Indolinespirocyclic derivatives, process for their preparation and their use in medicine

Abstract

Disclosed are a compound shown in formula I and racemate, stereoisomer, tautomer, isotopically labeled, nitroxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same, a preparation method thereof, and a use thereof as a GHSR agonist in the preparation of a drug for the diagnosis, prevention and / or treatment of growth hormone-dependent diseases, the structure of formula I is as follows:

Description

[0001] This application claims priority to an earlier application filed on April 25, 2021, with the China National Intellectual Property Administration, patent application number 202110450480.1, entitled "Indoline Spirocyclic Derivatives, Preparation Methods Thereof, and Their Applications in Medicine". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical compounds, specifically relating to an indoline spirocyclic derivative, its preparation method, and its application in medicine. Background Technology

[0003] Ghrelin is an endogenous growth hormone-releasing peptide containing 28 amino acids, and is an endogenous ligand for growth hormone secretagogue receptor 1a (GHSR 1a). Both in vivo and in vitro experiments have confirmed that ghrelin significantly promotes the secretion of growth hormone (GH). Clinical studies have also found that intravenous injection of ghrelin strongly stimulates growth hormone release in a dose-dependent manner.

[0004] Human growth hormone is a peptide hormone secreted by the anterior pituitary gland. It consists of 191 amino acids and acts directly or indirectly on peripheral organs by inducing the synthesis of insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF). Its main physiological functions include promoting linear growth of the body, promoting cell proliferation in muscles and skin, and playing an important role in tissue regeneration after trauma.

[0005] GH release is believed to treat physiological or pathophysiological conditions characterized by growth hormone secretion deficiencies, as well as conditions improved by the anabolic effects of growth hormone. Clinical findings suggest that GH holds promise for treating conditions such as muscle mass loss, adipose tissue accumulation, bone demineralization, and reduced tissue regeneration capacity after injury.

[0006] GH is synthesized and stored in the pituitary gland, but its release is controlled by hypothalamic hormones. Two hormones are known to be involved in GH release: growth hormone-releasing hormone (GHRH) and the inhibitory hormone somatostatin (SRIF). In most cases, GH deficiency involves GH release (hypothalamic deficiency) rather than GH synthesis (pituitary deficiency). Therefore, stimulating GH release from the pituitary gland with GHSR agonists may be a novel alternative to recombinant human growth hormone.

[0007] GHSR has two subtypes, 1a and 1b. Subtype 1a is a functional receptor subtype, while the function of subtype 1b requires further investigation. Within the central nervous system, GHS-R1a is distributed in the hypothalamus and multiple regions outside the hypothalamus, including the pituitary gland, the arcuate nucleus of the hypothalamus, and the ventromedial nucleus. Peripherally, GHSR is also expressed at low levels in the thyroid gland, pancreas, and myocardium. Therefore, ghrelin and its receptor GHSR1a may be involved in the regulation of various functions in vivo.

[0008] Studies have found that some peptides or peptide-like clinical compounds exhibit GHSR agonist activity, inducing GH release. Compounds currently in clinical trials include examorelin, tabimorelin, pralmorelin, ibutamoren, tesamorelin, anamorelin, and macimorelin. Among these, injectable peptide tesamorelin (used to reduce excess abdominal fat in HIV-infected individuals) and the small-molecule peptide-like drug macimorelin have been approved by the FDA. Macimorelin is the only orally approved drug for the diagnosis of adult growth hormone deficiency; however, macimorelin also has drawbacks such as poor oral bioavailability and potential cardiotoxicity risks.

[0009] Related studies have also found that, in addition to inducing GH secretion through GHSR1a activation, GHSR agonists also mediate other physiological functions through different receptors in other GHS receptor families or different binding sites on GHSR (such as GHSR1b, motilin receptor 1a, neurotensin receptor, and TRH receptor). Therefore, the application of GHSR agonists in gastrointestinal indications has been newly developed. Currently, there are no drugs marketed for this indication, but ulimorelin and relamorelin have entered phase III clinical trials.

[0010] Ghrelin has been shown to promote gastrointestinal motility through the vagus and pelvic nerves, but its short half-life hinders its drug development. Therefore, there is a need to develop GHSR agonists with enhanced pharmacokinetics to improve impaired gastrointestinal function in animals and humans. Studies have shown that ibutamoren exhibits good safety and some GHSR agonist activity in clinical trials, but it failed to reach its clinical endpoint after long-term administration. Therefore, developing a GHSR agonist based on ibutamoren, while avoiding its potential drawbacks, holds promising clinical application potential. Summary of the Invention

[0011] To address the problems existing in the prior art, the present invention provides a compound of Formula I and its racemic mixture, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof:

[0012]

[0013] in,

[0014] Ra is selected from H, -R, -C(=O)R or -C(=O)OR;

[0015] Rb is selected from H, -R, -C(=O)R or -C(=O)OR;

[0016] Alternatively, Rb can be connected to N in N-R3 to form a ring structure. At this point, R3 does not exist, and Rb is selected from... (C1-C) can be arbitrarily replaced by one, two or more Rc. 12 (aliphatic hydrocarbon group, Ra as defined above;)

[0017] The condition is that Ra and Rb are not both H at the same time;

[0018] The R is selected from the following groups optionally substituted with one, two or more Rc: (C1-C2) 20 (Aliphatic hydrocarbon group, optionally containing one, two or more heteroatoms (C1-C)) 20 aliphatic hydrocarbon group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 heteroaryl groups;

[0019] Each of the Rc atoms is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2, COOH, or optionally substituted with one, two or more Rd groups: (C1-C 12 (Aliphatic hydrocarbon group, optionally containing one, two or more heteroatoms (C1-C)) 12 aliphatic hydrocarbon group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0020] Each of the Rd groups is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH,(C1-C 12(Aliphatic hydrocarbon group, optionally containing one, two or more heteroatoms (C1-C)) 12 Aliphatic hydrocarbon groups;

[0021] R1, R2, R3, and R4 may be the same or different, and each is independently selected from H, and can be arbitrarily replaced by one, two, or more Rc (C1-C). 12 Aliphatic hydrocarbon groups;

[0022] The R' and R" are each independently selected from H, halogens, CN, OH, SH, NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH, optionally substituted with one, two or more Rd groups of the following groups: (C1-C 12 (Aliphatic hydrocarbon group, optionally containing one, two or more heteroatoms (C1-C)) 12 Aliphatic hydrocarbon group.

[0023] The n and m are each independently selected from 0, 1, 2, 3, 4 or 5.

[0024] According to an embodiment of the invention, the "optionally containing one, two or more heteroatoms (C1-C)" 20 In the aliphatic hydrocarbon group, the heteroatom may be selected from sulfur, nitrogen, oxygen, phosphorus and silicon, and optionally, the heteroatom is inserted into the aliphatic hydrocarbon group into optional C-C bonds and CH bonds;

[0025] The "(C1-C" 20 "Aliphatic hydrocarbon group" can be selected from (C1-C1) 20 )alkyl, (C2-C 20 )alkenyl, (C2-C 20 ) alkynyl group; the "(C1-C 20 "Aliphatic hydrocarbon group" can be selected from (C1-C1) 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 ) alkynyl group; the "(C1-C 12 "Aliphatic hydrocarbon group" can be selected from (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl.

[0026] The "halogen" is selected from F, Cl, Br, and I.

[0027] According to an embodiment of the present invention,

[0028] Ra is selected from H;

[0029] Rb is selected from -R, -C(=O)R, or -C(=O)OR;

[0030] Alternatively, Rb can be connected to N in N-R3 to form a ring structure. At this point, R3 does not exist, and Rb is selected from... The following groups may be substituted by one, two or more Rc groups: (C1-C 12 )alkylene, (C1-C 12 ) imidene group;

[0031] The R is selected from the following groups optionally substituted with one, two or more Rc: (C1-C2) 20 )alkyl, (C1-C 20 Alkenyl group, optionally containing one, two or more heteroatoms (C1-C) 20 )alkyl or (C1-C 20 )alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 heteroaryl groups;

[0032] Each of the Rc atoms is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2, COOH, or optionally substituted with one, two or more Rd groups: (C1-C 12 )alkyl, (C1-C 12 Alkenyl group, optionally containing one, two or more heteroatoms (C1-C) 12 )alkyl or (C1-C 12 )alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0033] Each of the Rd groups is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH,(C1-C 12 )alkyl, (C1-C 12 Alkenyl group, optionally containing one, two or more heteroatoms (C1-C) 12 )alkyl or (C1-C 12 alkenyl;

[0034] R1, R2, R3, and R4 may be the same or different, and each is independently selected from H, and can be arbitrarily replaced by one, two, or more Rc (C1-C). 12 )alkyl or (C1-C 12 alkenyl;

[0035] The R' and R" are each independently selected from H, halogens, CN, OH, SH, NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH, optionally substituted with one, two or more Rd groups of the following groups: (C1-C 12 )alkyl, (C1-C 12 Alkenyl group, optionally containing one, two or more heteroatoms (C1-C) 12 )alkyl or (C1-C 12 )alkenyl.

[0036] The n and m are each independently selected from 0, 1, 2, 3, 4 or 5.

[0037] According to an embodiment of the present invention,

[0038] Ra is selected from H;

[0039] Rb is selected from -R, -C(=O)R, or -C(=O)OR;

[0040] Alternatively, Rb can be connected to N in N-R3 to form a ring structure. At this point, R3 does not exist, and Rb is selected from... The following groups may be optionally substituted with one, two or more Rc groups: (C1-C6)alkylene, (C1-C6)alkenylene;

[0041] The R is selected from the following groups optionally substituted with one, two or more Rc: (C1-C2) 20 )alkyl, (C1-C 20 Alkenyl groups, optionally containing one, two or more oxygen atoms (C1-C2). 12 )alkyl or (C1-C 20 )alkenyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-9 quinone heteroaryl;

[0042] Each of the Rc groups is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(C1-C6 alkoxy)2, COOH, or optionally substituted with one, two or more Rd groups of the following: (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkyl or (C1-C6) alkenyl containing one, two or more oxygen atoms, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-9 quinone heteroaryl;

[0043] Each of the Rd groups is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2, COOH, (C1-C6)alkyl or (C1-C6)alkenyl, optionally containing one, two or more oxygen atoms of (C1-C6)alkyl or (C1-C6)alkenyl;

[0044] R1, R2, R3, and R4 may be the same or different, each independently selected from H, and optionally (C1-C6) alkyl or (C1-C6) alkenyl groups substituted by one, two or more Rc groups.

[0045] The R' and R" are each independently selected from H, halogens, CN, OH, SH, NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH, optionally substituted with one, two or more Rd groups of the following: (C1-C6)alkyl, (C1-C6)alkenyl, optionally containing one, two or more heteroatoms of (C1-C6)alkyl or (C1-C6)alkenyl.

[0046] The n and m are each independently selected from 0, 1, 2, 3, 4 or 5.

[0047] According to an embodiment of the present invention,

[0048] Ra is selected from H;

[0049] Rb is selected from -R, -C(=O)R, or -C(=O)OR, or Rb is connected to N in N-R3 to form a ring structure. At this point, R3 does not exist, and Rb is selected from... The following groups may be substituted by one, two or more Rc groups: (C1-C 12 )alkylene, (C1-C 12 ) imidene group;

[0050] The R is selected from the following groups optionally substituted with one, two or more Rc: (C1-C2) 20 )alkyl, (C1-C 20 )alkenyl, (C1-C6)alkylOCH(C1-C6alkyl)-, (C1-C 12 )alkyl OCH2-, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 heteroaryl groups;

[0051] Each of the Rc atoms is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C12 alkoxy)2, COOH, or optionally substituted with one, two or more Rd groups: (C1-C 12 )alkyl, (C1-C 12 )alkenyl, (C1-C6)alkylOCH(C1-C6alkyl)-, (C1-C 12 )alkyl OCH2-, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0052] Each of the Rd groups is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH,(C1-C 12 )alkyl, (C1-C 12 )alkenyl, (C1-C6)alkylOCH(C1-C6alkyl)-, (C1-C 12 )alkylOCH2-;

[0053] R1, R2, R3, and R4 may be the same or different, and each is independently selected from H, and can be arbitrarily replaced by one, two, or more Rc (C1-C). 12 )alkyl or (C1-C 12 alkenyl;

[0054] The R' and R" are each independently selected from H, halogens, CN, OH, SH, NH2, -OP(=O)(OH)2, -OP(=O)(Cl-C 12 alkoxy)2,COOH, optionally substituted with one, two or more Rd groups of the following groups: (C1-C 12 )alkyl, (C1-C 12 )alkenyl, (C1-C6)alkylOCH(C1-C6alkyl)-, (C1-C 12 )alkylOCH2-.

[0055] The n and m are each independently selected from 0, 1, 2, 3, 4 or 5.

[0056] According to an embodiment of the present invention,

[0057] Ra is selected from H;

[0058] Rb is selected from -R, -C(=O)R, or -C(=O)OR, or Rb is connected to N in N-R3 (in which case R3 does not exist), forming a ring structure. At this time, Rb is selected from The following groups may be optionally substituted with one, two or more Rc groups: (C1-C6)alkylene, (C1-C6)alkenylene;

[0059] The R is selected from the following groups optionally substituted with one, two or more Rc: (C1-C2) 20 )alkyl, (C1-C 20 )alkenyl, (C1-C6)alkylOCH(C1-C6alkyl)-, (C1-C 12 )alkyl OCH2-, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-9 quinone heteroaryl;

[0060] Each of the Rc groups is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(C1-C6 alkoxy)2, COOH, or optionally substituted with one, two or more Rd groups of the following: (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C3)alkylOCH(C1-C3 alkyl)-, (C1-C3)alkylOCH2-, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-9 quinone heteroaryl;

[0061] Each of the Rds is independently selected from halogens, CN, OH, SH, =O (oxo), NH2, -OP(=O)(OH)2, -OP(=O)(C1-C6 alkoxy)2, COOH, (C1-C6) alkyl or (C1-C6) alkenyl, (C1-C3) alkyl OCH(C1-C3 alkyl)-, (C1-C3) alkyl OCH2-;

[0062] R1, R2, R3, and R4 may be the same or different, each independently selected from H, and optionally (C1-C6) alkyl or (C1-C6) alkenyl groups substituted by one, two or more Rc groups.

[0063] The R' and R" are each independently selected from H, halogen, CN, OH, SH, NH2, -OP(=O)(OH)2, -OP(=O)(C1-C6alkoxy)2, COOH, and optionally the following groups substituted by one, two or more Rd: (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkylOCH(C1-C6alkyl)-, (C1-C6)alkylOCH2-.

[0064] The n and m are each independently selected from 0, 1, 2, 3, 4 or 5.

[0065] According to the present invention, in some embodiments, Ra is H;

[0066] Rb is selected from -R, -C(=O)R, or -C(=O)OR;

[0067] The R is selected from the following groups optionally substituted with one, two or more NH2 groups: (C1-C6)alkylC(=O) (C1-C6)alkyl-,HC(=O) (C1-C 12 )alkyl-, (C1-C 12 )alkylC(=O)OCH(C1-C 12 alkyl)-, (C1-C 12 )alkyl-,5-14-membered heteroaryl-(C1-C 12 )alkyl-;

[0068] Or, R is selected from (C1-C 12 )alkyl, (C1-C 12 )alkoxy, (C2-C 20 alkenyl;

[0069] Alternatively, R is selected from any of the following groups that are substituted by one, two or more OP(=O)(OH)2: (C1-C 12 )alkyl, (C1-C 12 )alkoxy;

[0070] Alternatively, R is selected from one, two or more -OP(O)(C1-C) 12 Alkyl)2-substituted (C1-C) 12 )alkyl;

[0071] Alternatively, R is selected from the following groups that are optionally substituted with one, two or more (C1-C6) alkyl groups: (C1-C6)alkylC(=O)(C2-C6)alken-,5-14 heteroaryl;

[0072] Or, R is selected from (C1-C 12 )alkylC(=O)OCH(C1-C 12 alkyl)-, C 3-12 Cycloalkyl C(=O)OCH(C1-C) 12 alkyl)-, (C1-C 12 )alkyl C(=O)OCH2-, C 3-12 Cycloalkyl C(=O)OCH(C1-C) 12 alkyl)-.

[0073] According to an embodiment of the present invention, the C 3-12 Cycloalkyl groups are preferably C 3-8 Cycloalkyl groups, such as those selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl;

[0074] The 3-12 membered heterocyclic group is preferably a 3-8 membered heterocyclic group, for example selected from tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 1,3-dioxazolyl;

[0075] The C 6-20 The aryl group is preferably C 6-10 Aryl groups, for example, selected from phenyl groups;

[0076] The 5-14 membered heteroaryl group is preferably a 5-10 membered heteroaryl group, which can be selected from indolyl, isoindolyl, pyridinyl, pyridinyl, pyrazinyl, triazinyl, thiophenyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and thia-4H-pyrazolyl.

[0077] According to embodiments of the present invention, in some embodiments, Rb is connected to N in N-R3 to form a ring structure. The ring structure is further preferably the following structure:

[0078] At this point, R3 does not exist, and R1, R2, and Ra are as defined in Equation I above.

[0079] According to embodiments of the present invention, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, NH2CH2-,

[0080] The R may optionally be further replaced by one, two or more Rc.

[0081] According to an embodiment of the present invention, the compound of formula I is further preferably of formula II:

[0082]

[0083] Rc1 and Rc2 may be the same or different, and each is independently selected from H or Rc as defined by the aforementioned formula I;

[0084] Rc, R', R”, n, m, R1, R2, R3, R4 are as defined in Equation I above.

[0085] According to an embodiment of the present invention, the compound of formula I is further preferably of formula III:

[0086]

[0087] According to an embodiment of the present invention, in the structure of Formula III, Rc1 and Rc2 may be the same or different, and each is independently selected from H or Rc as defined in Formula I above.

[0088] According to embodiments of the present invention, the compound of formula I is further preferably of formula IIIA or IIIB:

[0089]

[0090] According to an embodiment of the present invention, in the structures of Formula IIIA and Formula IIIB, Rc1 and Rc2 may be the same or different, and each is independently selected from H or Rc as defined in Formula I above.

[0091] According to an embodiment of the present invention, Rc1 is selected from C1-C 12 Alkyl, C3-C8 cycloalkyl, C1-C alkyl optionally substituted with one, two or more NH2 groups 12 Alkyl; Rc2 is selected from H or C1-C 12 alkyl.

[0092] According to an embodiment of the present invention, Rc1 is selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, aminomethyl, 1,5-diaminon-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0093] According to an embodiment of the present invention, Rc2 is selected from H or methyl.

[0094] According to embodiments of the present invention, exemplary, non-limiting examples of compounds of Formula I, including their racemates, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, are as follows:

[0095]

[0096]

[0097] According to embodiments of the present invention, the compound of formula I may further be selected from, for example, the following structures:

[0098]

[0099] This invention also provides a method for preparing the compound represented by Formula I and its racemic mixtures, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0100] Under suitable conditions, ibutamoren or its derivatives are reacted with a starting material containing Ra and / or Rb modifying groups in a suitable reagent to obtain an amino-modified product; and optionally, under suitable conditions, a protecting group addition and deprotection step is performed.

[0101] Or it may include the following steps: reacting ibuprofen or its derivatives under suitable conditions with potassium dihydrogen phosphate and acetone;

[0102] Alternatively, the reaction may include the following steps: reacting ibuprofen or its derivatives under suitable conditions in a chloroformate (or a substituted thiocarbonate) and alkaline conditions; wherein the alkaline conditions may be selected from triethylamine, and the solvent used in the reaction may be dichloromethane;

[0103] Alternatively, it may include the following steps: using a condensing agent to carry out an amide condensation reaction with an amino acid under alkaline conditions. The condensing agent may be selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and dicyclohexylcarbodiimide, and the alkaline conditions may be selected from triethylamine.

[0104] The present invention further provides a pharmaceutical composition comprising the compound of formula I described herein and its racemic, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the pharmaceutical compositions of the present invention further comprise therapeutically effective amounts of the compound of formula I of the present invention and its racemic, stereoisomer, tautomer, isotope label, nitride, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

[0106] The carrier in the pharmaceutical composition is "acceptable," compatible with (and preferably stabilizing) the active ingredient of the composition, and not harmful to the treated subject. One or more solubilizers may be used as pharmaceutical excipients for delivering the active compound.

[0107] The present invention further provides the use of the compound of Formula I and its racemates, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof or the pharmaceutical compositions thereof in the preparation of GHSR agonists.

[0108] The present invention further provides the use of the compound of Formula I and its racemates, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the diagnosis, prevention and / or treatment of growth hormone-dependent diseases.

[0109] The present invention also provides a method for treating a disease or condition, the method comprising administering, alone, a therapeutically effective amount of at least one compound of the present invention to a patient requiring such treatment, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0110] According to embodiments of the invention, the disease or condition is related to growth hormone deficiency or growth hormone dependence. Preferably, the compound can promote plasma growth hormone levels in humans and animals after administration. This property can be used to diagnose and treat physiological or medical symptoms characterized by growth hormone deficiency, such as the diagnosis of patients with growth hormone deficiency, slow growth and short stature in children with growth hormone deficiency, and to treat other diseases that can be improved by the physiological effects of growth hormone.

[0111] In some embodiments, the compounds of the present invention can be used to treat conditions requiring stimulation of growth hormone production or secretion, such as in humans with a natural growth hormone deficiency or in animals used for food production, in the latter case where growth hormone stimulation will result in larger and more productive animals. The compounds of the present invention are used to treat humans and animals to increase levels of growth hormone secretion.

[0112] In some embodiments, the compound is used as a GHSR agonist, including but not limited to: energy balance and food intake regulation; treatment of lipogenesis, obesity and weight loss; treatment of cachexia; improvement of gastrointestinal motility, treatment of gastroparesis and diabetic gastroparesis, treatment of postoperative intestinal obstruction; increase in muscle mass and skin thickness, decrease in adipose material and slight increase in bone density in elderly patients; treatment of burns, AIDS and cancer conditions, and wound and bone healing.

[0113] The compounds of the present invention can be used in combination with other therapeutic agents.

[0114] The present invention further provides a method for preventing and / or treating growth hormone-dependent diseases, the method comprising administering to a patient in need a therapeutically effective amount of first and second therapeutic agents, wherein the first therapeutic agent is a compound of the present invention. In some embodiments, the present invention provides a combination formulation of the compound of the present invention with additional therapeutic agents for simultaneous, separate, or sequential use in treatment.

[0115] Terminology Explanation:

[0116] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0117] The term “optional” (or “optionally”, “optionally”) in the general formula definition of this application means the case of being substituted by zero or one or more substituents. For example, “optionally substituted by one, two or more R” means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0118] The numerical ranges described in this application specification and claims, when defined as "integers" or as conventionally understood in the art as "integers," should be understood to include both endpoints of the range and every integer within that range. For example, when "0-12" represents the number of carbons, it should be understood to include every integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. "A plurality of" means two or more, and "more than" means three or more.

[0119] The term "halogen" refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I can be described as "halogens" in this specification.

[0120] The term "aliphatic hydrocarbon group" includes saturated or unsaturated, straight-chain or branched chain or cyclic hydrocarbon groups. The type of aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc. The number of carbon atoms in the aliphatic hydrocarbon group can be 1-20 (including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), preferably 1-12, and can also be 1-10. A further preferred range is 1-6. Specifically, it can include, but is not limited to, the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl. Isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The "aliphatic hydrocarbon group" portion in other groups is explained as above.

[0121] The term "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group. Preferably, it contains 1-20 carbon atoms in a straight-chain or branched saturated monovalent hydrocarbon group; for example, "C 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0122] The term "alkenyl" should be understood to refer to a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C2-8 "Alkenyl" contains one or more double bonds and has 2, 3, 4, 5, 6, 7, or 8 carbon atoms, for example, has 2, 3, 4, 5, or 6 carbon atoms (i.e., C64 ... 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0123] The term "alkynyl" should be understood to refer to a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C"). 2-8 "Alkyne group" has 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0124] The term "allelic hydrocarbon group" refers to a divalent aliphatic hydrocarbon chain. Those skilled in the art will understand that when an aliphatic hydrocarbon group is in a substitution position forming a divalent group in the structural formula, it is equivalent to an aliphatic hydrocarbon group. Therefore, in this application, the term "allelic hydrocarbon group" can also be interpreted as "allelic hydrocarbon group." For example, the type of the aliphatic hydrocarbon group can be selected from alkylene, alkenylene, ynylene, etc., and the number of carbon atoms in the aliphatic hydrocarbon group can be 1-20 (including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), preferably 1-12, and can also be 1-10, with a further preferred range of 1-6.

[0125] Term "C" 3-12 "Cycloalkyl" should be understood to refer to a saturated or unsaturated monovalent monocyclic or bicyclic ring having 3-12 carbon atoms, preferably C4. 3-8 Cycloalkyl, more preferably C10, 3-6 Cycloalkyl. For example, C10 3-8 Cycloalkyl should be understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic ring having 3, 4, 5, 6, 7, or 8 carbon atoms. The C... 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as tetrahydronaphthalene or decahydronaphthalene.

[0126] The term "3-12 membered heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic ring containing 1-5 (preferably 1-3) heteroatoms independently selected from N, O, and S. The heteroatom-containing group is non-aromatic, preferably a 3-10 membered heterocyclic group or a 3-8 membered heterocyclic group. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, tetrahydrothiophenyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 1,3-dioxazolyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopentano[c]pyrrolo-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazinol-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrroloyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzofused, for example, but not limited to, dihydroisoquinolinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyranyl (chromyl), 2,3-dihydrobenzo[b][1,4]dioxylalkyl. The 3-12 membered heterocyclic group can also be selected from, for example, the following groups:

[0127]

[0128] Term "C" 6-20 "Aryl" should be understood to preferably represent a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6-20 carbon atoms and possessing monovalent aromaticity or partial aromaticity, preferably "C". 6-14 "Aryl" or "C" 6-10 "Aromatic". Term C 6-20 The term "aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, particularly a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl, or a ring having 10 carbon atoms ("C9 aryl"). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”).14 Aryl), for example, anthracene.

[0129] The term "5-14 cyclic heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case may also be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc.

[0130] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0131] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0132] “DCM” refers to dichloromethane. “MeOH” refers to methanol. “DMF” refers to N,N-dimethylformamide. “DIPEA” refers to N,N-diisopropylethylamine. “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0133] Unless otherwise stated, heterocyclic or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophenyl or thiophene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl.

[0134] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate, or other carbohydrate derivatives or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0135] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires a available lone pair of electrons to be oxidized to nitrogen oxides; those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, and these methods include oxidizing heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxyethylene. These methods for preparing N-oxides have been extensively described and reviewed in the literature.

[0136] Pharmaceutically acceptable salts can be, for example, acid addition salts of compounds of the present invention that have sufficient basicity, having a nitrogen atom in the chain or ring.

[0137] In addition, basic nitrogen-containing groups can be quaternized using the following reagents: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl and phenethyl bromides. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, hydrogen sulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates, or meglumine salts.

[0138] Since the compounds of the present invention can have multiple salt-forming sites, the pharmaceutically acceptable salt includes not only the salt formed at one salt-forming site of the compound of the present invention, but also the salt formed at two, three, or all of the salt-forming sites. Therefore, the molar ratio of the compound of formula (I) to the anion of the acid or the cation of the base required for salt formation in the pharmaceutically acceptable salt can vary over a wide range, for example, from 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0139] Depending on the position and nature of the substituents, the compounds of the present invention may also contain one or more asymmetric centers. The asymmetric carbon atom may exist in (R) or (S) configuration; a racemic mixture is produced when there is only one asymmetric center, and a mixture of diastereomers is obtained when multiple asymmetric centers are present. In some cases, asymmetry may also exist due to hindered rotation around a specific bond, for example, where the central bond connects two substituted aromatic rings of a particular compound. Furthermore, the substituents may also exist in cis or trans isomeric forms.

[0140] The compounds of the present invention also include all possible stereoisomers thereof, which are either single stereoisomers or mixtures thereof in any proportion of said stereoisomers (e.g., R-isomers or S-isomers, or E-isomers or Z-isomers). The separation of single stereoisomers (e.g., single enantiomers or single diastereomers) of the compounds of the present invention can be achieved by any suitable prior art method (e.g., chromatography, particularly chiral chromatography).

[0141] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0142] In this invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of H, C, N, O, P, S, F, and Cl, respectively such as 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, their prodrugs, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those doped with radioactive isotopes (e.g.,... 3 H and 14 Compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H) substitution can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in some cases. The compounds of the invention claimed in the claims are particularly defined as being substituted with deuterium or tritium. Furthermore, the presence of hydrogen in the substituents without a separate mention of the terms deuterium or tritium does not exclude deuterium or tritium, but may also include deuterium or tritium.

[0143] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound of the present invention sufficient to achieve the intended application (including, but not limited to, the diagnosis, prevention, or treatment of diseases as defined above). Therapeutic effective amounts may vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. Specific dosages will vary depending on factors such as the specific compound selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0144] The term "solvent" refers to those forms of the compounds of the present invention that form complexes in a solid or liquid state through coordination with solvent molecules. A hydrate is a specific form of solvate in which coordination occurs with water. In the present invention, hydrates are preferred solvates. Further, pharmaceutically acceptable solvates (hydrates) of compounds of general formula I of the present invention refer to cocrystals and inclusion complexes formed by compound I with one or more stoichiometric molecules of water or other solvents. Solvents that can be used for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol, and acetic acid.

[0145] The term "prodrug" or "drug precursor" refers to the conversion of a compound into a compound represented by the aforementioned general formula or specific compound in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug of this invention can be an ester, and in this invention, esters that can serve as prodrugs include phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in this invention contains a hydroxyl / carboxyl group, which can be acylated to obtain the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. Attached Figure Description

[0146] Figure 1 Changes in body weight of rats after 14 consecutive days of gavage administration of compound 5

[0147] Beneficial effects

[0148] The compounds provided by this invention exhibit excellent GHSR agonist activity. They not only possess good biological activity and safety, but also demonstrate improved transmembrane activity and drug bioavailability. Addressing the numerous problems currently encountered in the domestic treatment of diseases using recombinant human growth hormone, such as poor adherence to injection administration and a lack of specific drugs for clinical diagnosis, the compounds of this invention improve clinical adherence and hold promise as a potential alternative to recombinant human growth hormone in various situations for the diagnosis, prevention, or treatment of diseases related to growth retardation. Detailed Implementation

[0149] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0150] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0151] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0152] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0153] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is in degrees Celsius.

[0154] Example 1

[0155] (2S)-2-amino-N-(1-{[((2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl}-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)pentanediamide

[0156]

[0157] first step

[0158] Preparation of N-[(1S)-1-[[1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl}-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-3-carbamoylpropyl]tert-butyl carbamate

[0159] Ibumolene 1a (350 mg, 0.66 mmol) was dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (255 mg, 1.98 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (376 mg, 0.99 mmol), and (2S)-2-{[[tert-butoxy]carbonyl]amino}-4-carbamoylbutyric acid (195 mg, 0.79 mmol) were added to the mixture. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the solvent was evaporated to obtain the crude product, which was then purified by reversed-phase column chromatography (acetonitrile:water = 1:1) to obtain N-[(1S)-1-[(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4'-piperidin]-1'-yl}-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-3-carbamoylpropyl] tert-butyl carbamate 1b (300 mg, white solid), yield: 54%.

[0160] MS m / z(ESI): 757.2 [M+1] + .

[0161] Step 2: Preparation of (2S)-2-amino-N-(1-{[((2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl}-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)pentanediamide

[0162] N-[(1S)-1-[[1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl}-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-3-carbamoylpropyl] tert-butyl carbamate 1b (300 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was evaporated to obtain the crude product. The crude product was then purified by reverse-phase column chromatography (acetonitrile:water = 2:3) to obtain product (2S)-2-amino-N-(1-{[((2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl}-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)glutaramide 1 (179 mg, pale yellow solid), yield: 68%.

[0163] MS m / z (ESI): 657.2 [M+1] + .

[0164] HPLC: 99.28% (214nm), 100% (254nm).

[0165] 1 H NMR(400MHz,MeOD)δ7.67(dd,J=24.4,8.0Hz,1H),7.36-7.25(m,7H),7.25-7.18(m,1H),7.06-6.96( m,1H),6.76(d,J=7.4Hz,1H),5.20-5.16(m,1H),4.56(s,1H),4.54-4.44(m,2H),4.10-4.04(m,1H), 3.98-3.84(m,3H),3.76-3.65(m,2H),3.28-3.09(m,1H),2.96(d,J=7.2Hz,3H),2.90-2.80(m,1H),2 .47(t,J=7.4Hz,2H),2.15-2.09(m,2H),1.99-1.85(m,1H),1.74-1.66(m,3H),1.51(t,J=6.0Hz,6H).

[0166] Example 2

[0167] N-(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-oxopropane-2-yl]

[0168] ethyl carbamoyl-1-methylethyl)carbamate

[0169]

[0170] first step

[0171] N-(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-oxopropane-2-yl]

[0172] Preparation of ethyl carbamoyl-1-methylethyl)carbamate

[0173] Ibumolene 1a (300 mg) was dissolved in dichloromethane (20 mL), and saturated sodium carbonate solution (4 mL) and ethyl chloroformate (75 mg) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was passed through a reverse-phase column (acetonitrile:water = 1:5) to give N-(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospirocyclic[indol-3,4-piperidin]-1-yl]-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)ethyl carbamate 2 (210 mg, white solid), yield: 62%.

[0174] MS m / z (ESI): 601.4 [M+1] + .

[0175] HPLC: 100% (214nm), 100% (254nm).

[0176] 1 H NMR (400MHz, CDCl3) δ7.41-7.31(m,4H),7.30-7.19(m,1H),7.24-7.19(m,1H),7.12-7.04(m,1H),6.98-6.94(m, 1H),6.61(d,J=7.2Hz,1H),5.21-5.12(m,2H),4.68-4.44(m,3H),4.08(dd,J=14.2,7.2Hz,2H),4.02-3.98(m,1H) ,3.89-3.81(m,1H),3.77(d,J=10.4Hz,1H),3.73-3.68(m,1H),3.62-3.58(m,1H),3.18-3.00(m,1H),2.90(d,J=4 .4Hz,2H),2.85-2.67(m,1H),1.94-1.83(m,1H),1.80-1.61(m,3H),1.52(d,J=8.4Hz,6H),1.23(t,J=7.2Hz,3H).

[0177] Example 3

[0178] (2S)-2,6-Diamino-N-(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-

[0179] [Oxypropane-2-yl]carbamoyl-1-methylethyl)hexamamide

[0180]

[0181] first step

[0182] Preparation of N-[(5S)-5-[(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-5-{[(tert-butoxy)carbonyl]amino}pentyl]carbamate tert-butyl

[0183] Ibumolene 1a (200 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N,N-diisopropylethylamine (147 mg, 1.14 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (216 mg, 0.57 mmol), and finally (2S)-2,6-bis({[(tert-butoxy)carbonyl]amino})hexanoic acid (158 mg, 0.46 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure, and the crude product was passed through a reverse-phase column (acetonitrile:water = 72%) to give N-[(5S)-5-[(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-5-{[(tert-butoxy)carbonyl]amino}pentyl]carbamate tert-butyl ester 3a (280 mg, white solid), yield: 86%.

[0184] MS m / z (ESI): 857.4 [M+1] + .

[0185] Step 2: (2S)-2,6-diamino-N-(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-

[0186] Preparation of oxopropane-2-yl]carbamoyl}-1-methylethyl)hexamamide

[0187] N-[(5S)-5-[(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-5-{[(tert-butoxy)carbonyl]amino}pentyl]carbamate tert-butyl ester 3a (280 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure. The crude product was then passed through a reverse-phase column (acetonitrile:water = 40%) to give (2S)-2,6-diamino-N-(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4-piperidin]-1-yl]-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)hexamamide 3 (210 mg, white solid), yield: 97%.

[0188] MS m / z (ESI+): 657.3 [M+1] + .

[0189] HPLC: 100% (214nm), 100% (254nm).

[0190] 1 H NMR(400MHz,d6-DMSO)δ8.61-8.48(m,1H),8.12-8.09(m,2H),7.84-7.78(m,3H),7.61(d,J=8.0Hz,0.5H),7.38-7. 22(m,6H),7.07-6.97(m,1H),6.88(d,J=8.0Hz,0.5H),4.99-4.96(m,1H),4.51(s,1H),4.47(d,J=9.2Hz,1H),4.43- 4.39(m,1H),3.95-3.85(m,3H),3.76(s,1H),3.65(dd,J=16.4,8.2Hz,1H),3.59-3.48(m,1H),3.34(s,3H),3.21-3 .11(m,1H),3.05(d,J=6.4Hz,3H),2.89-2.69(m,3H),1.80-1.52(m,8H),1.45(d,J=12.8Hz,3H),1.39-1.36(m,4H).

[0191] Example 4

[0192] (S)-2-amino-N-(1-(((R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-

[0193] (1H-indol-2-yl)-2-methyl-1-oxopropane-2-yl)-3-(1H-indol-2-yl)propionamide

[0194]

[0195] first step

[0196] 9H-fluorene-9-yl-methyl N-[(1S)-1-[(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospiro[indol-3,4'-piperidin]-1'-yl]-1-oxopropane-2-yl]carbamoyl}-1-methylethyl)carbamoyl]-2-(1H-indol-2-yl)ethyl]carbamic acid

[0197] Preparation of esters

[0198] Compound ibuprofen 1a (200 mg, 0.38 mmol) was dissolved in DMF (3 mL), and N,N-diisopropylethylamine (145 mg, 0.12 mmol), HATU (300 mg, 0.78 mmol), and ((9H-fluoro-9-yl)methoxy)carbonyl)-L-tryptophan (243 mg, 0.57 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (3 x 20 mL), washed with saturated brine (3 x 20 mL), and the residue obtained by concentration was purified by preparative chromatography (acetonitrile / water) to give compound 4a (250 mg, white solid). Yield: 71%.

[0199] MS m / z (ESI): 937.0 [M+1] + .

[0200] Step 2

[0201] Preparation of (S)-2-amino-N-(1-(((R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-3-(1H-indol-2-yl)propionamide

[0202] Compound 4a (200 mg) was dissolved in acetonitrile (10 mL), and piperidine (178 mg, 2.1 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The residue obtained by concentrating the reaction mixture was purified by preparative chromatography (acetonitrile / water) to give compound 4 (52.4 mg, white solid), yield: 33%.

[0203] MS m / z (ESI): 715.0 [M+1] +.

[0204] 1 H NMR (400MHz, DMSO) δ10.84(s,1H),8.14(d,J=12.4Hz,1H),7.81(dd,J=17.7,8.9Hz,1H),7.57(t,J=9.3Hz,1H),7.40–7.27(m,7H ),7.22(dd,J=16.0,8.2Hz,2H),7.16(s,1H),7.05(dd,J=16.6,10.7Hz,1H),6.96(dd,J=20.2,8.8Hz,2H),5.11-4.89(m,1H),4. 54–4.46(m,2H),4.37(dd,J=14.0,7.9Hz,1H),4.04–3.93(m,1H),3.93–3.84(m,2H),3.69(dd,J=10.3,2.8Hz,1H),3.60–3.47(m ,1H),3.41(dd,J=15.9,6.2Hz,2H),3.22–3.06(m,2H),3.05(d,J=4.8Hz,3H),2.83–2.70(m,2H),1.67-1.50(m,4H),1.38(s,6H).

[0205] Example 5

[0206] (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-isobutyrate

[0207]

[0208] first step

[0209] Preparation of o-(1-chloroethyl)thiocarbonate

[0210] Compound 1-chloroethyl chloroformate 5a (3 g, 0.02 mol) was dissolved in dichloromethane (10 mL), followed by the addition of tetrabutylammonium bromide (TBAB) (0.34 g). Sodium ethanethiol (1.76 g; 0.02 mol) was dissolved in water (10 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture separated into layers. The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 5b (2.0 g, yield: 56%) as a yellow oil.

[0211] 1H NMR (400MHz, CDCl3) δ6.60 (q, J = 5.8Hz, 1H), 2.97-2.86 (m, 2H), 1.81 (d, J = 5.8Hz, 3H), 1.34 (t, J = 7.4Hz, 3H).

[0212] Step 2

[0213] Preparation of 1-{[(ethylthio)carbonyl]oxy}ethyl isobutyrate

[0214] Compound 5b (700 mg; 4.15 mmol) was dissolved in isobutyric acid (2.2 g, 25 mmol), and then N,N-diisopropylethylamine (1.6 g, 12.5 mmol) was added. The reaction mixture was stirred at 55 °C for 48 hours. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate (3 x 30 mL), washed with saturated brine (2 x 20 mL), and concentrated to obtain residue 5c (850 mg, pale yellow oil).

[0215] 1 HNMR (400MHz, CDCl3): δ6.94 (q, J=5.4Hz, 1H), 2.92–2.83 (m, 2H), 2.59 (dt, J=4.3, 2.4Hz,

[0216] 1H), 1.50 (d, J = 5.5Hz, 3H), 1.32 (td, J = 7.3, 3.6Hz, 3H), 1.20 (d, J = 7.0Hz, 6H).

[0217] Step 3

[0218] Preparation of ethyl 1-((chlorocarbonyl)oxyisobutyrate)

[0219] Sulfonyl chloride (147 mg, 1.09 mmol) was slowly added dropwise to compound 1-{[(ethylsulfonyl)carbonyl]oxy}ethyl 2-methylpropionate ethyl 5c (200 mg, 0.91 mmol) at 0–5 °C, and the reaction solution was stirred at 25 °C for 45 minutes. The residue 5d obtained by concentrating the reaction solution can be used directly in the next step.

[0220] Step 4

[0221] 1-{[(1-{[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospirocyclic[indol-3,4'-piperidine]-1'-yl}-1-oxopropane-2-yl]

[0222] Preparation of ethyl carbamoyl-1-methylethyl)carbamoyloxy-2-methylpropionate

[0223] Compound 5d (60 mg, 0.11 mmol) and ibuprofen 1a were dissolved in dichloromethane (3 mL). Sodium hydroxide (22 mg, 0.22 mmol) was dissolved in 5 mL of water and slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 2 hours. The residue obtained by organic layer concentration was purified by preparative chromatography (acetonitrile / water) to give compound 5 (58 mg, white solid), yield: 72%.

[0224] MSm / z(ESI): 687.0 [M+1] + .

[0225] 1 HNMR(400MHz,MeOD)δ7.79–7.59(m,1H),7.42–7.26(m,6H),7.25–7.16(m,1H),6.99-6. 90(m,1H),6.81–6.66(m,1H),5.18–5.11(m,1H),4.59–4.49(m,2H),4.18–3.97(m,1H), 3.99–3.84(m,2H),3.81–3.63(m,2H),3.26–3.16(m,2H),2.96(d,J=6.4Hz,3H),2.87-2 .8(m,1H),2.52-2.50(m,1H),2.06–1.55(m,4H),1.51–1.31(m,9H),1.11-1.02(m,6H).

[0226] Example 6

[0227] (4R,11R)-7,7-dimethyl-4-(1-(methanesulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-isobutyrate (4R,11S)-7,7-dimethyl-4-(1-(methanesulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-isobutyrate

[0228]

[0229] Compound 5A and compound 5B were obtained by chiral resolution of the compound 5 prepared above. The separation conditions were as follows: column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH = 60 / 40; flow rate: 1.5mL / min; column temperature: 37℃.

[0230] Compound 5A:

[0231] t R =1.582min

[0232] MSm / z(ESI): 687.0 [M+1] + .

[0233] 1 H NMR(300MHz,dmso)δ7.80–7.49(m,2H),7.42–7.15(m,8H),7.08–6.85(m,2 H),6.67–6.56(m,1H),4.97(d,J=7.2Hz,1H),4.44(dd,J=30.4,12.1Hz,3H ),3.90(d,J=6.8Hz,3H),3.72–3.45(m,2H),3.15(s,1H),3.04(d,J=2.2Hz ,3H),2.80(s,1H),1.66(s,4H),1.45–1.28(m,9H),1.06(d,J=6.9Hz,6H).

[0234] Compound 5B:

[0235] t R =1.815min

[0236] MSm / z(ESI): 687.0 [M+1] + .

[0237] 1 H NMR(300MHz,dmso)δ7.77–7.50(m,2H),7.42–7.15(m,8H),7.09–6.85(m,2 H),6.67–6.57(m,1H),4.97(d,J=7.2Hz,1H),4.44(dd,J=28.5,13.9Hz,3H) ,3.97(dd,J=38.3,7.0Hz,3H),3.74–3.43(m,2H),3.15(s,1H),3.04(d,J=2 .3Hz,3H),2.80(s,1H),1.66(s,3H),1.45–1.30(m,9H),1.09–1.02(m,6H).

[0238] Example 7

[0239] (R)-4-amino-N-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)butanylamine

[0240]

[0241]

[0242] Step 1: Preparation of (R)-(4-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)amino)-4-oxobutyl)carbamate tert-butyl

[0243] Ibumolene 1a (150 mg, 0.28 mmol) was dissolved in dry DMF (5 mL), followed by the addition of 4-((tert-butyloxycarbonyl)amino)butyric acid (69 mg, 0.34 mmol), HATU (320 mg, 0.84 mmol), and DIPEA (181 mg, 1.40 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by preparative chromatography (acetonitrile / water) to give (R)-(4-((1-((3-benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)amino)-4-oxobutyl)carbamate tert-butyl ester 7a (162 mg, white solid), yield: 80%.

[0244] MS m / z (ESI): 714.3. [M+1] + .

[0245] Step 2

[0246] (R)-4-amino-N-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-

[0247] Preparation of 2-yl)amino)-2-methyl-1-oxopropane-2-yl)butamine

[0248] (R)-(4-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)amino)-4-oxobutyl)carbamate tert-butyl ester 7a (160 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After concentration, the reaction solution was purified by preparative chromatography (30% acetonitrile / water) to obtain (R)-4-amino-N-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)butanol 7 (28.1 mg, white solid), yield: 21%.

[0249] MS m / z (ESI): 615.3 [M+1] + .

[0250] 1 H NMR(400MHz, CDCl3)δ8.01(s,2H),7.63-7.45(m,1H),7.40-7.31(m,3H),7.28( s,1H),7.23(d,J=6.1Hz,2H),7.11-6.92(m,1H),6.70(d,J=7.5Hz,1H),5.13(br s,1H),4.59-4.42(m,2H),4.04(s,1H),3.87-3.74(m,2H),3.73-3.55(m,2H),3.20-3.08(m,1H),3.06-2.82(m,4H), 2.79-2.76(m,1H),2.47(s,2H),2.01-1.98(m,2H),1.92(s,1H),1.89-1.83(m,3H),1.70-1.63(m,2H),1.50(s,6H).

[0251] HPLC: 99.71% (214nm), 98.47% (254nm).

[0252] Example 8

[0253] (R)-N-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-

[0254] Methyl-1-oxopropane-2-yl)oleamide

[0255]

[0256]

[0257] Step 1 (R)-N-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-

[0258] Preparation of methyl-1-oxopropane-2-yl)oleamide

[0259] Compound ibuprofen 1a (200 mg, 0.38 mmol) was dissolved in DCM (5 mL), and N,N-diisopropylethylamine (147 mg, 1.14 mmol), HATU (288 mg, 0.76 mmol), and oleic acid (161 mg, 0.57 mmol) were added. The reaction mixture was stirred at 25 °C for 1 hour. The residue obtained by concentration of the reaction mixture was purified by high performance liquid chromatography (acetonitrile / water) to give compound 8 (150 mg, white solid), yield: 47%.

[0260] MS m / z(ESI)::793.5[M+1] + .

[0261] 1 H NMR(400MHz,CDCl3)δ7.40–7.30(m,4H),7.27 -2.25(m,2H),7.24–7.17(m,1H),7.11–6.91(m,2H),6.60(d,J=7.6Hz,1H),5.99(s,1H),5.43– 5.26(m,2H),5.21–5.04(m,1H),4.70–4.41(m,3H),4.19–3.91(m,1H),3.90–3.65(m,3H),3.59 -3.55(m,1H),3.18–2.98(m,1H),2.90(d,J=4.6Hz,3H),2.84–2.68(m,1H),2.24–2.13(m ,2H),2.00-1.98(m,3H),1.87-1.82(m,1H),1.74–1.66(m,2H),1.58-1.55(m,10H),1.26 -1.20(m,20H),0.88(t,J=6.8Hz,3H).

[0262] Example 9

[0263] (phosphonoyloxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-

[0264] 2-Methyl-1-oxopropane-2-yl)carbamate

[0265]

[0266] first step

[0267] Preparation of chloromethyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spirocyclic [indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)carbamate

[0268] Ibumolene 1a (264 mg, 0.50 mmol) and chloromethyl chloroformate (71 mg, 0.55 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of water (10 mL) and sodium hydroxide (40 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. After standing, the reaction mixture separated into layers. The organic phase was dried and concentrated to give chloromethyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spirocyclic[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)carbamate 9a (310 mg, colorless oil), yield: 100%.

[0269] MS m / z (ESI): 621.2 [M+1] + .

[0270] Step 2: Preparation of ((di-tert-butoxyphosphoryl)oxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0271] Chloromethyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)carbamate 9a (310 mg, 0.50 mmol) was dissolved in dry tetrahydrofuran (10 mL), followed by the addition of di-tert-butyl phosphate tetra-n-butylammonium salt (678 mg, 1.50 mmol) and sodium iodide (225 mg, 1.50 mmol). The reaction mixture was stirred at room temperature for 2 minutes. 4 hours. The residue obtained after concentration of the reaction solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ((di-tert-butoxyphosphoryl)oxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate 9b (200 mg, yellow oil), yield: 50%.

[0272] MS m / z (ESI): 817.2 [M+23] + .

[0273] Step 3: (phosphonoyloxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-

[0274] Preparation of 2-yl)carbamate

[0275] (119 mg, 0.15 mmol) of ((di-tert-butoxyphosphoryl)oxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate 9b was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After concentration, the reaction solution was purified by reverse-phase column chromatography (35% acetonitrile / water) to give (phosphonoyloxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)carbamate 9 (35.6 mg, white solid), yield: 34%.

[0276] MS m / z (ESI): 683.2 [M+1] + .

[0277] 1 H NMR (400MHz, DMSO) δ7.83-7.62(m,2H),7.44-7.10(m,7H),6.98-6.85(m,2H),5.4-5.32(m,2H),4.97(s,1H),4 .56-4.25(m,3H),3.88(s,3H),3.59-3.52(m,2H),3.23-3.10(m,1H),3.03(s,3H),2.85-2.70(m,1H),1.62(br s,4H),1.36(br s,6H).

[0278] Example 10

[0279] ((diethoxyphosphoryl)oxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indole-3,4'-piperidin]-1'-yl)-1-

[0280] (Oxypropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0281]

[0282]

[0283] first step

[0284] Preparation of chloromethyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spirocyclic [indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)carbamate

[0285] Ibumolene 1a (264 mg, 0.50 mmol) and chloromethyl chloroformate (71 mg, 0.55 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of water (10 mL) and sodium hydroxide (40 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. After standing, the reaction mixture separated into layers. The organic phase was dried and concentrated to give chloromethyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)carbamate 10a (310 mg, colorless oil), yield: 100%. MS m / z (ESI): 621.3 [M+1] + .

[0286] Step 2

[0287] Preparation of ((diethoxyphosphoryl)oxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0288] Chloromethyl(R)-(1-((3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)carbamate 10a (310 mg, 0.50 mmol) was dissolved in dry tetrahydrofuran (10 mL), and then diethyl phosphate tetrabutylammonium salt (593 mg, 1.50 mmol) and sodium iodide (225 mg, 1.50 mmol) were added. The reaction solution was stirred at room temperature for 24 hours. After concentration, the reaction solution was purified by preparative chromatography (55% acetonitrile / water) to obtain 10 (86 mg, white solid) of ((diethoxyphosphoryl)oxy)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate, yield: 12%.

[0289] MS m / z (ESI): 739.2 [M+1] + .

[0290] 1 H NMR (400MHz, CDCl3): δ7.43-7.27(m,5.5H),7.27-7.17(m,2H),7.11-6.96(m,2H),6.63(d ,J=7.4Hz,0.5H),5.82(s,1H),5.59(d,J=13.5Hz,2H),5.20-5.13(m,1H),4.69-4.42(m,3H ),4.22-4.07(m,4H),3.89-3.65(m,3H),3.63-3.58(m,1H),3.17-3.01(m,1H),2.91(d,J=4 .7Hz,3H),2.85-2.68(m,1H),1.84-1.67(m,4H),1.59-1.57(m,6H),1.34(t,J=7.0Hz,6H).

[0291] 31 P NMR (162MHz, CDCl3): δ-2.59 (s, 1H).

[0292] Example 11

[0293] (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-propionate

[0294]

[0295] first step

[0296] Preparation of ethyl 1-((ethylthio)carbonyl)oxypropionate

[0297] 2 g (0.0119 mol) of o-(1-chloroethyl)thioethyl carbonate was dissolved in 4.4 g (0.0595 mol) of propionic acid, and N,N-diisopropylethylamine (4.6 g (0.0357 mol) was added. The resulting solution was stirred at 55 °C for 48 h, and the reaction was stopped. The solution was washed with water (30 mL) and ethyl acetate (30 mL). The organic phase was washed with saturated NaHCO3 solution (3 x 30 mL), and then with brine (1 x 30 mL). The solvent was removed by distillation to give the desired product, ethyl 1-((ethylthio)carbonyl)oxypropionate (850 mg, yellow oil), yield: 83%.

[0298] 1H NMR (400MHz, CDCl3) δ6.94 (q, J=5.4Hz, 1H), 2.92–2.83 (m, 2H), 2.59 (dt, J=4.3, 2. 4Hz, 1H), 1.50 (d, J = 5.5Hz, 3H), 1.32 (td, J = 7.3, 3.6Hz, 3H), 1.20 (d, J = 7.0Hz, 6H).

[0299] Step 2

[0300] Ethyl (chlorocarbonyl)oxypropionate

[0301] Sulfonyl chloride (147 mg, 1.089 mmol) was added to ethyl 1-((ethylthio)carbonyl)oxypropionate (200 mg, 0.907 mmol) and stirred for 5 minutes at 0–5 °C. After adding all reagents, the mixture was stirred for another 45 minutes at room temperature. EtSCl was then removed by distillation at room temperature. This product was used in the next step without further purification.

[0302] Step 3: Preparation of (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-propionate

[0303] In a round-bottom flask, ibuprofen 1a (50 mg, 0.09 mmol) and ethyl (chlorocarbonyl)oxypropionate (51 mg, 0.28 mmol) were added to dichloromethane (15 mL). Then, sodium hydroxide (19 mg, 0.19 mmol) was added to water (5 mL), and the mixture was stirred at room temperature for 2 h. The organic layer was concentrated and purified by preparative chromatography (column: Kromasil-C18 100 x 21.2 mm, mobile phase: acetonitrile-water gradient: 30-40) to give (4R)-7,7-dimethyl-4-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-propionate 11 (23 mg, yellow solid), yield: 35%.

[0304] MS m / z (ESI): 673.2 [M+1] + .

[0305] 1H NMR (400MHz, DMSO) δ7.65 (dd, J=34.3, 11.5Hz, 2H), 7.52 (d, J=7.5Hz, 1H), 7.31–7.26 (m,5H),7.01(t,J=7.3Hz,1H),6.94(d,J=7.3Hz,1H),6.85(t,J=7.0Hz,1H),6.61(d,J =5.3Hz,1H),4.94(d,J=6.1Hz,1H),4.48–4.43(m,2H),3.93–3.60(m,6H),3.01(d,J=3 .9Hz,5H),1.63(s,4H),1.34(dd,J=10.5,5.2Hz,4H),1.29(s,6H),0.98–0.93(m,4H).

[0306] Example 12

[0307] (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-yl-2-methylbutyrate

[0308]

[0309]

[0310] first step

[0311] Preparation of ethyl 1-((ethio)carbonyloxy)2-methylbutyrate

[0312] (1-Chloroethoxy)(ethylsulfonyl) methyl ketone (2.00 g, 11.86 mmol) was dissolved in 2-methylbutyric acid (6.5 mL, 59.30 mmol), and then N,N-diisopropylethylamine (4.60 g, 35.58 mmol) was added. The reaction mixture was reacted at 55 °C for 48 hours. After cooling to room temperature, the reaction mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated sodium carbonate solution, followed by saturated brine. The organic phase was dried and concentrated to give ethyl 1-((ethylthio)carbonyloxy)-2-methylbutyrate (1.4 g, yellow oil), yield: 50%.

[0313] 1H NMR (400MHz, CDCl3) δ6.95(q,J=5.4Hz,1H),2.90-2.84(m,2H),2.41-2.35(m,1H),1.74-1.62(m,1H),1.51(d,J =5.5Hz,3H),1.48-1.41(m,1H),1.31(t,J=7.4Hz,3H),1.15(dd,J=7.0,3.5Hz,3H),0.91(td,J=7.4,1.8Hz,3H).

[0314] Step 2

[0315] Preparation of ethyl 1-((chlorocarbonyl)oxy)2-methylbutyrate

[0316] Sulfonyl chloride (138 mg, 1.02 mmol) was added dropwise to ethyl 1-((ethylthio)carbonyloxy)-2-methylbutyrate (200 mg, 0.85 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, crude ethyl 1-((chlorocarbonyl)oxy)-2-methylbutyrate (178 mg, yellow oil) was obtained, which was directly added to the next step.

[0317] Step 3

[0318] Preparation of (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-yl-2-methylbutyrate

[0319] Ibumolene 1a (50 mg, 0.095 mmol) and ethyl 1-((chlorocarbonyl)oxy)-2-methylbutyrate (28 mg, 0.28 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of water (5 mL) and sodium hydroxide (19 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was allowed to stand and separate into layers. The organic phase was dried and concentrated, and the residue was purified by reverse-phase column chromatography (55% acetonitrile / water) to give (4R)-7,7-dimethyl-4-(1-(methanesulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-yl 2-methylbutyrate 12 (9.1 mg, white solid), yield: 13%.

[0320] MS m / z (ESI): 701.2 [M+1] + .

[0321] 1H NMR (400MHz, CDCl3) δ7.39-7.28(m,5.5H),7.23-7.17(m 1H),7.07-6.96(m,2H),6.79-6.78(m,1H),6.64-6.61(m,0.5H),5.53-5.42(m,1H),5.23-5. 09(m,1H),4.69-4.39(m,3H),4.10-3.97(m,1H),3.91-3.51(m,4H),3.16-3.02(m,1H),2.90( d,J=4.4Hz,3H),2.87-2.73(m,1H),2.40-2.32(m,1H),1.96-1.77(m,2H),1.74-1.64(m,4H), 1.56-1.54(m,6H),1.45(t,J=5.7Hz,3H),1.13(dd,J=6.9,1.8Hz,3H),0.90(t,J=7.4Hz,3H).

[0322] Example 13

[0323] (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxo-1--1-phenyl-2,10-cyclohexanecarboxylic acid dioxa-5,8-diazadodecaneundecyl ester

[0324]

[0325] first step

[0326] Preparation of 1-(((ethylthio)carbonyl)oxy)ethylcyclohexane carboxylic acid ester

[0327] o-(1-chloroethyl)S-ethyl carbonate (2 g, 0.0119 mol) was dissolved in cyclohexanecarboxylic acid (7.6 g, 0.0595 mol), and then N,N-diisopropylethylamine (4.6 g, 0.0357 mol) was added. The resulting solution was stirred at 55 °C for 48 h, the reaction was stopped, and the mixture was washed with water (30 mL) and ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (3 x 30 mL), and then with saturated brine (2 x 30 mL). The solvent was removed by distillation to give the desired product, 1-(((((ethylthio)carbonyl)oxy)ethylcyclohexanecarboxylic acid ester (2 g, yellow oil), yield: 54%.

[0328] 1H NMR(400MHz, CDCl3) δ6.93(q,J=5.4Hz,1H),2.91-2.82(m,2H),2.36-2.29(m,1H),1.90(dd,J=14.1,3.1Hz,2H),1.77- 1.72(m,2H),1.71-1.52(m,2H),1.51-1.48(m,3H),1.47-1.41(m,2H),1.33-1.30(m,3H),1.25(dd,J=9.7,2.7Hz,2H).

[0329] Step 2

[0330] Preparation of 1-((chlorocarbonyl)oxy)ethylcyclohexane carboxylic acid ester

[0331] Sulfonyl chloride (125 mg, 0.922 mmol) was added to 1-((((ethylthio)carbonyl)oxy)ethylcyclohexane carboxylate (200 mg, 0.77 mmol), and the mixture was stirred at 0–5 °C for 5 minutes. After adding all reagents, the mixture was stirred at room temperature for another 45 minutes. EtSCl was then removed by distillation at room temperature. This product was used in the next step without further purification.

[0332] Step 3: Preparation of (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxo-1--1-phenyl-2,10-cyclohexanecarboxylic acid dioxa-5,8-diazadodecaneundecyl ester

[0333] In a round-bottom flask, ibuprofen 1a (50 mg, 0.09 mmol) and [1-(cyclohexyloxy)ethyl]chloroformate (66.6 mg, 0.28 mmol) were dissolved in dichloromethane (15 mL). Then, NaOH (19.2 mg, 0.19 mmol) was added to 5 mL of water and added dropwise to the reaction solution. The mixture was stirred at room temperature for 2 h. The organic layer was purified by preparative chromatography (column: Kromasil-C18100 x 21.2 mm 5; mobile phase: acetonitrile-water gradient: 30-40) to give (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxo-1--1-phenyl-2,10-cyclohexanecarboxylic acid dioxa-5,8-diazadodecaneundecyl ester 13 (23 mg, yellow solid), yield: 33%.

[0334] MS m / z (ESI): 727.2 [M+1] + .

[0335] 1H NMR (400MHz, DMSO) δ7.74(s,1H),7.65(d,J=12.0Hz,1H),7.57(d,J=8.7Hz,1H),7.35–7.22(m,5H),7. 04(s,1H),6.98(d,J=7.0Hz,1H),6.87(s,1H),4.96(d,J=7.1Hz,1H),4.46(dd,J=22.7,19.3Hz,2H),3. 90(d,J=11.8Hz,2H),3.55(d,J=24.5Hz,2H),3.04(d,J=4.2Hz,3H),2.54–2.52(m,4H),2.31–2.24(m, 1H), 1.79 (t, J=41.2Hz, 4H), 1.61 (d, J=39.3Hz, 6H), 1.37 (dd, J=28.3, 15.6Hz, 9H), 1.26–1.02 (m, 4H).

[0336] Example 14

[0337] (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-acetate

[0338]

[0339] first step

[0340] Preparation of 1-((ethylthio)carbonyl)oxyethyl acetate

[0341] (1-Chloroethoxy)(ethylsulfonyl) methyl ketone (2.00 g, 11.86 mmol) was dissolved in acetic acid (3.6 mL, 59.30 mmol), and then N,N-diisopropylethylamine (4.6 g, 35.58 mmol) was added. The reaction mixture was reacted at 55 °C for 48 hours. After cooling to room temperature, the reaction mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated sodium carbonate solution, followed by saturated brine. The organic phase was dried and concentrated to give 1-((ethylthio)carbonyl)oxyethyl acetate (1.2 g, yellow oil), yield: 53%.

[0342] 1 H NMR (400MHz, CDCl3) δ6.94 (q, J = 5.5Hz, 1H), 2.95-2.81 (m, 2H), 2.09 (s, 3H), 1.51 (d, J = 5.5Hz, 3H), 1.32 (t, J = 7.4Hz, 3H).

[0343] Step 2

[0344] Preparation of (chlorocarbonyl)oxyethyl acetate

[0345] Sulfonyl chloride (253 mg, 1.87 mmol) was added dropwise to 1-((ethylthio)carbonyl)oxyethyl acetate (300 mg, 1.56 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude (chlorocarbonyl)oxyethyl acetate (178 mg, yellow oil), yield: 100%. This crude product was directly used in the next step.

[0346] Step 3

[0347] Preparation of (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-acetic acid ester

[0348] Ibumolene 1a (50 mg, 0.095 mmol) and ethyl (chlorocarbonyl)oxyethyl acetate (47 mg, 0.28 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of water (5 mL) and sodium hydroxide (19 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was allowed to stand and separate into layers. The organic phase was dried and concentrated, and the residue was purified by reverse-phase column chromatography (55% acetonitrile / water) to give (4R)-7,7-dimethyl-4-(1-(methanesulfonyl)spiro[indole-3,4'-piperidine]-1'-carbonyl)-6,9-dioxa-1-phenyl-2,10-dioxa-5,8-diazadodecane-11-acetic acid 14 (16.27 mg, white solid), yield: 26%.

[0349] MS m / z (ESI): 659.2 [M+1] + .

[0350] 1H NMR (400MHz, CDCl3) δ7.46-7.27(m,5H),7.25-7.17(m,1H),7.14-6.90(m,2H),6.81-6.73(m, 1H),6.73-6.46(m,1H),5.43(s,1H),5.21-5.13(m,1H),4.71-4.39(m,3H),4.15-3.94(m,1H) ,3.92-3.52(m,4H),3.17-3.02(m,1H),2.89(d,J=4.4Hz,3H),2.83-2.62(m,1H),2.06(d,J=4 .3Hz,3H),1.93-1.84(m,1H),1.71-1.69(m,3H),1.54(d,J=5.9Hz,6H),1.46(t,J=5.5Hz,3H).

[0351] Example 15

[0352] (R)-5,5-dimethyl-8-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecyl isobutyrate

[0353]

[0354] first step

[0355] Preparation of O-(chloromethyl)S-ethyl thiocarbonate

[0356] Sodium ethanethiol (3.07 g, 36.5 mmol) was dissolved in dichloromethane (20 mL), and tetrabutylammonium bromide (0.59 g, 1.8 mmol) was added. Chloromethyl chloroformate (4.71 g, 36.5 mmol) was then slowly added dropwise. The reaction was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to give O-(chloromethyl)S-ethyl thiocarbonate (3 g, yellow oily liquid), yield: 50%.

[0357] 1 H NMR (400MHz, DMSO) δ5.96(s,1H),2.96–2.87(m,1H),1.31–1.20(m,2H).

[0358] Step 2

[0359] Preparation of methyl isobutyrate

[0360] Isobutyric acid (8.95 g, 97 mmol) was placed in a round-bottom flask, and O-(chloromethyl)S-ethylthiocarbonate (3 g, 19.4 mmol) was added, followed by N,N-diisopropylethylamine (6.9 g, 53 mmol). The reaction was stirred at 55 °C for 48 hours. After the reaction was complete, sodium bicarbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to give methyl ((((ethylthio)carbonyl)oxy)isobutyrate (1.85 g, orange oily liquid), yield: 44%.

[0361] 1 H NMR (400MHz, DMSO) δ5.78(s,2H),4.03(q,J=7.2Hz,3H),2.88(q,J=7.2Hz,1H),2.66–2.55(m,1H),1.20–1.15(m,4H),1.10(d,J=7.2Hz,6H).

[0362] Step 3

[0363] Preparation of methyl ((chlorocarbonyl)oxy)isobutyrate

[0364] Methyl ((((((ethylthio)carbonyl)oxy)isobutyrate) (500 mg, 2.42 mmol)) was placed in a round-bottom flask, and sulfonyl chloride (1 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was evaporated to obtain crude methyl ((chlorocarbonyl)oxy)isobutyrate (437 mg, brown solid), yield: 99%. The crude product was directly added to the next step of the reaction without purification.

[0365] Step 4

[0366] (R)-5,5-Dimethyl-8-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-

[0367] Preparation of dioxin-4,7-diazadodecyl isobutyrate

[0368] Methyl ((chlorocarbonyl)oxy)isobutyrate (437 mg, 2.42 mmol) was dissolved in dichloromethane (10 mL), and epomolum 1a (200 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL). The solutions were combined, and water (5 mL) and 2N sodium hydroxide solution (0.2 mL) were added. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (acetonitrile:water (0.1% formic acid) to obtain (R)-5,5-dimethyl-8-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecyl isobutyrate 15 (34 mg, white solid), yield: 2%.

[0369] MS m / z (ESI) 673.3 [M+1] + .

[0370] 1H NMR (400MHz, DMSO) δ7.76(dd,J=16.7,11.1Hz,2H),7.59(d,J=8.0Hz,1H),7.34(s,8H),7.01(dt,J=19.7,7.2Hz,1H), 6.89(d,J=7.4Hz,0.5H),5.60(s,2H),4.97(dd,J=13.2,6.6Hz,1H),4.51(s,1H),4.47(d,J=4.1Hz,1H),4.44–4.33(m, 1H),3.94–3.85(m,1H),3.70–3.62(m,1H),3.61–3.54(m,1H),3.50(dd,J=9.4,5.4Hz,1H),3.17(dd,J=25.5,12.3Hz, 1H), 3.04 (d, J = 3.9Hz, 3H), 2.80 (t, J = 11.5Hz, 1H), 1.61 (dd, J = 34.8, 11.5Hz, 1H), 1.34 (s, 2H), 1.07 (t, J = 5.7Hz, 2H).

[0371] Example 16

[0372] (R)-2-(2-aminoacetamido)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[0373]

[0374] Step 1 (R)-(2-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)amino)-2-

[0375] Preparation of tert-butyl methyl-1-oxopropane-2-yl)carbamate

[0376] Ibumolene 1a (212 mg, 0.40 mmol) was dissolved in dry DMF (5 mL), followed by the addition of BOC-glycine (105 mg, 0.60 mmol), HATU (457 mg, 1.20 mmol), and DIPEA (259 mg, 2.00 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by preparative chromatography (55% acetonitrile / water) to give tert-butyl(R)-(2-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate 16a (220 mg, white solid), yield: 80%.

[0377] MS m / z (ESI): 686.3 [M+1] + .

[0378] Step 2: Preparation of (R)-2-(2-aminoacetamido)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[0379] (R)-(2-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl 16a (150 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After concentration, the reaction mixture was purified by preparative chromatography (30% acetonitrile / water) to give (R)-2-(2-aminoacetamido)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide 16 (35 mg, white solid), yield: 27%.

[0380] MS m / z (ESI): 586.3 [M+1] + .

[0381] 1H NMR (400MHz, DMSO) δ8.37(d,J=3.6Hz,1H),7.97-7.94(m,3H),7.79(d,J=8.2Hz,0.5H),7.4 2-7.15(m,6H),7.12-6.95(m,1H),6.90(d,J=7.5Hz,0.5H),5.01-4.94(m,1H),4.62-4.45( m,2H),4.42-4.39(m,1H),4.06-3.81(m,3H),3.79-3.68(m,1H),3.63-3.43(m,3H),3.21-3 .13(m,1H),3.05(d,J=5.9Hz,3H),2.84-2.76(m,1H),1.84-1.54(m,4H),1.49-1.23(m,6H).

[0382] Example 17

[0383] (5-Methyl-2-oxo-1,3-dioxane-4-yl)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0384]

[0385] first step

[0386] Preparation of (5-methyl-2-oxo-1,3-dioxane-4-yl)methyl(4-nitrophenyl) carbonate

[0387] 4-(hydroxymethyl)-5-methyl-1,3-dioxane-2-one (1 g, 7.7 mmol) and pyridine (0.67 g, 8.47 mmol) were dissolved in dichloromethane (10 mL). 4-nitrophenyl chloroformate (1.55 g, 7.7 mmol) was dissolved in dichloromethane (20 mL) and added dropwise to the chloroformate under ice bath conditions. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was washed successively with 1% sodium hydroxide aqueous solution, 1N hydrochloric acid, water, and saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to give (5-methyl-2-oxo-1,3-dioxane-4-yl)methyl(4-nitrophenyl) carbonate (2.4 g, yellow solid), yield: 79%.

[0388] 1H NMR (400MHz, DMSO) δ8.36–8.30(m,2H),7.64–7.54(m,2H),5.19(s,2H),2.25–2.11(s,3H).

[0389] Step 2: Preparation of (5-methyl-2-oxo-1,3-dioxane-4-yl)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate

[0390] Ibumolene 1a (107 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), and (5-methyl-2-oxo-1,3-dioxane-4-yl)methyl(4-nitrophenyl) carbonate (200 mg, 0.81 mmol) and pyridine (64 mg, 0.81 mmol) were added. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by reverse-phase column chromatography (acetonitrile / water (0.1% formic acid)) to obtain (5-methyl-2-oxo-1,3-dioxane-4-yl)methyl(R)-(1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate 17 (48 mg, white solid), yield: 8%.

[0391] MS m / z (ESI) 685.3 [M+1] + .

[0392] 1H NMR (400MHz, DMSO) δ7.76(d,J=8.4Hz,0.5H),7.59(d,J=16.4Hz,2H),7.42–7.17(m,6H),7.03(dd,J=22.9,7.1Hz, 1H),6.89(d,J=7.6Hz,0.5H),4.96(m,1H),4.82(d,J=10.9Hz,1H),4.51(s,1H),4.47(d,J=7.1Hz,1H),4.41(d,J= 14.4Hz,1H),3.90(d,J=10.5Hz,1H),3.63(d,J=7.2Hz,1H),3.55(m,1H),3.49(m,1H),3.14(m,1H),3.04(d,J=4.3 Hz,3H),2.79(m,2H),2.10(d,J=7.7Hz,3H),2.04–1.93(m,1H),1.64(d,J=12.9Hz,1H),1.34(s,3H),1.23(s,3H).

[0393] Example 18

[0394] (R)-3-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-

[0395] Methyl-1-oxopropane-2-yl)carbamoyl)-1-methylpyridine-1-quaternary ammonium salt

[0396]

[0397] Step 1 (R)-3-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)amino)-2-

[0398] Preparation of methyl-1-oxopropan-2-yl)carbamoyl)-1-methylpyridine-1-ammonium chloride

[0399] Trigonelline hydrochloride (985 mg, 5.67 mmol) was dissolved in N,N-dimethylformamide (10 mL), and ibuprofen 1a (500 mg, 0.95 mmol), N,N-diisopropylethylamine (611 mg, 4.73 mmol), and 1-propylphosphonic anhydride (903 mg, 2.84 mmol) were added. The reaction was stirred at room temperature for 48 hours. After the reaction was completed, the reaction solution was directly purified by reverse-phase column chromatography (acetonitrile / water) to give (R)-3-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamoyl)-1-methylpyridine-1-quaternary ammonium salt 18 (352 mg, white solid), yield: 54%.

[0400] MS m / z (ESI): 648.3 [M+1] + .

[0401] 1 H NMR (400MHz, DMSO) δ9.61 (s, 2H), 9.09 (s, 1H), 8.92 (s, 1H), 8.39 (d, J = 8.1Hz, 0.5H), 8.15 (d, J = 7.9Hz, 1H), 7.36–7.19(m,7H),7.15(d,J=7.3Hz,0.5H),6.98(dt,J=12.9,6.9Hz,1H),4.93(m,1H),4.48(m,1H),4.44(d, J=12.9Hz,4H),3.89(m,3H),3.72(d,J=7.7Hz,2H),3.53(dd,J=9.2,5.5Hz,1H),3.46(dd,J=9.1,5.1Hz,1H) ,3.17(dd,J=25.6,12.3Hz,1H),3.04(s,3H),2.76(t,J=12.2Hz,1H),1.86(m,2H),1.64(s,2H),1.49(s,6H).

[0402] Example 19

[0403] (R,Z)-N-(3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-2-methyl

[0404] -2-((4-oxopen-2-en-2-yl)amino)propionamide

[0405]

[0406] first step

[0407] (R,Z)-N-(3-(benzyloxy)-1-(1-(methylsulfonyl)spiro[indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-2-

[0408] Preparation of methyl-2-((4-oxopen-2-en-2-yl)amino)propionamide

[0409] In a sealed tube, ibuprofen 1a (150 mg, 0.28 mmol) was dissolved in acetylacetone (2 mL). The sealed tube was placed in a microwave reactor and heated to 130 °C under microwave radiation of 150 W with stirring for 10 minutes. After the reaction was completed, the reaction solution was directly purified and separated using a reverse-phase column (acetonitrile / water (0.1% NH3)) to give (R,Z)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spirocyclic [indol-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-2-methyl-2-((4-oxopenten-2-en-2-yl)amino)propionamide 19 (48 mg, white solid), yield: 26%.

[0410] MS m / z(ESI): 611.3 [M+1] + .

[0411] 1 H NMR(400MHz,DMSO)δ8.15(d,J=8.2Hz,1H),8.07(d,J=8.3Hz,1H),7.43–7.15(m,7H),7.0 7(s,1H),7.00(s,1H),6.66(s,2H),5.34–5.29(m,1H),5.00(s,2H),4.51(s,1H),4.48(d, J=6.3Hz,1H),4.37(d,J=12.5Hz,2H),3.90(m,3H),3.19(m,2H),3.05(d,J=3.3Hz,3H),2. 00(dd,J=14.2,6.7Hz,2H),1.90(s,2H),1.80(d,J=7.7Hz,2H),1.44(s,3H),1.23(s,6H).

[0412] Example 20

[0413] (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxo-1--1-phenyl-2,10-dioxo-5,8-diazadodecaneundecylneovale ester

[0414]

[0415] first step

[0416] Preparation of ethyl 1-(((ethylthio)carbonyl)oxy)oxyneopentaate

[0417] O-(1-chloroethyl)S-ethyl carbonate (2 g, 11.90 mmol) was dissolved in 2,2-dimethylpropionic acid (7.29 g, 71.40 mmol), and N,N-diisopropylethylamine (4.61 g, 35.70 mmol) was added. The reaction mixture was reacted at 70 °C for 48 hours. After the reaction was complete, water (100 mL) and dichloromethane (3 x 50 mL) were added, and the mixture was extracted and separated. The organic phases were combined, washed with saturated sodium bicarbonate solution (3 x 50 mL), washed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. The solution was concentrated to give ethyl 1-(((ethylthio)carbonyl)oxy)oxypentanoate (1.20 g, yellow oil), yield: 39%.

[0418] 1 H NMR (400MHz, CDCl3) δ6.94-6.90(m,1H),2.90-2.84(m,2H),1.50(d,J=5.2Hz,3H),1.31(t,J=7.2Hz,3H),1.20(s,9H).

[0419] Step 2

[0420] Preparation of 1-((chlorocarbonyl)oxy)ethyl neopentanoate

[0421] Sulfonyl chloride (766 mg, 5.67 mmol) was slowly added to ethyl 1-(((ethylthio)carbonyl)oxy)oxypentanoate (665 mg, 2.84 mmol), and the reaction mixture was stirred at 0 °C for 5 minutes. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to obtain crude 1-((chlorocarbonyl)oxy)ethyl neopentanoate, which was directly added to the next reaction without purification.

[0422] Step 3: Preparation of (4R)-7,7-dimethyl-4-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxo-1--1-phenyl-2,10-dioxo-5,8-diazadodecaneundecyl neopentyl ester

[0423] (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide (200 mg, 0.72 mmol) and 1-((chlorocarbonyl)oxy)ethyl neopentanoate (600 mg, 1.12 mmol) were dissolved in dichloromethane (15 mL), followed by the addition of sodium hydroxide (272 mg, 6.80 mmol) in water (10 mL). The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative chromatography to prepare (4R)-7,7-dimethyl-4-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-6,9-dioxo-1--1-phenyl-2,10-dioxo-5,8-diazadodecaneundecyl neopentyl ester (79.0 mg, white solid), yield: 30%.

[0424] MS m / z (ESI): 400.1 [M+1] + .

[0425] 1 H NMR (400MHz, CDCl3) δ7.40-7.32(m,5H),7.29(s,1H),7.23-7.16(m,1H),7.10-7.02(m,1H),7.00-6.95(m,1H ),6.76-6.72(m,1H),6.63-6.61(m,1H),5.46-5.38(m,1H),5.21-5.10(m,1H),4.66-4.57(m,1H),4.55-4.45 (m,2H),4.11-3.97(m,1H),3.89-3.68(m,3H),3.62-3.56(m,1H),3.16-3.01(m,1H),2.91(d,J=3.6Hz,3H),2 .87-2.74(m,1H),1.93-1.82(m,1H),1.75-1.65(m,3H),1.62(br,s,3H),1.45(t,J=5.6Hz,3H),1.19(s,9H).

[0426] Example 21

[0427] (R)-5,5-dimethyl-8-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecylpentanoate

[0428]

[0429]

[0430] first step

[0431] Preparation of methyl terpentine

[0432] Pteropenic acid (1.65 g, 16.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and O-(chloromethyl)S-ethylthiocarbonate (500 mg, 3.23 mmol) was added, followed by N,N-diisopropylethylamine (1.25 g, 9.70 mmol). The reaction was stirred at 55 °C for 48 hours. After the reaction was complete, sodium bicarbonate solution (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to give methyl (((ethylthio)carbonyl)oxy)teropenic acid (600 mg, pale yellow oily liquid), yield: 80%.

[0433] 1 H NMR (400MHz, CDCl3) δ5.81 (s, 2H), 2.89 (q, J = 7.4Hz, 2H), 1.34 (d, J = 7.4Hz, 3H), 1.22 (s, 9H).

[0434] Step 2

[0435] Preparation of methyl ((chlorocarbonyl)oxy)terpentine

[0436] 400 mg (1.82 mmol) of methyl ((((ethylthio)carbonyl)oxy)pivalate) was placed in a round-bottom flask, and 1 mL of sulfonyl chloride was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was evaporated to obtain crude methyl ((chlorocarbonyl)oxy)pivalate (400 mg, brown solid). The crude product was directly added to the next step of the reaction without purification.

[0437] Step 3: Preparation of (R)-5,5-dimethyl-8-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecyl isobutyrate

[0438] Methyl ((chlorocarbonyl)oxy)pentanoate (400 mg, 2.06 mmol) was dissolved in dichloromethane (10 mL), and ibuprofen (200 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL). The solutions were combined, and water (5 mL) and 2N sodium hydroxide solution (0.2 mL) were added. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by preparative chromatography (acetonitrile:water (0.1% TFA)) to obtain (R)-5,5-dimethyl-8-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecylpentanate (50 mg, white solid), yield: 18%.

[0439] MS m / z (ESI) 687.3 [M+1] + .

[0440] 1 H NMR (400MHz, DMSO) δ7.82–7.69(m,1H),7.57(d,J=7.9Hz,0.5H),7.38–7.19(m,8H),7.06–6.96(m ,1H),6.88(d,J=7.5Hz,0.5H),5.59(s,2H),4.97(d,J=6.7Hz,1H),4.51(s,1H),4.47(d,J=4.3Hz ,1H),4.44–4.34(m,2H),3.70–3.62(m,1H),3.61–3.53(m,1H),3.50(dd,J=9.5,5.2Hz,1H),3.16 (dd,J=25.0,12.2Hz,2H),3.04(d,J=4.4Hz,3H),1.66(m,4H),1.34(s,6H),1.13(d,J=4.3Hz,9H).

[0441] Example 22

[0442] (R)-5,5-Dimethyl-8-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecyl acetate

[0443]

[0444] first step

[0445] Preparation of methyl ((((ethylthio)carbonyl)oxy)acetate)

[0446] Acetic acid (1.95 g, 32.5 mmol) was placed in a round-bottom flask, and O-(chloromethyl)S-ethyl thiocarbonate (1 g, 6.5 mmol) was added, followed by N,N-diisopropylethylamine (2.52 g, 19.5 mmol). The reaction was stirred at 55 °C for 48 hours. After the reaction was complete, sodium bicarbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to give methyl (((ethylthio)carbonyl)oxy)acetate (826 mg, pale yellow oily liquid), yield: 65%.

[0447] 1 H NMR (400MHz, CDCl3) δ5.80 (s, 2H), 2.90 (q, J = 7.4Hz, 2H), 2.13 (s, 3H), 1.36–1.32 (m, 3H).

[0448] Step 2

[0449] Preparation of ((chlorocarbonyl)oxy)acetic acid methyl ester

[0450] 200 mg (1.23 mmol) of methyl ((((ethylthio)carbonyl)oxy)acetate) was placed in a round-bottom flask, and 1 mL of sulfonyl chloride was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was evaporated to obtain crude methyl ((chlorocarbonyl)oxy)acetate (172 mg, pale yellow oily liquid). The crude product was directly added to the next step of the reaction without purification.

[0451] Step 3: Preparation of (R)-5,5-dimethyl-8-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecyl acetate

[0452] Methyl ((chlorocarbonyl)oxy)acetate (173 mg, 1.13 mmol) was dissolved in dichloromethane (10 mL), and epomolum (200 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL). The solutions were combined, and water (5 mL) and 2N sodium hydroxide solution (0.2 mL) were added. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 30 mL) and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by preparative chromatography (acetonitrile:water (0.1% FA)) to obtain (R)-5,5-dimethyl-8-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carbonyl)-3,6-dioxo-11-phenyl-2,10-dioxin-4,7-diazadodecyl acetate (45 mg, white solid), yield: 18%.

[0453] MS m / z (ESI) 645.3 [M+1] + .

[0454] 1 H NMR (400MHz, DMSO) δ7.81(d,J=7.9Hz,1H),7.73(d,J=13.8Hz,1H),7.62(d,J=8.2Hz,0.5H),7.34(t,J=3.5Hz,2H ),7.32–7.19(m,5H),7.07–6.96(m,2H),6.91(d,J=7.6Hz,0.5H),5.57(s,2H),5.00–4.94(m,1H),4.52(s,1H),4. 47(d,J=4.4Hz,1H),3.93–3.86(m,2H),3.70–3.63(m,1H),3.58(d,J=5.6Hz,1H),3.54–3.45(m,1H),3.17(d,J=1 2.1Hz,2H),3.04(d,J=3.7Hz,3H),2.79(d,J=10.7Hz,1H),2.04(d,J=5.0Hz,3H),1.74–1.59(m,4H),1.34(s,6H).

[0455] Example 23

[0456] (R)-3-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropane-2-yl)-

[0457] 2,2,5,5-Tetramethylimidazolin-4-one

[0458]

[0459] first step

[0460] The compound ibumolene 1a (1.056 g, 2 mmol) was dissolved in acetone (5 mL), and then potassium dihydrogen phosphate (54 mg, 0.4 mmol) was added. The mixture was stirred at 80 °C for 5 h. TLC monitoring showed that a new product spot was formed. The mixture was then cooled to room temperature and extracted three times with ethyl acetate / water. The final product was obtained by column chromatography (petroleum ether: ethyl acetate = 1:3) to give the target product 23 (1 g), yield: 87%.

[0461] MS m / z (ESI): 570.28 [M+1] + .

[0462] 1 H NMR (300MHz, DMSO-d6) δ7.40–7.19(m,8H),7.05(t,J=7.3Hz,1H),5.15(t,J=7.1Hz,1H),4.60-4.38(m,3H),3 .93-3.62(m,5H),3.04(s,3H),2,95-2.60(m,2H),1.92-1.80(m,1H),1.75-1.60(m,3H),1.45-1.15(m,12H).

[0463] Example 24

[0464] 3-[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospirocyclic[indol-3,4'-piperidine]-1'-yl}-1-oxopropane-2-yl]-5,5-

[0465] Dimethylimidazoline-2,4-dione

[0466]

[0467]

[0468] first step

[0469] Preparation of 3-[(2R)-3-(benzyloxy)-1-{1-methanesulfonyl-1,2-dihydrospirocyclic[indol-3,4'-piperidine]-1'-yl}-1-oxopropane-2-yl]-5,5-dimethylimidazoline-2,4-dione

[0470] Compound ibuprofen 1a (200 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (115 mg, 1.12 mmol) and ethyl chloroformate (30 mg, 0.13 mmol) were slowly added to the reaction solution, which was stirred at 25 °C for 2 hours. The residue obtained by concentration of the reaction solution was purified by preparative chromatography (acetonitrile / water) to give compound 24 (70 mg, white solid), yield: 33%.

[0471] MS m / z (ESI): 555.0 [M+1] + .

[0472] 1 H NMR(400MHz,MeOD)δ7.34-7.30(m,5H),7.28–7.19(m,2H),7.18–7.10(m,1H ),7.04(t,J=7.3Hz,1H),5.21(dd,J=9.5,5.3Hz,1H),4.59-4.48(m,3H),4.2 5(t,J=10.1Hz,1H),4.07–3.88(m,3H),3.81-3.79(m,1H),3.29–3.19(m,1H) ,2.96(s,3H),2.87-2.82(m,1H),1.85-1.75(m,4H),1.35(d,J=10.0Hz,6H).

[0473] Biological evaluation

[0474] Test Example 1: Determination of the activity of the compound of the present invention against human GHSR

[0475] This method is used to determine the agonistic effect of the compounds in this invention on the activity of human GHSR protein expressed in human GHSR / CHO stable cell line cells.

[0476] I. Experimental Materials and Instruments

[0477] 1. Culture medium

[0478] F12 (Gibco, Cat#11765-047);

[0479] FBS (Corning, Cat#35-076-CV);

[0480] Geneticin (Invitrogen, Cat#10131);

[0481] Penicillin / Streptomycin (Invitrogen, Cat#15140).

[0482] 2. Reagents

[0483] Fluo-4 Direct(Invitrogen,Cat#F10471);

[0484] HBSS(Gibco,Cat#14025076);

[0485] HEPES (Gibco, Cat#15630080);

[0486] Bonine Serum Albumin (Sgima, Cat#B2064-100G).

[0487] 3. Instrument Consumables

[0488] 384well Poly-D-Lysine protein coating plate (Greiner, Cat#781946);

[0489] FLIPR (Molecular Devices);

[0490] Vi-cell XR Cell Viability Analyzer (Beckman Coulter);

[0491] Incubator (Thermo).

[0492] II. Experimental Procedure

[0493] Compound gradient preparation: Ghrelin and the compound of the present invention were diluted 5 times to prepare 10 concentration gradients, and then transferred to compound plates, 900 nL per well.

[0494] Prepare the buffer solution: HBSS(1X):HEPES(1M) = 49:1, and add 0.5% BSA.

[0495] Cells containing the stable human GHSR / CHO transgenic line were seeded into 384-well plates. After overnight incubation, the cell culture plates were removed, the culture medium was discarded, and 20 μL of buffer was slowly added to each well. Then, 20 μL of 2X Fluo-4 Direct was added to each well. TMNo-wash loading buffer. Incubate the cell culture plate at 37°C with 5% CO2 for 50 min, then remove and let it sit at room temperature for 10 min. Add 30 μL of buffer to each well of the compound plate; prepare another buffer plate with 30 μL of buffer added to each well. For compound agonist testing: Use a FLIPR instrument and run the software. Transfer 10 μL of buffer to the cell culture plate and read the fluorescence signal value. Transfer 10 μL of the compound to the cell culture plate and read the fluorescence signal value. Use the FLIPR program to calculate the maximum-minimum value from the 91st signal point to the 230th signal point. EC5 of the compound. 50 The value can be obtained by software calculation using fluorescence values ​​corresponding to different concentrations.

[0496] III. Experimental Results:

[0497] The agonistic activity of the compound against human GHSR in this invention was determined through the above experiments, and the measured EC50 was... 50 The values ​​are shown in Table 1.

[0498] Table 1. Activation activity of compounds in this invention on human GHSR EC 50 value

[0499] Compound numbering <![CDATA[EC 50 (nM)]]> Ghrelin 1.36 1 15.6 5 14.6 10 151.7 12 35.9 14 47.2 15 4.3 16 9.8 17 24.5 18 15.1 19 24.3 20 37.7 21 18.3 22 9.3

[0500] IV. Experimental Conclusions:

[0501] The above data show that the compound of the present invention has good agonistic activity against human GHSR.

[0502] Test Example 2: In vivo pharmacodynamic testing of the compounds of the present invention in rats.

[0503] In humans and rodents, growth hormone is stimulated by growth hormone-releasing hormone (GHRH), secreted from the pituitary gland into the circulation, and acts on liver tissue to produce effector factors such as insulin-like growth factor-1 (IGF-1), thereby exerting metabolic regulatory effects such as promoting growth and development. Therefore, a male rat model (to avoid inter-individual differences introduced by the physiological cycle of female rats) was used as a test compound to promote the GH / IGF-1 signaling pathway and to evaluate the effect of the compound of the present invention on the circulating level of growth hormone (GH).

[0504] Juvenile male Sprague-Dawley (SD) rats (60-80g) were purchased from Liaoning Changsheng Biotechnology Co., Ltd. (Liaoning, China). All animals were housed in cages of three in a temperature-controlled room (22±2℃) and 55±15% relative humidity, with a 12 / 12-hour light / dark cycle (lights were turned off at 8:00 PM). After arrival, the animals were allowed one week to acclimatize to their new environment, with free access to labeled feed and sterilized water. Cage bedding was changed twice weekly. The day before the study, the animals were fasted for 14 hours, but access to drinking water was permitted.

[0505] ibutamoren and the compounds of the present invention were prepared in 10% HS15 and administered at a dose of 4 mpk, corresponding to the molar concentrations of ibutamoren (6.4 nmol / kg), compound 5 (5.8 nmol / kg), and compound 14 (6.1 nmol / kg).

[0506] Following baseline sampling (at 0 minutes), rats were orally administered the compound of this invention. Blood samples were then collected at multiple time points (15 minutes, 30 minutes, and 60 minutes) after administration. Blood samples were obtained via the ophthalmic venous plexus, collected into EP tubes containing heparin sodium, and immediately centrifuged. Plasma samples were collected and stored at -80°C until assay. GH levels in the plasma of each experimental animal were detected using an enzyme-linked immunosorbent assay kit from MERK-Rat / Mouse Growth Hormone ELISA (USA).

[0507] Experimental results:

[0508] The effects of the compounds of this invention on the circulating GH levels in SD rats are shown in Table 2.

[0509] Table 2. Effects of compounds on GH concentration in rats.

[0510]

[0511] Experimental conclusion:

[0512] When tested in male rats as described above, compounds 5 and 14 of the present invention significantly increased the circulating GH level in rats 15 minutes after administration, achieving the same efficacy at a lower concentration than ibutamoren. Compound 14 was significantly superior to ibutamoren.

[0513] Test Example 3: Caco-2 Cell Transport Experiment

[0514] The transport buffer used in this study was HBSS containing 10.0 mM HEPSS, pH 7.40 ± 0.05. Assay compounds were tested bidirectionally at 2.00 μM, with a final DMSO concentration required to be less than 1%. Cell plates were incubated at 37 ± 1 °C in a CO2 incubator under 5% CO2 and saturated humidity for 2 hours. All samples were mixed with acetonitrile containing an internal standard and centrifuged at 3200 x g for 10 minutes. For the test compounds, 100 μL of the supernatant was diluted with 100 μL of ultrapure water for LC-MS / MS analysis. The concentrations of the test compounds and control compounds (Digoxin as the model validation compound and ibutamoren as the positive control) in the starting, donor, and receiver solutions were quantified by LC-MS / MS using the analyte / internal standard peak area ratio. After the transport assay, fluorescein yellow rejection assay was used to determine the integrity of the Caco-2 cell monolayer.

[0515] Table 3-1 Cell transport experiments of compound 5Caco-2 of the present invention

[0516]

[0517] Table 3-2 Cell transport experiments of compound 19Caco-2 of the present invention.

[0518]

[0519] Experimental conclusion:

[0520] The data above show that the model was successfully constructed, and the cell permeability of the compound of this invention is significantly better than that of the reference compound ibutamoren.

[0521] Test Example 4: Subacute Toxicity Test in Rats

[0522] Male Sprague-Dawley (SD) rats (180-220g) were purchased from Liaoning Changsheng Biotechnology Co., Ltd. (Liaoning, China). All animals were housed in cages of three in a temperature-controlled room (22±2℃) and 55±15% relative humidity, with a 12 / 12-hour light / dark cycle (lights were turned off at 8:00 PM). After arrival, the animals were allowed one week to acclimate to their new environment, with free access to labeled feed and sterilized water. Cage bedding was changed twice weekly.

[0523] The compound of the present invention was formulated in 10% HS15.

[0524] Rats were orally administered multiple doses (30 mpk, 100 mpk, and 300 mpk) of the compound of the present invention. The administration was once daily for 14 consecutive days, with rat body weight measured twice weekly. After administration, all rats underwent a 14-day recovery period, with rat body weight measured twice weekly. Compound 5 was administered by gavage for 14 consecutive days. After a 2-week recovery period, there were no significant abnormalities in food intake, daily behavior, or body weight changes among the groups. Figure 1 The autopsy revealed no abnormalities visible to the naked eye.

[0525] Experimental results:

[0526] The changes in body weight of rats in each group are shown in the attached figure. Figure 1 As shown.

[0527] Experimental conclusion:

[0528] The above data show that no obvious abnormalities were observed in the subacute toxicity test of compound 5 in rats at 80 times the administered dose, indicating that compound 5 has good safety.

[0529] Comparison of test example 5 and compound 5 in vivo metabolism experiment in rats

[0530] Compound 5 was designed as a prodrug and its amount of active ingredient ibutamoren was tested in rats to evaluate the advantages and disadvantages of the candidate and the positive control ibutamoren.

[0531] Experimental procedure:

[0532] Six animals underwent a first fasting period two days prior to drug administration, lasting at least 12 hours, followed by a uniform feeding. A second fasting period of at least 12 hours was implemented the day before drug administration, with feeding resumed 4 hours after drug administration. Each fasting period did not exceed 20 hours. Free access to water was provided during this time. Two days prior to drug administration, the same person in charge conducted acclimatization training on the animals by touching and handling them, at least once a day.

[0533] Before the first administration, the animals were divided into two groups based on their body weight. Each group consisted of three animals. Group 1 animals were administered compound 5 via a single gavage solution (preparation method: medium-chain triglycerides / polyethylene glycol 1000 vitamin E succinate / ethanol / propylene glycol / water = 6 / 2 / 1 / 1 / 90, 1 mg / mL); Group 2 animals were administered ibutamoren via a single gavage solution (water, 1 mg / mL, prepared using ibutamoren mesylate). The administration volume for both groups was 3 mL / kg. Animal weight was measured before administration, and the administration volume was calculated based on body weight.

[0534] Sample collection time: before administration (approximately -0.25 h) and 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 5, 7, and 10 h after administration; at each specified time point, animals were briefly anesthetized with isoflurane, and whole blood samples (approximately 0.23 mL per group) were collected by jugular vein puncture. Quantitatively, 50 μL of whole blood sample was taken and added to an EP tube containing 50 μL of pre-cooled 1 mM PMSF methanol solution. The tube was vortexed for ~3 s, and immediately 250 μL of precipitant containing internal standard was added. The tube was vortexed for ~5 s, centrifuged for 15 min, and the supernatant was collected for LC-MS / MS analysis.

[0535] Experimental results:

[0536] Table 4. Data from drug metabolism experiments in rats

[0537]

[0538] Experimental conclusion:

[0539] The above data show that, in the drug metabolism experiment of compound 5 of the present invention administered by gavage to rats, Cmax and AUC were significantly better than those of the positive control ibutamoren, indicating better drug-like properties.

[0540] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of Formula II, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Formula II in, The Rc1 is a group optionally substituted with one, two or more Rd groups, such as (C1-C1). 12 aliphatic hydrocarbon group or C 3-12 cycloalkyl; The Rc2 is H, a halogen, or optionally substituted with one, two, or more halogens (C1-C2). 12 Aliphatic hydrocarbon groups; Each of the Rd groups is independently selected from halogens, CN, OH, SH, =O (oxo), and NH2; R1, R2, R3, and R4 may be the same or different, each independently selected from H, and optionally substituted with one, two, or more halogens (C1-C4). 12 Aliphatic hydrocarbon groups; The R' and R'' are each independently selected from H, halogen, CN, or (C1-C) 12 Aliphatic hydrocarbon groups; The n and m are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound represented by Formula II according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The "(C1-C" 12 "Aliphatic hydrocarbon group" is selected from (C1-C 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 ) yyn group.

3. The compound represented by Formula II according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The (C1-C) 12 The aliphatic hydrocarbon group is selected from (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)ynyl.

4. The compound represented by Formula II according to any one of claims 1-3, its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound of formula II is of formula III as follows: Formula III Rc1 and Rc2 are defined as in any one of claims 1-3.

5. The compound represented by Formula II according to any one of claims 1-3, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound of formula II is of formula IIIA and formula IIIB as follows: Formula IIIA Formula IIIB Rc1 and Rc2 are defined as in any one of claims 1-3.

6. The compound represented by Formula II according to any one of claims 1-3, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The Rc1 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkyl optionally substituted with one, two or more NH2; The Rc2 is selected from H or C1-C6 alkyl groups.

7. The compound of Formula I according to any one of claims 1-3, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, Rc1 is selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, aminomethyl, 1,5-diaminon-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

8. The compound represented by Formula I according to claim 7, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The Rc2 is selected from H or methyl.

9. A compound, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The structure is as follows: 。 10. The compound represented by Formula II according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The structure is as follows: 。 11. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound according to any one of claims 1-10, its racemate, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

12. The use of the compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, or the pharmaceutical composition of claim 11, in the preparation of a GHSR agonist or in the preparation of a medicament for the diagnosis, prevention, and / or treatment of growth hormone-dependent diseases or conditions.

13. The use according to claim 12, characterized in that, The disease or condition is related to growth hormone deficiency or growth hormone dependence.

14. The use according to claim 12, characterized in that, The compound represented by Formula II, its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, can promote growth hormone levels in plasma in humans and animals after administration.

15. The use according to claim 12, characterized in that, The intended use is for the preparation of a drug for diagnosing growth hormone deficiency.

16. The use according to claim 13, wherein the disease or condition is slow growth or short stature in children.

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