to 40 kDa. 1 The molecular weight of the multi-arm polymer-P of step (b) is 1 to 20 kDa. 1 The molecular weight of the multi-arm polymer-P of step (b) is 1 to 10 kDa. 1 The molecular weight of the multi-arm polymer-P of step (b) is 1 to 5 kDa. 1 The molecular weight of the multi-arm polymer-P of step (b) is about 20kDa. 1 The molecular weight of the multi-arm polymer-P of step (b) is about 40kDa. 1 The molecular weight of the multi-arm polymer-P of step (b) is about 60kDa. 1 The molecular weight is approximately 80 kDa.

[0940] In certain embodiments, the -P of step (b) 1 and -P of formula (PL-4) or (PL-4') 2 Contains polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene imine (PEI), dextran, hyaluronic acid or a copolymer thereof. In certain embodiments, the -P of step (b) 1 and P of formula (PL-4) or (PL-4') 2 is a PEG-based polymer. In certain embodiments, the -P 1 and P of formula (PL-4) or (PL-4') 2 It is a hyaluronic acid-based polymer.

[0941] In certain embodiments, -R 1 and -R 2 are independently electron-withdrawing groups, alkyl groups or -H, and wherein -R 1 and -R 2 At least one of them is an electron-withdrawing group.

[0942] In certain embodiments, -R 1 and -R 2 The electron withdrawing group is -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -COR3 、-SOR 3 or-SO2R 3 , where -R 3 is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 8 or -NR 8 2, where each -R 8 are independently -H or optionally substituted alkyl, or two -R 8 The groups, together with the nitrogen to which they are attached, form a heterocyclic ring; or -SR 9 , where -R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl.

[0943] In certain embodiments, -R 1 and -R 2 The electron withdrawing group is -CN. In certain embodiments, -R 1 and -R 2 The electron withdrawing group is -NO2. In certain embodiments, -R 1 and -R 2 The electron withdrawing group is an optionally substituted aryl group containing 6 to 10 carbon atoms. In certain embodiments, -R 1 and -R 2 The electron withdrawing group of is an optionally substituted phenyl, naphthyl or anthracenyl. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron withdrawing group of is an optionally substituted heteroaryl group comprising 3 to 7 carbon atoms and containing at least one N, O or S atom. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron withdrawing group is an optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl or indenyl. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2 The electron withdrawing group of is an optionally substituted alkenyl group containing 2 to 20 carbon atoms. In certain embodiments, -R of formula (PL-4) or (PL-4') 1 and -R 2The electron withdrawing group of is an optionally substituted alkynyl group containing 2 to 20 carbon atoms. In certain embodiments, -R of formula (PL-4) or (PL-4') 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, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 8 or -NR 8 2, where each -R 8 are independently -H or an optionally substituted alkyl group containing 1 to 20 carbon atoms, or two -R 8 The groups together with the nitrogen to which they are attached form a heterocyclic ring. In certain embodiments, -R 1 and -R 2 The electron-withdrawing group is -SR 9 , where -R 9 is an optionally substituted alkyl group containing 1 to 20 carbon atoms, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaralkyl group. 1 and -R 2 At least one of them is -CN or -SO2R 3 .

[0944] In certain embodiments, -R 1 and -R 2 At least one of them is -CN, -SOR 3 or-SO2R 3 In certain embodiments, -R 1 and -R 2 At least one of them is -CN or -SO2R 3 In certain embodiments, -R 1 and -R 2 At least one of them is -CN or -SO2R 3 , where -R 3 is optionally substituted alkyl, optionally substituted aryl or -NR 8 2. In certain embodiments, -R 1 and -R 2At least one of them is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted by -SO2, phenyl substituted by -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3) or -SO2N(CH2CH2OCH3)2.

[0945] 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 are independently C1-C3 alkyl. In certain embodiments, -R 4 All are methyl.

[0946] In certain embodiments, -Y and -Y" are independently selected from the group consisting of amine, aminooxy, ketone, aldehyde, maleimido, thiol, alcohol, azide, 1,2,4,6-tetrazinyl, trans-cyclooctenyl, bicyclononynyl, cyclooctynyl, and protected variants thereof.

[0947] In certain embodiments, Y and -Y" can react with each other, such as in a selective manner. For example, when -Y is amino, -Y" is a carboxylic acid, an activated ester, or an activated carbonate that yields a residual linking functional group -Y*- (i.e., an amide or carbamate). For another example, when -Y is an azide, -Y" is an alkynyl, a bicyclononynyl, or a cyclooctynyl that yields a residual linking functional group -Y*- (i.e., a 1,2,3-triazole). For another example, when -Y is NH2O, -Y" is a ketone or aldehyde that yields a residual linking functional group -Y*- (i.e., an oxime). For another example, when -Y is SH, -Y" is a maleimide or a halocarbonyl that yields a residual linking functional group -Y*- (i.e., a thiosuccinimidyl or thioether). Similarly, the roles of -Y and -Y" can be reversed to yield -Y*- in the opposite direction.

[0948] In certain embodiments, -Y*- comprises an amide, an oxime, a 1,2,3-triazole, a thioether, a thiosuccinimide, or an ether. In certain embodiments, -Y*- is -L 2 -.

[0949] These coupling reactions can be carried out under conditions known in the art. For example, when -Y is an azide and -Y" is a cyclooctyne, the coupling reaction can occur in any solvent in which both components exhibit sufficient solubility, although aqueous solutions are known to exhibit better reaction rates. When mixed in a suitable solvent (typically an aqueous buffer with a pH of 2 to 7 when -Y and -Y" are azides / cyclooctynes; or an aqueous buffer with a pH of 6 to 9 when -Y and -Y" are active esters and amines), the -Y and -Y" groups react to form an insoluble hydrogel matrix containing crosslinks of formula (PL-4'). This process can be carried out in the bulk phase or under emulsification conditions in an organic / aqueous mixed system to form a microparticle suspension suitable for injection, such as microspheres.

[0950] In the context of formula (PL-4) and (PL-4') only, the terms used have the following meanings:

[0951] The term "alkyl" refers to a straight chain, branched chain, 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, the alkyl group is straight chain or branched chain. Examples of straight chain alkyl groups or branched chain alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In certain embodiments, the alkyl group is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0952] The term "alkoxy" refers to an alkyl group bound to oxygen and includes methoxy, ethoxy, isopropoxy, cyclopropyloxy, and cyclobutyloxy.

[0953] 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.

[0954] 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.

[0955] The term "aryl" refers to an aromatic hydrocarbon group of 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl and anthracenyl. The term "heteroaryl" refers to an aromatic ring containing 3 to 15 (preferably 3 to 7) carbon atoms and containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl and indenyl.

[0956] In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moiety can be coupled to the remainder of the molecule through an alkyl bond. In such cases, the substituent will be referred to as alkenylalkyl, alkynylalkyl, aralkyl, or heteroaralkyl, indicating that the alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl moiety is coupled.

[0957] The term "halogen" or "halo" refers to bromine, fluorine, chlorine, or iodine.

[0958] The term "heterocycle" or "heterocyclyl" refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl." In certain embodiments, the heterocycle or heterocyclyl is non-aromatic. In certain embodiments, the heterocycle or heterocyclyl is aromatic.

[0959] 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) identical or different substituents. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -OR aa 、-SR aa 、-NR aa R bb 、-NO2、-C=NH(OR aa ),-C(O)R aa 、-OC(O)R aa 、-C(O)OR aa 、-C(O)NR aa R bb 、-OC(O)NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)OR bb 、-S(O)R aa 、-S(O)2R aa 、-NR aa S(O)R bb 、-C(O)NR aa S(O)R bb 、-NR aa S(O)2R bb 、-C(O)NR aa S(O)2R bb 、-S(O)NR aa R bb 、-S(O)2NR aa R bb 、-P(O)(ORaa )(OR bb ), heterocyclyl, heteroaryl or aryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are each independently optionally replaced by -R cc Substitution, where -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, they form a heterocyclic group, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy or -CN, and wherein: each -R cc are independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN or -NO2.

[0960] In certain embodiments, the first PTH compound is a compound of formula (I)

[0961]

[0962] in

[0963] The unlabeled dashed line represents the nitrogen attached to the N-terminal amine group of the PTH portion of SEQ ID NO: 51; and

[0964] Dotted lines marked with an asterisk indicate connections to parts

[0965]

[0966] in

[0967] m and p are independently integers ranging from about 400 to 500.

[0968] In certain embodiments, m and p of Formula (I) are independently integers ranging from 400 to 500. In certain embodiments, m and p of Formula (I) are independently integers ranging from about 450 to 500. In certain embodiments, m and p of Formula (I) are independently integers ranging from 450 to 500.

[0969] The compound of formula (I) is also known as parofemetadine, TransCon PTH or ACP-014.

[0970] It will be understood that the nitrogen of the N-terminal amino group of the PTH moiety of formula (I) forms an amide bond with the carbonyl group (-(C=O)-) to the left of the unlabeled dashed line.

[0971] The PTH compound of formula (I) releases PTH (PTH 1-34) of SEQ ID NO: 51, which means that its active PTH is PTH 1-34.

[0972] In certain embodiments, the first PTH compound is a compound of formula (I), and the first average interval is about one day. In certain embodiments, the first PTH compound is a compound of formula (I), and the first average interval is one day. In certain embodiments, the first PTH compound is a compound of formula (I), the first average interval is about one day and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of formula (I), the first average interval is one day and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of formula (I), the first average interval is about one day and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of formula (I), the first average interval is one day and is administered 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 ranging from about 450 to 500, the first average interval is one day, and is administered 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 ranging from 450 to 500, the first average interval is one day and is administered via subcutaneous injection using a pen injector.

[0973] In certain embodiments, the first PTH compound is a compound of formula (I), and the first interval is about one day. In certain embodiments, the first PTH compound is a compound of formula (I), and the first interval is one day. In certain embodiments, the first PTH compound is a compound of formula (I), the first interval is about one day and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of formula (I), the first interval is one day and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound of formula (I), the first interval is about one day and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of formula (I), the first interval is one day and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is a compound of formula (I), the first interval is one day and is administered 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 ranging from about 450 to 500, the first interval is one day and is administered 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 ranging from 450 to 500, the first interval is one day and is administered via subcutaneous injection using a pen injector.

[0974] In certain embodiments, the first PTH compound is PTH 1-34 (SEQ ID NO: 51), also known as The active PTH in Forteo is PTH 1-34.

[0975] In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 8 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is 8 hours. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is about 8 hours and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is 8 hours and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is about 8 hours and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is 8 hours and is administered via subcutaneous injection using a pen injector.

[0976] In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is about 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, the first interval is about 8 hours, and the administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is 8 hours, and the administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is about 8 hours, and the administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is 8 hours, and the administration is via subcutaneous injection using a pen injector.

[0977] In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about 12 hours. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is 12 hours. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is about 12 hours, and the administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is 12 hours, and the administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is about 12 hours, and the administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is 12 hours, and the administration is via subcutaneous injection using a pen injector.

[0978] In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is about 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, the first interval is about 12 hours, and the administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is 12 hours, and the administration is via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is about 12 hours, and the administration is via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is 12 hours, and the administration is via subcutaneous injection using a pen injector.

[0979] In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is about one day. In certain embodiments, the first PTH compound is PTH 1-34, and the first average interval is one day. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is about one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is about one day, and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, the first average interval is one day, and is administered via subcutaneous injection using a pen injector.

[0980] In certain embodiments, the first PTH compound is PTH 1-34, and the first interval is about 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, the first interval is about one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is about one day, and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-34, the first interval is one day, and is administered via subcutaneous injection using a pen injector.

[0981] In certain embodiments, the first PTH compound is PTH 1-84 (SEQ ID NO: 1), also known as or The active PTH in Natpara / Natpar is PTH 1-84.

[0982] In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is about one day. In certain embodiments, the first PTH compound is PTH 1-84, and the first average interval is one day. In certain embodiments, the first PTH compound is PTH 1-84, the first average interval is about one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, the first average interval is one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, the first average interval is about one day, and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-84, the first average interval is one day, and is administered via subcutaneous injection using a pen injector.

[0983] In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is about one day. In certain embodiments, the first PTH compound is PTH 1-84, and the first interval is one day. In certain embodiments, the first PTH compound is PTH 1-84, the first interval is about one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, the first interval is one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is PTH 1-84, the first interval is about one day, and is administered via subcutaneous injection using a pen injector. In certain embodiments, the first PTH compound is PTH 1-84, the first interval is one day, and is administered via subcutaneous injection using a pen injector.

[0984] 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:

[0985] AVAEIQLMHQRAKWIQDARRRAFLHKLIAEIHTAEI(SEQ ID NO:122)

[0986] The active PTH of AZP-3601 is the protein of SEQ ID NO:122.

[0987] In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first average interval is about one 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 one day. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, the first average interval is about one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, the first average interval is one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, the first average interval is about one day, and is administered 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, the first average interval is one day, and is administered via subcutaneous injection using a pen injector.

[0988] In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, and the first interval is about 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, the first interval is about one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, the first interval is one day, and is administered via subcutaneous injection. In certain embodiments, the first PTH compound is a compound having the sequence of SEQ ID NO: 122, the first interval is about one day, and is administered 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, the first interval is one day, and is administered via subcutaneous injection using a pen injector.

[0989] In certain embodiments, step (a) is administering a compound of formula (I) to a patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0990] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are independently integers ranging from about 450 to 500, to a patient suffering from chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0991] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are independently integers ranging from 450 to 500, to a patient suffering from chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0992] In certain embodiments, step (a) is administering a compound of formula (I) to an adult patient with chronic hypoparathyroidism, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0993] In certain embodiments, step (a) is administering a compound of formula (I) wherein m and p are integers ranging from about 450 to 500 to an adult patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0994] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are integers from 450 to 500, to an adult patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0995] In certain embodiments, step (a) is administering a compound of formula (I) to a pediatric patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0996] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are integers ranging from about 450 to 500, to a pediatric patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0997] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are integers from 450 to 500, to a pediatric patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0998] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient suffering from hypoparathyroidism due to surgery, genetic reasons, immune system-related parathyroid damage, or congenital hypoparathyroidism, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[0999] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to surgery, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1000] In certain embodiments, step (a) is administering a compound of formula (I) wherein m and p are integers ranging from about 450 to 500 to an adult patient with chronic hypoparathyroidism due to surgery via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1001] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to surgery, wherein m and p are integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, and the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1002] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to surgery, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1003] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are independently integers ranging from about 450 to 500, to a pediatric patient with chronic hypoparathyroidism due to surgery via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1004] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to surgery, wherein m and p are independently integers ranging from 450 to 500, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1005] In certain embodiments, step (a) is administering a compound of formula (I) to an adult patient suffering from chronic hypoparathyroidism due to genetic reasons via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1006] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient suffering from chronic hypoparathyroidism due to genetic reasons, wherein m and p are independently integers ranging from about 450 to 500, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1007] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient suffering from chronic hypoparathyroidism due to genetic reasons, wherein m and p are independently integers ranging from 450 to 500, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1008] In certain embodiments, step (a) is administering a compound of formula (I) to a pediatric patient with chronic hypoparathyroidism due to genetic causes via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1009] In certain embodiments, step (a) is administering a compound of formula (I) wherein m and p are independently integers ranging from about 450 to about 500 to a pediatric patient with chronic hypoparathyroidism due to genetic causes via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1010] In certain embodiments, step (a) is administering a compound of formula (I) wherein m and p are independently integers ranging from 450 to about 500 to a pediatric patient suffering from chronic hypoparathyroidism due to genetic causes via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplementation.

[1011] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient suffering from chronic hypoparathyroidism due to immune-related parathyroid damage, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1012] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are independently integers ranging from about 450 to 500, to an adult patient suffering from chronic hypoparathyroidism due to immune-related parathyroid gland damage via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1013] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient suffering from chronic hypoparathyroidism due to immune-related parathyroid damage, wherein m and p are independently integers ranging from 450 to 500, with a first treatment period of one week to five years, a first inter-administration interval of one day, and adjusting the dose as necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1014] 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-related parathyroid gland damage, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1015] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are independently integers ranging from about 450 to 500, to a pediatric patient suffering from chronic hypoparathyroidism due to immune-related damage to the parathyroid glands via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1016] In certain embodiments, step (a) is administering a compound of formula (I), wherein m and p are independently integers ranging from 450 to 500, to a pediatric patient with chronic hypoparathyroidism due to immune-related parathyroid damage via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1017] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient suffering from chronic hypoparathyroidism due to surgery, genetic reasons, immune system-related parathyroid damage, or congenital hypoparathyroidism, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there are no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1018] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to surgery, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1019] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to surgery, wherein m and p are independently integers ranging from about 450 to 500, the first treatment period is one week to five years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1020] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to surgery, wherein m and p are independently integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1021] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to surgery, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1022] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to surgery, wherein m and p are independently integers ranging from about 450 to 500, the first treatment period is one week to five years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1023] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to surgery, wherein m and p are independently integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1024] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to genetic reasons, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there are no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1025] In certain embodiments, step (a) is administering a compound of formula (I) to an adult patient with chronic hypoparathyroidism due to genetic causes via subcutaneous injection, wherein m and p are independently integers ranging from about 450 to 500, the first treatment period is one week to five years, the first administration interval is one day, and the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1026] In certain embodiments, step (a) is administering a compound of formula (I) to an adult patient with chronic hypoparathyroidism due to genetic causes via subcutaneous injection, wherein m and p are independently integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, and the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1027] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to genetic causes, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1028] In certain embodiments, step (a) is administering a compound of formula (I) to a pediatric patient with chronic hypoparathyroidism due to genetic causes via subcutaneous injection, wherein m and p are independently integers ranging from about 450 to 500, the first treatment period is one week to five years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1029] In certain embodiments, step (a) is administering a compound of formula (I) to a pediatric patient with chronic hypoparathyroidism due to genetic causes via subcutaneous injection, wherein m and p are independently integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1030] 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-related parathyroid gland damage, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1031] 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-related parathyroid gland damage, wherein m and p are independently integers ranging from about 450 to 500, the first treatment period is one week to five years, the first administration interval is one day, and the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1032] 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-related parathyroid gland damage, wherein m and p are independently integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, and the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1033] In certain embodiments, step (a) is administering a compound of formula (I) via subcutaneous injection to a pediatric patient having chronic hypoparathyroidism due to immune-related parathyroid gland damage, with a first treatment period of one week to five years, a first administration interval of one day, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1034] 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-related parathyroid gland damage, wherein m and p are independently integers ranging from about 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1035] 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-related parathyroid gland damage, wherein m and p are independently integers ranging from 450 to 500, the first treatment period is one week to 5 years, the first administration interval is one day, the dose is adjusted if necessary to determine a dose that maintains the patient's serum calcium level within the normal range in the absence of active vitamin D and calcium supplements, and wherein the patient is a stable patient and there have been no dose adjustments in the last two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen administration intervals of the first treatment period prior to administration of the first dose of the second PTH compound.

[1036] In certain embodiments, step (a) is administering PTH 1-34 to a patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of eight hours, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1037] In certain embodiments, step (a) is administering PTH 1-34 to an adult patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of eight hours, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1038] In certain embodiments, step (a) is administering PTH 1-34 to a pediatric patient with chronic hypoparathyroidism via subcutaneous injection, with a first treatment period of one week to five years, a first administration interval of eight hours, and adjusting the dose as needed to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1039] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to surgery, with a first treatment period of one week to five years, a first administration interval of eight hours, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1040] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to surgery, with a first treatment period of one week to five years, a first administration interval of eight hours, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1041] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to an adult patient with chronic hypoparathyroidism due to genetic causes, with a first treatment period of one week to five years, a first administration interval of 8 hours, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements.

[1042] In certain embodiments, step (a) is administering PTH 1-34 via subcutaneous injection to a pediatric patient with chronic hypoparathyroidism due to genetic causes, with a first treatment period of one week to five years, a first administration interval of eight hours, and adjusting the dose if necessary to determine a dose that maintains the patient's serum calcium le...

Claims

1. Use of a first and a second PTH compound in a method for treating chronic hypoparathyroidism, the method comprising: (a) administering a first PTH compound to a patient with chronic hypoparathyroidism a plurality of times at a first average administration interval, adjusting the dose as needed, to determine a dose that maintains the patient's serum calcium level within a normal range without the use of active vitamin D and calcium supplements; (b) using the dose determined in step (a), determining an initial dose of a second PTH compound to be administered to the patient multiple times at a second average interval that is longer than the first average interval; and (c) administering a second PTH compound to the patient a plurality of times at a second average administration interval, starting from the initial dose determined in step (b), and adjusting the dose as needed, until the patient's serum calcium remains within a normal range without the use of active vitamin D and calcium supplements.

2. The use of a first and a second PTH compound according to claim 1, wherein the first average administration interval is 8 hours.

3. The use of a first and a second PTH compound according to claim 1, wherein the first average administration interval is 12 hours.

4. The use of a first and a second PTH compound according to claim 1, wherein the first average administration interval is one day.

5. Use of a first and a second PTH compound according to any one of claims 1 to 4, wherein the second average administration interval is one week.

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

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

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

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

10. The use of a first and a second PTH compound 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 topical, injection or infusion methods, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcutaneous, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via an implantable device that allows delivery to brain tissue or cerebral fluid, direct intracerebroventricular injection or infusion, injection or infusion into the brain or brain-related areas, injection into the subchoroidal space, retro-orbital injection or ocular instillation.

11. Use of a first and a second PTH compound according to any one of claims 1 to 10, wherein the first PTH compound is administered subcutaneously, such as by subcutaneous injection.

12. The use of a first and a second PTH compound according to any one of claims 1 to 11, wherein the second PTH compound is administered to a patient topically, enterally or parenterally, or by topical, injection or infusion methods, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcutaneous, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via an implanted device that allows delivery to brain tissue or cerebral fluid, direct intracerebroventricular injection or infusion, injection or infusion into the brain or brain-related areas, injection into the subchoroidal space, retro-orbital injection or ocular instillation.

13. Use of a first and a second PTH compound according to any one of claims 1 to 12, wherein the second PTH compound is administered subcutaneously, such as by subcutaneous injection.

14. The use of a first and a second PTH compound according to any one of claims 1 to 13, wherein the first and / or second PTH compound is independently a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof: in Each -D is independently a PTH moiety; Each -L 1 - is independently a linker moiety covalently and reversibly linked to -D; Each -L 2 - is independently a single chemical bond or a spacer moiety; Each -Z is independently a carrier moiety, such as a fatty acid derivative or a polymer; x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25; and y is an integer selected from 2, 3, 4 and 5.

15. Use of a first and a second PTH compound according to any one of claims 1 to 14, wherein the first PTH compound is a compound of formula (I): in The unlabeled dashed line represents the nitrogen attached to the N-terminal amine group of the PTH portion of SEQ ID NO: 51; and Dashed lines marked with an asterisk indicate connections to parts: wherein m and p are independently integers ranging from about 400 to 500.

16. Use of a first and a second PTH compound according to any one of claims 1 to 13, wherein the first PTH compound is PTH 1-34.

17. Use of a first and a second PTH compound according to any one of claims 1 to 13, wherein the first PTH compound is PTH 1-84.

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

122.

19. Use of a first and a second PTH compound according to any one of claims 1 to 18, wherein the second PTH compound is a compound of formula (II-b): in The dotted line represents the nitrogen attached to the N-terminal amine group of the PTH moiety having the sequence of SEQ ID NO: 51; and Each n is independently an integer ranging from about 200 to 250.

20. The use of a first and a second PTH compound according to any one of claims 1 to 19, wherein The PTH compound administered weekly is a compound of formula (II-b'): wherein the dotted line represents the nitrogen attached to the N-terminal amine group of the PTH moiety having the sequence of SEQ ID NO: 51; and Each n is independently an integer ranging from about 200 to 250.

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

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

23. The use of a first and a second PTH compound according to any one of claims 1 to 18, wherein the second PTH compound is a compound of formula (II-i): k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLR KKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)–OH(II–I), Where k is d-Lys; γE is the l -isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is sarcosine; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

24. Use of a first and a second PTH compound according to any one of claims 1 to 18, wherein the second PTH compound is a compound of formula (II-i'): k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLR KKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH(II-I), in k is d-Lys; γE is the l -isomer of γ-glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is sarcosine; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

25. The use of a first and a second PTH compound according to any one of claims 1 to 24, wherein the active PTH of the first and second PTH compounds is the same, the initial dose of the second PTH compound is D2 ± 25%, and wherein D2 is calculated using the following equation: in D1 is a dose of the first PTH compound that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements; T1 is the first administration interval; and T2 is the second administration interval.

26. The use of a first and a second PTH compound according to any one of claims 1 to 24, wherein the active PTH of the first and second PTH compounds is different, and the initial dose of the second PTH compound is calculated by first calculating the correction factor CF using the following equation: in D supp1 It completely suppresses health Subject The dose of the first PTH compound secreted by the patient's endogenous PTH 1-84; D supp2 is the dose of the second PTH compound that completely inhibits endogenous PTH 1-84 secretion in healthy subjects; T supp1 is the length of a first interval for administering a first PTH compound to a healthy subject; and T supp2 is the length of a second interval for administering a second PTH compound to healthy subjects; D2 is then calculated using the following equation: in D1 is a dose of the first PTH compound that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements; T1 is the first administration interval; T2 is the second administration interval; And wherein the initial dose of the second PTH compound is D2±25%.

27. The use of a first and a second PTH compound 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. Use of a first and a second PTH compound according to any one of claims 1 to 27, wherein the first PTH compound is a drug comprising only PTH or a PTH portion administered to the patient during a first treatment period.

29. Use of a first and a second PTH compound according to any one of claims 1 to 28, wherein the second PTH compound is a medicament comprising only PTH or a PTH portion which is administered to a patient during treatment with the second PTH compound.

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

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

32. The use of a first and a second PTH compound 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 parathyroid damage or is congenital.

33. The use of a first and a second PTH compound according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is induced by surgery.

34. The use of a first and a second PTH compound according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is due to genetic causes.

35. The use of a first and a second PTH compound 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 use of a first and a second PTH compound according to any one of claims 1 to 32, wherein the chronic hypoparathyroidism is congenital.

37. Use of a PTH compound for treating chronic hypoparathyroidism, wherein the treatment comprises the step of administering a weekly dose of a PTH compound to a patient suffering from chronic hypoparathyroidism once a week, 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.

38. The use of a PTH compound according to claim 37, wherein the patient suffers from chronic hypoparathyroidism due to surgery, genetic reasons, immune system-related parathyroid damage, or the hypoparathyroidism is congenital.

39. Use of a PTH compound according to claim 37 or 38, wherein the patient is being treated with a first PTH compound prior to starting the weekly PTH compound.

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

41. The use of a PTH compound according to claim 39 or 40, wherein the first PTH compound is administered multiple times at a first average administration interval, and the dosage is adjusted as needed, and wherein the first average interval is one day.

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

43. The use of a PTH compound 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 use of a PTH compound according to any one of claims 39 to 43, wherein the first PTH compound is a compound having formula (I): in The unlabeled dashed line represents the nitrogen attached to the N-terminal amine group of the PTH portion of SEQ ID NO: 51; and Dashed lines marked with an asterisk indicate connections to parts: wherein m and p are independently integers ranging from 400 to 500.

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

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

47. The use of a PTH compound according to any one of claims 39 to 46, wherein all administration intervals of the first PTH compound are of the same length.

48. The use of a PTH compound according to any one of claims 39 to 47, wherein the first treatment period, i.e. the period from the first administration of the first PTH compound to the last administration of the first PTH compound, lasts from one week to 20 years.

49. The use of a PTH compound according to claim 48, wherein the first treatment period continues at least until the patient's serum calcium level is within the normal range and active vitamin D and calcium supplements have been discontinued.

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

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

52. The use of a PTH compound according to any one of claims 39 to 51, wherein the active PTH of the first PTH compound and the weekly PTH compound are the same, the initial dose of the weekly PTH compound is D2 ± 25%, and wherein D2 is calculated using the following equation: in D1 is a dose of the first PTH compound that maintains the patient's serum calcium level within the normal range without the use of active vitamin D and calcium supplements; T1 is the first administration interval; and T2 is the second administration interval.

53. The use of a PTH compound according to any one of claims 39 to 51, wherein 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 calculated by first calculating a correction factor CF using the following equation: in D supp1 It completely suppresses health Subject The dose of the first PTH compound secreted by the patient's endogenous PTH 1-84; D supp2 It completely suppresses health Subject The weekly dose of PTH compounds that can increase the secretion of endogenous PTH 1-84 in patients with leukemia; T supp1 It is towards health Subject a first interval length for administering a first PTH compound; and T supp2 It is towards health Subject The length of the second interval of weekly administration of PTH compounds; Then calculate D2 using the following equation in D1 is not use a dose of the first PTH compound at which the patient's serum calcium level is maintained within the normal range with active vitamin D and calcium supplementation; T1 is the first administration interval; T2 is the second administration interval; The initial dose of the PTH compound per week is D2±25%.

54. The use of a PTH compound according to any one of claims 39 to 53, wherein the time between the last administration of the first PTH compound and the first administration of the weekly PTH compound is equivalent to the average administration interval of the first PTH compound.

55. Use of a PTH compound according to any one of claims 37 to 54, wherein the weekly PTH compound is a medicament comprising only PTH or a PTH portion which is administered to a patient during treatment with the weekly PTH compound.

56. The use of a PTH compound according to any one of claims 37 to 55, wherein the weekly PTH compound is a compound of formula (II-a): in The dotted line represents the nitrogen attached to the N-terminal amine group of the PTH moiety having the sequence of SEQ ID NO: 51; and Each n is independently an integer ranging from 200 to 250.

57. The use of a PTH compound according to any one of claims 37 to 55, wherein the weekly PTH compound is a compound of formula (II-i): k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLR KKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)–OH(II–I), in k is d-Lys; γE is the l -isomer of γ-glutamic acid; miniPEG is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is sarcosine; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

58. The use of a PTH compound according to any one of claims 37 to 55, wherein the weekly PTH compound is a compound of formula (II-i'): k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLR KKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)–OH(II–I), in k is d-Lys; γE is the l -isomer of γ-glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC 16 H 32 CO2H is a C18 diacid; (N-Me)G is sarcosine; K is the l-isomer of lysine; and -OH indicates that the C-terminal amino acid has a terminal carboxylic acid.

59. The use of a PTH compound according to any one of claims 37-58, wherein during treatment with the weekly PTH compound, treatment continues as long as the patient benefits from the administration of the weekly PTH compound.

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