Cysteine derivative, use thereof as expectorant, and pharmaceutical composition thereof

Abstract

Provided in the present disclosure is the use of a compound as represented by formula I, or a stereoisomer, deuterated compound, pharmaceutically acceptable salt or solvate thereof in the preparation of a drug, wherein the drug is a drug having a mucolytic function.

Description

Cysteine ​​derivatives, their use as expectorants, and pharmaceutical compositions thereof Technical Field

[0001] This disclosure relates to the field of biochemistry, specifically to a cysteine ​​derivative, a pharmaceutical composition, and its use as an expectorant. Background Technology

[0002] Patients with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and bronchial asthma often experience hyperplasia and hypertrophy of the respiratory mucosal glands, leading to increased mucus secretion and a tendency for sputum retention. Rapid clearance of accumulated secretions is often necessary to maintain airway patency and correct hypoxia. Because sputum can form clumps that obstruct the airways, continuous or intermittent nebulization of expectorants is commonly used clinically to humidify the respiratory tract, dissolve and dilute the sputum, quickly clear it, and alleviate clinical symptoms.

[0003] Mucus is a mixture of mucin secreted by goblet cells in the trachea and bronchi, and water, carbohydrates, proteins, lipids, and minerals secreted by submucosal glands. Water accounts for 97% of the mixture, while solids make up 3%. Mucin is a large glycoprotein rich in serine and threonine residues, linked to sugar chains via hydroxyl groups, and accounts for less than 30% of the solids. Mucin is 50-90% carbohydrate, with most terminal sugars containing carboxyl or sulfate groups, making it highly anionic. Secretory mucin is rich in cysteine ​​domains at its terminals, enabling the formation of disulfide bonds, thus forming polymers with gel-like properties (Mary Callaghan Rose, Judith A Voynow. Physiol Rev. 2006 Jan; 86(1):245-78). MUC5AC and MUC5B are highly expressed in the airways. In healthy individuals, MUC5AC is mainly produced by surface goblet cells in the proximal airways, while MUC5B is produced by surface secretory cells and submucosal glands throughout the airways. Under pathological conditions, the secretion of mucin and non-mucin polymers (such as DNA) increases, mucin polymers undergo lateral cross-linking, and various mechanisms such as hydration and biochemical components change.

[0004] Mucus, with its adhesive and viscoelastic properties, plays a crucial role in lung and airway defense. This gel-like layer traps and clears bacteria, inhibits bacterial and biofilm formation, and prevents inhaled irritants and fluid loss. The mucus secretion and clearance process is an important lung defense mechanism, involving the capture of pathogens and particles, which are then cleared through the coordinated action of cough and cilia (Paola Rogliani, Gian Marco Manzetti, Shima Gholamalishahi. Int J Chron Obstruct Pulmon Dis. 2024 Oct 29:19:2347-2360.). Under the influence of various pathogenic factors such as smoking, infection, and oxidative stress, the airways can produce a large number of secretory factors that act on secretory cells, leading to hypertrophy and hyperplasia of airway goblet cells and the production of excessive mucus (John V. Fahy, Burton F. Dickey. N Engl J Med. 2010 Dec 2; 363(23):2233–2247). When mucus secretion increases and inflammation reduces ciliary clearance, resulting in insufficient coughing ability, mucus cannot be effectively expelled and accumulates in the airways, forming sputum together with oral, nasal, and pharyngeal secretions and cell debris. High airway mucus secretion and ciliary dysfunction are characteristic pathophysiological changes in chronic obstructive pulmonary disease, asthma, and bronchiectasis. The main clinical manifestations include chronic cough, sputum production, chest tightness, and dyspnea. In severe cases, it can obstruct the airways and even endanger life. Data from 2019 shows that chronic respiratory diseases, including asthma and chronic obstructive pulmonary disease, are the third leading cause of death worldwide, causing approximately 4 million deaths annually. (Michela Abrami, Alice Biasin, Fabiana Tescione. Int J Mol Sci. 2024 Feb 5; 25(3):1933).

[0005] Expectorants can be classified into the following categories: (a) mucodynamic drugs that improve ciliary function, such as ambroxol; (b) mucolytic drugs that reduce secretory viscosity by adding water to the airway (expectorants and ion channel modulators), dissociating the mucoprotein network (classic mucolytics), breaking down abnormal polymers in mucus (including DNA and filamentous actin), or dispersing polymers through charge shielding, such as acetylcysteine, calitone, erdosteine, and DNase; (c) mucolytic drugs that reduce excessive mucus production, such as roflumilast; and (d) drugs that improve cough clarity by increasing airflow or reducing mucus, such as salbutamol (Advanced Drug Delivery Reviews 54 (2002) 1475–1490). Among these, mucolytics work by opening the disulfide bonds (SS) of high molecular weight glycoproteins in mucus through the presence of free thiol groups (-SH), preventing them from participating in the cross-linking of the mucus gel layer and thus reducing the viscoelasticity of the mucus. Inhalation is the preferred route of administration for achieving mucus dissolution. NAC (N-acetylcysteine) is currently the only approved and widely used inhaled mucolytic agent. However, due to its low reducing activity and slow rate of disulfide bond reduction, NAC often requires high concentrations to have a noticeable effect on mucus dissolution. Furthermore, high concentrations may cause side effects such as bronchoconstriction (Ehre C. Am J Respir Crit Care Med 2018; 199:171–180). In addition, NAC is also used as an antidote for acetaminophen poisoning and as an antioxidant to increase glutathione levels in the body.

[0006] Currently, small molecule mucolytics such as MUC031, P2119, and P3001 are under development, and preclinical studies have shown that they have superior mucolytic effects compared to NAC. Developing novel mucolytics with stronger activity, faster onset of action, and fewer adverse drug reactions is of great significance for improving treatment efficacy and enhancing the quality of life for patients with chronic respiratory diseases. Summary of the Invention

[0007] To address the aforementioned problems, this disclosure provides a class of compounds or compositions with mucus-dissolving properties, offering new possibilities for the development of expectorant drugs.

[0008] This disclosure first provides the use of the compound of Formula I, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, solvates (e.g., hydrates), in the preparation of a medicament having mucolytic properties;

[0009] in,

[0010] Indicates a chemical single or double bond;

[0011] X is selected from O or NH;

[0012] R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups;

[0013] R 2 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0014] R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0015] R 4 Selected from hydrogen, hydroxyl, or amino;

[0016] R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

[0017] In some embodiments of this disclosure, the compound represented by Formula I is as shown in Formula II:

[0018] Among them, X and R 1 R 2 R 3 R 4 R 5 The definition is as described above.

[0019] In some embodiments of this disclosure, in compounds of formula I or II, X is selected from O; R 1 Selected from hydrogen.

[0020] In some embodiments of this disclosure, the compounds represented by Formula I or Formula II are shown in Formulas IIIA to IIID as follows:

[0021] in,

[0022] R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 2 Selected from hydroxylated methyl groups;

[0023] R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R3 Selected from hydroxylated methyl groups;

[0024] R 4 Selected from hydroxyl or amino groups;

[0025] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0026] In some embodiments, in the compounds represented by Formula I, Formula II, or Formulas IIIA to IIID,

[0027] R 2 Selected from hydrogen, oxygen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted n-propyl, or hydroxy-substituted isopropyl; preferably, R 2 Methyl group selected from those substituted with hydrogen, oxygen, or hydroxyl groups;

[0028] R 3 Selected from hydrogen, oxygen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted n-propyl, or hydroxy-substituted isopropyl; preferably, R 3 Methyl group selected from hydrogen, oxygen, hydroxyl, or hydroxyl-substituted methyl groups;

[0029] R 4 Selected from hydrogen, hydroxyl or amino; preferably, R 3 and R 4 Not both hydroxyl groups;

[0030] R 5 Selected from hydrogen, methyl, ethyl; preferably R 5 It is hydrogen.

[0031] In some embodiments, in the compounds represented by Formula I and Formula II,

[0032] With R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, or hydroxylated isopropyl; preferably, with R 3 Connected Indicates a double bond and R 3 For oxygen; or with R3 Connected Indicates a single bond and R 3 Methyl group selected from hydrogen, hydroxyl, or hydroxyl-substituted methyl groups;

[0033] With R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, or hydroxylated isopropyl; preferably, with R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from methyl groups substituted with hydrogen or hydroxyl groups;

[0034] R 4 Selected from hydrogen, hydroxyl or amino; preferably, R 3 and R 4 Not both hydroxyl groups;

[0035] R 5 Selected from hydrogen, methyl, ethyl; preferably R 5 It is hydrogen.

[0036] In some embodiments, in the compounds represented by Formula I and Formula II,

[0037] With R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or -CH(CH3)CH2OH; preferably, with R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, or -CH2OH;

[0038] With R 2 Connected Indicates a double bond and R 2 For oxygen; or with R2 Connected Indicates a single bond and R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or -CH(CH3)CH2OH; preferably, with R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen or -CH2OH;

[0039] R 4 Selected from hydrogen, hydroxyl or amino; preferably, R 3 and R 4 Not both hydroxyl groups;

[0040] R 5 Selected from hydrogen, methyl, ethyl; preferably R 5 It is hydrogen.

[0041] In some embodiments, in the compounds represented by Formula I and Formula II,

[0042] With R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, or -CH2OH;

[0043] With R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen or -CH2OH;

[0044] R 4 Selected from hydrogen, hydroxyl, or amino, and R 3 and R 4 Not both hydroxyl groups;

[0045] R 5 It is hydrogen.

[0046] In some embodiments, the compound represented by Formula I or Formula II is a compound of Formula IV:

[0047] in, Indicates a single bond or a double bond;

[0048] R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or -CH(CH3)CH2OH (preferably, R 2 (for hydrogen or -CH2OH);

[0049] R 3 Selected from hydrogen, oxygen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(CH3)CH2OH (preferably, Indicates a double bond and R 3 For oxygen, or Indicates a single bond and R 3 (For hydrogen or hydroxyl);

[0050] R 4 Selected from hydrogen or hydroxyl (preferably, R) 3 and R 4 (Not both hydroxyl groups).

[0051] In some specific embodiments of this disclosure, the compounds represented by Formula I, Formula II, or Formulas IIIA to IIID are specifically:

[0052] In some embodiments of this disclosure, the drug with mucolytic function is a drug that treats a disease of mucus accumulation in the airway or eyes of a subject by reducing mucus elasticity or mucus viscosity; preferably, the drug with mucolytic function is an expectorant (also known as an "expectorant").

[0053] In some embodiments of this disclosure, the subject has mucus accumulation in his / her airway.

[0054] In some embodiments of this disclosure, the airway is located in the upper respiratory tract of the subject; preferably, the airway is located in the nasal passage, paranasal sinuses, pharynx, and / or larynx of the subject.

[0055] In some embodiments of this disclosure, the airway is located in the lower respiratory tract of the subject; preferably, the airway is located in the trachea, main bronchus, lobar bronchus, segmental bronchus, subsegmental bronchus, conductive bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, alveolar sacs, or alveoli of the subject.

[0056] In some specific embodiments of this disclosure, the diseases mentioned are chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), asthma, chronic asthma, acute asthma, bronchitis, chronic bronchitis, bronchiectasis, traction bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, pneumonia, mechanical ventilation-related lung injury, sinusitis, chronic rhinitis, acute sinusitis, chronic sinusitis, chronic sinusitis with nasal polyps, chronic sinusitis without nasal polyps, nasal discharge or posterior nasal drip.

[0057] In some embodiments of this disclosure, the subject has mucus accumulation in his / her eyes.

[0058] In some specific embodiments of this disclosure, the disease is filamentous keratitis, keratitis xerotica, dry eye syndrome, blepharitis, or conjunctivitis.

[0059] This disclosure also provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, a solvate (e.g., a hydrate), and a pharmaceutically acceptable carrier;

[0060] in,

[0061] Indicates a chemical single or double bond;

[0062] X is selected from O or NH;

[0063] R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups;

[0064] R 2 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0065] R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0066] R 4 Selected from hydrogen, hydroxyl, or amino;

[0067] R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

[0068] In some embodiments of this disclosure, the compound represented by Formula I in the composition is represented by Formula II:

[0069] Among them, X and R 1 R 2 R 3 R 4 R5 The definition is as described above.

[0070] In some embodiments of this disclosure, the compounds of formula I or II in the composition are represented by formulas IIIA to IIID as follows:

[0071] in,

[0072] R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 2 Selected from hydroxylated methyl groups;

[0073] R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 3 Selected from hydroxylated methyl groups;

[0074] R 4 Selected from hydroxyl or amino groups;

[0075] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0076] In some embodiments, in the compounds represented by Formula I, Formula II, or Formulas IIIA to IIID,

[0077] R 2 Selected from hydrogen, oxygen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxy-substituted methyl, hydroxyl-substituted (e.g., 1-2 hydroxyl groups) ethyl, hydroxyl-substituted (e.g., 1-3 hydroxyl groups) n-propyl, or hydroxyl-substituted (e.g., 1-3 hydroxyl groups) isopropyl; preferably, R 2 Methyl group selected from those substituted with hydrogen, oxygen, or hydroxyl groups;

[0078] R 3 Selected from hydrogen, oxygen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxy-substituted methyl, hydroxyl-substituted (e.g., 1-2 hydroxyl groups) ethyl, hydroxyl-substituted (e.g., 1-3 hydroxyl groups) n-propyl, or hydroxyl-substituted (e.g., 1-3 hydroxyl groups) isopropyl; preferably, R3 Methyl group selected from hydrogen, oxygen, hydroxyl, or hydroxyl-substituted methyl groups;

[0079] R 4 Selected from hydrogen, hydroxyl or amino; preferably, R 3 and R 4 Not both hydroxyl groups;

[0080] R 5 Selected from hydrogen, methyl, ethyl; preferably R 5 It is hydrogen.

[0081] In some embodiments, in the compounds represented by Formula I and Formula II,

[0082] With R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, or hydroxylated isopropyl; preferably, with R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Methyl group selected from hydrogen, hydroxyl, or hydroxyl-substituted methyl groups;

[0083] With R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, or hydroxylated isopropyl; preferably, with R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from methyl groups substituted with hydrogen or hydroxyl groups;

[0084] R 4 Selected from hydrogen, hydroxyl or amino; preferably, R 3 and R 4 Not both hydroxyl groups;

[0085] R 5Selected from hydrogen, methyl, ethyl; preferably R 5 It is hydrogen.

[0086] In some embodiments, in the compounds represented by Formula I and Formula II,

[0087] With R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or -CH(CH3)CH2OH; preferably, with R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, or -CH2OH;

[0088] With R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or -CH(CH3)CH2OH; preferably, with R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen or -CH2OH;

[0089] R 4 Selected from hydrogen, hydroxyl or amino; preferably, R 3 and R 4 Not both hydroxyl groups;

[0090] R 5 Selected from hydrogen, methyl, ethyl; preferably R 5 It is hydrogen.

[0091] In some embodiments, in the compounds represented by Formula I and Formula II,

[0092] With R 3 Connected Indicates a double bond and R 3 For oxygen; or with R 3 Connected Indicates a single bond and R 3 Selected from hydrogen, hydroxyl, or -CH2OH;

[0093] With R 2 Connected Indicates a double bond and R 2 For oxygen; or with R 2 Connected Indicates a single bond and R 2 Selected from hydrogen or -CH2OH;

[0094] R 4 Selected from hydrogen, hydroxyl, or amino, and R 3 and R 4 Not both hydroxyl groups;

[0095] R 5 It is hydrogen.

[0096] In some embodiments, the compound represented by Formula I or Formula II is a compound of Formula IV:

[0097] in, Indicates a single bond or a double bond;

[0098] R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or -CH(CH3)CH2OH (preferably, R 2 (for hydrogen or -CH2OH);

[0099] R 3 Selected from hydrogen, oxygen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(CH3)CH2OH (preferably, Indicates a double bond and R 3 For oxygen, or Indicates a single bond and R 3 (For hydrogen or hydroxyl);

[0100] R 4 Selected from hydrogen or hydroxyl (preferably, R) 3 and R 4 (Not both hydroxyl groups).

[0101] In some embodiments of this disclosure, the compounds represented by Formula I, Formula II, or Formulas IIIA to IIID in the composition are specifically:

[0102] In some embodiments of this disclosure, the pharmaceutically acceptable carrier is a pulmonary drug carrier.

[0103] In some embodiments of this disclosure, the pulmonary drug carrier is a pulmonary drug liquid or a pulmonary drug powder (i.e., the carrier is in liquid or powder form).

[0104] In some embodiments of this disclosure, the pulmonary drug fluid comprises a polar liquid, and the compound is dissolved or suspended in the polar liquid; preferably, the polar liquid is water.

[0105] In some embodiments of this disclosure, the composition is contained within a pulmonary drug delivery device.

[0106] In some embodiments of this disclosure, the pulmonary drug delivery device is a pulmonary drug nebulizer, a pulmonary drug soft fog inhaler, a pulmonary drug dry powder inhaler, or a pulmonary drug pressurized metering inhaler.

[0107] This disclosure also provides compounds, or stereoisomers thereof, deuterated compounds, pharmaceutically acceptable salts, and solvates, as shown below: Attached Figure Description

[0108] Figure 1 shows the results of the DTNB method in Test Example 1 for testing the breaking of disulfide bonds in the compound disclosed herein.

[0109] Figure 2 shows the test results of the disclosed compound reducing egg white viscosity in Test Example 3.

[0110] Figure 3 shows the test results of the disclosed compound reducing sputum viscosity in Test Example 4.

[0111] Figure 4 shows the efficacy test results of the mouse asthma model in Test Example 5.

[0112] Invention Details

[0113] Regarding the definitions of terms used in this disclosure: Unless otherwise stated, the initial definitions provided herein apply to the group or term throughout the specification; for terms not specifically defined herein, their meanings should be given based on the disclosure and context, as would be the meanings that a person skilled in the art would assign to them. Unless stated to the contrary, the terms used in the specification and claims have the following meanings. It should be noted that this application is supported by the Sichuan Provincial Science and Technology Program.

[0114] The compounds and derivatives provided in this disclosure may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems.

[0115] The term "stereoisomer" in this application refers to compounds having the same chemical structure but different spatial arrangements of atoms or groups. The compounds disclosed herein may contain asymmetric centers or chiral centers, thus exhibiting different stereoisomers. All stereoisomeric forms of the compounds disclosed herein, including but not limited to conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, blocked rotation isomers, and mixtures thereof, such as racemic mixtures, constitute a part of this disclosure. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. These stereoisomers have the same chemical structure, but their stereostructures differ. "Stereoisomer" includes enantiomers or diastereomers. Specific stereoisomers may be enantiomers, and mixtures of isomers are generally referred to as enantiomer mixtures.

[0116] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I mentioned in the groups and compounds described in this application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen mentioned in the groups and compounds described in this application may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 127 iodine, 129 Iodine and 131 Iodine. The “deuterated compound” disclosed herein refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0117] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups; or the replacement of lone pairs of electrons of atoms in a molecule by other atoms or groups.

[0118] "Optional" or "optionally" means that the event or condition described below may but may not occur, and the description includes both cases where the event or condition occurs and cases where it does not occur. For example, "optionally substituted" includes both substituted and unsubstituted. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but may not be present, and the description includes both cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0119] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes. For example, the prefixes Ca to Cb alkyl indicate any alkyl group containing "a" to "b" carbon atoms. Therefore, C1 to C6 alkyl refers to alkyl groups containing 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms.

[0120] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with multiple carbon atoms, preferably an alkyl group with 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), more preferably an alkyl group with 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The alkyl group may optionally be further substituted by one or more substituents. The alkyl group may also be part of other groups, such as -O (C1 to C6 alkyl).

[0121] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of member atoms. Ca–Cb alkylene refers to an alkylene group having a to b carbon atoms; for example, C1–C6 alkylene refers to an alkylene group containing 1, 2, 3, 4, 5, or 6 carbon atoms. Alkylene groups include branched and straight-chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structures: Similarly, -CH2- or -(CH2) n - can also represent a straight-chain alkylene structure, for example, -(CH2)2- represents ethylene.

[0122] An acyl group is a structure formed by a carbonyl functional group attached to a hydrogen atom or a substituent group, and can be written as -COR'. In this disclosure, R' represents alkyl, alkenyl, alkynyl, etc. C1 to C6 acyl groups refer to carbonyl functional groups having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of acyl groups include formyl, acetyl, propionyl, and butyryl.

[0123] "Alkoxy" refers to a group formed by the attachment of an alkyl group to an oxygen atom. The definition of alkyl is the same as that of "alkyl" as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkoxy group may optionally be further substituted by one or more substituents.

[0124] The terms "-OR", "-N(R)2", etc., used in this disclosure refer to R groups being connected to oxygen or nitrogen atoms by a single bond.

[0125] The term “=O” in this disclosure refers to an oxygen atom replacing two hydrogen atoms in a molecule through a double bond.

[0126] In this disclosure, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond.

[0127] The functional group described in this disclosure It is used to describe the position of the substituent group.

[0128] In this disclosure, "amino" refers to -NH2.

[0129] When the “alkyl”, “alkoxy”, “carbocyclic”, “alkenyl”, “alkynyl”, “aromatic”, “aromatic heterocyclic”, and “heterocyclic” mentioned above are substituted, they may optionally be further substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C1-6 alkylamino, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-10 aryl, and C5-10 heteroaryl.

[0130] The term "hydroxyl-substituted C1-C6 alkyl" as used herein refers to a group formed by replacing one or more hydrogen atoms on one or more C atoms with one or more hydroxyl groups (e.g., 1-5, 1-4, 1-3, 1-2 or 1), including, for example, hydroxymethyl, hydroxyethyl, etc.

[0131] The term "pharmaceutically acceptable" means that certain carriers, delivery systems, diluents, excipients, and / or the salts formed therefrom are generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0132] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkyl ammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds, or their stereoisomers, with an appropriate (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium.

[0133] The term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the disease develops, but also prevention of disease recurrence after treatment.

[0134] The term “treatment” means to reverse, alleviate or eliminate the progression of one or more symptoms of a disease or condition to which such term is applied.

[0135] Unless otherwise stated, the terms “comprise”, “comprises”, and “comprising” or their equivalents (contain, contain, containing, include, include, including) used herein are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0136] Unless otherwise stated, all figures used herein to represent amounts of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0137] Unless the context clearly indicates otherwise, singular terms in this document cover the plural referents, and vice versa.

[0138] The term “subject” is used interchangeably with “patient” and “individual” and refers to a human or a non-human animal (e.g., a mammal, such as a non-human primate, rodent, etc.), such as a mouse, rat, cat, dog, pig, sheep, cow, goat, horse, rabbit, and monkey.

[0139] In some embodiments, one or more compounds of this disclosure may be used in combination with each other. Alternatively, the compounds of this disclosure may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0140] In a first aspect of this disclosure, the use of a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, or a solvate (e.g., a hydrate) in the preparation of a medicament having mucolytic properties is provided.

[0141] in,

[0142] Indicates a chemical single or double bond;

[0143] X is selected from O or NH;

[0144] R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups;

[0145] R 2 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0146] R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0147] R 4 Selected from hydrogen, hydroxyl, or amino;

[0148] R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

[0149] Those skilled in the art should be able to do so based on R 2 To choose by definition It is a chemical single or double bond; for example, R 2 When it is hydrogen, It should be a chemical single bond; for example, R 2 When it is oxygen, It should be a chemical double bond.

[0150] In some embodiments, this disclosure provides compounds of Formula I, or stereoisomers thereof, deuterated compounds, pharmaceutically acceptable salts, or solvates (e.g., hydrates) for use as medicaments with mucolytic functions.

[0151] In some embodiments, this disclosure provides compounds of Formula I, or stereoisomers thereof, deuterated compounds, pharmaceutically acceptable salts, and solvates (e.g., hydrates) for use in dissolving mucus.

[0152] In some embodiments, this disclosure provides a method for dissolving mucus in a subject in need, comprising administering to the subject a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, or a solvate (e.g., a hydrate). In some embodiments, this disclosure provides a method for treating a disease of mucus accumulation in the airways or eyes in a subject in need, comprising administering to the subject a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, or a solvate (e.g., a hydrate).

[0153] In some embodiments of this disclosure, the compound represented by Formula I is as shown in Formula II:

[0154] in,

[0155] Indicates a chemical single or double bond;

[0156] X is selected from O or NH;

[0157] R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups;

[0158] R 2 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0159] R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0160] R 4 Selected from hydrogen, hydroxyl, or amino;

[0161] R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

[0162] In some embodiments of this disclosure, in compounds of formula I or II, X is selected from O; R 1 X is selected from hydrogen; in other embodiments of this disclosure, in compounds of formula I or II, X is selected from NH; R 1 Selected from hydrogen.

[0163] In some embodiments of this disclosure, the compounds represented by Formula I or Formula II are shown in Formula IIIA below:

[0164] in,

[0165] R 3Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 3 Selected from hydroxylated methyl groups; wherein the hydroxylated methyl group is -CH2OH;

[0166] R 4 Selected from hydroxyl or amino; preferably hydroxyl;

[0167] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0168] In some embodiments of this disclosure, compounds represented by formula IIIA are as shown by formula IIIAa or formula IIIAb:

[0169] in,

[0170] R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 3 Selected from hydroxylated methyl groups; wherein the hydroxylated methyl group is -CH2OH;

[0171] R 4 Selected from hydroxyl or amino; preferably hydroxyl;

[0172] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0173] In some embodiments of this disclosure, the compounds represented by Formula I or Formula II are shown in Formula IIIB as follows:

[0174] in,

[0175] R 2Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 2 Selected from hydroxylated methyl groups; wherein the hydroxylated methyl group is -CH2OH;

[0176] R 4 Selected from hydroxyl or amino; preferably hydroxyl;

[0177] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0178] In some embodiments of this disclosure, the compounds represented by Formula I or Formula II are shown in Formula IIIC below:

[0179] Among them, R 4 Selected from hydroxyl or amino; preferably amino;

[0180] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0181] In some embodiments of this disclosure, the compounds represented by Formula I or Formula II are shown in Formula IIID below:

[0182] Among them, R 4 Selected from hydroxyl or amino groups;

[0183] R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

[0184] In some specific embodiments of this disclosure, the compounds represented by Formula I, Formula II, or Formulas IIIA to IIID are specifically:

[0185] In some embodiments of this disclosure, the drug with mucolytic function is a drug that treats a disease of mucus accumulation in the airway or eye of a subject by reducing mucus elasticity or mucus viscosity.

[0186] In some embodiments of this disclosure, the drug with mucolytic function is an expectorant.

[0187] In some embodiments of this disclosure, the subject has mucus accumulation in his / her airway.

[0188] In some embodiments of this disclosure, the airway is located in the upper respiratory tract of the subject; preferably, the airway is located in the nasal passage, paranasal sinuses, pharynx, and / or larynx of the subject.

[0189] In some embodiments of this disclosure, the airway is located in the lower respiratory tract of the subject; preferably, the airway is located in the trachea, main bronchus, lobar bronchus, segmental bronchus, subsegmental bronchus, conductive bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, alveolar sacs, or alveoli of the subject.

[0190] In some specific embodiments of this disclosure, the diseases mentioned are chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), asthma, chronic asthma, acute asthma, bronchitis, chronic bronchitis, bronchiectasis, traction bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, pneumonia, mechanical ventilation-related lung injury, sinusitis, chronic rhinitis, acute sinusitis, chronic sinusitis, chronic sinusitis with nasal polyps, chronic sinusitis without nasal polyps, nasal discharge or posterior nasal drip.

[0191] In some embodiments of this disclosure, the subject has mucus accumulation in his / her eyes.

[0192] In some specific embodiments of this disclosure, the disease is filamentous keratitis, keratitis xerotica, dry eye syndrome, blepharitis, or conjunctivitis.

[0193] This disclosure also provides a method for reducing mucoelasticity or mucovisivity in a subject, the method comprising administering an effective amount of the aforementioned compound to the subject. In some embodiments, the method is used to reduce mucoelasticity or mucovisivity in the airways or eyes of a subject.

[0194] In some embodiments of this disclosure, the method includes reducing the subject's mucoelasticity. In some specific embodiments of this disclosure, the method includes reducing the subject's mucovisibility.

[0195] Reducing mucoelasticity and viscosity can be used for a variety of medical indications. For example, in some specific embodiments of this disclosure, as is known in the art, administration of the compounds disclosed herein can be used to alleviate upper and lower airway congestion through the physiological mechanism of mucociliary clearance. Specifically, it is known that a reduction in mucoelasticity and viscosity contributes to mucociliary clearance. In some specific embodiments of this disclosure, increased mucociliary clearance improves airflow and measures of lung function, such as forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). In some specific embodiments of this disclosure, improved mucociliary clearance reduces airway mucus obstruction (e.g., complete occlusion of the airway lumen), which will be reflected in improvements in chest imaging scores that quantify the amount of airway mucus obstruction.

[0196] In some embodiments of this disclosure, the lungs are a desirable target organ. In some specific embodiments of this disclosure, the method comprises administering the aforementioned compound to the lungs of a subject in need. In some specific embodiments of this disclosure, the subject suffers from lung conditions including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), chronic asthma with symptoms of excessive mucus production, chronic asthma with airflow obstruction, chronic asthma in which airway mucus obstruction is found on chest imaging studies, acute severe asthma, acute severe asthma in which mucus obstruction is life-threatening, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, pneumonia, and mechanical ventilation-related lung injury in which mucus pathology is prominent. In some embodiments, the method can be used to prevent or treat oxidative cross-linking of pulmonary mucins that cause airway mucus problems in subjects undergoing inhaled oxygen therapy or positive pressure mechanical ventilation.

[0197] In some embodiments of this disclosure, the upper respiratory tract is an ideal target organ. In some specific embodiments of this disclosure, the subject is a patient suffering from chronic rhinitis, acute sinusitis, chronic sinusitis, chronic sinusitis with mucocele, chronic sinusitis with nasal polyps, chronic sinusitis without nasal polyps, or chronic postnasal drip from any cause.

[0198] In some embodiments of this disclosure, the subject presents with symptoms such as acute airflow obstruction, acute shortness of breath, acute asphyxia, acute symptoms of obstructive pulmonary disease (COPD), acute symptoms of cystic fibrosis (CF), acute asthma with airflow obstruction, acute asthma with mucus obstruction, acute asthma with life-threatening mucus obstruction, acute symptoms of bronchiectasis, acute symptoms of bronchiolitis, acute symptoms of allergic bronchopulmonary aspergillosis, acute symptoms of pneumonia, or acute symptoms of mechanical ventilation-associated lung injury with prominent mucus pathology.

[0199] In some embodiments of this disclosure, the compounds described herein provide less diffusion from the site of action (e.g., the lungs) and rapid onset of action. Therefore, in some embodiments of this disclosure, less dosage and less time are required to achieve beneficial results (e.g., reduction of acute airflow obstruction), thus implying lower dosage requirements and higher efficacy compared to compounds conventionally used in therapeutic situations.

[0200] In some embodiments of this disclosure, the eye is an ideal target organ. In some embodiments of this disclosure, the subject suffers from filamentous keratitis, keratitis xerotica, dry eye syndrome, blepharitis, conjunctivitis, or any acute or chronic eye disease that causes excessive mucus buildup on the eye.

[0201] In some embodiments of this disclosure, the use of a compound of Formula I, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, as a single active pharmaceutical ingredient in the preparation of a medicament having mucolytic properties is provided. "Single active pharmaceutical ingredient" means that the prepared medicament does not contain other mucolytic active pharmaceutical ingredients.

[0202] In some embodiments, the compound represented by Formula I, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, can be used to prepare a solution that reduces lung resistance and improves lung compliance. In some embodiments, the compound represented by Formula I, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, can be used to treat or improve asthma.

[0203] In some embodiments, the compound represented by Formula I, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, is administered to the subject in a therapeutically effective amount.

[0204] In another aspect of this disclosure, a pharmaceutical composition is also provided, comprising a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, a solvate, and a pharmaceutically acceptable carrier;

[0205] in,

[0206] Indicates a chemical single or double bond;

[0207] X is selected from O or NH;

[0208] R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups;

[0209] R 2Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0210] R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl;

[0211] R 4 Selected from hydrogen, hydroxyl, or amino;

[0212] R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

[0213] "Pharmaceutical composition" in its usual and customary sense means a composition generally considered safe and effective for administration to a subject. "Pharmaceutically acceptable carrier" and the like in its usual and customary sense means a pharmaceutical excipient suitable for enteral or parenteral administration that does not react adversely with the active agent, such as a pharmaceutically or physiologically acceptable organic or inorganic carrier substance. Suitable pharmaceutically acceptable carriers include water, saline solutions (e.g., Ringer's solution), alcohols, oils, gelatin, and carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, mannitol, and parent sugars of dithiol sugar mucolytics as disclosed herein, wherein the dithiol sugar mucolytic lacks a thiol functional group, such as D-glucopyranose, D-galactopyranose, D-mannopyranose, D-glucopyranoside, D-galactopyranoside, D-mannopyranoside, sucrose, lactose, lactulose, maltose, trehalose, cellobiose, chitobiose, or maltose. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not adversely react with the compounds of this disclosure, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, and / or aromatic substances. The compounds described in this disclosure can be administered alone or co-administered to a subject. Co-administration is intended to involve the simultaneous or sequential administration of compounds, alone or in combination (more than one compound). The formulations can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation).

[0214] In some embodiments of this disclosure, the pharmaceutically acceptable carrier is a pulmonary drug carrier.

[0215] In some embodiments of this disclosure, the pulmonary drug carrier is a pulmonary drug liquid or a pulmonary drug powder.

[0216] In some embodiments of this disclosure, the pulmonary drug liquid comprises a polar liquid, and the compound is dissolved or suspended in the polar liquid; preferably, the polar liquid is water.

[0217] In some embodiments of this disclosure, the composition is contained within a pulmonary drug delivery device.

[0218] In some embodiments of this disclosure, the pulmonary drug delivery device is a pulmonary drug nebulizer, a pulmonary drug soft fog inhaler, a pulmonary drug dry powder inhaler, or a pulmonary drug pressurized metering inhaler.

[0219] In another aspect of this disclosure, compounds, or stereoisomers thereof, deuterated compounds, pharmaceutically acceptable salts, and solvates, as shown below, are also provided:

[0220] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, or a solvate. In some embodiments, the pharmaceutical composition is administered to a subject in a therapeutically effective amount.

[0221] The effective therapeutic dose described in this article can be determined by clinicians based on the patient's age, weight, gender, general health status, family history, disease severity, and route of administration.

[0222] The compounds disclosed herein, or their stereoisomers, deuterated compounds, pharmaceutically acceptable salts, solvates (e.g., hydrates), or pharmaceutical compositions may be administered via any conventional route known in the art, including but not limited to pulmonary inhalation.

[0223] Obviously, based on the above content of this disclosure, and in accordance with ordinary technical knowledge and common practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure. Detailed Implementation

[0224] Unless otherwise specified, the instruments used in this disclosure are conventional instruments and the reagents used are conventional reagents.

[0225] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0226] NMR shift (δ) with 10 -6 The unit (ppm) is given. NMR measurements were performed using a Broker Avance III 400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0227] MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0228] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, and the diameter of the thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0229] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0230] The room temperature described in this invention is 20℃~25℃.

[0231] Explanation of the abbreviations used in this disclosure:

[0232] ACN represents acetonitrile; HOAc represents glacial acetic acid; NaOAc represents sodium acetate; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; DMP represents Dysmart reagent; TEA represents triethylamine; TFA represents trifluoroacetic acid; K2CO3 represents potassium carbonate; MeOH represents methanol; NaCl represents sodium chloride; NaHCO3 represents sodium bicarbonate; Na2S2O3 represents sodium thiosulfate; NaSO4 represents sodium sulfate; Na(OAc)3BH represents sodium triacetoxyborohydride; HClO4 represents perchloric acid; EDT represents 1,2-ethylenedithiol.

[0233] The present disclosure will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions are used in the embodiments. The embodiments are provided to better illustrate the present disclosure, but should not be construed as limiting the disclosure to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above disclosure are still within the scope of protection of this disclosure.

[0234] Example 1: Preparation of (2,3-dihydroxypropyl)-L-cysteine

[0235] Step 1: Preparation of N-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine

[0236] (S)-triphenylmethyl-L-cysteine ​​(7.26 g, 20 mmol), 2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (3.9 g, 30 mmol), and NaOAc (820 mg, 10 mmol) were dissolved in DCM (200 mL). Then, HOAc (2.4 g, 40 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 0.5 hours. Then, Na(OAc)3BH (8.48 g, 40 mmol) was added, and the reaction mixture was stirred at room temperature for another 12 hours. After the reaction was complete, saturated NaHCO3 was added to the reaction solution to adjust the pH to approximately 7. DCM was added for extraction three times, and the organic phases were combined. The organic phase was washed once with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated. The crude product was then separated by silica gel column chromatography to obtain 2.34 g of N-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine. MS (ESI) m / z (MH) - =476. 1 H NMR(400MHz,Chloroform-d)δ7.46–7.36(m,6H),7.29–7.20(m,6H),7.20–7.10(m,3H),4.22(s,1H),3.94(t,J=8.5,6.2Hz,1H),3.53(q,J= 8.6,5.4Hz,1H),2.87(s,1H),2.75(dd,J=13.3,4.8Hz,1H),2.65(dd,J=13.6,8.4Hz,2H),2.40(t,J=9.8Hz,1H),1.32(s,3H),1.24(s,3H).

[0237] Step 2: Preparation of (2,3-dihydroxypropyl)-L-cysteine

[0238] Under nitrogen protection, N-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine ​​(2.34 g, 4.9 mmol) and triethylsilane (2.84 g, 24.5 mmol) were dissolved in a DCM / TFA ratio of 1 / 1 (24.5 mL / 24.5 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure (DCM was added several times to remove some TFA) to obtain a crude product. Ice-cold diethyl ether was added, and the mixture was stirred at 0 °C for 1 hour. The resulting white solid was filtered, dissolved in MeOH, and purified by prep-HPLC to give 108 mg of (2,3-dihydroxypropyl)-L-cysteine. MS (ESI) m / z (MH) - =194. 1H NMR(400MHz,Chloroform-d)δ4.13(q,J=6.7,5.7Hz,1H),3.96(td,J=8.6,3.9Hz,1 H),3.58(qd,J=11.3,4.9Hz,2H),3.32(dd,J=12.7,3.5Hz,1H),3.17–3.04(m,3H).

[0239] Example 2: Preparation of ((S)-2,3-dihydroxypropyl)-L-cysteine

[0240] Step 1: Preparation of N-(((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine

[0241] (S)-triphenylmethyl-L-cysteine ​​(3.63 g, 10 mmol), (S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (3.9 g, 15 mmol), and NaOAc (410 mg, 5 mmol) were dissolved in DCM (100 mL). Then, HOAc (1.2 g, 20 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 0.5 hours. Then, Na(OAc)3BH (4.24 g, 20 mmol) was added, and the reaction mixture was stirred at room temperature for another 12 hours. After the reaction was complete, saturated NaHCO3 was added to the reaction solution to adjust the pH to approximately 7. DCM was added for extraction three times, and the organic phases were combined. The organic phase was washed once with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was then separated by silica gel column chromatography to obtain 3.11 g of N-(((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine. MS (ESI) m / z (MH) - =476.

[0242] Step 2: Preparation of ((S)-2,3-dihydroxypropyl)-L-cysteine

[0243] Under nitrogen protection, N-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine ​​(3.11 g, 6.5 mmol) and triethylsilane (3.72 g, 32.5 mmol) were dissolved in a DCM / TFA ratio of 1 / 1 (32.5 mL / 32.5 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure (DCM was added several times to remove some TFA) to obtain a crude product. Ice-cold diethyl ether was added, and the mixture was stirred at 0 °C for 1 hour. The resulting white solid was filtered, dissolved in MeOH, and purified by prep-HPLC to give 384 mg of ((S)-2,3-dihydroxypropyl)-L-cysteine. MS (ESI) m / z (MH) - =194. 1 H NMR (400MHz, DMSO-d6) δ4.07(t,J=4.9Hz,1H),3.82(d,J=5.3Hz,1H),3.43(dd,J=11.0,4.8Hz,1H),3.32 (dd,J=11.0,6.3Hz,1H),3.15(dd,J=12.6,3.1Hz,1H),3.12–2.95(m,2H),2.88(dd,J=12.6,9.2Hz,1H).

[0244] Example 3: Preparation of ((R)-2,3-dihydroxypropyl)-L-cysteine

[0245] Step 1: Preparation of N-(((R)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine

[0246] (S)-triphenylmethyl-L-cysteine ​​(3.63 g, 10 mmol), (R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (4.47 g, 15 mmol), and NaOAc (410 mg, 5 mmol) were dissolved in DCM (100 mL). Then, HOAc (1.2 g, 20 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 0.5 hours. Then, Na(OAc)3BH (4.24 g, 20 mmol) was added, and the reaction mixture was stirred at room temperature for another 12 hours. After the reaction was complete, saturated NaHCO3 was added to the reaction solution to adjust the pH to approximately 7. DCM was added for extraction three times, and the organic phases were combined. The organic phase was washed once with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was then separated by silica gel column chromatography to obtain 2.06 g of N-(((R)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine. MS (ESI) m / z (MH) - =476.

[0247] Step 2: Preparation of ((R)-2,3-dihydroxypropyl)-L-cysteine

[0248] Under nitrogen protection, N-(((R)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-S-triphenylmethyl-L-cysteine ​​(2.06 g, 4.3 mmol) and triethylsilane (2.5 g, 21.5 mmol) were dissolved in a DCM / TFA ratio of 1 / 1 (21.5 mL / 21.5 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure (DCM was added several times to remove some TFA) to obtain a crude product. Ice-cold diethyl ether was added, and the mixture was stirred at 0 °C for 1 hour. The resulting white solid was filtered, dissolved in MeOH, and purified by prep-HPLC to obtain 130 mg of (2,3-dihydroxypropyl)-L-cysteine. MS (ESI) m / z (MH) - =194. 1 H NMR (400MHz, DMSO-d6) δ4.07(t,J=4.9Hz,1H),3.82(d,J=5.3Hz,1H),3.43(dd,J=11.0,4.8Hz,1H),3.32 (dd,J=11.0,6.3Hz,1H),3.15(dd,J=12.6,3.1Hz,1H),3.12–2.95(m,2H),2.88(dd,J=12.6,9.2Hz,1H).

[0249] Example 4: Preparation of (1,3-dihydroxypropyl-2-yl)-L-cysteine

[0250] Step 1: Preparation of 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-one

[0251] At room temperature, 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-one (7.11 g, 20 mmol) was dissolved in DCM (100 mL), and then DMP (21.2 g, 50 mmol) was added in portions. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, a 1 / 1 ratio of saturated Na₂S₂O₃ solution to quench the reaction was added to the reaction solution. After stirring for 30 minutes, DCM was added and the mixture was extracted three times. The organic phases were combined, washed once with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was separated by silica gel column chromatography to obtain 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-one (6.6 g). MS (ESI) m / z (M+H) + =319.

[0252] Step 2: Preparation of N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-yl)-S-triphenylmethyl-L-cysteine

[0253] Under nitrogen protection, S-triphenylmethyl-L-cysteine ​​(5.08 g, 14 mmol), 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-one (6.6 g, 20.8 mmol), and NaOAc (574 mg, 7 mmol) were dissolved in DCM (140 mL). Then, HOAc (1.68 g, 28 mmol) was added, and the reaction system was stirred at room temperature for 0.5 hours. Then, Na(OAc)3BH (5.94 g, 28 mmol) was added, and the reaction system was continued to react at room temperature for 12 hours. After the reaction was complete, saturated NaHCO3 solution was added to the reaction solution to adjust the pH to approximately 7. DCM was added for extraction three times, and the organic phases were combined. The organic phase was washed once with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was dissolved in MeOH and purified by prep-HPLC to obtain 4.99 g of N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-yl)-S-triphenylmethyl-L-cysteine. MS (ESI) m / z (MH) - =664.1 H NMR(400MHz,Chloroform-d)δ7.44–7.38(m,6H),7.32–7.25(m,6H),7.24–7.17(m,3H),3.61–3.42(m,4H),3.09(dd,J=9.7,3.8Hz, 1H),2.83(dd,J=12.8,3.7Hz,1H),2.58–2.54(m,1H),2.45(dd,J=12.8,9.7Hz,1H),0.87(s,9H),0.84(s,9H),0.05–-0.01(m,12H).

[0254] Step 3: Preparation of (1,3-dihydroxypropyl-2-yl)-L-cysteine

[0255] N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloxane-6-yl)-S-triphenylmethyl-L-cysteine ​​(4.99 g, 7.5 mmol) and triethylsilane (4.35 g, 37.5 mmol) were dissolved in a DCM / TFA ratio of 1 / 1 (37.5 mL / 37.5 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure (DCM was added several times to remove some TFA) to obtain a crude product. Ice-cold diethyl ether was added, and the mixture was stirred at 0 °C for 1 hour. The resulting white solid was filtered, dissolved in MeOH, and purified by prep-HPLC to obtain 360 mg of (1,3-dihydroxypropyl-2-yl)-L-cysteine. MS (ESI) m / z (MH) - =194. 1 H NMR (400MHz, DMSO-d6) δ4.41(t,J=4.8Hz,1H),3.67(dd,J=10.0,5.3Hz,4H),3.26(t,J=5.3Hz,1H),3.09(qd,J=14.6,4.9Hz,2H).

[0256] Example 5: Preparation of glycyl-L-cysteine

[0257] Step 1: Preparation of N-(tert-butoxycarbonyl)glycyl)-S-triphenylmethyl-L-cysteine

[0258] At 0 °C, 1.4 g (5 mmol) of 2,5-dioxopyrrolidone-1-yl(tert-butoxycarbonyl)glycine ester was dissolved in 30 mL of DMF. Then, 0.7 mL of TEA and 1.8 g (5 mmol) of S-triphenylmethyl-L-cysteine ​​were slowly added dropwise. The reaction mixture was then stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, extracted with 200 mL of 0.1 N hydrochloric acid and 300 mL of ethyl acetate, and the organic phase was collected and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated, and the crude product was recrystallized from petroleum ether and ethyl acetate to give 1.9 g of N-(tert-butoxycarbonyl)glycyl)-S-triphenylmethyl-L-cysteine. MS (ESI) m / z (M+H) + =521.

[0259] Step 2: Preparation of glycyl-L-cysteine

[0260] N-(tert-butoxycarbonyl)glycyl)-S-triphenylmethyl-L-cysteine ​​(1.9 g, 3.65 mmol) was dissolved in TFA (15 mL) and 1,2-ethylenedithiol (0.78 mL) and stirred at room temperature for 3 hours. After the reaction was complete, the reaction system was concentrated under reduced pressure, and ice-cold diethyl ether was added at 0 °C and stirred for 5 minutes. The mixture was filtered, and the solid was collected. The crude product was purified by HPLC to obtain 300 mg of glycyl-L-cysteine. MS (ESI) m / z (M+H) + =179. 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),8.73(d,J=7.4Hz,1H),8.01(s,2H),4.51(td,J=7.2,4.4Hz,1H),3.65(s,2H),2.85(m,2H).

[0261] Example 6: Preparation of (carboxymethyl)-L-cysteine

[0262] Step 1: Preparation of S-triphenylmethyl-L-cysteine ​​tert-butyl ester

[0263] (S)-Triphenylmethyl-L-cysteine ​​(7.26 g, 20 mmol) was dissolved in tert-butyl acetate (130 mL). HClO4 (6 mL, 100 mmol) was added dropwise with vigorous stirring, and the reaction mixture was stirred at room temperature for 70 minutes. After the reaction was complete, ethyl acetate (200 mL) was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated NaHCO3. After filtration to remove the precipitate, the mother liquor was extracted with ethyl acetate. The combined organic phases were washed once each with 0.5 N HCl and saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 4.57 g of S-triphenylmethyl-L-cysteine ​​tert-butyl ester. MS (ESI) m / z (M+Na) + =442. 1 H NMR (400MHz, Chloroform-d) δ7.46–7.39(m,6H),7.32–7.24(m,6H),7.22–7.15(m,3H),3.43(t,J=5.5Hz,1H),2.82(t,J=5.8Hz,2H),1.38(s,9H).

[0264] Step 2: Preparation of N-(2-(tert-butoxy)-2-oxoethyl)-S-triphenylmethyl-L-cysteine ​​tert-butyl ester

[0265] S-triphenylmethyl-L-cysteine ​​tert-butyl ester (4.57 g, 11 mmol), tert-butyl bromoacetate (2.15 g, 11 mmol), and K₂CO₃ (3.04 g, 22 mmol) were dissolved in ACN (55 mL), and the reaction mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain the crude product. After dissolving in methanol, the crude product was purified by prep-HPLC to obtain 3.15 g of N-(2-(tert-butoxy)-2-oxoethyl)-S-triphenylmethyl-L-cysteine ​​tert-butyl ester. MS (ESI) m / z (M+H) + =534. 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),8.73(d,J=7.4Hz,1H),8.01(s,2H),4.51(td,J=7.2,4.4Hz,1H),3.65(s,2H),2.85(m,2H).

[0266] Step 3: Preparation of (carboxymethyl)-L-cysteine

[0267] N-(2-(tert-butoxy)-2-oxoethyl)-S-triphenylmethyl-L-cysteine ​​tert-butyl ester (3.15 g, 5.9 mmol) and triethylsilane (3.42 g, 29.5 mmol) were dissolved in a DCM / TFA ratio of 1 / 1 (29.5 mL / 29.5 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure (DCM was added several times to remove some TFA) to obtain a crude product. Ice-cold diethyl ether was added to maintain the reaction mixture at 0 °C. The resulting white solid was filtered, dissolved in MeOH, and purified by prep-HPLC to obtain 470 mg of (carboxymethyl)-L-cysteine. MS (ESI) m / z (MH) - =178. 1 H NMR (400MHz, DMSO-d6) δ3.97(t,J=4.8Hz,1H),3.73(s,2H),2.97(qd,J=14.4,4.9Hz,2H).

[0268] Example 7: Preparation of (2-amino-2-oxoethyl)-L-cysteine

[0269] Step 1: Preparation of N-(2-amino-2-oxoethyl)-S-triphenylmethyl-L-cysteine ​​tert-butyl ester

[0270] S-triphenylmethyl-L-cysteine ​​tert-butyl ester (4.78 g, 11.4 mmol), bromoacetamide (1.57 g, 11.4 mmol), and K₂CO₃ (3.15 g, 22.8 mmol) were dissolved in ACN (57 mL). The reaction mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was then dissolved in methanol and purified by prep-HPLC to obtain 2.39 g of N-(2-amino-2-oxoethyl)-S-triphenylmethyl-L-cysteine ​​tert-butyl ester. MS (ESI) m / z (M+Na) + =499. 1 H NMR (400MHz, Chloroform-d) δ7.46–7.39(m,6H),7.32–7.24(m,6H),7.22–7.15(m,3H),3.43(t,J=5.5Hz,1H),2.82(t,J=5.8Hz,2H),1.38(s,9H).

[0271] Step 2: Preparation of (2-amino-2-oxoethyl)-L-cysteine

[0272] N-(2-amino-2-oxoethyl)-S-triphenylmethyl-L-cysteine ​​tert-butyl ester (2.39 g, 5 mmol) and triethylsilane (2.9 g, 25 mmol) were dissolved in a DCM / TFA ratio of 1 / 1 (25 mL / 25 mL). The reaction mixture was stirred at rt for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure (DCM was added several times to remove some TFA) to obtain a crude product. Ice-cold diethyl ether was added to maintain the reaction mixture at 0 °C, and the resulting white solid was filtered. After dissolving in MeOH, the solution was purified by prep-HPLC to obtain 313 mg of (2-amino-2-oxoethyl)-L-cysteine. MS (ESI) m / z (M+H) + =179. 1 H NMR (400MHz, DMSO-d6) δ7.43(s,1H),7.19(s,1H),3.34–3.30(m,2H),3.26(s,1H),3.19(s,1H),2.85–2.67(m,2H).

[0273] The effects of the disclosed compounds are illustrated below through test examples:

[0274] Test Example 1: DTNB-Ellman Test

[0275] 1. Experimental Objective

[0276] DTNB method for testing the rate and strength of disulfide bond cleavage in mercapto-containing compounds

[0277] 2. Experimental Principle

[0278] 5,5'-Dithiobis-(2-nitrobenzoic)acid (DTNB), also known as Ellman's reagent, is a compound containing a disulfide bond. It reacts with free thiol groups in equimolar amounts, breaking the disulfide bond to form 2-nitro-5-mercaptobenzoic acid (TNB2-), which is yellow in color and has a characteristic absorption peak at 412 nm. By detecting the absorbance at 412 nm, the DTNB method can quantitatively analyze free thiol groups in solution, thus providing a sensitive and reliable method for determining thiol content.

[0279] 3. Experimental Methods

[0280] (1) Prepare a 1 mM DTNB solution using 1×PBS (pH=7.4), sonicate for 1 h to ensure complete dissolution of DTNB powder, prepare and use immediately. Before use, dilute with 1×PBS to 40 μM, and add 90 μL to each well of a 96-well plate.

[0281] (2) Prepare 100mM stock solutions of compounds (including compounds from Examples 1-7 and control compound NAC) using 1×PBS. Prepare fresh solutions immediately and dilute 250 times to 400μM (10×), 10μL per well. Also, set up solvent control wells: add an equal volume of 1×PBS. Immediately after mixing, place the solution in a microplate reader to detect the OD value at 412nm. Perform 15s / cycle, for a total of 60 cycles, 15min.

[0282] All reagents used in the reaction were pre-cooled on wet ice to maintain a low temperature, and the DTNB solution was wrapped in aluminum foil to protect it from light.

[0283] 4. Experimental Results

[0284] The results show that the compounds prepared in the embodiments of this disclosure all have good ability to reduce disulfide bonds, and therefore can be used for mucus dissolution.

[0285] Test Example 2: Stability test of the compound in 4% BSA

[0286] 1. Preparation of sample stock solution

[0287] The weighed compound was dissolved in 1×PBS (pH=7.4) to prepare a 125mM stock solution, which was prepared and used immediately.

[0288] 2. Experimental Methods

[0289] (1) At 0 min, add 10 μL of internal standard aqueous solution (containing 6 μg / mL (S)-2-amino-2-methyl-3-phenylpropionic acid) to 50 μL PBS, then add 48 μL of 4% BSA, shake vigorously for 1 min, add 400 μL of precipitant (pure acetonitrile), shake vigorously for 5 min to mix, add 2 μL of each compound stock solution, shake to mix for 1 min, centrifuge at 4400 rpm for 30 min, take 170 μL of supernatant, add 30 μL of pure water to mix, and then test on the instrument (sample n=2).

[0290] (2) Add 48 μL of 4% BSA matrix to a 96-well plate, then add 2 μL of each compound stock solution. The concentration gradient of the stability sample is 5 mM (1 mM in Example 7). Start timing accurately, shake vigorously for 1 min to mix, then switch to gentle shaking at 500 rpm. This is the matrix stability sample (n=2). After 60 min, add 50 μL of PBS and 10 μL of internal standard aqueous solution (containing 6 μg / mL (S)-2-amino-2-methyl-3-phenylpropionic acid), vortex to mix, then add 400 μL of precipitant (pure acetonitrile), shake vigorously for 5 min to mix, centrifuge at 4400 rpm for 30 min, take 170 μL of supernatant, add 30 μL of pure water to mix, and then test on the instrument. (n=2).

[0291] 3. LC-MS / MS Analysis Method

[0292] Chromatographic column: Agilent EC-C18 2.7μm 2.1*50mm; Mobile phase: Phase A: water, Phase B: acetonitrile; LC: LC-40DXS; MS: AB SCIEX 5500+qtrap; Injection volume: 5μL

[0293] 4. Experimental Results

[0294] The results show that the compounds in the present invention exhibit stability comparable to or significantly better than the control compound NAC.

[0295] Test Example 3: The Effect of Compounds on Egg White Viscosity

[0296] 1. Experimental Objective

[0297] Evaluate the effect of compounds on reducing egg white viscosity

[0298] 2. Experimental Principle

[0299] Egg white is rich in mucin, whose molecules form a highly cross-linked network structure through disulfide bonds, which is the main reason for its high viscosity. When a test compound is added to egg white, if it reacts with the disulfide bonds in the mucin and disrupts the intermolecular cross-linking structure, the viscosity of the egg white will decrease. By using a viscometer to monitor the viscosity of egg white in real time, and analyzing the rate and magnitude of viscosity change over time, the speed and extent to which the compound reduces the viscosity of egg white can be assessed, thus reflecting the activity of the compound.

[0300] 3. Test Methods

[0301] The test compound solution was prepared using physiological saline at a concentration of 100 mM. The test compound solution was mixed with egg white at a volume ratio of 1:9 and allowed to stand for approximately 2.5 minutes. The viscosity of the sample was measured using a rotational viscometer (Brookfield, DVNextLV) at 60 rpm and 25°C for 10 minutes. The average viscosity per minute was calculated, and a viscosity change curve was plotted with the average viscosity as the ordinate (Y-axis) and time as the abscissa (X-axis) to characterize the change in sample viscosity over time.

[0302] The experimental results are shown in Figure 2. The disclosed compound can reduce the viscosity of egg white, and at the same concentration, the viscosity is even lower, showing better results than NAC. Test Example 4: Effect of the compound on sputum viscosity

[0303] 1. Experimental Objective

[0304] Evaluate the effect of compounds in reducing sputum viscosity

[0305] 2. Experimental Principle

[0306] By using a viscometer to monitor sputum viscosity in real time, and analyzing the rate and magnitude of viscosity change over time, the speed and extent to which compounds reduce sputum viscosity can be assessed, thereby reflecting the activity of the compounds.

[0307] 3. Test Methods

[0308] Sputum samples were collected from clinical patients. After removing saliva, the samples were inverted and mixed thoroughly. A 600 mM solution of the test compound was prepared using physiological saline. The test compound solution was mixed with sputum at a volume ratio of 1:9 and then inverted before being fed into the instrument (IKA ROTAVISC LO-VI). The instrument was operated at 30 rpm and 37°C for 10 minutes. The viscosity of the sample after 1 minute of operation was taken as 100%, and the percentage change in viscosity over time for each sample was calculated. A viscosity change curve was plotted with viscosity percentage on the ordinate (Y-axis) and time on the x-axis to characterize the change in sample viscosity over time.

[0309] The experimental results are shown in Figure 3. The compound disclosed herein can reduce sputum viscosity. At the same concentration, the viscosity reduction is faster and the effect is stronger, which is better than that of NAC.

[0310] Test Example 5: Pharmacodynamic study of the compound on an ovalbumin (OVA)-induced mouse asthma model

[0311] 1. Experimental Objective

[0312] This study investigates the role of the disclosed compound in an OVA-induced mouse asthma model.

[0313] 2. Test Methods

[0314] (1) Establishment of an asthma model

[0315] Sensitization phase: Female Balb / c mice were sensitized on days 0, 7 and 14 by intraperitoneal injection of 100 μL of 0.30 mg / mL OVA / Alum solution. Animals in the Sham group were sensitized with PBS instead.

[0316] Challenge phase: Animals in the drug administration group and solvent control group were challenged by nebulization with 1% OVA solution for 30 minutes on days 27-31, while animals in the Sham group were challenged with PBS instead.

[0317] (2) Drug administration and airway hyperreactivity (AHR) detection

[0318] 24 hours after the last OVA nebulization challenge, the animals were anesthetized, and the vein and main trachea were surgically bluntly dissected. Intravenous and tracheal intubation was performed, and the DSI Buxco RC system was connected to record the baseline RI. Subsequently, 40 μL and 80 μL of 0.2 mg / mL MCh (acetylcholine) were administered intravenously in sequence for AHR detection, and the corresponding lung resistance (RI, resistance to air in and out of the lungs) and dynamic lung compliance (Cdyn, used to describe the elastic properties of lung tissue during dynamic respiration) were recorded.

[0319] (3) Compound concentration and atomization settings:

[0320] NAC: 100 mg / mL; Example 6: 130 mg / mL; Example 4: 118.5 mg / mL.

[0321] Nebulization settings: The compound was administered 3 min before each MCh dose excitation, with a nebulization volume of 20 μL, a nebulization time of 15 s, and a nebulization rate of 80 μL / min.

[0322] The experimental results are shown in Figure 4. The compound disclosed herein can significantly reduce airway resistance (RI) and improve lung compliance (Cdyn) in MCh-induced OVA mice.

[0323] For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0324] Those skilled in the art will recognize that the scope of this application is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, and all such modified solutions fall within the protection scope of this application.

Claims

1. A compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, or a solvate thereof, used as a drug with mucolytic function; in, Indicates a chemical single or double bond; X is selected from O or NH; R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups; R 2 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl; R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl; R 4 Selected from hydrogen, hydroxyl, or amino; R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

2. The compound used as a medicament with mucolytic function according to claim 1, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, wherein, The compounds represented by Formula I are shown in Formula II: Among them, X and R 1 R 2 R 3 R 4 R 5 The definition is as described in claim 1.

3. The compound used as a medicament with mucolytic function according to claim 1 or 2, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, wherein, X is selected from O; R 1 Selected from hydrogen.

4. The compound used as a medicament with mucolytic function according to any one of claims 1-3, or its stereoisomer, deuterated compound, pharmaceutically acceptable salt, or solvate, wherein, The compounds represented by Formula I or Formula II are shown in Formulas IIIA to IIID below: in, R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 2 Selected from hydroxylated methyl groups; R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 3 Selected from hydroxylated methyl groups; R 4 Selected from hydroxyl or amino groups; R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

5. The compound used as a medicament with mucolytic function according to any one of claims 1-4, or its stereoisomer, deuterated compound, pharmaceutically acceptable salt, or solvate, wherein, The compounds represented by Formula I, Formula II, or Formulas IIIA to IIID are specifically:

6. The compound used as a medicament with mucolytic function according to any one of claims 1-5, or its stereoisomer, deuterated compound, pharmaceutically acceptable salt, or solvate, wherein, The drug with mucolytic function is a drug that treats a disease of mucus accumulation in the airway or eyes of a subject by reducing mucus elasticity or mucus viscosity; preferably, the drug with mucolytic function is an expectorant.

7. The compound used as a medicament with mucolytic function according to claim 6, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, wherein, The subject had mucus accumulation in his / her airway; Preferably, the airway is located in the subject's upper respiratory tract; preferably, the airway is located in the subject's nasal passage, paranasal sinuses, pharynx, and / or larynx; or Preferably, the airway is located in the lower respiratory tract of the subject; preferably, the airway is located in the trachea, main bronchus, lobar bronchus, segmental bronchus, subsegmental bronchus, conductive bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, alveolar sacs, or alveoli of the subject. Preferably, the diseases causing airway mucus accumulation include chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), asthma, chronic asthma, acute asthma, bronchitis, chronic bronchitis, bronchiectasis, traction bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, pneumonia, mechanical ventilation-related lung injury, sinusitis, chronic rhinitis, acute sinusitis, chronic sinusitis, chronic sinusitis with nasal polyps, chronic sinusitis without nasal polyps, nasal discharge, or posterior nasal drip.

8. The compound used as a medicament with mucolytic function according to claim 6, or its stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates, wherein, The subject had mucus accumulation in his / her eyes; Preferably, the disease causing the accumulation of mucus in the eye is filamentous keratitis, keratitis xerotica, dry eye syndrome, blepharitis, or conjunctivitis.

9. A pharmaceutical composition comprising a compound of Formula I, or a stereoisomer thereof, a deuterated compound, a pharmaceutically acceptable salt, a solvate, and a pharmaceutically acceptable carrier; in, Indicates a chemical single or double bond; X is selected from O or NH; R 1 Selected from hydrogen, C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl groups; R 2 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl; R 3 Selected from hydrogen, oxygen, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl; R 4 Selected from hydrogen, hydroxyl, or amino; R 5 It is selected from hydrogen, C1-C6 alkyl or C1-C6 acyl.

10. The composition according to claim 9, wherein, The compounds represented by Formula I are shown in Formula II: Among them, X and R 1 R 2 R 3 R 4 R 5 The definition is as described in claim 9.

11. The composition according to claim 9 or 10, wherein, The compounds represented by Formula I or Formula II are shown in Formulas IIIA to IIID below: in, R 2 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 2 Selected from hydroxylated methyl groups; R 3 Selected from hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxylated methyl, hydroxylated ethyl, hydroxylated n-propyl, hydroxylated isopropyl, hydroxylated n-butyl, hydroxylated isobutyl, or hydroxylated tert-butyl; preferably, R 3 Selected from hydroxylated methyl groups; R 4 Selected from hydroxyl or amino groups; R 5 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, or tert-butyryl; preferably, R 5 It is selected from hydrogen, methyl, ethyl or acetyl.

12. The composition according to any one of claims 9-11, wherein, The compounds represented by Formula I, Formula II, or Formulas IIIA to IIID are specifically:

13. The composition according to any one of claims 9-12, wherein, The pharmaceutically acceptable carrier is a pulmonary drug carrier; preferably, the pulmonary drug carrier is a pulmonary drug liquid or a pulmonary drug powder. Preferably, the pulmonary drug liquid comprises a polar liquid, and the compound is dissolved or suspended in the polar liquid; preferably, the polar liquid is water.

14. The composition according to any one of claims 9-13, wherein, The composition is contained within a pulmonary drug delivery device; preferably, the pulmonary drug delivery device is a pulmonary drug nebulizer, a pulmonary drug soft fog inhaler, a pulmonary drug dry powder inhaler, or a pulmonary drug pressurized metering inhaler.

15. The following compounds, or their stereoisomers, deuterated compounds, pharmaceutically acceptable salts, or solvates:

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