NO donor compound and its pharmaceutical composition and application

Abstract

The present invention relates to the field of medical technology, and in particular to an NO donor compound that can be used to treat pulmonary arterial hypertension, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof. The compound can release nitric oxide (NO) and other pathway targeted therapeutic drugs for pulmonary arterial hypertension (PAH) in vivo, and can achieve a good dual-target treatment effect for PAH through simple and convenient administration.

Description

[0001] This application claims priority to Chinese patent application No. CN2022101085143, filed on January 28, 2022, entitled “NO donor compounds, pharmaceutical compositions and applications thereof”, the entire text of which is hereby incorporated by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to an NO donor compound, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application thereof. Background Art

[0003] Pulmonary Arterial Hypertension (PAH) is a disease in which the pulmonary circulation resistance increases progressively due to the narrowing and blockage of the small pulmonary blood vessels, eventually leading to the patient's right heart failure and death. The core feature of pulmonary hypertension is the irreversible remodeling of the cardiopulmonary vascular unit. Pulmonary hypertension includes idiopathic (primary) pulmonary hypertension, secondary pulmonary hypertension and hereditary pulmonary hypertension. There are millions of PAH patients in China, among which PAH complicated by congenital heart disease is the number one cause in China. In addition, idiopathic pulmonary hypertension has been classified as a rare disease by the World Health Organization due to its rare incidence. It is reported that the incidence of idiopathic pulmonary hypertension is about 2-5 cases per million people per year. Although the incidence of pulmonary hypertension is not high, it is a malignant disease, and most of the patients are young. If it is not treated, the average life expectancy after diagnosis is less than three years, which is worse than some malignant tumors. Only under the premise of adequate treatment with targeted drugs can the patient's 5-year survival rate reach 70%. Due to the low social awareness, the rate of missed diagnosis and misdiagnosis of pulmonary arterial hypertension in clinical practice is relatively high. Many patients lose precious treatment opportunities during the long diagnosis process and are not diagnosed until the disease progresses to the late stage, resulting in unsatisfactory treatment effects and a high mortality rate.

[0004] Nitric oxide (NO) is an endothelial-derived relaxing factor (EDRF), which is mainly produced in vascular endothelial cells. It has strong lipophilicity and can easily pass through the cell membrane. When it enters the smooth muscle cell membrane, it activates guanylate activating enzyme, which increases cGMP, thereby dilating pulmonary vasodilation and reducing pulmonary artery pressure. In recent years, the relationship between nitric oxide (NO) and pulmonary hypertension has been continuously deepened, providing a new means for the treatment of pulmonary hypertension. Early clinical trials have shown that inhaled NO can selectively act on pulmonary vasculature, dilate pulmonary arteries, and avoid systemic vasodilation causing systemic hypotension. Inhaled NO is widely used as the main treatment for pulmonary hypertension in children and even newborns. However, the safety and controllability of traditional inhaled NO treatment is poor. After stopping the inhalation of NO, the patient will experience a rebound phenomenon of PAH. Therefore, it has not been approved for marketing by relevant competent authorities in some countries. Even in countries and regions where it is approved for marketing, it must be strictly limited to hospital use. Compared with the traditional inhaled NO method, PDE-5 inhibitors can indirectly work by reducing the degradation of cyclic guanosine monophosphate (cGMP) and increasing cGMP concentration to cause vasodilation, which is safer, but their half-life is shorter, the drug resistance period is short, and the effect on patients with insufficient PDE5 response is poor. A soluble guanylate cyclase (sGC) agonist, Riociguanidine (Adempas), which was launched in 2020, can directly stimulate sGC and enhance its sensitivity to low levels of nitric oxide (NO), which to a certain extent alleviates the progression of the disease in patients with insufficient PDE5 response.

[0005] In addition, two major categories of drugs, prostaglandins and endothelin receptor antagonists (ERA), achieve vasodilation through different pathways, improve patients' cardiopulmonary function, and improve patients' quality of life and survival period.

[0006] With the improvement of diagnosis and treatment technology for pulmonary arterial hypertension in recent years, and the gradual in-depth understanding of the pathogenesis of pulmonary arterial hypertension, new treatment strategies have been continuously tried, evolving from the initial monotherapy to the initial oral combination therapy. AMBITION (ambrisentan + tadalafil) was proposed as the first initial oral combination therapy for PAH. Compared with monotherapy, AMBITION significantly reduced the clinical failure rate and had a more significant therapeutic effect. Subsequently, a large number of combination therapy plans were proposed. However, the clinical satisfaction rate of AMBITION was as high as 61%, which could not effectively maintain the low-risk status of patients.

[0007] Therefore, it is necessary to further develop therapeutic drugs for pulmonary arterial hypertension that are easy to administer and have good efficacy. Summary of the invention

[0008] Based on this, an object of the present invention is to provide a NO donor compound or a pharmaceutically acceptable salt thereof that can be used to treat pulmonary arterial hypertension, which can release nitric oxide (NO) and a targeted therapeutic drug for pulmonary arterial hypertension (PAH) in vivo, and can achieve a good dual-target treatment effect for PAH through simple and convenient administration.

[0009] The above-mentioned object of the invention can be achieved through the following technical solutions.

[0010] According to a first aspect of the present invention, there is provided an NO donor compound, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments of the present invention, the structure of the NO donor compound is: (AL-) q D;

[0012] in,

[0013] A is a NO donor group;

[0014] q is an integer greater than or equal to 1;

[0015] L is a chemical bond or a linking group; when q is greater than 1, multiple ALs are independent of each other and may be the same or different;

[0016] D is the residue of TD, wherein TD is a prostacyclin drug or an ERA drug;

[0017] Preferably, q is any integer of 1 to 10, more preferably 1, 2, 3, 4, 5 or 6.

[0018] According to the second invention of the present invention, a method for preparing the NO donor compound shown in the first aspect of the present invention is provided.

[0019] According to the third aspect of the present invention, there is provided a pharmaceutical composition comprising: the NO donor compound described in the first aspect of the present invention or the NO donor compound obtained by the preparation method described in the second aspect of the present invention; and a pharmaceutically acceptable carrier.

[0020] According to the fourth aspect of the present invention, there is provided the use of the NO donor compound described in the first aspect of the present invention, or the NO donor compound obtained by the preparation method described in the second aspect of the present invention, or the pharmaceutical composition described in the third aspect of the present invention in the preparation of a drug for treating pulmonary arterial hypertension.

[0021] The NO donor compound provided by the present invention carries both the NO release unit and the PAH targeted drug release unit (releasing PAH targeted therapeutic drugs that are different from the NO pathway) in one compound molecule. After entering the organism, the NO donor compound can release nitric oxide (NO) and pulmonary arterial hypertension (PAH) targeted therapeutic drugs (such as prostacyclin drugs or ERA drugs) in the organism by utilizing the organism's tissue environment, including but not limited to its own enzyme action, to achieve combined treatment. Compared with existing single-target drugs, the NO donor compound provided by the present invention has better efficacy. In addition, significantly different from the current PAH combined treatment scheme, the compound of the present application can use only a single drug molecule, which is decomposed in the organism and converted into two effective targeted drug molecules, so that the purpose of combined treatment can be achieved through a single drug molecule, and a good dual-target treatment effect of PAH can be achieved through simple and convenient administration.

[0022] The present application adopts the slow release of NO molecules in vivo, which can avoid the shortcomings of using inhaled NO or PDE-5 inhibitors (type 5 phosphodiesterase inhibitors). The compounds provided in the present application can stably and continuously release NO under physiological conditions, will not cause rebound of pulmonary hypertension in patients, have better safety, and can be used for children and newborns; at the same time, it can also be accompanied by the release of PAH targeted therapeutic drugs from other treatment pathways, can directly act on the lesions, can more effectively relieve pulmonary artery smooth muscle cells, and achieve better therapeutic effects. In addition, the intake of NO donors can be controlled relatively accurately, and a therapeutically effective amount of NO can be provided at a lower drug intake, greatly improving safety. Early scientific research shows that the use of NO can reduce the use of single-targeted drugs, with better safety, and it is possible to increase the dosage and achieve better control. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more completely understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for describing the embodiments.

[0024] Figure 1 This is a schematic diagram of a dual-target NO donor compound for PAH treatment through dual-pathway administration via a single molecule in one embodiment of the present invention; wherein the NO donor compound is exemplified by an IP receptor agonist and an NO donor group;

[0025] Figure 2 The graph is a result of some exemplary NO donor compounds of the present invention inhibiting the proliferation of pulmonary artery smooth muscle cells;

[0026] Figure 3The graph is a result of some exemplary NO donor compounds of the present invention inhibiting the proliferation of pulmonary artery smooth muscle cells; wherein Concentration is the concentration, and %Cell proliferation indicates the cell proliferation rate;

[0027] Figure 4 Schematic diagram of the experimental route in Example 3 of the present invention; wherein ic represents subcutaneous administration through the back of the neck;

[0028] Figure 5 The figure shows a comparison of the effects of some exemplary NO donor compounds of the present invention and some control drugs on the changes in body weight of rats. DETAILED DESCRIPTION

[0029] The present invention will be further described in detail below in conjunction with the accompanying drawings, embodiments and examples. It should be understood that these embodiments and examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The purpose of providing these embodiments and examples is to make the understanding of the disclosure of the present invention more thorough and comprehensive. It should also be understood that the present invention can be implemented in many different forms and is not limited to the embodiments and examples described herein. Those skilled in the art can make various changes or modifications without violating the connotation of the present invention, and the equivalent form obtained also falls within the protection scope of the present application. In addition, in the description below, a large number of specific details are given in order to provide a more comprehensive understanding of the present invention. It should be understood that the present invention can be implemented without one or more of these details.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing implementation modes and embodiments and are not intended to limit the present invention.

[0031] the term

[0032] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0033] The terms "and / or", "or / and", and "and / or" used in this article have a selection range that includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the arbitrary and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and "a combination of A and B". For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0034] In the present application, when at least three features are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it is equivalent to the expression "having any one or any multiple features", for example, "TA, and / or, TB, and / or, TC, and / or, TD" is equivalent to "having any one or any multiple of the following features: TA, TB, TC and TD".

[0035] In the present invention, "plurality", "multiple", "multiple times", etc., unless otherwise specified, refer to a number greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0036] As used herein, "combinations thereof", "any combinations thereof", "any combination thereof", etc. include all suitable combinations of any two or more of the listed items. In the present invention, unless otherwise specified, "one or more" means any one of the listed items or any combination of the listed items. Similarly, "one or more" and the like, when used in other ways to mean "one or more", shall be understood in the same manner unless otherwise specified.

[0037] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc., shall be based on the ability to implement the technical solution of the present invention, solve the technical problem of the present invention, and achieve the expected technical effect of the present invention.

[0038] Herein, "preferred", "better", "more preferred" and "suitable" are only used to describe implementation methods or examples with better effects, and it should be understood that they do not constitute a limitation on the scope of protection of the present invention. If multiple "preferred" items appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "preferred" item is independent.

[0039] In the present invention, "further", "further", "particularly", "for example", "such as", "example", "for example", etc. are used for descriptive purposes, indicating that the previous and subsequent different technical solutions are related in terms of the contents covered, but should not be understood as limiting the previous technical solution, nor can they be understood as limiting the scope of protection of the present invention. In the present invention, unless otherwise specified, A (such as B) means that B is a non-limiting example of A, and it can be understood that A is not limited to B.

[0040] In the present invention, "optionally", "optional", and "optional" mean optional, that is, any one of the two parallel solutions of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" is independent.

[0041] In the present invention, in "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", "the second solvent", etc., the terms "first", "second", "third", "fourth", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0042] As used herein, the terms "comprising", "including" and "comprising" are synonymous and are inclusive or open-ended and do not exclude additional, unrecited members, elements or method steps.

[0043] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0044] In the present invention, it is related to a numerical interval (i.e., a numerical range). If not otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum value and the maximum value) of the numerical range, and each numerical value between the two numerical endpoints. If not otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In this article, it is equivalent to directly listing each integer, such as "t is an integer selected from 1 to 10" or "t is any integer from 1 to 10", indicating that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, a percentage, a ratio, etc. "Numerical interval" allows broadly including numerical interval types such as percentage intervals, ratio intervals, and ratio intervals.

[0045] In the present invention, when it comes to approximate numbers (such as "about 20"), unless otherwise specified, the fluctuation range is generally ±10%, and may further refer to ±8%, ±5%, ±3%, etc. The approximate numbers in the present invention provide both the listed values ​​and the numerical range represented by the approximate numbers. For example, about 500 Da provides both the technical solution of "500 Da" and the technical solution of the numerical range consisting of "500 Da ± fluctuation range".

[0046] The temperature parameters in the present invention, if not specifically limited, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0047] In the present invention, the term "room temperature" generally refers to 4°C to 35°C, and a preferred embodiment is 20°C ± 5°C. In some embodiments of the present invention, room temperature refers to 20°C to 30°C.

[0048] In the present invention, when it comes to the unit of the data range, if there is a unit only after the right endpoint, it means that the units of the left endpoint and the right endpoint are the same. For example, 3-5h means that the units of the left endpoint "3" and the right endpoint "5" are both h (hours).

[0049] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as a reference separately. Unless they conflict with the invention purpose and / or technical solution of the present application, the cited documents involved in the present invention are cited with all contents and all purposes. When the present invention involves cited documents, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the present invention involves cited documents, the examples and preferred embodiments of the cited relevant technical features may also be incorporated into this application as references, but are limited to the ability to implement the present invention. It should be understood that when the content of the citation conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0050] In the present invention, if there are multiple steps involved in the method flow, unless otherwise specified herein, there is no strict order restriction on the execution of these steps, and they can be executed in other orders than described. Moreover, any step can include multiple sub-steps or multiple stages, and these sub-steps or stages are not necessarily executed at the same time, but can be executed at different times, and their execution order is not necessarily sequential, but can be executed in turn, alternating or simultaneously with other steps or parts of sub-steps or stages of other steps.

[0051] In this article, the number of carbon atoms can be used to define a group or molecule. For example, if the number of carbon atoms is 1 to 6, the following can be used: 1-6 , C 1～6 , C1-C6, C1~C6, C1-C6, C1~C6, 1 to 6 carbon atoms or other similar descriptions, each time it appears, can independently be C1, C2, C3, C4, C5 or C6.

[0052] As used herein, the term "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C 1-9"Alkyl" refers to an alkyl group containing 1 to 9 carbon atoms, and each occurrence may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl or C9 alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH 3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3 -methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3- Methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0053] As used herein, the term "cycloalkyl" (also referred to as "non-aromatic cycloalkyl") refers to a monovalent residue formed by the loss of a hydrogen atom on a ring from a non-aromatic hydrocarbon (saturated or unsaturated hydrocarbon) containing a ring carbon atom, i.e., a monovalent attachment site formed directly on the ring. A cycloalkyl group may be a monocyclic alkyl group, a spirocyclic alkyl group, or a bridged cycloalkyl group. Phrases containing this term, such as "C3-C9 cycloalkyl" or C 3-9"Cycloalkyl" refers to a cycloalkyl group containing 3 to 9 carbon atoms, each occurrence of which can be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl or C9 cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl Cyclobutyl Cyclopentyl Cyclohexyl In addition, "cycloalkyl" (also referred to as "non-aromatic cycloalkyl") may also contain one or more double bonds, and representative examples of cycloalkyl containing double bonds include cyclopentenyl (including but not limited to ), cyclohexenyl (including but not limited to ), cyclohexadiene (including but not limited to ) group, cyclopentadienyl (including but not limited to ) and cyclobutadienyl (including but not limited to ). Further, the "cycloalkyl" involved in the present invention may be a saturated group.

[0054] Herein, the term "aryl" refers to a monovalent aromatic hydrocarbon group derived from an aromatic ring compound by losing a hydrogen atom on the aromatic ring, that is, a monovalent attachment site is formed directly on the ring. The aryl group can be a monocyclic aryl group, a condensed ring aryl group, or a polycyclic aryl group. For polycyclic rings, at least one is an aromatic ring system. For example, "C5-C 10 Aryl" or "C 5-10 "Aryl" refers to an aromatic group containing 5 to 10 carbon atoms, each occurrence of which can be independently C6 aromatic group, C8 aromatic group, C9 aromatic group, C 10 Aryl, etc. Also for example, "C6~C 10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, each occurrence of which can be independently C6 aryl, C8 aryl, C9 aryl or C 10 Aryl. For example, "C6~C 20 "Aryl" refers to an aromatic group containing 6 to 20 carbon atoms, and each occurrence can be independently but not limited to C6 aryl aryl (such as phenyl), C6 aryl aryl (such as benzocyclobutenyl), C8 aryl (such as phenylcyclobutenyl), C9 aryl (such as indenyl), C 10 Aryl (such as naphthyl), C 12 Aryl (such as acenaphthenyl, biphenyl), C 13 Aryl (such as fluorenyl), C 14 Aryl (such as anthracenyl, phenanthrenyl), C 18 Aryl (such as triphenylene) or C 20Aryl (e.g., perylene). Examples of suitable aromatic hydrocarbon compounds include, but are not limited to, benzene, styrylcyclobutene, biphenyl, indene, naphthalene, acenaphthene, fluorene, anthracene, phenanthrene, triphenylene, perylene, and derivatives thereof. Further, suitable examples may include, but are not limited to, aryl derived from the following aromatic hydrocarbons: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and hydrocarbon derivatives thereof.

[0055] Herein, "arylalkyl" refers to a monovalent hydrocarbon group derived from at least one hydrogen atom bonded to a carbon atom on an alkyl group replaced by an aryl group. The aryl moiety may include 5 to 20 carbon atoms, and the alkyl moiety may include 1 to 9 carbon atoms. Suitable examples include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, and 2-naphthophenylethyl-1-yl.

[0056] As used herein, "alkenyl" refers to a group containing at least one unsaturated site (i.e., a carbon-carbon sp 2 A monovalent residue formed by the loss of a hydrogen atom from a hydrocarbon having a double bond. Phrases containing this term, for example, "C2-C9 alkenyl" or "C 2-9 “Alkenyl” refers to an alkenyl group containing 2 to 9 carbon atoms, and each occurrence may be independently C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, C6 alkenyl, C7 alkenyl, C8 alkenyl or C9 alkenyl. Suitable examples include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7) and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0057] Herein, the term "heteroalkyl" refers to that at least one carbon atom is replaced by a non-carbon atom on the basis of an alkyl group, and the non-carbon atom can be an N atom, an O atom, an S atom, a P atom, etc. O, N, S are used as examples for illustration. For example, if the carbon atom connected to an adjacent group in an alkyl group is replaced by a non-carbon atom O, N, S, the obtained heteroalkyl group is an alkoxy group (e.g., -OCH3, etc.), an amino group (e.g., -NHCH3, -N(CH3)2, etc.) or a thioalkyl group (e.g., -SCH3). If the carbon atom not directly connected to an adjacent group in an alkyl group is replaced by a non-carbon atom O, N, S, the obtained heteroalkyl group is an alkoxyalkyl group (e.g., -CH2CH2-O-CH3, etc.), an alkylaminoalkyl group (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.) or an alkylthioalkyl group (e.g., -CH2-S-CH3). If the terminal carbon atom of an alkyl group is replaced by a non-carbon atom, the resulting heteroalkyl group can be a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or a mercaptoamino group (e.g., -CH2CH2-SH). Phrases containing the term "heteroalkyl" such as "C1-C9 heteroalkyl" or "C1-9 “Heteroalkyl” refers to a heteroalkyl group containing 1 to 9 carbon atoms, which at each occurrence may be independently C1 heteroalkyl, C2 heteroalkyl, C3 heteroalkyl, C4 heteroalkyl, C5 heteroalkyl, C6 heteroalkyl, C7 heteroalkyl, C8 heteroalkyl or C9 heteroalkyl.

[0058] Herein, "heterocycloalkyl" (also referred to as "non-aromatic heterocycloalkyl") refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom, such as an N atom, an O atom, or an S atom. Heterocycloalkyl can be a saturated ring or a partially unsaturated ring. Phrases containing this term, such as "C4-C9 heterocycloalkyl" or "C 4-9 "Heterocycloalkyl" refers to a heterocycloalkyl group containing 4 to 9 carbon atoms, which, at each occurrence, may be independently C4 heterocycloalkyl, C5 heterocycloalkyl, C6 heterocycloalkyl, C7 heterocycloalkyl, C8 heterocycloalkyl or C9 heterocycloalkyl. Suitable examples include, but are not limited to, dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothienyl, thioxylated tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindole.

[0059] Herein, the term "heteroaryl" refers to an aromatic heterocyclic group, which may be a monovalent group formed by replacing at least one carbon atom of an aryl group with a non-carbon atom, or a monovalent group formed by replacing at least one carbon atom of a cyclopentadienyl group with a non-carbon atom, wherein the non-carbon atom may be, but is not limited to, an N atom, an O atom, an S atom, a P atom, etc. For example, "C1-C 10 The term "heteroaryl" refers to a heteroaryl group containing 1 to 10 carbon atoms, and each occurrence may be independently a C1 heteroaryl group (such as tetrazolyl, etc.), a C2 heteroaryl group (such as triazolyl, oxadiazolyl, etc.), a C3 heteroaryl group (such as imidazolyl, etc.), a C4 heteroaryl group (such as furanyl, etc.), a C5 heteroaryl group (such as pyridyl, etc.), a C6 heteroaryl group, a C7 heteroaryl group (such as benzimidazole, etc.), a C8 heteroaryl group (such as indolyl, etc.), a C9 heteroaryl group (such as quinolyl, etc.), or a C 10 Heteroaryl (such as pyrrolobipyridinyl). Also for example, "C3~C 20 "Heteroaryl" refers to a heteroaryl group containing 3 to 20 carbon atoms, each occurrence of which can be independently but not limited to C2 heteroaryl, C3 heteroaryl, C4 heteroaryl, C5 heteroaryl, C6 heteroaryl, C8 heteroaryl, C9 heteroaryl, C 10 Heteroaryl, C 12 Heteroaryl, C 13 Heteroaryl, C 14 Heteroaryl, C 18 Heteroaryl or C 20 Heteroaryl. For example, "C3~C 10 Heteroaryl" or "C 3-10The term "heteroaryl" refers to a heteroaryl group containing 3 to 10 carbon atoms, which, at each occurrence, can be independently C3 heteroaryl, C4 heteroaryl, C5 heteroaryl, C6 heteroaryl, C7 heteroaryl, C8 heteroaryl, C9 heteroaryl or C 10 Heteroaryl. Suitable examples include, but are not limited to, heteroaryl groups derived from the following heteroaromatic rings (with the number of carbon atoms indicated in parentheses): furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, thienopyridine, furopyridine, benzoxazole, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primary idine, quinazoline, and quinazolinone.

[0060] As used herein, the term "alkylene" refers to a divalent saturated hydrocarbon group having two monovalent radical centers derived from an alkane by removing two hydrogen atoms (or derived from an alkyl by losing another hydrogen atom), which may be a saturated branched alkyl group or a saturated straight chain alkyl group. For example, "C1-C9 alkylene" or "C 1-9 "Alkylene" means that the alkyl portion contains 1 to 9 carbon atoms and each occurrence can be independently C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, C6 alkylene, C7 alkylene, C8 alkylene or C9 alkylene. Suitable examples include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-) and 1,4-butyl (-CH2CH2CH2CH2-).

[0061] As used herein, the term "cycloalkylene" (also referred to as "non-aromatic cycloalkylene") refers to a divalent residue having two monovalent radical centers derived from a cycloalkyl group by losing a hydrogen atom on the ring. The ring skeleton of the cycloalkylene group may be a monocyclic ring, a spirocyclic ring, or a bridged ring. Phrases containing this term, such as "C3-C9 cycloalkylene" or "C 3-9"Cycloalkylene" refers to a cycloalkylene group containing 3 to 9 carbon atoms, and each occurrence can be independently C3 cycloalkylene, C4 cycloalkylene, C5 cycloalkylene, C6 cycloalkylene, C7 cycloalkylene, C8 cycloalkylene or C9 cycloalkylene. Suitable examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene. In addition, "cycloalkylene" may also contain one or more double bonds, and representative examples of cycloalkylene groups containing double bonds include cyclopentenylene, cyclohexenylene, cyclohexadienylene and cyclobutadienylene.

[0062] Herein, the term "arylene" refers to a divalent residue having two monovalent radical centers derived from an aryl group by losing a hydrogen atom on an aromatic ring. The arylene group can be a monocyclic arylene group, a condensed ring arylene group, or a polycyclic arylene group. For polycyclic rings, at least one is an aromatic ring system. For example, "C5-C 10 "Arylene" or "C 5-10 "Arylene" refers to an arylene group containing 5 to 10 carbon atoms, each occurrence of which can be independently C6 arylene, C8 arylene, C9 arylene, C 10 Arylene, etc. For example, "C6~C 10 "Arylene" or "C 6-10 "Arylene" refers to an arylene group containing 6 to 10 carbon atoms, each occurrence of which can be independently C6 arylene, C8 arylene, C9 arylene or C 10 Arylene. Suitable examples include, but are not limited to, arylene groups derived from the following aromatic rings: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof.

[0063] Herein, the term "divalent heteroalkyl" refers to a divalent residue with two monovalent group centers derived from a heteroalkyl group by losing a hydrogen atom. The non-hydrogen atoms of the divalent heteroalkyl group include at least one non-carbon atom, which can be an N atom, an O atom, an S atom, a P atom, etc. Phrases containing the term "divalent heteroalkyl" include, for example, "C1-C9 divalent heteroalkyl" or "C 1-9"Divalent heteroalkyl" refers to a divalent heteroalkyl group containing 1 to 9 carbon atoms, and each occurrence can be independently C1 divalent heteroalkyl, C2 divalent heteroalkyl, C3 divalent heteroalkyl, C4 divalent heteroalkyl, C5 divalent heteroalkyl, C6 divalent heteroalkyl, C7 divalent heteroalkyl, C8 divalent heteroalkyl or C9 divalent heteroalkyl. Among them, C1 divalent heteroalkyl groups are exemplified by -C(=O)-, -C(=S)-, -C(=NH)-, -CH2-O-, -CH2-S-, -CH2-NH-, etc.; C2 Examples of divalent heteroalkyl groups include -CH2OCH2-, -CH2CH2S-, -OCH2CH2NH-, -CH2-N(CH3)-, -CH2-C(=O)-, -CH2-C(=O)O-, -CH2-NHC(=O)O-, -CH2-NHC(=O)-, etc.; examples of C2 divalent heteroalkyl groups include -CH2-OCH2CH2-O-, -NH-CH2CH2CH2-NH-, -C(=O)-CH2CH2CH2-C(=O)-, etc.

[0064] Herein, "divalent heterocycloalkyl" refers to a divalent residue with two monovalent radical centers derived from a heterocycloalkyl group by losing a hydrogen atom on a heterocyclic ring. The non-hydrogen atoms of the divalent heterocycloalkyl group include at least one non-carbon atom, which can be an N atom, an O atom, an S atom, etc. The divalent heterocycloalkyl group can be a saturated ring or a partially unsaturated ring. Phrases containing this term, for example, "C4-C9 divalent heterocyclic group" or "C 4-9 "Divalent heterocyclic group" refers to a divalent heterocyclic group containing 4 to 9 carbon atoms, which can be independently C4 divalent heteroalkyl, C5 divalent heteroalkyl, C6 divalent heteroalkyl, C7 divalent heteroalkyl, C8 divalent heteroalkyl or C9 divalent heteroalkyl at each occurrence. Suitable examples include, but are not limited to, divalent heterocyclic alkyl groups derived from the following heterocyclic alkyl groups: dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindole. Specific examples of divalent heterocyclic alkyl groups ...hydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothienyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindole. wait.

[0065] Herein, the term "divalent heteroaryl" refers to a divalent residue with two monovalent group centers derived from a heteroaryl group by losing a hydrogen atom on a heteroaryl ring. The non-hydrogen atoms of the divalent heteroaryl group include at least one non-carbon atom, which can be an N atom, an O atom, an S atom, a P atom, etc. For example, "C1-C 10 Divalent heteroaryl" or "C 1-10 "Divalent heteroaryl" refers to a divalent heteroaryl group containing 1 to 10 carbon atoms. For example, "C3~C 10 Divalent heteroaryl" or "C 3-10The term "divalent heteroaryl" refers to a divalent heteroaryl group containing 3 to 10 carbon atoms, and each occurrence thereof can be independently a C3 divalent heteroaryl group, a C4 divalent heteroaryl group, a C5 divalent heteroaryl group, a C6 divalent heteroaryl group, a C7 divalent heteroaryl group, a C8 divalent heteroaryl group, a C9 divalent heteroaryl group or a C 10 Divalent heteroaryl. Suitable examples include, but are not limited to, divalent heteroaryl derived from the following heteroaromatic rings: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, thienopyridine, furopyridine, benzoxazole, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primary pyridine, quinazoline and quinazolinone. Divalent heteroaryl specifically includes, for example wait.

[0066] In this article, Indicates the point of attachment of a group to an adjacent atom or group.

[0067] As used herein, the term "phenylene" may be represented by -Ph-, which may be

[0068] In this paper, a single line is used to penetrate into the ring. represents a monovalent radical center formed from any suitable ring atom, for example Etc. For example, you can

[0069] As used herein, "halogen" or "halo" refers to F, Cl, Br or I.

[0070] Herein, "amino acid" may be a natural amino acid or a non-natural amino acid. L -type, D -Type or L / D As used herein, "amino acid" may be selected from: including but not limited to glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, sarcosine, serine, threonine, cysteine, methionine, tyrosine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, histidine, tryptophan, hydroxyproline, ornithine, etc.

[0071] Herein, "peptide bond" refers to the "C(=O)-N" bonding mode formed between two amino acids by removing a molecule of water.

[0072] Herein, "ester bond" refers to a "C(=O)-O" bonding pattern formed by C(=O) bonded to carbon and O bonded to carbon.

[0073] Herein, "carbamate bond" refers to an "NH-C(=O)-O" bonding pattern in which both ends are bonded to carbon.

[0074] Herein, the "reversible" in "reversible connection" means that the chemical bond can be broken under certain conditions, thereby being able to degrade one molecule into two or more molecules. There is no particular limitation on the conditions for reversibility, as long as the PAH targeted therapeutic drugs (NO and TD) of the present invention can be released. Examples of reversible conditions include, but are not limited to: light, heat, enzymes, redox, acidity, alkalinity, physiological conditions, in vitro simulated environmental conditions, etc. For example, Can release two molecules of NO and At this time, -ONO2 and D (the residue of TD) are connected by a chemical bond, and this connection can be considered reversible. For another example, Can release one molecule of NO and At this time, a degradable ester group (-C(=O)-O-) is included between -ONO2 and D (the residue of TD), and the connection mode is reversible.

[0075] As used herein, the term "derivative" refers to a compound with a similar structure formed from a base compound through chemical changes. The aforementioned chemical changes include, but are not limited to, chemical changes such as ionization, deionization, complexation, decomplexation, hydration, dehydration, esterification, oxidation, reduction, electron rearrangement, structural rearrangement, protection, deprotection (activation), etc. After the base compound undergoes a derivatization reaction, the function and / or activity may change. As used herein, "isofunctional derivative" means a compound that, after derivatization, still has the same function as the base compound through basically the same mechanism, and in terms of activity, may be slightly lower, similar (including basically the same) or better than the base compound. "Slightly lower" means that the effect is slightly worse, but it can still meet the treatment needs. As used herein, "isofunctional" at least includes the same function in the treatment of PAH. For example, an isofunctional derivative of prostacyclin refers to a derivative obtained from a prostacyclin base compound, and the derivative exerts a PAH therapeutic effect through basically the same mechanism as prostacyclin. As used herein, "basically the same activity" means that there is no pharmaceutically acceptable significant difference in activity.

[0076] Herein, the term "analog", if not specifically limited, refers to "analogs with equivalent functions", which means that although the structure is not derived from the reference compound, it can exert the same function as the reference compound and has a slightly lower, similar (including substantially the same) or better activity effect. For those skilled in the art, as long as the reference compound is determined, it is possible to distinguish whether a certain compound belongs to the category of "analogs" of the present application through effect testing, and therefore, the "analogs" in the present application are clear. For example, the "prostacyclin drugs" or "analogs with equivalent functions of prostacyclin" herein include iloprost, beraprost, treprostinil, etc.

[0077] A first aspect of the present invention

[0078] According to a first aspect of the present invention, there is provided an NO donor compound, or a pharmaceutically acceptable salt thereof.

[0079] In the present invention, the NO donor compound has both a NO releasing unit and a PAH targeted drug releasing unit (releasing a PAH targeted therapeutic drug in a different pathway from NO) in one compound molecule. After entering the organism, the NO donor compound utilizes the organism's microenvironment, including but not limited to its own enzyme action, to release nitric oxide (NO) and pulmonary arterial hypertension (PAH) targeted therapeutic drug TD (such as prostacyclin drugs or ERA drugs) in the organism, thereby achieving combined treatment.

[0080] Herein, "pharmaceutically acceptable salt" refers to a salt suitable for use as a drug formed by any compound in the structure shown and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Among them, one type of salt is a salt formed by a compound of the present invention and an acid. Another type of salt is a salt formed by a compound of the present invention and a base.

[0081] In some embodiments of the present invention, the structure of the NO donor compound is shown in formula (I):

[0082] (AL-) q D formula (I);

[0083] in,

[0084] A is a NO donor group;

[0085] q is an integer greater than or equal to 1;

[0086] L is a chemical bond or a linking group; when q is greater than 1, multiple ALs are independent of each other and may be the same or different;

[0087] D is a residue of TD, wherein TD is a prostacyclin drug or an ERA drug. Further, the connection between A and D is a reversible connection.

[0088] In the present invention, the NO donor compound includes a NO donor group (A) and a drug residue (TD), wherein the terminal group of A can release NO, the number of A is q, q is an integer greater than or equal to 1, and when q is greater than 1, each A is independently connected to TD through a corresponding L, and the connection between A and D is designed to be reversible, so that TD molecules (prostacyclin drugs or ERA drugs) can be released.

[0089] In some embodiments, the NO donor compound can provide NO in a suitable manner selected from the following: including but not limited to nitrates, furazan nitrogen oxides, azodiol olefin salts, oximes, NO-metal complexes, S-nitrosothiol, sterone imines, guanidines, hydroxylamines and N-hydroxyureas. Suitable examples of NO donor groups can also be selected from the following literature: "Wang Bing, Li Na, Liu Teng, Wang Yingai, Wang Xiaojing, Sun Jie. Research Progress on Synthesis Methods of Nitric Oxide Donor Compounds [J]. Organic Chemistry, 2017, 37(04): 777-797".

[0090] In some embodiments, the prostacyclin drugs include, but are not limited to, prostacyclin receptor agonists, prostacyclin, analogous derivatives of prostacyclin, and analogous prostacyclin.

[0091] In some embodiments, the ERA drug is preferably an endothelin receptor antagonist.

[0092] At present, pulmonary artery drugs on the market are roughly divided into three categories: prostacyclin analogs, endothelin receptor antagonists and PDE5 inhibitors. These three categories of drugs act on different pathogenic pathways, play a role in dilating pulmonary arterioles and reducing pulmonary vascular resistance.

[0093] In the present invention, a single molecule is used to metabolize into two effective drugs in the body by utilizing the metabolism of the organism itself, respectively acting on two different pathogenic pathways to synergistically treat PAH. Figure 1 . Among them, IP is one of about 10 prostacyclin receptors, but it is considered to be the main receptor for vasodilation. Some drugs such as selexipag can target IP with high selectivity. IP receptor agonists refer to prostacyclin drugs that selectively stimulate IP receptors, such as prostacyclin, treprostinil, iloprost and selexipag.

[0094] Therapeutic mechanism

[0095] NO is an important vasodilator factor, which achieves a vasodilation effect by maintaining the concentration of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells. The compounds provided in this application can release NO under physiological conditions, directly exert a vasodilation effect, and can be accompanied by the release of PAH targeted therapeutic drugs from other treatment pathways to achieve the release of a safe and effective amount of NO, which can directly act on the lesions, avoiding the waste caused by inhaling NO, and can provide a therapeutically effective amount of NO at a lower intake by relatively accurately controlling the intake of NO donors, greatly improving safety.

[0096] Endothelin-1 receptor antagonist (ERA). Endothelin plays an important role in the pathogenesis of PAH. Endothelin-1 can bind to endothelin receptors A and B in pulmonary vascular smooth muscle cells, causing vasoconstriction and promoting mitosis, and participates in the occurrence and development of PAH. ERA can treat PAH by intervening in the endothelin pathway.

[0097] Prostacyclin is produced by vascular endothelial cells, has a strong vasodilator effect, and is also the strongest endogenous platelet aggregation inhibitor. Studies have shown that the expression of prostacyclin synthase in the pulmonary artery of PAH patients is decreased, and the metabolic level in urine is reduced. Artificially synthesized prostacyclin analogs can be used to treat PAH. The prostacyclin drugs used in the present invention are mainly prostacyclin analogs or prostacyclin receptor agonists. The "prostacyclin analogs" herein refer to a class of compounds that can produce PAH therapeutic effects that are substantially the same as or better than prostacyclin through the prostacyclin pathway, including but not limited to iloprost and iloprost.

[0098] The NO donor compound of the present application can reduce the usage of single-target drugs to a certain extent, has better safety, and reduces metabolic pressure. Compared with existing single-target drugs, the NO donor compound provided by the present invention is intended to have better PAH therapeutic efficacy. In addition, significantly different from the current PAH combined treatment scheme, the compound of the present application can use only a single drug molecule, which is decomposed in the body and converted into two effective targeted drug molecules, and the purpose of combined treatment can be achieved through a single drug molecule, and a good dual-target treatment effect of PAH can be achieved through simple and convenient administration.

[0099] NO release mechanism

[0100] The NO release mechanism in the present invention is known to those skilled in the art. Please refer to "Wang Bing, Li Na, Liu Teng, Wang Yingai, Wang Xiaojing, Sun Jie. Research Progress on Synthesis Methods of Nitric Oxide Donor Compounds [J]. Organic Chemistry, 2017, 37(04): 777-797".

[0101] Taking A having a nitrate terminal group as an example, NO can be released in the following manner.

[0102] -ONO2→-OH+NO

[0103] Taking A having an azodiol olefin salt terminal group as an example, NO can be released in vivo in the manner shown in the following formula.

[0104]

[0105] In the present invention, one A can release one or more NO molecules.

[0106] In the present invention, the NO donor compound can carry one or more A, corresponding to q being an integer greater than or equal to 1. In this case, one molecule of the NO donor compound can release one or more NO molecules.

[0107] In some embodiments of the present invention, q is any integer from 1 to 10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0108] In some embodiments of the present invention, q is any integer from 1 to 6, for example 1, 2, 3, 4, 5, 6.

[0109] In some embodiments of the present invention, q is any integer from 1 to 3, for example 1, 2, or 3.

[0110] In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0111] In formula (1), each occurrence of A may be the same or different. In some embodiments of the present invention, in the same molecule, all A are the same.

[0112] In formula (I), each occurrence of AL may be the same or different. In some embodiments of the present invention, in the same molecule, all AL are the same.

[0113] TD release mechanism

[0114] The release mechanism of TD is: after coupling the NO donor group (A) to the drug molecule TD, a reversible linkage RL (reversible linkage) is generated. Under physiological conditions or external stimulation, the reversible linkage can be broken, thereby releasing the TD molecule again. The way in which the "reversible linkage" breaks includes, but is not limited to, hydrolysis, enzymatic hydrolysis, photodegradation, thermal degradation and other clinically acceptable conditions or stimuli. For example, hydrolysis can occur using the pH microenvironment provided by the organism; for example, enzymatic hydrolysis can occur using the enzyme catalytic reaction in the organism; for example, photodegradation occurs by applying clinically acceptable light stimulation (such as infrared, mid-infrared, far-infrared, etc.); for example, thermal degradation occurs by local heating of biological tissues (preferably not exceeding 42°C). The breaking rate of RL directly affects the release rate of TD. Therefore, the control of the release rate of TD can be achieved by controlling the type of RL. In this article, examples of acceptable RL include, but are not limited to, ester groups, carbamate groups, disulfide bonds, etc. The choice of RL type is also related to the type of reactive groups in the TD molecule. For example, when the TD molecule has -COOH, a reversible connection RL can be provided through -COO-, -CONH-, etc., and can be converted back to -COOH when TD is released; for example, when the TD molecule has -OH, it can be converted into the NO donor group -ONO2, and when NO is released, the end group can be converted back to -OH, or a reversible connection RL can be provided through -OC(=O)-, -OC(=O)NH-, etc., and can also be converted back to -OH when TD is released; for example, when the TD molecule has a primary amino group -NH2 , a reversible connection RL can be provided by -NH-CO-, -NH-COO-, -NH-CO-NH-, etc., and can be converted back to -NH2 when TD is released; for example, when the TD molecule has a secondary amino group >NH, a reversible connection RL can be provided by >N-CO-, >NH-COO-, >N-CO-NH, etc., and can be converted back to >NH when TD is released; for example, when the TD molecule has -SH, a reversible connection can be provided by -S-CO-, -SS-, etc., and can be converted back to -SH when TD is released. It should be understood that some of the RL examples listed above are only some examples in the present invention, and the acceptable RL in the present invention is not limited thereto. For example, when the aforementioned "NH" is involved, the "H" therein is allowed to be substituted by some acceptable groups, such as methyl. It should be understood that L in formula (I) is a part of RL. RL may also include a part of D in formula (I), such as the part remaining after the reactive group of TD reacts and forms a chemical bond, such as the -C(=O)- remaining from -COOH. Likewise, the RL may also include a portion of the NO donor group (A).

[0115] In the present invention, one molecule of NO donor compound carries one PAH targeted therapeutic drug molecule (TD molecule).

[0116] In some embodiments, one molecule of NO donor compound carries one molecule of PAH targeted therapeutic drug (TD molecule).

[0117] In the present invention, by controlling q in formula (I), the ratio of released NO to TD can be controlled. By controlling the type of reversible linker (RL), the release rate of TD can be controlled. The release rate of NO can be controlled by the selection of NO donor groups and the type of RL. By the rational design of the molecular formula and the coordinated matching of the molecular features, a flexible dosing regimen can be provided.

[0118] In formula (I), each A is independent of each other. That is, when q is greater than 1, multiple A's are independent of each other and may be the same or different.

[0119] In some embodiments of the present invention, each occurrence of the NO donor group (A) independently has at least one of the following terminal groups: -ONO2, -CR 05 =NOH, -NR 06 -N + (O - )=N-OR5、 Wherein, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl.

[0120] In some embodiments of the present invention, each occurrence of the NO donor group (A) independently has at least one of the following terminal groups: -ONO2, -CR 05 =NOH, -NR 06 -N + (O - )=N-OR5、 Wherein, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl.

[0121] In some embodiments of the present invention, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl (further C 5-20 Aryl, 5- to 20-membered heteroaryl, substituted C 5-20 Aryl or substituted 5- to 20-membered heteroaryl, further C 5-10 Aryl, 5- to 10-membered heteroaryl, substituted C 5-10 Aryl or substituted 5- to 10-membered heteroaryl, further C 5-6 Aryl, 5- to 6-membered heteroaryl, substituted C 5-6 Aryl or substituted 5- to 6-membered heteroaryl, further phenyl or substituted phenyl, further phenyl);

[0122] R 05 H or C 1-6 Alkyl (further H or methyl, further H);

[0123] R 06 is an alkyl group (further C 1-20 Alkyl, further C 1-12 Alkyl, further C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 Alkyl, further methyl or ethyl, further methyl);

[0124] R5 is alkyl, alkenyl, substituted alkyl or substituted alkenyl, and further is C 1-6 Alkyl, -CH=CH-R 5a or R 5b O-substituted C 1-6 Alkyl (wherein R 5a H or C 1-20 Alkyl, further H or C 1-6 Alkyl, further H or methyl, further H; R 5b is an alkyl group or a carbonyl group, further comprising C 1-6 Alkyl or C 1-6 Carbonyl, further C 1-6 carbonyl, further acetyl), further C 1-6 Alkyl, -CH=CH-R 5a or R 5b O-CH2-, further -CH=CH-R 5a or R 5b O-CH2-;

[0125] The ring Cy1 is an unsubstituted or substituted 5- to 20-membered nitrogen heterocyclic ring, wherein the 5- to 20-membered nitrogen heterocyclic ring is further a 5- to 6-membered nitrogen heterocyclic ring, and further a pyrrole ring, a tetrahydropyrrole ring, a piperazine ring or a piperidine ring.

[0126] In some embodiments of the present invention, A provides NO through a single type of terminal group, and the single type of terminal group can be selected from any one of nitrates, furazan nitrogen oxides, azodiol olefin salts, oximes, NO-metal complexes, S-nitrosothiol, sterone imines, guanidines, hydroxylamines, N-hydroxyureas, etc.

[0127] In some embodiments of the invention, all A have terminal groups At least one of the following, wherein Ar is phenyl; further, none of them contain other types of terminal groups that release NO. In some embodiments of the present invention, all A have terminal groups Any one of the following, wherein Ar is phenyl.

[0128] In some embodiments of the present invention, all A have terminal groups -ONO2, and further, do not contain other types of terminal groups that release NO.

[0129] In some embodiments of the invention, all A have terminal groups Ar is a phenyl group; further, none of the groups contain other types of terminal groups that release NO.

[0130] In some embodiments of the present invention, all A's have a terminal group -CH=NOH; further, none of them contain other types of terminal groups that release NO.

[0131] In some embodiments of the invention, all A have terminal groups -NR 06 -N=N + (O - )-OR5;R 06 C 1-3 Alkyl (preferably methyl); R5 is -CH=CH2 or -CH2O-C(=O)CH3; further, neither contains other types of terminal groups that release NO.

[0132] In some embodiments of the invention, all A have terminal groups Cyc1

[0133] R5 is -CH=CH2 or

[0134] -CH2O-C(=O)CH3. Furthermore, none of them contain other types of terminal groups that release NO.

[0135] In some embodiments of the present invention, all A provide NO via -ONO2, that is, the terminal groups providing NO are limited to -ONO2.

[0136] In some embodiments of the invention, all A are At least one of the above provides NO, wherein Ar is as defined above.

[0137] In some embodiments of the invention, all A are Any one of provides NO, wherein Ar is as defined above.

[0138] In some embodiments of the invention, all A are Providing NO, wherein Ar is as defined above.

[0139] In some embodiments of the invention, all A are replaced by -CR 05 =NOH provides NO, where R 05 As defined above.

[0140] In some embodiments of the invention, all A are represented by -NR 06 -N + (O - )=N-OR5 provides NO, where R 06 , R5 are as defined above.

[0141] In some embodiments of the invention, all A are Providing NO, wherein ring Cy1 and R5 are as defined above.

[0142] In some embodiments of the present invention, each occurrence of A independently comprises at least one of the following structures:

[0143] In some embodiments of the present invention, each occurrence of A independently comprises at least one of the following structures:

[0144] In some embodiments of the present invention, X1 is a chemical bond, or a linear, branched or ring-containing linking group (further a chemical bond, or a linear or branched linking group, further a chemical bond or a linear linking group).

[0145] In some embodiments, X1 can be a chemical bond, or X1 can be an alkylene group, a cycloalkylene group, an arylene group, a divalent heteroalkyl group, a divalent heterocycloalkyl group, a divalent heteroaryl group, a substituted alkylene group, a substituted cycloalkylene group, a substituted arylene group, a substituted divalent heteroalkyl group, a substituted divalent heterocycloalkyl group, a substituted divalent heteroaryl group, or a suitable divalent linking group formed by a combination of multiple divalent groups thereof.

[0146] Further, X1 is a chemical bond, or X1 is C 1-20 Alkylene, C 3-20 Cycloalkylene, C 5-20 Arylene, C 1-20 divalent heteroalkyl, 3- to 20-membered divalent heterocycloalkyl, 5- to 20-membered divalent heteroaryl, substituted C 1-20 Alkylene, substituted C 3-20 Cycloalkylene, substituted C 5-20 Arylene, substituted C 1-20 A suitable divalent linking group can be a divalent heteroalkyl group, a substituted 3- to 20-membered divalent heterocycloalkyl group, a substituted 5- to 20-membered divalent heteroaryl group, or a combination of multiple divalent groups thereof.

[0147] Furthermore, X1 is a chemical bond, or X1 is C 1-10 Alkylene, C 3-10 Cycloalkylene, C 5-10 Arylene, C 1-10 divalent heteroalkyl, 3- to 10-membered divalent heterocycloalkyl, 5- to 10-membered divalent heteroaryl, substituted C 1-10 Alkylene, substituted C 3-10 Cycloalkylene, substituted C 5-10 Arylene, substituted C 1-10 A suitable divalent linking group may be a divalent heteroalkyl group, a substituted 3- to 10-membered divalent heterocycloalkyl group, a substituted 5- to 10-membered divalent heteroaryl group, or a combination of divalent groups thereof.

[0148] Furthermore, X1 is a chemical bond, or X1 is C 1-6 Alkylene, C 3-6 Cycloalkylene, C 5-6 Arylene, C 1-6 divalent heteroalkyl, 3- to 6-membered divalent heterocycloalkyl, 5- to 6-membered divalent heteroaryl, substituted C 1-6 Alkylene, substituted C 3-6 Cycloalkylene, substituted C 5-6 Arylene, substituted C 1-6 A suitable divalent linking group may be a divalent heteroalkyl group, a substituted 3- to 6-membered divalent heterocycloalkyl group, a substituted 5- to 6-membered divalent heteroaryl group, or a combination of divalent groups thereof.

[0149] In some embodiments, X1 is a chemical bond or is -Z1-, -Ar0-, -Z1-Ar0-, -Z1-Ar0-Z2- or -Ar0-Z2-.

[0150] In some embodiments of the present invention, Z1 and Z2 are each independently a linear, branched or ring-containing linking group, further a linear or branched linking group, and further a linear linking group.

[0151] In some embodiments, Z1 and Z2 are each independently C 1～20 Alkylene (independently further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 Alkylene), C 3～20 Cycloalkylene (independently further C 3～15 Cycloalkylene, further C 3～10 Cycloalkylene, further C 3～6 Cycloalkylene), C 1～20 The divalent heteroalkyl group (independently further C1～15 A divalent heteroalkyl group, further comprising C 1～10 A divalent heteroalkyl group, further comprising C 1～6 divalent heteroalkyl) or C 3～20 The divalent heterocycloalkyl group (independently further C 3～15 A divalent heterocycloalkyl group, further comprising C 3～10 A divalent heterocycloalkyl group, further comprising C 3～6 divalent heterocycloalkyl), or a substituted form of any of the foregoing; further, Z1 and Z2 are each independently C 1～20 Alkylene (independently further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 Alkylene) or C 1～20 The divalent heteroalkyl group (independently further C 1～15 A divalent heteroalkyl group, further comprising C 1～10 A divalent heteroalkyl group, further comprising C 1～6 divalent heteroalkyl); further, Z1 and Z2 are each independently C 1～20 Alkylene (independently further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 alkylene), or a substituted form of any of the foregoing; further, Z1 and Z2 are each independently a chemical bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2-. In some embodiments, Z1 and Z2 are each independently a linear or branched C 1～20 Alkylene (further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 Alkylene), further a straight chain C 1～20 Alkylene (further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 alkylene).

[0152] In some embodiments, Ar0 is C 5-20 Arylene (independently preferably C 5～15 Arylene, further C 5～10 Arylene, further C 5～6 arylene, further phenylene), substituted arylene (independently preferably substituted C 5～15 Arylene, further substituted C5～10 Arylene, further substituted C 5～6 Ar0 is C 5-20 Arylene (independently preferably C 5～15 Arylene, further C 5～10 Arylene, further C 5～6 Ar0 is phenylene or substituted phenylene. In some embodiments, Ar0 is phenylene.

[0153] In some embodiments, Z1 and Z2 are each independently a linear or branched C 1～20 Alkylene (further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 Alkylene), further a straight chain C 1～20 Alkylene (further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 alkylene); and / or,

[0154] Ar0 is phenylene.

[0155] In some embodiments, X1 is a chemical bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2-, -Ph-, or -CH2-Ph-.

[0156] In some embodiments of the present invention, X2 and X3 are each independently a linear, branched or ring-containing linking group (further a linear or branched linking group, and further a linear linking group).

[0157] In some embodiments, X2 and X3 can each independently be an alkylene group, a cycloalkylene group, an arylene group, a divalent heteroalkyl group, a divalent heterocycloalkyl group, a divalent heteroaryl group, a substituted alkylene group, a substituted cycloalkylene group, a substituted arylene group, a substituted divalent heteroalkyl group, a substituted divalent heterocycloalkyl group, a substituted divalent heteroaryl group, or a suitable divalent linking group formed by a combination of multiple divalent groups thereof;

[0158] Further, X2 and X3 are each independently C 1-20 Alkylene, C 3-20 Cycloalkylene, C 5-20 Arylene, C 1-20 divalent heteroalkyl, 3- to 20-membered divalent heterocycloalkyl, 5- to 20-membered divalent heteroaryl, substituted C 1-20 Alkylene, substituted C 3-20 Cycloalkylene, substituted C 5-20 Arylene, substituted C 1-20 A suitable divalent linking group can be a divalent heteroalkyl group, a substituted 3- to 20-membered divalent heterocycloalkyl group, a substituted 5- to 20-membered divalent heteroaryl group, or a combination of multiple divalent groups thereof.

[0159] Further, X2 and X3 are each independently C 1-10 Alkylene, C 3-10 Cycloalkylene, C 5-10 Arylene, C 1-10 divalent heteroalkyl, 3- to 10-membered divalent heterocycloalkyl, 5- to 10-membered divalent heteroaryl, substituted C 1-10 Alkylene, substituted C 3-10 Cycloalkylene, substituted C 5-10 Arylene, substituted C 1-10 A suitable divalent linking group composed of a divalent heteroalkyl group, a substituted 3- to 10-membered divalent heterocycloalkyl group, a substituted 5- to 10-membered divalent heteroaryl group, or a combination of multiple divalent groups thereof; further, X2 is C 1-6 Alkylene, C 3-6 Cycloalkylene, C 5-6 Arylene, C 1-6 divalent heteroalkyl, 3- to 6-membered divalent heterocycloalkyl, 5- to 6-membered divalent heteroaryl, substituted C 1-6 Alkylene, substituted C 3-6 Cycloalkylene, substituted C 5-6 Arylene, substituted C 1-6 A suitable divalent linking group may be a divalent heteroalkyl group, a substituted 3- to 6-membered divalent heterocycloalkyl group, a substituted 5- to 6-membered divalent heteroaryl group, or a combination of multiple divalent groups thereof.

[0160] In some embodiments, X2 and X3 are each independently C 1-20Alkylene, C 3-20 Cycloalkylene, C 1-20 Divalent heteroalkyl, 3 to 20-membered divalent heterocycloalkyl, substituted C 1-20 Alkylene, substituted C 3-20 Cycloalkylene, substituted C 1-20 Suitable divalent linking groups include divalent heteroalkyl groups, substituted 3- to 20-membered divalent heterocycloalkyl groups, or combinations of multiple divalent groups thereof.

[0161] Furthermore, X2 and X3 are each independently C 1-10 Alkylene, C 3-10 Cycloalkylene, C 1-10 Divalent heteroalkyl, 3 to 10-membered divalent heterocycloalkyl, substituted C 1-10 Alkylene, substituted C 3-10 Cycloalkylene, substituted C 1-10 Suitable divalent linking groups include divalent heteroalkyl groups, substituted 3- to 10-membered divalent heterocycloalkyl groups, or combinations of multiple divalent groups thereof.

[0162] Furthermore, X2 and X3 are each independently C 1-6 Alkylene, C 3-6 Cycloalkylene, C 1-6 Divalent heteroalkyl, 3- to 6-membered divalent heterocycloalkyl, substituted C 1-6 Alkylene, substituted C 3-6 Cycloalkylene, substituted C 1-6 Suitable divalent linking groups include divalent heteroalkyl groups, substituted 3- to 6-membered divalent heterocycloalkyl groups, or combinations of multiple divalent groups thereof.

[0163] In some embodiments, X2 and X3 are each independently C 1～20 Alkylene (independently further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 Alkylene) or C 3～20 Cycloalkylene (independently further C 3～15 Cycloalkylene, further C 3～10 Cycloalkylene, further C 3～6 cycloalkylene); further, X2 and X3 are each independently C 1～20 Alkylene (independently further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 alkylene).

[0164] In some embodiments, X2 and X3 are each independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2-.

[0165] In some embodiments, X1 is a chemical bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2-, -Ph-, or -CH2-Ph-; and / or,

[0166] X2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-.

[0167] In some embodiments of the present invention, X4 is a linear, branched or ring-containing linking group (further a linear or branched linking group, and further a linear linking group).

[0168] In some embodiments, X4 can be an alkylene group; further, X4 is C 1～20 Alkylene, further C 1～15 Alkylene, further C 1～10 Alkylene, further C 1～6 Alkylene, further C 1～3 The alkylene group is further a methylene group or the ethylene group is further a methylene group.

[0169] In some embodiments of the present invention, X5 is a chemical bond, or a linear, branched or ring-containing linking group (further a chemical bond, or a linear or branched linking group, further a chemical bond or a linear linking group).

[0170] In some embodiments, X5 can be a chemical bond or an alkylene group; further, X5 can be a chemical bond or a C 1～20 Alkylene, further chemical bond or C 1～15 Alkylene, further chemical bond or C 1～10 Alkylene, further chemical bond or C 1～6 Alkylene, further chemical bond or C 1～3 Alkylene.

[0171] In some embodiments of the present invention, A in formula (I) comprises X1 is as defined in any embodiment herein.

[0172] In some embodiments of the present invention, A in formula (I) comprises X2 and Ar are as defined in any embodiment herein.

[0173] In some embodiments of the present invention, A in formula (I) comprises X2 and Ar are as defined in any embodiment herein.

[0174] In some embodiments of the present invention, A in formula (I) comprises X3, R 05 As defined in any embodiment herein.

[0175] In some embodiments of the present invention, A in formula (I) comprises X4, R 06 , R5 is as defined in any embodiment herein.

[0176] In some embodiments of the present invention, A in formula (I) comprises Cy1, X5, and R5 are as defined in any embodiment herein.

[0177] In some embodiments of the present invention, X1 is a chemical bond, or a linear, branched or ring-containing linking group (further a chemical bond, or a linear or branched linking group, further a chemical bond or a linear linking group); and / or,

[0178] X2 and X3 are each independently a linear, branched or ring-containing linking group (further a linear or branched linking group, further a linear linking group); and / or,

[0179] X4 is a linear, branched or ring-containing linking group (further a linear or branched linking group, further a linear linking group); and / or,

[0180] X5 is a chemical bond, or a linear, branched or ring-containing linking group (further a chemical bond, or a linear or branched linking group, further a chemical bond or a linear linking group).

[0181] In some embodiments of the present invention, Ar is phenyl.

[0182] In some embodiments of the present invention, A in formula (I) comprises In some preferred embodiments, X1 is a chemical bond, -Z1-, -Ph-, -Z1-Ph-, -Z1-Ph-Z2- or -Ph-Z2-; Z1 and Z2 are each independently defined as above. Further, Z1 and Z2 are each independently preferably C 1～6 Alkylene (for example, methylene, ethylene, propylene, butylene, pentylene, hexylene). It should be understood that Z1 and Z2 may be the same or different.

[0183] When X1 is a chemical bond, the NO donor compound is exemplified by At this time, the -OH site in the TD molecule is connected to A through a chemical bond. At this time, A is -ONO2, L is a chemical bond, and -OH is regenerated when TD is released.

[0184] In some embodiments of the present invention, X1 is a chemical bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -Ph-, -CH2-Ph-.

[0185] In some embodiments of the present invention, A is -ONO2, -Z1-ONO2, -Ph-ONO2, -Z1-Ph-ONO2, -Z1-Ph-Z2-ONO2 or -Ph-Z2-ONO2. Wherein, the definitions, preferences and examples of Z1 and Z2 are consistent with those above. Further, A can be -ONO2, -(CH2)3-ONO2 or -Ph-ONO2.

[0186] In some embodiments of the present invention, the A comprises One or more of .

[0187] In some embodiments of the present invention, the A comprises

[0188] In some preferred embodiments, X2 is C 1～6 Examples of the alkylene group include methylene, ethylene, propylene, butylene, pentylene and hexylene.

[0189] In some embodiments of the present invention, X2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-. Further, the hydrogen atoms in X2 are allowed to be substituted by one or more substituents Q in a suitable manner, wherein the substituent Q is exemplified by C 1～6 Alkyl, further such as methyl.

[0190] In some embodiments of the present invention, A is In some embodiments of the present invention, A is Wherein, the definition, preference and examples of X2 are independently consistent with the above. Further, A can be Furthermore, the A can be

[0191] In some embodiments of the present invention, the A comprises at least one of the following structures:

[0192] In some embodiments of the present invention, the A comprises at least one of the following structures:

[0193] In some embodiments of the present invention, each occurrence of A is independently selected from: -ONO2, -Z1-ONO2, -Ar0-ONO2, -Z1-Ar0-ONO2, -Z1-Ar0-Z2-ONO2 and -Ar0-Z2-ONO2; in some embodiments, each occurrence of A is independently selected from: -ONO2, -(CH2)3-ONO2 and -Ph-ONO2; in some embodiments, each occurrence of A is independently selected from: -ONO2, -Z1-ONO2, -Ph-ONO2, -Z1-Ph-ONO2, -Z1-Ph-Z2-ONO2 and -Ph-Z2-ONO2).

[0194] In some embodiments of the invention, each occurrence of A is independently selected from the group consisting of:

[0195] (a) Group: -ONO2, -Z1-ONO2, -Ar0-ONO2, -Z1-Ar0-ONO2, -Z1-Ar0-Z2-ONO2, and -Ar0-Z2-ONO2 (in some embodiments, it may be -ONO2, -(CH2)3-ONO2, and -Ph-ONO2; in some embodiments, it may be -ONO2, -Z1-ONO2, -Ph-ONO2, -Z1-Ph-ONO2, -Z1-Ph-Z2-ONO2, and -Ph-Z2-ONO2); and

[0196] Group (b): Furthermore, group (b) can be

[0197] Group (c):

[0198] Group (d)

[0199] Among them, Z1, Z2, Ar0, X2, X3, X4, X5, R 05 , R 06 , R5, and Cy1 may be independently as defined above.

[0200] In some embodiments, each occurrence of A is independently selected from one or more of the following groups: -ONO2, -Z1-ONO2, -Ar0-ONO2, -Z1-Ar0-ONO2, -Z1-Ar0-Z2-ONO2 and -Ar0-Z2-ONO2; further, each occurrence of A can be independently selected from one or more of the following groups: -ONO2, -Z1-ONO2, -Ph-ONO2, -Z1-Ph-ONO2, -Z1-Ph-Z2-ONO2 and -Ph-Z2-ONO2; further, each occurrence of A can be independently selected from one or more of the following groups: -ONO2, -Z1-ONO2, -Ph-ONO2, -Z1-Ph-ONO2, -Z1-Ph-Z2-ONO2 and -Ph-Z2-ONO2.

[0201] In some embodiments of the invention, each occurrence of A is independently selected from the group consisting of:

[0202] (a) Group: -ONO2, -Z1-ONO2, -Ph-ONO2, -Z1-Ph-ONO2, -Z1-Ph-Z2-ONO2 and -Ph-Z2-ONO2; and

[0203] Group (b): Furthermore, group (b) can be The definitions, preferences and examples of Z1, Z2 and X2 are independently consistent with those in the above text.

[0204] In some preferred embodiments of the present invention, each occurrence of A is independently selected from the group consisting of the following groups:

[0205] (a) Group: -ONO2, -(CH2)3-ONO2 and -Ph-ONO2;

[0206] Group (b): Furthermore, group (b) can be

[0207] Group (c):

[0208] Group (d)

[0209] Among them, Ar, R 05 , R 06 , R5 are each independently as defined above; preferably, Ar is phenyl, R 05 For H, R 06 C 1-3 Alkyl (preferably methyl), R5 is -CH=CH2 or -CH2O-C(=O)CH3.

[0210] In some embodiments, each occurrence of A is independently selected from: R 06 , R5 can be independently defined as above, for example R 06 C 1-3 Alkyl (preferably methyl), R5 is -CH=CH2 or -CH2O-C(=O)CH3.

[0211] When q is greater than 1, that is, one NO donor compound molecule contains more than or equal to 2 NO donor groups (A). At this time, these NO donor groups (A) can be the same or different. When different A is used, NO can be released in different ways, achieving different NO release rates, and realizing a flexible release scheme for the active ingredient.

[0212] In some embodiments of the present invention, all A's in the same molecule are the same.

[0213] In formula (I), each AL is independent of each other. That is, when q is greater than 1, multiple ALs are independent of each other and can be the same or different from each other. It should be understood that different Ls can be selected for the same A, and the same L can be selected for different A.

[0214] In some embodiments of the present invention, each AL is independently selected from: -ONO2, -O-X1-ONO2, -NR 04a -X1-ONO2 and -C(=O)-X1-ONO2, wherein the definition, preference and examples of X1 are independently consistent with the above text; R 04a H or C 1-20 Alkyl (independently further H or C 1-10 Alkyl, further H or C 1-6 Alkyl, further H or C 1-3 Alkyl, independently preferably H or methyl, further preferably H); further, each AL can be independently selected from the group consisting of -ONO2, -O-(CH2)2-ONO2, -O-(CH2)3-ONO2 and -C(=O)-(CH2)3-ONO2.

[0215] In some embodiments of the invention, each AL is independently selected from:

[0216] The definitions, preferences and examples of X2 and Ar are independently consistent with those in the above text. 04b Each independently is H or C 1-20 Alkyl (independently further H or C 1-10 Alkyl, further H or C 1-6 Alkyl, further H or C 1-3alkyl, independently preferably H or methyl, further preferably H). In some embodiments, AL is In some embodiments, AL is

[0217] In some embodiments of the invention, each AL is independently selected from the group consisting of:

[0218] (h) Group: -ONO2, -O-X1-ONO2, -NR 04a -X1-ONO2 and -C(=O)-X1-ONO2; and

[0219] (i) Group: Wherein, the definitions, preferences and examples of X1, X2 and Ar are independently consistent with those in the above text. In some embodiments, R 04a , R 04b Each independently is H or C 1-20 Alkyl (independently further H or C 1-10 Alkyl, further H or C 1-6 Alkyl, further H or C 1-3 alkyl, independently preferably H or methyl, further preferably H). In some embodiments, R 04a Can be H or C 1-6 Alkyl, further such as H or methyl.

[0220] In some embodiments of the invention, each AL is independently selected from the group consisting of:

[0221] (h) Group: -ONO2, -O-(CH2)2-ONO2, -O-(CH2)3-ONO2 and -C(=O)-(CH2)3-ONO2; and

[0222] (i) Group:

[0223] In the present invention, when NO and TD are released, other molecules may be generated. Taking group (h) as an example, other molecules that may be generated include: HO-X1-OH, HNR 3 -X1-OH, HOC(=O)-X1-OH. Based on the biological safety of the released molecules, -ONO2 and Examples of these molecules are HO-(CH2)2-OH, HO-(CH2)3-OH, and HO-C(=O)-(CH2)3-OH.

[0224] In some embodiments of the invention, each AL is independently selected from: The definitions, preferences and examples of X2 and Ar are independently consistent with those in the above text. 04b Each independently is H or C 1-20 Alkyl (independently further H or C 1-10 Alkyl, further H or C 1-6 Alkyl, further H or C 1-3 alkyl, independently preferably H or methyl, further preferably H). In some embodiments, AL is

[0225] In some embodiments of the invention, each AL is independently selected from the group consisting of:

[0226] (h) Group: -ONO2, -O-X1-ONO2, -NR 04a -X1-ONO2 and -C(=O)-X1-ONO2; and

[0227] (i) Group: Wherein, the definitions, preferences and examples of X1, X2 and Ar are independently consistent with those in the above text. In some embodiments, R 04a , R 04b Each independently is H or C 1-20 Alkyl (independently further H or C 1-10 Alkyl, further H or C 1-6 Alkyl, further H or C 1-3 alkyl, independently preferably H or methyl, further preferably H). In some embodiments, R 04a Can be H or C 1-6 Alkyl, further such as H or methyl.

[0228] In some embodiments of the invention, each AL is independently selected from the group consisting of:

[0229] (h) Group: -ONO2, -O-(CH2)2-ONO2, -O-(CH2)3-ONO2 and -C(=O)-(CH2)3-ONO2; and

[0230] (i) Group:

[0231] In the present invention, when NO and TD are released, other molecules may be generated. Taking group (h) as an example, other molecules that may be generated include: HO-X1-OH, HNR 3 -X1-OH, HOC(=O)-X1-OH. Based on the biological safety of the released molecules, -ONO2 and Examples of these molecules are HO-(CH2)2-OH, HO-(CH2)3-OH, and HO-C(=O)-(CH2)3-OH.

[0232] In some embodiments of the present invention, all ALs in the same molecule are the same.

[0233] In some embodiments of the present invention, TD is selected from the group consisting of:

[0234] (i) Group A is a prostacyclin class of drug molecules: Selexipag, Ralinepag, Treprostinil, Iloprost, Prostacyclin, Beraprost, any of the foregoing analogs, and any of the foregoing analogs; and

[0235] Group (ii) is ERA class drug molecules: Bosentan, Macietan and Ambrisentan, analogs of any of the foregoing, and analogs of any of the foregoing.

[0236] In some embodiments of the invention, D is adjacent to one or more L via one or more positions in any of the following residues:

[0237]

[0238]

[0239] Wherein, “*” indicates the site in D that is connected to L.

[0240] It should be understood that there may be one or more reactive sites in the TD molecule, so that one or more A's may be connected. When multiple A's are connected, each A is independent.

[0241] It should also be understood that there may be one or more reactive sites in the TD molecule, which may generate one or more types of reversibly linked RLs. For example, TD may have both -COOH and -OH. In this case, different RLs may be generated by reacting with the same or different NO-releasing molecules. Different RLs may be generated for the same type of reactive sites in TD. For example, for -NH2 in TD, -NH-CO-A may be obtained, or -NH-CO-OA may be obtained. For different reactive sites in TD, the same AL may be obtained. For example, when the reactive sites in TD are -NH, -OH, and -SH, the ALs obtained by reacting with A-COOH are all AC(=O)-.

[0242] As used herein, "NO-releasing molecules" refer to molecules that can release NO.

[0243] In some embodiments of the present invention, the reactive sites in the TD molecule may be selected from the group consisting of: -COOH, -NH2, >NH, -OH.

[0244] In some embodiments of the present invention, the linking group formed by L and D, each time it appears, is independently selected from any one of the following connection modes: chemical bond, -O-, -NH-, *-OC(=O)-, *-C(=O)O-, *-NHC(=O)-, *-C(=O)NH-, *-OC(=O)NH- and *-NHC(=O)O-; wherein "*" represents the site in L that is connected to D.

[0245] In some embodiments of the present invention, the linking group formed by L and D is selected from any of the following connection modes: chemical bond, *-OC(=O)-, *-C(=O)O-, *-NHC(=O)- and *-C(=O)NH-; wherein "*" represents the site in L that is connected to D.

[0246] In some embodiments, the linker formed by L and D, each time it appears, is independently selected from any one of the following connection modes: a chemical bond, *-OC(=O)- and *-C(=O)O-; wherein "*" represents the site in L that is connected to the D.

[0247] In some embodiments of the present invention, L is selected from any one of the following connection modes: chemical bond, -O-, -C(=O)- and -NH-; wherein "*" represents the site in L that is connected to D.

[0248] In some embodiments, at least one connection between A and D is a reversible connection.

[0249] In some embodiments, all connections between A and D are reversible connections.

[0250] In some embodiments, the linkage between A and D contains at least one of an ester bond, a peptide bond, a carbamate bond, and a disulfide bond.

[0251] In this document, each occurrence of the "heterocycloalkyl" group independently satisfies that the ring skeleton contains one or more heteroatoms W; the heteroatoms W are selected from one, two or three of N, O and S; when the number of W is multiple, these W are independent of each other and can be the same or different.

[0252] In this document, each occurrence of "heteroaryl" independently satisfies that the aromatic ring skeleton contains one or more heteroatoms W; the heteroatoms W are selected from one, two or three of N, O and S; when the number of W is multiple, these W are independent of each other and can be the same or different.

[0253] As used herein, "substituted" each time it appears independently satisfies: the number of substituents is 1 or more, and when the number of substituents is more than one, these substituents are each independent and may be the same or different.

[0254] In some embodiments, each occurrence of "substituted" is independently selected from one or more of the substituent group G, wherein the substituent group G consists of the following groups: deuterium, halogen, -CN, -OH, -COOH, -NH2, -NHR 01 、-NR 02 R 03 , -SH, -OR1, -SR1, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR 01 、-C(=O)NR 02 R 03 , -S(=O)2OR1, -S(=O)OR1, -OC(=O)R2, -NR 04 C(=O)R2, -S(=O)2R2, -S(=O)R2, -OS(=O)2R2, -OS(=O)R2, -NR 04 S(=O)2R2、-NR 04 S(=O)R2、-S(=O)2NR 01 、-S(=O)NR 01 , C 1-20 Alkyl (independently further C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 Alkyl), C 3-20 Cycloalkyl (independently further C 3-10 Cycloalkyl, further C 3-6 Cycloalkyl), C 5-20 Aryl (independently further C 5-10 Aryl, further C 5-6 Aryl), C 1-20 Heteroalkyl (independently further C 1-10 Heteroalkyl, further C 1-6 Heteroalkyl, further C 1-3 3 to 20 membered heterocycloalkyl (independently further 3 to 10 membered heterocycloalkyl, further 3 to 6 membered heterocycloalkyl), 5 to 20 membered heteroaryl (independently further 5 to 10 membered heteroaryl, further 5 to 6 membered heteroaryl);

[0255] Among them, R 01 C 1-20 Alkyl (independently preferably C 1-10Alkyl, further C 1-6 Alkyl, further C 1-3 Alkyl, preferably methyl);

[0256] R 02 and R 03 Each independently is C 1-20 Alkyl (each independently preferably C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 alkyl, each independently preferably methyl); R 02 and R 03 Can form a ring (further a 3- to 12-membered ring, further a 4- to 5-membered ring, further a 5- or 6-membered ring; can be a saturated ring or an unsaturated ring)

[0257] R 04 H or C 1-20 Alkyl (independently preferably H or C 1-10 Alkyl, further H or C 1-6 Alkyl, further H or C 1-3 Alkyl, independently preferably H or methyl, more preferably H);

[0258] R1 is C 1-20 Alkyl (independently preferably C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 alkyl, preferably methyl or ethyl) or C 5-20 Aryl (independently preferably C 5-15 Aryl, further C 5-10 Aryl, further C 5-6 Aryl, further phenyl); preferably, R1 is C 1-20 Alkyl (independently preferably C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 alkyl, preferably methyl or ethyl) or aryl (independently preferably C 5-20 Aryl, further C 5-15 Aryl, further C 5-10 Aryl, further C 5-6 Aryl, further phenyl);

[0259] R2 is C 1-20 Alkyl (independently preferably C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 alkyl, preferably methyl) or C 6-25 Arylalkyl (independently preferably C6-20 Arylalkyl, further C 6-15 Arylalkyl, further C 6-10 Arylalkyl, further benzyl); preferably, R2 is C 1-20 Alkyl (independently preferably C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 alkyl, preferably methyl).

[0260] In some embodiments, the substituent group G is composed of the following groups: deuterium, F, Cl, -CN, -OH, -COOH, -NH2, -OR1, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR 01 、-C(=O)NR 02 R 03 、-OC(=O)R2、-NR 04 C(=O)R2 and C 1-20 Alkyl (independently further C 1-10 Alkyl, further C 1-6 Alkyl, further C 1-3 alkyl);

[0261] Furthermore, the substituent group G is composed of the following groups: deuterium, F, Cl, -CN, -OH, -COOH, -NH2 and C 1-6 Alkyl (further C 1-3 alkyl).

[0262] In some embodiments of the present invention, the NO donor compound is selected from any one of the following compounds:

[0263]

[0264]

[0265] Among them, "abs" in ZQN-1101-10-P1 represents ABsolute Stereochemistry, absolute configuration. ZQN-1101-10 can also be marked as ZQN-1101-10-P1 in the present invention. The difference between ZQN-1101-10-P1 and ZQN-1101-10-P2 is that the NO donor group is different. ZQN-1101-10-P1 is an off-white solid and easily absorbs moisture.

[0266] In the above NO donor compounds having treprostinil residues, the residue part of treprostinil and the chirality of the hydrogen atoms on the ring, taking ZQN-1101-2 and ZQN-1101-10 as examples, respectively have the following chiral structures:

[0267]

[0268] The NO donor compound in the present invention can also be selected from the appropriate compounds having PAH therapeutic effects in patent document CN102099330A.

[0269] According to the second invention of the present invention, a method for preparing the NO donor compound described in the first aspect of the present invention can be provided.

[0270] In some embodiments of the present invention, the TD drug molecule is obtained by nitric acid esterification of the hydroxyl group. For example, in Example 8, the hydroxyl group is first converted into bromine and then reacted with nitrate to achieve nitric acid esterification (introducing -ONO2). In Example 9, the hydroxyl group is reacted with nitric acid (under the action of acetic anhydride) to achieve nitric acid esterification (directly converting -OH into -ONO2).

[0271] In some embodiments of the present invention, the HO-X1-ONO2 can be obtained by coupling reaction with a TD drug molecule with -COOH, such as HO-(CH2)3-ONO2, HO-(CH2)4-ONO2, etc., and also exemplified by Example 3, Example 4, and Example 6.

[0272] In some embodiments of the present invention, the HOOC-X1-ONO2 can be obtained by coupling reaction with a TD drug molecule with -OH or -NH2, such as HOOC-(CH2)3-ONO2, etc. For example, Example 10.

[0273] In some embodiments of the present invention, the NH2-S(=O)2-Ph-X1-ONO2 can be coupled with a TD drug molecule with -COOH to obtain the NH2-S(=O)2-Ph-X1-ONO2. For example, Example 2 and Example 7.

[0274] In some embodiments of the present invention, It is obtained by coupling reaction with TD drug molecules with -COOH. Etc. Also take Example 5 as an example.

[0275] In the second aspect of the present invention, when the molecular formula of the NO donor compound is determined, those skilled in the art can prepare it by known chemical methods.

[0276] According to the third aspect of the present invention, there is provided a pharmaceutical composition comprising: the NO donor compound described in the first aspect of the present invention or the NO donor compound obtained by the preparation method described in the second aspect of the present invention; and a pharmaceutically acceptable carrier.

[0277] As used herein, "drug" includes any agent, compound, composition or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited, and may be systemic effects or may only produce effects locally. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances, or an inert substance that does not interact.

[0278] In the present invention, the "pharmaceutical composition" refers to a composition that has a pharmaceutical preventive and / or therapeutic effect and can be used as a medicine.

[0279] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0280] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars; (2) starches; (3) cellulose and its derivatives; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils; (10) glycols; (12) esters; (13) agar; (14) buffers; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate-buffered saline; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0281] In some embodiments, the pharmaceutical composition is an oral preparation. In addition to the NO donor compound of the present invention, the pharmaceutical composition also contains a pharmaceutically acceptable carrier suitable for oral preparations.

[0282] In some embodiments, the pharmaceutical composition (oral preparation) is an aqueous solution or suspension containing the NO donor compound of the present invention, wherein the concentration of the NO donor compound in the aqueous solution or suspension is preferably such that it is convenient to accurately administer the drug according to a preset dose.

[0283] In some embodiments, the pharmaceutical composition (oral preparation) contains methylcellulose. It should be understood that the methylcellulose used is a pharmaceutically acceptable carrier and is suitable for oral preparations. Further, it is soluble in the oral preparation and its concentration is a concentration that does not affect the oral nature of the preparation.

[0284] In some embodiments, the pharmaceutical composition is an oral preparation, and the mass volume concentration of methylcellulose in the oral preparation can be 0 to 0.8 (w / v), further can be 0.1% to 0.8% (w / v), and can also be any of the following concentrations or an interval consisting of any two of the following concentrations: 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 0.4% (w / v), 0.5% (w / v), 0.6% (w / v), 0.7% (w / v), 0.8% (w / v), etc. In some embodiments, the mass volume concentration of methylcellulose in the oral preparation is 0.5% (w / v), that is, 0.5g of methylcellulose is contained in every 100mL of the oral preparation. Further, the oral preparation is an aqueous solution or suspension, and the solvent is mainly water (the volume proportion of water can be ≥99%, can be 99% to 100%, and can further be 100%), and further, the solvent is water.

[0285] In some embodiments, the pharmaceutical composition is an oral preparation, and the solvent is mainly water. Further, the volume proportion of water in the solvent can be ≥99%, can be 99% to 100%, and can further be 100%. In some embodiments, the solvent is a mixed solvent of water and a second solvent. The second solvent can be one or more of dimethyl sulfoxide (DMSO), ethanol, glycerol, etc. In some embodiments, the second solvent is DMSO. In some embodiments, in the mixed solvent composed of water and the second solvent, the volume proportion of the second solvent does not exceed 1%. In some embodiments, the solvent of the oral preparation is water.

[0286] In some embodiments, the pharmaceutical composition comprises the NO donor compound of the present invention, methylcellulose, DMSO and water, wherein the contents of the NO donor compound, methylcellulose and DMSO can be independently as described above, and the contents of the NO donor compound, methylcellulose and DMSO can also be combined in a suitable manner.

[0287] According to the fourth aspect of the present invention, there is provided the use of the NO donor compound described in the first aspect of the present invention, or the NO donor compound obtained by the preparation method described in the second aspect of the present invention, or the pharmaceutical composition described in the third aspect of the present invention in the preparation of a drug for treating pulmonary arterial hypertension.

[0288] In some embodiments, the use includes but is not limited to treatment of pulmonary hypertension.

[0289] In some embodiments, the application also includes application in the preparation of drugs for treating cardiovascular, pulmonary and vascular diseases, in some of which TD is treprostinil.

[0290] The NO donor compound provided by the present invention has good safety, and the weight change and survival can achieve the same effect as the healthy control group. The NO donor compound provided by the present invention can significantly reduce the right ventricular systolic pressure (RVSP value) and Fulton index, and can achieve a better PAH treatment effect.

[0291] Under certain dosage conditions, compared with traditional single target molecules (such as treprostinil, bosentan, etc.), the NO donor compound provided in the present application can better reduce right ventricular systolic pressure (RVSP value) and Fulton index, and can provide better PAH treatment effect.

[0292] According to some exploratory experiments, under certain dosage conditions (such as 5 mpk, 5 mg per kilogram of body weight per day), NO donor compounds can produce a significant dose-related decrease in mean arterial pressure (MAP) in anesthetized rats (such as a MAP decrease of ≥100 mmHg), while according to existing reports and studies, traditional single target molecules, such as treprostinil, can only achieve a MAP decrease of about 30 mmHg.

[0293] According to the fifth aspect of the present invention, a method for treating pulmonary arterial hypertension (PAH) is provided, comprising administering a therapeutically effective amount of the NO donor compound of the present invention to a patient in need thereof, that is, administering the NO donor compound of the present invention to the patient.

[0294] As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, cattle, sheep, horses, humans, etc., preferably primates, more preferably humans.

[0295] As used herein, "therapeutically effective amount" refers to the amount of a compound that will cause a biological or medical response in an individual, for example, the amount of a pharmaceutical active ingredient (such as the NO donor compound described in the present invention) that brings about a physiological and / or pharmacologically positive effect to an individual, wherein the physiological and / or pharmacologically positive effect includes but is not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression, or preventing disease, etc.

[0296] Mode of administration

[0297] The dosage form and administration method of the compound of the present invention or its pharmaceutical composition are not particularly limited.

[0298] Representative routes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration, inhalation.

[0299] In some embodiments of the invention, administration is by inhalation.

[0300] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or bulking agent; (b) binder; (c) humectant; (d) disintegrant; (e) buffer; (f) absorption accelerator; (g) wetting agent; (h) adsorbent; and (i) lubricant. In capsules, tablets and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above excipients.

[0301] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may include inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers. In addition to these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices. For example, a suspension may include a suspending agent.

[0302] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0303] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required under sterile conditions.

[0304] The embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. These examples are only for illustrating the present invention, and are intended to illustrate the specific formulation composition, preparation method and its function and effect of the present invention, and should not be construed as any form of limitation on the scope of the present invention. Without departing from the technical principles of the present invention, some improvements and adjustments can also be made, and these improvements and adjustments should also be regarded as protection scope of the present invention. The experimental methods for which specific conditions are not indicated in the following examples are preferably referred to the guidance given in the present invention, and can also be according to the experimental manual or normal conditions of this area, and can also be according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art.

[0305] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0306] In the following examples, "room temperature" refers to 20°C to 30°C.

[0307] In the following examples, ET-1 represents plasma endothelin-1; TsCl represents p-toluenesulfonyl chloride; EA represents ethyl acetate; heptane represents n-heptane; CH3CN represents acetonitrile; Py represents pyridine; CH2Cl2 represents dichloromethane; EtOH represents ethanol; HOAc or AcOH represents acetic acid; toluene represents toluene; reflux represents reflux; DMSO represents dimethyl sulfoxide; TEA represents triethylamine; TFA represents trifluoroacetic acid; DMF represents dimethylformamide; DCM represents dichloromethane; CDI represents 3-(4-aminosulfonylphenoxy)propyl nitrate; THF represents tetrahydrofuran; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; acetone represents acetone; DMAP represents 4-dimethylaminopyridine; and dioxane represents dioxane.

[0308] 1. Preparation Example

[0309] Table 1. Example compounds

[0310]

[0311]

[0312]

[0313] Preparation Example 1: NO Source

[0314] Preparation Example 1.1.

[0315]

[0316] Under nitrogen protection, in a 50mL reaction bottle, 3-bromo-1-propanol (1.38g, 10mmol) was dissolved in 10mL acetonitrile, and silver nitrate (1.69g, 10mmol) was added, and stirred at room temperature in dark for 24 hours. Stirring was stopped, insoluble matter in the system was filtered off, 50mL ether was added to the filtrate, the organic phase was washed three times with water, the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed and evaporated to remove the organic solvent to obtain 1.3g of light yellow oil M01 (3-hydroxypropyl nitrate).

[0317] Preparation Example 1.2.

[0318]

[0319] Under nitrogen protection, in a 50mL reaction bottle, 3-bromo-1-butanol (1.38g, 10mmol) was dissolved in 10mL acetonitrile, and silver nitrate (1.69g, 10mmol) was added, and stirred at room temperature in dark for 24 hours. Stirring was stopped, insoluble matter in the system was filtered off, and 50mL ether was added to the filtrate, the organic phase was washed with water three times, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed and evaporated to remove the organic solvent to obtain 1.35g of light yellow oily substance M02 (3-hydroxybutyl nitrate).

[0320] Preparation Example 1.3.

[0321]

[0322] Under nitrogen protection, in a 50mL reaction bottle, 4-bromo-1-butyric acid (1.66g, 10mmol) was dissolved in 10mL acetonitrile, and silver nitrate (1.69g, 10mmol) was added, and stirred for 24 hours in dark at room temperature. Stirring was stopped, insoluble matter in the system was filtered off, and 50mL ether was added to the filtrate, the organic phase was washed three times with water, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed and evaporated to remove the organic solvent to obtain 400g of a light yellow oily substance M03 (4-nitrooxybutyric acid).

[0323] Preparation Example 1.4.

[0324]

[0325] In a 25mL reaction bottle, 3-hydroxypropyl nitrate (500mg, 4.1mmol) was dissolved in 5.0mL dichloromethane, pyridine (1.0mL) was added, the reaction was placed in an ice bath to cool and stir evenly, and a dichloromethane solution (5.0mL) of TsCl (800mg, 4.2mmol) was slowly added dropwise. After the addition was complete, the system was naturally returned to room temperature and stirred overnight. TLC (thin layer chromatography) monitored the reaction. After the reaction was complete, the system was poured into 20mL water and extracted with 100ml of EA, separated, the organic phase was washed with 20ml saturated brine, the organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=4:1) to obtain a yellow oil M04a (800mg).

[0326] In a 25mL reaction bottle, 4-hydroxybenzenesulfonamide (684mg, 4.0mmol) was dissolved in 10mL ethanol, and NaOH (200mg, 5.0mmol), water (0.1mL) and the above yellow oil (800mg, 2.9mmol) were added in sequence, and the oil bath was heated to 80°C and stirred overnight. TLC was used to monitor the reaction. After the reaction was complete, the system was cooled to room temperature, 10mL of water was added, and the pH was adjusted to 6 with 1N hydrochloric acid. The aqueous phase was extracted with EA twice, and the organic phase was washed with 20ml saturated brine. The organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=2:1) ​​to obtain a yellow solid M04 (320mg).

[0327] Preparation Example 1.5.

[0328]

[0329] In a 25mL reaction bottle, (E)-3-phenylprop-2-en-1-ol (5.37g, 40mmol) was dissolved in glacial acetic acid (8mL), and a saturated aqueous solution of sodium nitrite (10mL, 120mmol) was slowly added dropwise for about 1.5 hours. The temperature of the system did not exceed 70°C during the addition. After the addition was completed, stirring was continued for 1 hour. The system was poured into 100mL of water, the aqueous phase was extracted with EA twice, the organic phase was washed with 20mL of saturated brine, the organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=8:1) to obtain a yellow solid M05a (3.2g).

[0330] The above yellow solid was dissolved in 50 mL of toluene, refluxed with stirring for 3 days, and the reaction was monitored by TLC. After the reaction was completed, the system was cooled to room temperature, the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (Hepatne:EA=8.5:1.5) to obtain a yellow oil M05 (350 mg).

[0331] Preparation Example 2. Preparation of NO Donor Compounds

[0332]

[0333] In a 50 mL sealed tube, add 5-chloro-2,3-diphenylpiperazine (2.66 g, 10 mmol) and 4-(isopropylamino)butanol (1.31 g, 10 mmol), heat to 190°C (where Neat means no solvent) and stir for 12 hours. After the reaction is complete as monitored by TLC, the system is cooled to room temperature, water is added to the system, and extracted with 100 ml of EA, the organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (heptane:EA=2:1) ​​to obtain a yellow oil P01a (3.2 g).

[0334]

[0335] In a 50mL three-necked flask, under nitrogen protection, 4-[N-(5,6-diphenylpyrazine-2-yl)-N-(isopropylamino)]-1-butanol (2.2g, 6mmol) was dissolved in 25mL dichloromethane, and rhodium acetate (168mg, 0.6mmol) was added. The system was cooled to -10°C, tert-butyl diazoacetate (0.95g, 8.4mmol) was slowly added dropwise, and after about 15 minutes of complete addition, the mixture was naturally returned to room temperature and stirred overnight. 10ml of saturated brine was added to the system, the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (heptane:EA=4:1) to obtain a yellow oil P01b (900mg).

[0336] The H NMR results of compound P01b are 1 H NMR (CDCl 3, 400MHz, TMS) δ: 1.24~1.29(m,6H),1.49(s,9H),1.68~1.75(m,4H),2.32(s,3H),2.33(s,3H),3.42~3.46(m,2H),3.57~ 3.61(m,2H),3.95(s,2H),4.79~4.84(m,1H),7.03~7.09(m,4H),7.24~7.29(m,2H),7.34~7.38(m,2H),7.96ppm(s,1H).

[0337]

[0338] In a 25 mL reaction bottle, tert-butyl 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-(isopropylamino)]butoxy}acetate (900 mg, 1.89 mmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise under stirring. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction was detected by TLC, and the system was decompressed and dried to obtain a yellow oily product, which was directly used in the next step.

[0339]

[0340] In a 25 mL reaction bottle, 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-(isopropylamino)]butoxy}acetic acid (100 mg, 0.25 mmol) was dissolved in 5 mL of THF. Under nitrogen protection, N,N'-carbonyldiimidazole (40 mg, 0.25 mmol) was added and stirred at room temperature for 30 minutes. The reaction was heated to reflux for 30 minutes, then the system was cooled to room temperature, 3-(4-sulfamoylphenoxy)propyl nitrate (40 mg, 0.14 mmol) was added, and after stirring for 10 minutes, DBU (0.075 mL) was added and stirred at room temperature overnight. After the reaction was completed as monitored by TLC, 10 mL of water was added, and the pH was adjusted to about 3 with 1N hydrochloric acid. The aqueous phase was extracted twice with EA, and the organic phase was washed with 20 mL of saturated brine. The organic phases were collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (CHCl3:MeOH=70:1) to give a yellow solid ZQN-1101-12 (70 mg).

[0341] H NMR results of compound ZQN-1101-12. 1 H NMR (CDCl 3, 400MHz, TMS) δ: 1.24~1.29(m,6H),1.68~1.75(m,4H),2.12-2.25(m,2H),3.42~3.46(m,2H),3.57~3.61(m,2H),3.95(s,2H),4.12- 4.19(m,2H),4.59-4.62(m,2H)4.79~4.84(m,1H),6.84-6.92(m,2H),7.24~7.29(m,6H),7.34~7.38(m,4H),7.97-8.05ppm(m,3H).

[0342] Preparation Example 3. NO Donor Compound:

[0343]

[0344] In a 100mL reaction bottle, 4-chlorodiphenylamine (10g, 49.1mmol) was dissolved in 30mL dichloromethane. After the reaction bottle was placed in an ice bath and cooled to 0°C, triphosgene (Triphosgene, 16.03g, 54.0mmol) was added, and a dichloromethane solution (10mL) of pyridine (5.56ml, 68.7mmol) was slowly added dropwise. After the addition was complete, the system was stirred in an ice bath for 15 minutes, the ice bath was removed, the system was returned to room temperature and stirred at room temperature for 1 hour. TLC monitored the reaction. After the reaction was complete, the system was placed in an ice bath and cooled, and water (20mL) was slowly added dropwise to quench the reaction. The liquid was separated, and the aqueous phase was extracted twice with 100mL dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (hepatane:DCM=(9:1)-(6:4)) to give a yellow oil P02a (12.34 g, yield 93%).

[0345] H NMR results of compound P02a. 1 H NMR (400MHz, DMSO-d6) δ: 7.31-7.81ppm (m, 9H).

[0346]

[0347] In a 50 mL reaction bottle, (4-chlorophenyl)(phenyl)carbamic acid chloride (1.2 g, 4.5 mmol) was dissolved in 5 mL pyridine, and ((1r, 4r)-cyclohexane-1,4-diacyl) dimethanol (600 mg, 4.1 mmol) was added, and the reaction was heated to reflux overnight. TLC monitored the reaction. After the reaction was complete, the system was cooled to room temperature, poured into 20 mL of water, and extracted with 100 mL of EA, separated, and the organic phase was washed with 20 mL of saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (Hepatne:EA=4:1) to obtain a white solid P02b (800 mg).

[0348] H NMR results of compound P02b. 1 H NMR(400MHz, DMSO-d6)δ:0.73-0.92(m,4H),1.13-1.27(m,1H),1.36-1.48(m,1H),1.53-1.62(m,2H),1.62-1.73 (m,2H),3.17(d,J=6.19Hz,2H),3.89(d,J=6.06Hz,2H),4.29(brs,1H),7.23-7.32(m,5H),7.34-7.45ppm(m,4H).

[0349]

[0350] In a 50mL three-necked flask, under nitrogen protection, ((1r, 4r)-4-(hydroxymethyl)cyclohexyl)methyl(4-chlorophenyl)(phenyl)carbamate (300mg, 0.8mmol) was dissolved in 15mL dichloromethane, and rhodium acetate (50mg, 0.11mmol) was added. The system was cooled to -10°C, and a dichloromethane solution (5mL) of tert-butyl diazoacetate (0.5mL) was slowly added dropwise. After about 15 minutes of complete addition, the mixture was naturally returned to room temperature and stirred overnight. 10mL of saturated brine was added to the system, the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (heptane:EA=2:1) ​​to obtain a yellow oil P02c (300mg).

[0351] H NMR results of compound P02c. 1 H NMR(400MHz,DMSO-d6)δ:0.77-0.95(m,4H),1.33-1.50(m,2H),1.42(s,9H),1.52-1.62(m,2H),1.63 -1.75(m,2H),3.22(d,J=6.32Hz,2H),3.83-3.93(m,4H),7.23-7.32(rn,5H),7.35-7.44ppm(m,4H).

[0352]

[0353] In a 25 mL reaction bottle, tert-butyl acetate 2-((1r,4r)-4-((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy (300 mg, 0.6 mmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise under stirring. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction was detected by TLC, and the system was decompressed and dried to obtain a yellow oily product P02d, which was directly used in the next step.

[0354]

[0355] In a 25 mL reaction bottle, 2-((1r, 4r)-4-((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxyacetic acid (84 mg, 0.2 mmol) was dissolved in DMF (2 mL), triethylamine (0.5 mL), 3-hydroxypropyl nitrate (100 mg, 0.8 mmol), HATU (115 mg, 0.3 mmol) were added in sequence, and stirred at room temperature overnight. TLC was used to monitor the reaction. After the reaction was complete, the system was poured into 10 ml of water and extracted twice with 50 ml of EA. The organic phase was separated and washed with 20 ml of saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=4:1) to obtain a light yellow oil ZQN-1101-3 (30 mg).

[0356] H NMR results of compound ZQN-1101-3. 1 H NMR (400MHz, CDCl3, TMS) δ: 0.77-0.95 (m, 4H), 1.51-1.65 (m, 6H), 1.78-1.80 (m, 2H), 2.05-2.11 (m, 2H), 3.30 (d, J= 8.0Hz,2H),3.96(d,J=8.0Hz,2H),4.04(s,2H),4.23(t,J=8.0Hz,2H),4.52(t,J=8.0Hz,2H),7.14-7.34ppm(m,9H).

[0357] Preparation Example 4.

[0358]

[0359] In a 25 mL reaction bottle, 2-((1r, 4r)-4-((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxyacetic acid (84 mg, 0.2 mmol) was dissolved in DMF (2 mL), and triethylamine (0.5 mL), 3-hydroxybutyl nitrate (108 mg, 0.8 mmol), and HATU (115 mg, 0.3 mmol) were added in sequence, and stirred at room temperature overnight. TLC was used to monitor the reaction. After the reaction was complete, the system was poured into 10 mL of water and extracted twice with 50 mL of EA. The organic phase was separated and washed with 20 ml of saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=2:1) ​​to obtain a light yellow product P4 (34 mg).

[0360] H NMR results of compound P4. 1H NMR (400MHz, CDCl3, TMS) δ: 0.88-0.3(m,4H),1.24-1.30(m,2H),1.46-1.65(m,6H),1.78-1.80(m,2H),2.05-2.11(m,2H),3. 30(d,J=8.0Hz,2H), 3.96(d,J=8.0Hz,2H), 4.04(s,2H), 4.24(t,J=8.0Hz,2H), 4.52(t,J=8.0Hz,2H), 7.14-7.34ppm(m,9H).

[0361] Preparation Example 5.

[0362]

[0363] In a 25 mL reaction bottle, 2-((1r, 4r)-4-((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxyacetic acid (50 mg, 0.12 mmol) was dissolved in DMF (1 mL), and triethylamine (0.1 mL), 4-(hydroxymethyl)-3-phenyl-1,2,5-oxadiazole 2-oxide (30 mg, 0.15 mmol), HATU (50 mg, 0.13 mmol) were added in sequence, and stirred at room temperature overnight. TLC monitored the reaction. After the reaction was complete, the system was poured into 10 mL of water and extracted twice with 50 mL of EA, separated, and the organic phase was washed with 20 mL of saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=3:1) to obtain a light yellow oil ZQN-1101-7 (45 mg).

[0364] H NMR results of compound ZQN-1101-7. 1 H NMR (400MHz, CDCl3, TMS) δ:0.83-0.94(m,4H),1.24-1.30(m,2H),1.46-1.65(m,6H),1.74-1.76(m,2H),3.25 (d,J=8.0Hz,2H),3.94(d,J=8.0Hz,2H),4.06(s,2H),5.36(s,2H),7.14-7.34(m,9H),7.41-7.52ppm(m,5H).

[0365] Preparation Example 6.

[0366]

[0367] In a 25mL reaction bottle, treprostinil (332mg, 1mmol) was dissolved in DMF (2mL), and triethylamine (260mg, 2.5mmol), 3-hydroxypropyl nitrate (242mg, 2mmol), HATU (481mg, 1.25mmol) were added in sequence, and stirred at room temperature overnight. TLC monitored the reaction. After the reaction was complete, the system was poured into 10mL of water and extracted twice with 50mL of EA, separated, and the organic phase was washed with 20mL of saturated brine. The organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Hepatne:EA=1:1) to obtain light yellow ZQN-1101-2 (34mg).

[0368] H NMR results of compound ZQN-1101-2. 1 H NMR (400MHz, CDCl3, TMS) δ: 0.87 (t, J = 8.0Hz, 3H), 1.12-1.21 (m, 1H), 1.27-1.30 (m, 5H), 1.42-1.45 ( m,2H),1.54-1.57(m,2H),1.6242-1.66(m,2H),1.70-2.10(m,5H),2.01-2.10(m,2H),2.10-2.30(m,2 H),2.40-2.58(m,2H),2.69-2.80(m,2H),3.55-3.62(m,1H),3.68-3.75(m,1H),4.25-4.30(m,2H),4. 37-4.46(m,2H),4.63(s,2H),6.59(d,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),7.05ppm(t,J=8.0Hz,1H).

[0369] Preparation Example 7.

[0370]

[0371] In a 25 mL reaction bottle, treprostinil (50 mg, 0.15 mmol) was dissolved in DMF (1 mL), triethylamine (0.1 mL), 4-(hydroxymethyl)-3-phenyl-1,2,5-oxadiazole 2-oxide (30 mg, 0.15 mmol), HATU (50 mg, 0.13 mmol) were added in sequence, and stirred at room temperature overnight. TLC monitored the reaction, and after the reaction was complete, the system was poured into 10 mL of water and extracted twice with 50 ml of EA, separated, the organic phase was washed with 20 mL of saturated brine, the organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (DCM / EA=6 / 4) to obtain a light yellow oil ZQN-1101-10 (25 mg).

[0372] H NMR results of compound ZQN-1101-10. 1 H NMR (400MHz, CDCl3, TMS) δ: 0.87 (t, J = 8.0Hz, 3H), 1.12-1.21 (m, 1H), 1.27-1.30 (m, 5H), 1.35-1.53 (m,5H),1.54-1.57(m,2H),1.70-2.10(m,1H),2.01-2.10(m,2H),2.25-2.52(m,5H),2.40-2.58(m, 2H),2.69-2.80(m,2H),3.55-3.62(m,1H),3.68-3.75(m,1H),4.65(s,2H),5.37(s,2H),6.59(d,J= 8.0Hz,1H),6.79(d,J=8.0Hz,1H),7.05(t,J=8.0Hz,1H),7.38-7.52(m,3H),7.55-7.62ppm(m,2H).

[0373] Preparation Example 8.

[0374]

[0375] In a 25 mL reaction bottle, (1R, 2R, 3aS, 9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopentane[b]naphthalene-2,5-diol (1.6 g, 48 mmol) was dissolved in acetone (40 mL), potassium carbonate (5.37 g, 289 mmol) and tert-butyl bromoacetate (1.4 g, 72 mmol) were added in sequence, heated to reflux and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, the system was cooled to room temperature, filtered, and the organic solvent was removed by vacuum rotary evaporation to obtain a crude product P08a, which was directly used in the next step.

[0376]

[0377] In a 25 mL reaction bottle, tert-butyl 2-((1R, 2R, 3aS, 9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a, 4,9,9a-hexahydro-1H-cyclopentane[b]naphthalen-5-yl)oxy)acetate (600 mg, 1.34 mmol) and N,N-dimethylpyridine (514 mg, 4.00 mmol) were dissolved in dichloromethane (10 mL), 4-bromobutyryl chloride (622 mg, 3.3 mmol) was added dropwise, and stirred at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, the organic solvent was removed by vacuum rotary evaporation to obtain a crude product, which was purified by column chromatography (Hepatne:EA=2:1) ​​to obtain light yellow P08b (680 mg).

[0378]

[0379] Under nitrogen protection, in a 50 mL reaction bottle, (S)-1-((1R, 2R, 3aS, 9aS)-2-((4-bromobutyryl)oxy)-5-(2-(tert-butoxy)-2-oxoethoxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopentyl[b]naphthalen-1-yl)octan-3-yl 4-bromobutyrate (250 mg, 0.3 mmol) was dissolved in 10 mL acetonitrile, and silver nitrate (0.51 g, 3 mmol) was added. The mixture was stirred at room temperature in the dark for 24 hours. Stirring was stopped, the insoluble matter in the system was filtered off, and 50 mL of ether was added to the filtrate. The organic phase was washed with water three times, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the organic solvent. The crude product was purified by column chromatography (heptane:EA=1:1) to obtain an oily substance P08c (210 mg).

[0380] The above oily substance P08c (100 mg) was dissolved in 5 mL of 1 M HCl in dioxane and stirred at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, the organic solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH = (20:1) to (10:1)) to obtain an oily substance ZQN-1101-9 (32 mg).

[0381] H NMR results of compound ZQN-1101-9. 1H NMR (400MHz, CDCl3, TMS) δ: 0.87 (t, J = 8.0Hz, 3H), 1.12-1.21 (m, 1H), 1.27-1.30 (m, 5H), 1.42-1.45 ( m,2H),1.54-1.57(m,2H),1.62-1.66(m,2H),1.70-2.10(m,5H),2.01-2.10(m,4H),2.10-2.30(m,2H ),2.40-2.58(m,2H),2.69-2.80(m,2H),3.55-3.62(m,1H),3.68-3.75(m,1H),4.25-4.30(m,4H),4. 37-4.46(m,4H),4.52(s,2H),6.59(d,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),7.05ppm(t,J=8.0Hz,1H).

[0382] In addition, the preparation of compound ZQN-1101-6 can refer to the preparation method of compound ZQN-1101-9. The carboxyl group and the hydroxyl group on the ring can be selectively protected and then the hydroxyl group on the carbon chain can be grafted.

[0383] Preparation Example 9.

[0384]

[0385] In a 25 mL reaction bottle, tert-butyl 2-((1R, 2R, 3aS, 9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a, 4,9,9a-hexahydro-1H-cyclopentane[b]naphthalen-5-yl)oxy)acetate (200 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0°C. Nitric acid (2 mL) and acetic anhydride (5 mL) were mixed and cooled to 0°C and slowly added dropwise to the reaction bottle. After the addition was complete, the mixture was kept at 0°C and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was slowly added dropwise to a saturated sodium carbonate aqueous solution, and the aqueous phase was extracted twice with 50 mL of EA. The organic solvent was removed by decompression, and the crude product was purified by column chromatography (Hepatne:EA=1:1) to obtain a light yellow oil P09a (180 mg).

[0386] The above oily substance P09a (150 mg) was dissolved in 5 mL of 1 M HCl in dioxane solution and stirred at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, the organic solvent was removed by vacuum vortexing, and the crude product was purified by column chromatography (DCM / MeOH = (20:1) to (10:1), 2% AcOH) to obtain an oily substance ZQN-1101-5 (78 mg).

[0387] H NMR results of compound ZQN-1101-5. 1 H NMR (400MHz, CDCl3, TMS) δ: 0.87 (t, J = 8.0Hz, 3H), 1.12-1.21 (m, 1H), 1.27-1.30 (m, 5H) ),1.42-1.45(m,2H),1.54-1.57(m,2H),1.62-1.66(m,2H),1.70-2.10(m,5H),2.10-2 .30(m,2H),2.40-2.58(m,2H),2.69-2.80(m,2H),3.83-3.88(m,1H),4.14-4.20(m,1H ), 4.52 (s, 2H), 6.59 (d, J = 8.0Hz, 1H), 6.79 (d, J = 8.0Hz, 1H), 7.05ppm (t, J = 8.0Hz, 1H).

[0388] Preparation Example 10.

[0389]

[0390] In a 25 mL reaction bottle, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methyl-phenoxy)-[2,2']dipyrimidin-4-yl]benzenesulfonamide (50 mg, 0.09 mmol) was dissolved in DMF (1.5 mL), triethylamine (1 mL), 4-nitrosobutyric acid (70 mg, 0.47 mmol), HATU (70 mg, 0.18 mmol) were added in sequence, and stirred at room temperature overnight. TLC monitored the reaction. After the reaction was complete, the system was poured into 10 mL of water and extracted twice with 50 mL of EA, separated, the organic phase was washed with 20 mL of saturated brine, the organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by column chromatography (Heptane:EA=1:1) to obtain a light yellow solid ZQN-1101-8 (24 mg).

[0391] 2. Drug activity detection

[0392] 2.1. Drug activity detection model

[0393] According to the analysis of PAH patients, the most significant feature of PAH patients is the hyperplasia of pulmonary artery smooth muscle, which makes the inner wall of pulmonary artery thicken, leading to pulmonary hypertension. In order to detect whether the molecules designed by our company have anti-proliferative activity on smooth muscle cells, human pulmonary artery smooth muscle cells (PASMC) are used as a research example to establish a detection model. The specific model is as follows:

[0394] To evaluate the concentration-dependent effects of putative antiproliferative agents (0.01–10,000 nM), HPASMCs from PAH patients were cultured at 1 × 10 4 The density of cells was seeded into 96- (MTS assay) or 6- (cell counting) well plates / mL (total volume of 100 μL or 2 mL, respectively). Cells were grown in SMBM medium (ScienCell) containing 9% FBS, and after 24 hours, the medium was replaced with SMBM alone and cultured for 48 hours to inhibit cell growth. Subsequently, the cells were incubated for 4 days in SMBM containing 9% FBS and 3nM ET-1 in the absence and presence of 0.1% dimethyl sulfoxide (DMSO) with and without the test compound. The proliferation response was compared with cells incubated without the addition of growth factors for the same period of time (time control). Each intervention was performed in quintuplicate (MTS) or duplicate (cell counting).

[0395] Among them, MTS assay is lymphocyte proliferation detection; FBS is fetal bovine serum, and SMBM is smooth muscle cell basal medium.

[0396] 2.2. Test for inhibition of PASMC cell proliferation

[0397] Seed plate: 96-well cell culture plate, cell density 20,000 / mL, 100 μL / well, 3 replicates;

[0398] Starvation: When the cell confluence was about 50%, starve the cells in serum-free or low-serum (2.5% FBS) SMCM medium (smooth muscle cell medium, Gibco) for 48 hours;

[0399] Co-incubation: restore normal serum (12.5% ​​FBS) to SMCM medium and continue culturing, add 3nM ET-1 for synergistic stimulation, and co-incubate with different concentrations (0.01nM-10000nM) of the test compound for 96 hours;

[0400] Determine OD value: discard the original culture medium, add RPMI-1640 culture medium containing 10% CCK-8 (100 μL / well), continue incubation for 2 hours, and measure the OD value at a wavelength of 450 nm using an enzyme reader.

[0401] The calculation formula of cell proliferation rate is: (OD of drug-treated cells-OD of blank cells) / (OD of control cells-OD of blank cells)×100%.

[0402] The compounds to be tested in each group are shown in Table 1. Among them, ZQN-1101-1 is bosentan, ZQN-1101-4 is treprostinil, and ZQN-1101-11 is selexipag.

[0403] Test results such as Figure 2 and Figure 3 The results showed that ZQN-1101-2 and ZQ-1101-10 both showed a certain ability to inhibit cell proliferation in PASMC cells. Compared with a single targeted molecule, ZQN-1101-2 had a better inhibitory effect than treprostinil.

[0404] 2.3. Inhibitory activity

[0405] Table 2 shows the inhibitory activity data of some NO donor compounds of the present invention on the proliferation of pulmonary artery smooth muscle cells. The IC 50 The values ​​were obtained using Graphpad software.

[0406] Table 2. Data on the inhibitory activity against pulmonary artery smooth muscle cell proliferation.

[0407]

[0408]

[0409] Note: The corresponding IC cannot be calculated for the test results of other compounds 50 value.

[0410] Example 3. Animal Experiment

[0411] Experimental plan

[0412] 3.1.1. Animal purchase and pre-adaptation

[0413] 42 7-week-old male Sprague-Dawley rats (average weight 200-250 g) were purchased from Vital River and acclimatized for 1 week at the experimental site (temperature 20-26°C, humidity 30-70%, day-night ratio 1:1) until they were 8 weeks old.

[0414] 3.1.2. Grouping

[0415] 42 rats were randomly divided into 9 groups as shown in Table 3, including drug treatment group, positive control group, negative control group and healthy control group, and ear-tagged with serial numbers.

[0416] Table 3. Dosage regimen

[0417]

[0418] Note 1: Groups 1, 2, and 4 are experimental drugs of the treprostinil class, and groups 3 and 5 are treprostinil positive control groups; Group 6 is an experimental drug of the bosentan class, and group 7 is a bosentan positive control group; Group 8 is a negative control group, and group 9 is a healthy control group.

[0419] Note 2: Regarding the last digit "M" and "H" of the drug numbers in Groups 1-5, the suffix M represents a medium dose (3 mpk); H represents a high dose (6 mpk). Among them, mpk means mg / kg / day, and 1 mpk means 1 mg per kilogram of body weight per day.

[0420] Note 3: The dosage refers to the dosage of the drugs listed in the column of “Oral Gavage Drugs”.

[0421] Among them, the MCT modeling situation is as follows:

[0422] (1) Preparation of Monocrotaline (MCT) solution: Weigh a sufficient amount of MCT into 50 mL of 20% ethanol-saline solution, shake gently and slowly, transfer to a 50 mL centrifuge tube, tilt and place in a constant temperature shaker at 37°C and 220 rpm for 12-14 hours to fully dissolve the MCT until no crystal particles are visible to the naked eye.

[0423] (2) MCT solution injection: The skin on the back of the rat's neck was gently lifted, and the MCT solution was subcutaneously injected at a dose of 60 mg / kg using a 1 mL syringe and recorded as day 0.

[0424] (3) Healthy controls: The same dose of normal saline was injected using the same method.

[0425] 3.1.3. Preparation of drug solutions for each experimental group

[0426] (1) Drug sources: Except for bosentan, which is a purchased product, all drugs including experimental drugs and treprostinil positive control drugs are provided by Zhongqiang Pharmaceuticals; drug structure and purity information are shown in Table 4:

[0427] Table 4. Drug information

[0428]

[0429]

[0430] (2) ZQN-1101-6, ZQN-1101-9 and bosentan solutions can be stored stably for a long time. According to the concentration of 0.6, 1.2 or 10 mg / mL (3, 6, 10 mg / kg / day dose groups), the appropriate weight of the drug was weighed or aspirated to the bottom of a 50 mL centrifuge tube and the corresponding volume of 5% (w / v) methyl cellulose (MC) solution was measured with a 100 mL measuring cylinder for later use. The concentration of the methyl cellulose solution was 5 g methyl cellulose per 100 mL solution, and the solvent was water.

[0431] (3) Pipette the corresponding volume of dimethyl sulfoxide (DMSO) at a ratio of 10 μl / mL three times and add it to a 50 mL centrifuge tube to rinse and shake to dissolve the drug.

[0432] (4) Use a pipette to draw about 2 mL of MC solution and drop it into the bottom of the ceramic mortar to wet the mortar.

[0433] (5) Use a pipette to drop the experimental drug-DMSO solution into the center of the mortar, and use the pestle to continuously grind to avoid the formation of lumps or films, so that the drug is fully dispersed into a fine powder.

[0434] (6) Use a pipette to draw up the MC solution and drip it into the mortar drop by drop. Use the pestle to grind continuously. Repeat this process three times to increase the speed of dripping the liquid.

[0435] (7) Use a dropper to draw 2 mL of MC solution to rinse a 50 mL centrifuge tube three times. Use the dropper to squeeze the drug adhering to the tube wall and pour it into a mortar.

[0436] (8) Collect the liquid in the mortar, rinse it twice with the remaining MC solution and collect it in a storage bottle, and refrigerate it in a refrigerator at 4°C. The content of each component in the liquid pharmaceutical preparation is as follows: the content of methylcellulose is in the range of 0.3% to 0.8% (w / v), the solvent is a mixture of water and DMSO, and the volume proportion of DMSO in the solvent is ≤1%.

[0437] (9) ZQN-1101-8 solution cannot be stored stably for a long time and needs to be prepared and used immediately. The preparation method and the proportion of each component in the drug solution are consistent with those of ZQN-1101-6, ZQN-1101-9 and bosentan mentioned above.

[0438] (10) ZQ08 can be directly dissolved in water. According to the concentration of 0.6 mg / mL or 1.2 mg / mL (3 mg / kg or 6 mg / kg dosage group), the corresponding weight of the drug is weighed and dissolved in the corresponding volume of distilled water (ddH2O) to form a transparent solution.

[0439] Dosage regimen

[0440] Starting from the 14th day, rats were weighed daily and given corresponding solutions (drugs or saline) by gavage according to the grouping scheme until the 27th day, for a total of 14 days; the gavage dose was 0.5 mL / 100 g / day, and the body weight and survival data of the rats were recorded.

[0441] 3.1.5. Hemodynamic measurements

[0442] On day 28, the hemodynamic status of the rats was assessed using right cardiac catheterization:

[0443] (1) Prepare the PE-50 catheter, pressure transducer and pressure measuring workstation; flush the tubing with heparinized saline to ensure that there are no bubbles in the tubing; zero the catheter;

[0444] (2) The rat was anesthetized with 2% by volume (in air) isoflurane at a flow rate of 2 L / min, and the limbs and incisors were fixed on the operating table with the head facing the operator;

[0445] (3) Skin preparation of the surgical area of ​​the neck;

[0446] (4) Cut the neck skin along the midline, use hemostatic forceps to pull and fix the neck skin, and use scissors to separate the tissue layer by layer to expose the right internal jugular vein;

[0447] (5) Use hemostatic forceps to perform blunt separation and free the internal jugular vein;

[0448] (6) Use 4-0 suture to ligate the distal end of the internal jugular vein and pass the suture through the proximal end of the internal jugular vein for later use;

[0449] (7) Use ophthalmic scissors to make a V-shaped incision on the internal jugular vein and insert the PE-50 catheter through this site. After the catheter is inserted, tie the pre-placed suture at the proximal end of the internal jugular vein to fix the catheter;

[0450] (8) The catheter reaches the right atrium and right ventricle in turn; the right atrial pressure and right ventricular pressure are recorded; at least five stable waveforms are recorded at each site; five continuous waveforms are taken as segments, and more than two segments are intercepted to calculate the right ventricular systolic pressure (RVSP);

[0451] (9) Remove the PE-50 catheter and complete the examination.

[0452] 3.1.6. Collection of materials

[0453] (1) After the hemodynamic evaluation was completed, the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate at a dose of 0.5 mL / 100 g, and the samples were collected after weighing;

[0454] (2) After opening the abdominal cavity, use a 5 ml syringe to draw as much blood as possible from the inferior vena cava into an EDTA anticoagulant tube and shake it upside down 6-8 times;

[0455] (3) Continue to open the chest cavity to expose the lungs and heart;

[0456] (4) Cut open the left atrial appendage, use a 5 ml syringe to draw a tube of heparinized saline into the right atrial appendage, and slowly inject to flush the pulmonary blood vessels;

[0457] (5) The rat heart, lung, liver, spleen and kidney tissues were cryopreserved and fixed with formaldehyde solution.

[0458] 3.1.7. Fulton index measurement

[0459] After separating the heart, cut off the parts other than the ventricle, such as the atrium, blood vessels, and valve ring, use forceps to remove the thrombus in the ventricle as much as possible, and then use straight scissors to cut the right ventricle (RV) and left ventricle (LV) + ventricular septum (LV+S) along the junction of the tight right ventricle (RV) and interventricular septum (S), use gauze to absorb moisture, and weigh them separately. Calculate the weight ratio RV / (LV+S), which is the Fulton index.

[0460] 3.2.Technical route

[0461] The experimental route of Example 2 is as follows Figure 4 shown.

[0462] 3.3 Experimental results

[0463] 3.3.1. Weight changes

[0464] The body weight changes of the animals in each group are as follows, and can also be found in Table 5 and Figure 5 According to the experimental results of body weight changes, the NO donor compound provided in the present application has substantially the same or better effects than the healthy control.

[0465] Body weight on day 0: The average body weights on day 0 of groups 1-9 were 315±2.80g, 323±15.76g, 330±25.11g, 315±3.93g, 316±4.35g, 316±5.22g, 316±4.78g, 316±13.50g, and 314±5.35g, respectively, with no significant differences among the groups.

[0466] Body weight on day 14: The average body weights of groups 1-9 on day 14 were 409±12.90g, 403±7.95g, 430±34.15g, 399±23.05g, 413±15.81g, 376±65.70g, 407±31.36g, 406±33.50g, and 425±20.48g, respectively, with no significant differences among the groups.

[0467] Body weight: The average body weights of groups 1-9 on the 14th day were 438±27.21g, 419±22.60g, 431±58.03g, 375±49.12g, 436±9.65g, 393±27.14g, 425±45.29g, 406±42.45g, and 445±25.06g, respectively, with no significant differences among the groups.

[0468] Table 5. Comparison of body weight changes of rats in each group

[0469]

[0470]

[0471] 3.3.2. Survival status: One rat died in Group 6 and Group 7 on the 22nd and 27th days respectively. No rat died in the other groups during the experiment and the survival time was 28 days.

[0472] 3.3.3. Hemodynamic results

[0473] (1) The RVSP of groups 1-9 were 48±18.49 mmHg, 52±5.39 mmHg, 46±13.45 mmHg, 43±9.20 mmHg, 38±8.86 mmHg, 47±11.11 mmHg, 45±15.61 mmHg, 63±7.34 mmHg, and 22±2.41 mmHg, respectively. The RVSP of the modeling groups were significantly higher than those of the healthy control group; see Table 6.

[0474] Table 6. Comparison of RVSP values ​​of rats in each group

[0475] Group drug Dosage (mg / kg / day) RVSP (mmHg) 1 ZQN-1101-6M 3 48±18.49 2 ZQN-1101-9M 3 52±5.39 3 ZQ08M 3 46±13.45 4 ZQN-1101-9H 6 43±9.20 5 ZQ08H 6 38±8.86 6 ZQN-1101-8 10 47±11.11 7 Bosentan 10 45±15.61 8 Negative control / 63±7.34 9 Healthy controls 22±2.41

[0476] (2) Experimental results of the 3 mg / kg dose group of treprostinil-type experimental drugs: The positive control drug, treprostinil, can significantly reduce RVSP (46±13.45 vs 63±7.34 mmHg, P=0.013), and the antihypertensive effects of the 3 mg / kg dose group and the 6 mg / kg dose group of ZQ08 are similar, with no significant difference (46±13.45 vs 38±8.86 mmHg, P=0.205), but both cannot be reduced to the level of healthy controls; the RVSP of rats in the ZQN-1101-9 experimental drug treatment group decreased, but there was no significant difference with the negative control group (52±5.39 vs 63±7.34 mmHg, P=0.092); the ZQN-1101-6 experimental drug can effectively reduce the RVSP of rats (48±18.49 vs 63±7.34 mmHg, P=0.035), and the pulmonary vasodilation effect was not significantly different from that of the same dose of treprostinil (48±18.49 vs 46±13.45 mmHg, P=0.815).

[0477] (3) Treprostinil-type experimental drug 6 mg / kg dose group: ZQN-1101-9 experimental drug can effectively reduce rat RVSP (43±9.20 vs 63±7.34 mmHg, P=0.005), and the pulmonary vasodilating effect is close to that of the same dose of treprostinil (43±9.20 vs 38±8.86 mmHg, P=0.439).

[0478] (4) Experimental results of bosentan-type experimental drugs: The experimental drug ZQN-1101-8 can effectively reduce the RVSP of rats (47±11.10 vs 63±7.34 mmHg, P=0.041), and its pulmonary vasodilation effect is close to that of the same dose of bosentan (47±11.10 vs 45±15.61 mmHg, P=0.772), and the effect is similar to that of the treprostinil treatment group.

[0479] 3.3.4.Fulton Index Results:

[0480] (1) The Fulton indexes of groups 1-9 were 0.47±0.087, 0.48±0.072, 0.38±0.101, 0.49±0.092, 0.37±0.071, 0.48±0.049, 0.47±0.104, 0.61±0.080, and 0.29±0.023, respectively. The Fulton indexes of the modeling groups were significantly higher than those of the healthy control group; see Table 7.

[0481] Table 7. Comparison of Fulton index of rats in each group

[0482] Group drug Dosage (mg / kg / day) Fulton Index 1 ZQN-1101-6M 3 0.47±0.087 2 ZQN-1101-9M 3 0.48±0.072 3 ZQ08M 3 0.38±0.101 4 ZQN-1101-9H 6 0.49±0.092 5 ZQ08H 6 0.37±0.071 6 ZQN-1101-8 10 0.48±0.049 7 Bosentan 10 0.47±0.104 8 Negative control / 0.61±0.080 9 Healthy controls 0.29±0.023

[0483] (2) Experimental results of the 3 mg / kg dose group of treprostinil-type experimental drugs: The positive control drug, treprostinil, can significantly reduce the Fulton index (0.38±0.101 vs 0.61±0.080, P=0.014), and the antihypertensive effects of the 3 mg / kg dose group and the 6 mg / kg dose group of ZQ08 are similar, with no significant difference (0.38±0.101 vs 0.37±0.071, P=0.926), but both cannot be reduced to the level of healthy controls; ZQN-1101-6 experimental drug can effectively reduce the Fulton index of rat hearts (0.47±0.087 vs 0.61±0.080, P=0.017), and there is no significant difference with the same dose of treprostinil (0.47±0.087 vs 0.38±0.101, P=0.077); the cardiac Fulton index of rats in the ZQN-1101-9 experimental drug treatment group was also significantly lower than that of the negative control (0.48±0.072 vs 0.61±0.080, P=0.013), and had the same effect as the same dose of treprostinil (0.48±0.072 vs 0.38±0.101, P=0.057), but inferior to 6 mg / kg dose of treprostinil (0.48±0.072 vs 0.37±0.071, P=0.047).

[0484] (3) Experimental results of the 6 mg / kg dose group of treprostinil-type experimental drugs: The experimental drug ZQN-1101-9 can effectively reduce the Fulton index of rats (0.48±0.092 vs 0.61±0.080, P=0.03), but is inferior to the same dose of treprostinil (0.48±0.092 vs 0.37±0.071, P=0.043).

[0485] (4) Bosentan experimental drugs: The experimental drug ZQN-1101-8 can effectively reduce the Fulton index (0.48±0.049 vs 0.61±0.080, P=0.038), and is close to the same dose of bosentan (0.48±0.049 vs 0.47±0.104, P=0.827), but is still significantly higher than the healthy control group (0.48±0.049 vs 0.29±0.023, P=0.003).

[0486] According to the experimental research of the inventors of the present application, it is proved that the NO donor compound provided by the present invention has good safety, and the weight change and survival can achieve the effect basically equivalent to that of the healthy control group. The NO donor compound provided by the present invention can significantly reduce the right ventricular systolic pressure (RVSP value) and Fulton index, and can achieve a good PAH treatment effect. This also indirectly reflects that NO can be released from the NO donor compound, thereby obtaining a TD molecule (prostacyclin drug or ERA drug) with pharmaceutical activity.

[0487] According to some exploratory experiments, under certain dosage conditions, compared with traditional single target molecules (such as treprostinil, bosentan, etc.), the NO donor compound provided in the present application can better reduce right ventricular systolic pressure (RVSP value) and Fulton index, and can provide better PAH treatment effect.

[0488] According to some exploratory experiments, under some dosage conditions (such as 5 mpk, 5 mg per kilogram of body weight per day), NO donor compounds can produce a significant dose-related decrease in mean arterial pressure (MAP) in anesthetized rats (such as a MAP decrease of ≥100 mmHg), while according to existing reports and studies, traditional single target molecules, such as treprostinil, can only achieve a MAP decrease of about 30 mmHg.

[0489] The technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. To make the description concise, not all possible combinations of the technical features in the above-mentioned implementation modes and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0490] The above-described embodiments only express several implementation methods of the present invention, which is convenient for understanding the technical solutions of the present invention in detail, but cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that, for those of ordinary skill in the art, without departing from the concept of the present invention, several variations and improvements can be made, which all belong to the protection scope of the present invention. In addition, it should be understood that after reading the above-mentioned teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that the technical solutions obtained by those skilled in the art on the basis of the technical solutions provided by the present invention through logical analysis, reasoning or limited experiments are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description and drawings can be used to explain the contents of the claims.

Claims

1. A NO donor compound, or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the NO donor compound is: (AL-) q D; in, A is a NO donor group; q is an integer greater than or equal to 1; L is a chemical bond or a linking group; when q is greater than 1, multiple ALs are independent of each other and may be the same or different; D is the residue of TD, wherein TD is treprostinil.

2. The NO donor compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: q is any integer from 1 to 10.

3. The NO donor compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The NO donor compound provides NO in a manner selected from one or more of nitrates, furazan nitrogen oxides, azodiol olefin salts, oximes, NO-metal complexes, S-nitrosothiol, sterone imines, guanidines, hydroxylamines and N-hydroxyureas.

4. The NO donor compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of A independently has at least one of the following terminal groups: -ONO2, -CR 05 =NOH, -NR 06 -N + (O - )=N-OR5、 Where Ar is C 5-20 Aryl, 5- to 200-membered heteroaryl, substituted C 5-20 Aryl or substituted 5- to 20-membered heteroaryl; R 05 H or C 1-6 alkyl; R 06 C 1-20 alkyl; R5 is C 1-6 Alkyl, -CH=CH-R 5a or R 5b O-substituted C 1-6 Alkyl; wherein R 5a H or C 1-20 Alkyl; R 5b C 1-6 Alkyl or C 1-6 Carbonyl; Ring Cy1 is a 5- to 6-membered nitrogen monocyclic ring; Wherein, each occurrence of "substituted" is independently selected from one or more of the substituent group G, wherein the substituent group G is composed of the following groups: deuterium, halogen, -CN, -OH, -COOH, -NH2, -NHR 01 、-NR 02 R 03 , -SH, -OR1, -SR1, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR 01 、-C(=O)NR 02 R 03 , -S(=O)2OR1, -S(=O)OR1, -OC(=O)R2, -NR 04 C(=O)R2, -S(=O)2R2, -S(=O)R2, -OS(=O)2R2, -OS(=O)R2, -NR 04 S(=O)2R2、-NR 04 S(=O)R2、-S(=O)2NR 01 、-S(=O)NR 01 , C 1-20 Alkyl, C 3-20 Cycloalkyl, C 5-20 Aryl, C 1-20 heteroalkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl; Among them, R 01 C 1-20 alkyl; R 02 and R 03 Each independently is C 1-20 Alkyl; R 02 and R 03 The ring is 3 to 12-membered; R 04 H or C 1-20 alkyl; R1 is C 1-20 Alkyl or C 5-20 Aryl; R2 is C 1-20 Alkyl or C 6-25 Arylalkyl.

5. The NO donor compound according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of A independently comprises at least one of the following structures: in, X1 is a chemical bond, or X1 is C 1-20 Alkylene, C 3-20 Cycloalkylene, C 5-20 Arylene, C 1-20 divalent heteroalkyl, 3- to 20-membered divalent heterocycloalkyl, 5- to 20-membered divalent heteroaryl, substituted C 1-20 Alkylene, substituted C 3-20 Cycloalkylene, substituted C 5-20 Arylene, substituted C 1-20 A suitable divalent linking group composed of a divalent heteroalkyl group, a substituted 3- to 20-membered divalent heterocycloalkyl group, a substituted 5- to 20-membered divalent heteroaryl group, or a combination of multiple divalent groups thereof; X2 and X3 are each independently C 1-20 Alkylene, C 3-20 Cycloalkylene, C 5-20 Arylene, C 1-20 divalent heteroalkyl, 3- to 20-membered divalent heterocycloalkyl, 5- to 20-membered divalent heteroaryl, substituted C 1-20 Alkylene, substituted C 3-20 Cycloalkylene, substituted C 5-20 Arylene, substituted C 1-20 A suitable divalent linking group composed of a divalent heteroalkyl group, a substituted 3- to 20-membered divalent heterocycloalkyl group, a substituted 5- to 20-membered divalent heteroaryl group, or a combination of multiple divalent groups thereof; X4 for C 1～20 Alkylene; X5 is a chemical bond or C 1～20 Alkylene; Wherein, each occurrence of "substituted" is independently selected from one or more of the substituent group G, wherein the substituent group G is composed of the following groups: deuterium, halogen, -CN, -OH, -COOH, -NH2, -NHR 01 、-NR 02 R 03 , -SH, -OR1, -SR1, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR 01 、-C(=O)NR 02 R 03 , -S(=O)2OR1, -S(=O)OR1, -OC(=O)R2, -NR 04 C(=O)R2, -S(=O)2R2, -S(=O)R2, -OS(=O)2R2, -OS(=O)R2, -NR 04 S(=O)2R2、-NR 04 S(=O)R2、-S(=O)2NR 01 、-S(=O)NR 01 , C 1-20 Alkyl, C 3-20 Cycloalkyl, C 5-20 Aryl, C 1-20 heteroalkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl; Among them, R 01 C 1-20 alkyl; R 02 and R 03 Each independently is C 1-20 Alkyl; R 02 and R 03 The ring is 3 to 12-membered; R 04 H or C 1-20 alkyl; R1 is C 1-20 Alkyl or C 5-20 Aryl; R2 is C 1-20 Alkyl or C 6-25 Arylalkyl.

6. The NO donor compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: X2 and X3 are each independently C 1-20 Alkylene, C 3-20 Cycloalkylene, C 1-20 Divalent heteroalkyl, 3 to 20-membered divalent heterocycloalkyl, substituted C 1-20 Alkylene, substituted C 3-20 Cycloalkylene, substituted C 1-20 Suitable divalent linking groups include divalent heteroalkyl groups, substituted 3- to 20-membered divalent heterocycloalkyl groups, or combinations of multiple divalent groups thereof.

7. The NO donor compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: X2 and X3 are each independently C 1～20 Alkylene or C 3～20 Cycloalkylene.

8. The NO donor compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: X1 is a chemical bond or -Z1-, -Ar0-, -Z1-Ar0-, -Z1-Ar0-Z2- or -Ar0-Z2-; Wherein, Z1 and Z2 are independently C 1～20 Alkylene, C 3～20 Cycloalkylene, C 1～20 Divalent heteroalkyl or C 3～20 divalent heterocycloalkyl, or a substituted form of any of the foregoing; Ar0 is C 5-20 arylene, substituted arylene, 5- to 20-membered divalent heteroaryl, or substituted 5- to 20-membered divalent heteroaryl; Wherein, each occurrence of "substituted" is independently selected from one or more of the substituent group G, wherein the substituent group G is composed of the following groups: deuterium, halogen, -CN, -OH, -COOH, -NH2, -NHR 01 、-NR 02 R 03 , -SH, -OR1, -SR1, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR 01 、-C(=O)NR 02 R 03 , -S(=O)2OR1, -S(=O)OR1, -OC(=O)R2, -NR 04 C(=O)R2, -S(=O)2R2, -S(=O)R2, -OS(=O)2R2, -OS(=O)R2, -NR 04 S(=O)2R2、-NR 04 S(=O)R2、-S(=O)2NR 01 、-S(=O)NR 01 , C 1-20 Alkyl, C 3-20 Cycloalkyl, C 5-20 Aryl, C 1-20 heteroalkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl; Among them, R 01 C 1-20 alkyl; R 02 and R 03 Each independently is C 1-20 Alkyl; R 02 and R 03 Cycling and the formed ring is a 3 to 12-membered ring; R 04 H or C 1-20 alkyl; R1 is C 1-20 Alkyl or C 5-20 Aryl; R2 is C 1-20 Alkyl or C 6-25 Arylalkyl.

9. The NO donor compound according to claim 8, or a pharmaceutically acceptable salt thereof, characterized in that: Z1 and Z2 are each independently a linear or branched C 1～20 Alkylene; and / or, Ar0 is phenylene.

10. The NO donor compound according to claim 9, or a pharmaceutically acceptable salt thereof, characterized in that: Z1 and Z2 are each independently a linear or branched C 1～6 Alkylene.

11. The NO donor compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: X1 is a chemical bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-, -Ph- or -CH2-Ph-; and / or, X2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-.

12. The NO donor compound according to claim 8, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of A is independently selected from the group consisting of the following groups: (a) Group: -ONO2, -Z1-ONO2, -Ar0-ONO2, -Z1-Ar0-ONO2, -Z1-Ar0-Z2-ONO2 and -Ar0-Z2-ONO2; and Group (b):

13. The NO donor compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of A is independently selected from the group consisting of the following groups: (a) Group: -ONO2, -(CH2)3-ONO2 and -Ph-ONO2; Group (b):

14. The NO donor compound according to claim 13, or a pharmaceutically acceptable salt thereof, characterized in that: Ar is phenyl, R 05 For H, R 06 C 1-3 Alkyl, R5 is -CH=CH2 or -CH2O-C(=O)CH3.

15. The NO donor compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: Each AL is independently selected from the group consisting of: (h) Group: -ONO2, -O-X1-ONO2, -NR 04a -X1-ONO2 and -C(=O)-X1-ONO2; and (i) Group: Among them, R 04a , R 04b Each independently is H or C 1-20 alkyl.

16. The NO donor compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that: Each AL is independently selected from the group consisting of: (h) Group: -ONO2, -O-(CH2)2-ONO2, -O-(CH2)3-ONO2 and -C(=O)-(CH2)3-ONO2; and (i) Group:

17. The NO donor compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: The D is correspondingly adjacent to one or more L via one or more positions in any of the following residues: Wherein, "*" indicates the site in the D that is connected to the L.

18. The NO donor compound according to claim 17, or a pharmaceutically acceptable salt thereof, characterized in that: The D is adjacent to one or more L via one or more of the following residues:

19. The NO donor compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: The linking group formed by the L and the D, each time it appears, is independently selected from any one of the following connection modes: chemical bond, -O-, -NH-, *-OC(=O)-, *-C(=O)O-, *-NHC(=O)-, *-C(=O)NH-, *-OC(=O)NH- and *-NHC(=O)O-; wherein "*" represents the site in the L that is connected to the D.

20. The NO donor compound according to claim 19, or a pharmaceutically acceptable salt thereof, characterized in that: The L is selected from any of the following connection modes: chemical bond, -O-, -C(=O)- and -NH-; Wherein, "*" indicates the site in L that is connected to D.

21. The NO donor compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: The q is 1, 2 or 3.

22. The NO donor compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: In the same molecule, all A's are the same.

23. The NO donor compound according to claim 22, or a pharmaceutically acceptable salt thereof, characterized in that: In the same molecule, all ALs are the same.

24. The NO donor compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of heterocycloalkyl independently satisfies that the ring skeleton contains one or more heteroatoms W; the heteroatoms W are selected from one, two or three of N, O and S; when the number of W is multiple, these W are independent of each other and may be the same or different; and / or, Each occurrence of the heteroaryl group independently satisfies that the aromatic ring skeleton contains one or more heteroatoms W; the heteroatoms W are selected from one, two or three of N, O and S; when the number of W is plural, these W are independent of each other and may be the same or different.

25. The NO donor compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of "substituted" independently satisfies: the number of substituents is 1 or more, and when the number of substituents is more than one, these substituents are each independent and may be the same or different.

26. The NO donor compound according to claim 25, or a pharmaceutically acceptable salt thereof, characterized in that: Each occurrence of "substituted" is independently selected from one or more of the substituents in the substituent group G; The substituent group G is composed of the following groups: deuterium, F, Cl, -CN, -OH, -COOH, -NH2, -OR1, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR 01 、-C(=O)NR 02 R 03 、-OC(=O)R2、-NR 04 C(=O)R2 and C 1-20 alkyl.

27. The NO donor compound according to claim 26, or a pharmaceutically acceptable salt thereof, characterized in that: The substituent group G is composed of the following groups: deuterium, F, Cl, -CN, -OH, -COOH, -NH2 and C 1-6 alkyl.

28. The NO donor compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: The Ar is a phenyl group.

29. The NO donor compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: All A have a terminal group -ONO2.

30. The NO donor compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: All A have terminal groups In any one of the above, Ar is phenyl.

31. The NO donor compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that: Each AL is independently -C(=O)-X1-ONO2; wherein X 1_ is Z1, Z1 is a straight chain C 1～6 Alkylene.

32. The NO donor compound according to claim 16, or a pharmaceutically acceptable salt thereof, characterized in that: Each AL is independently -C(=O)-(CH2)3-ONO2.

33. The NO donor compound according to claim 20, or a pharmaceutically acceptable salt thereof, characterized in that: The linking group formed by the L and the D, each time it appears, is independently connected in the following manner: *-OC(=O)-, *-C(=O)O-; wherein "*" represents the site in the L that is connected to the D; The L is selected from the following connection modes: -C(=O)-.

34. The NO donor compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: The connection between A and D is a reversible connection.

35. The NO donor compound according to claim 34, or a pharmaceutically acceptable salt thereof, characterized in that: The connection between A and D contains at least one of an ester bond, a peptide bond, a carbamate bond and a disulfide bond.

36. The NO donor compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized in that: The linking group formed by the L and the D, each time it appears, is independently selected from any one of the following connection modes: a chemical bond, *-OC(=O)-, *-C(=O)O-, *-NHC(=O)- and *-C(=O)NH-; wherein "*" represents the site in the L that is connected to the D.

37. The NO donor compound according to claim 36, or a pharmaceutically acceptable salt thereof, characterized in that: The linking group formed by the L and the D, each time it appears, is independently selected from any one of the following connection modes: chemical bond, *-OC(=O)- and *-C(=O)O-; wherein "*" represents the site in the L that is connected to the D.

38. The NO donor compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The NO donor compound is selected from any one of the following compounds:

39. A pharmaceutical composition, characterized in that The invention comprises: the NO donor compound according to any one of claims 1 to 38; and a pharmaceutically acceptable carrier.

40. Use of the NO donor compound according to any one of claims 1 to 38 or the pharmaceutical composition according to claim 39 in the preparation of a medicament for treating pulmonary hypertension.

41. The use according to claim 40, characterized in that The application also includes application in the preparation of medicines for treating cardiovascular and pulmonary vascular diseases, wherein the TD is treprostinil.

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