Nitric oxide donor-containing compounds

Abstract

The invention relates to the technical field of medicine, in particular to a compound containing a nitric oxide (NO) donor or pharmaceutically acceptable salt, a preparation method of the compound or the pharmaceutically acceptable salt, a pharmaceutical composition of the compound or the pharmaceutically acceptable salt, and application of the compound or the pharmaceutically acceptable salt to treatment or prevention of ophthalmic intraocular hypertension related diseases and optic nerve injury related diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and particularly to a class of compounds or pharmaceutically acceptable salts containing nitric oxide (NO) donors, methods for their preparation, pharmaceutical compositions thereof, and their use in the treatment or prevention of ocular hypertension-related diseases and optic nerve injury-related diseases. Background Technology

[0002] Glaucoma is a group of eye diseases characterized by retinal ganglion cell degeneration, specific optic nerve atrophy, and progressive visual field loss. It is primarily associated with pathological increases in intraocular pressure and is the most common cause of irreversible blindness. The signaling pathways involved in the pathogenesis of glaucoma are highly complex, with downstream signaling factors often interfering with each other. The main pathological mechanisms involve the upregulation of pro-apoptotic gene expression, the downregulation of neuroprotective and regenerative factors, and the production and action of factors that promote optic nerve damage. A series of changes at the molecular and cellular levels lead to impaired aqueous humor drainage and optic nerve damage, ultimately resulting in blindness.

[0003] Nitric oxide (NO) is an important intercellular signaling agent. In vivo, NO binds to soluble guanylate cyclase (sGC), which then converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP). cGMP acts as a second messenger, regulating smooth muscle relaxation and vasodilation, as well as many other important biological processes, such as cell growth and differentiation, and platelet inhibition.

[0004] NO plays an important physiological role in regulating optic nerve head blood flow and intraocular pressure (IOP).

[0005] In the optic disc, NO donors reduce vascular resistance by relaxing smooth muscle, leading to local vasodilation and increased blood flow to the optic disc. Conversely, damage to the NO pathway reduces blood flow to the optic disc, resulting in ischemia.

[0006] Structural nitric oxide synthase (cNOS) is present in the trabecular meshwork, Schlemm's tubes, effusion ducts, and the circular, radial, and longitudinal fibers of the ciliary muscle. Multiple pieces of evidence demonstrate that NO can reduce intraocular opacity (IOP). NO can increase aqueous humor outflow from the trabecular meshwork (TM) in the anterior segment of the human eye. NO donors can reduce IOP in animal models. Mice overexpressing endothelial nitric oxide synthase (eNOS) have lower IOP; in contrast, eNOS knockout mice (mice lacking the functional eNOS gene, and therefore without endogenous eNOS) have elevated IOP. Furthermore, sGC knockout mice show elevated IOP and optic nerve degeneration. The mechanism by which NO reduces IOP appears to be through inhibition of actin-myosin interactions, thereby relaxing cells in the TM and Schlemm's tubes, leading to increased aqueous humor outflow and decreased IOP.

[0007] Treatment of glaucoma presents several challenges. For example, primary open-angle glaucoma is a chronic, progressive optic neuropathy characterized by optic nerve damage and obstruction of aqueous humor outflow from the trabecular meshwork. Clinically, there are currently no drugs that target the pathological mechanisms of glaucoma.

[0008] There is an urgent need in this field for drugs that can reduce intraocular pressure, protect and repair damaged optic nerves during the development of ophthalmic diseases, thereby fundamentally treating or preventing related diseases. Summary of the Invention

[0009] On the one hand, compounds of formula (I-1) are provided: in, R 1 Selected from hydrogen, -OH, -OC 1-10 Alkyl and Each alkyl group is unsubstituted or is selected independently from R. X1 Substituents of the substituents; R 2 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A2 R B2 -OR A2 -SR A2 -C(=O)R A2 -C(=O)OR A2 -OC(=O)R A2 -C(=O)NR A2 R B2 -NR A2 C(=O)R B2 -NR A2 C(=NR E2 )R B2 -OC(=O)NR A2 R B2 -NR A2 C(=O)OR B2 -NR A2 C(=O)NR A2 R B2 -NR A2C(=S)NR A2 R B2 -NR A2 C(=NR E2 )NR A2 R B2 -S (=O) r R A2 -S(=O)(=NR) E2 )R B2 -N = S(=O)R A2 R B2 -S(=O)2OR A2 -OS(=O)2R A2 -NR A2 S(=O) r R B2 -NR A2 S(=O)(=NR E2 )R B2 -S (=O) r NR A2 R B2 -S(=O)(=NR) E2 )NR A2 R B2 -NR A2 S(=O)2NR A2 R B2 -NR A2 S(=O)(=NR E2 )NR A2 R B2 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X2 Substituents of the substituents; R 3 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A3 R B3 -OR A3 -SR A3 -C(=O)R A3 -C(=O)OR A3-OC(=O)R A3 -C(=O)NR A3 R B3 -NR A3 C(=O)R B3 -NR A3 C(=NR E3 )R B3 -OC(=O)NR A3 R B3 -NR A3 C(=O)OR B3 -NR A3 C(=O)NR A3 R B3 -NR A3 C(=S)NR A3 R B3 -NR A3 C(=NR E3 )NR A3 R B3 -S (=O) r R A3 -S(=O)(=NR) E3 )R B3 -N = S(=O)R A3 R B3 -S(=O)2OR A3 -OS(=O)2R A3 -NR A3 S(=O) r R B3 -NR A3 S(=O)(=NR E3 )R B3 -S (=O) r NR A3 R B3 -S(=O)(=NR) E3 )NR A3 R B3 -NR A3 S(=O)2NR A3 R B3 -NR A3 S(=O)(=NR E3 )NR A3 R B3 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X3 Substituents of the substituents; R 4 Selected from hydrogen, halogens, C 1-10Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A4 R B4 -OR A4 -SR A4 -C(=O)R A4 -C(=O)OR A4 -OC(=O)R A4 -C(=O)NR A4 R B4 -NR A4 C(=O)R B4 -NR A4 C(=NR E4 )R B4 -OC(=O)NR A4 R B4 -NR A4 C(=O)OR B4 -NR A4 C(=O)NR A4 R B4 -NR A4 C(=S)NR A4 R B4 -NR A4 C(=NR E4 )NR A4 R B4 -S (=O) r R A4 -S(=O)(=NR) E4 )R B4 -N = S(=O)R A4 R B4 -S(=O)2OR A4 -OS(=O)2R A4 -NR A4 S(=O) r R B4 -NR A4 S(=O)(=NR E4 )R B4 -S (=O) r NR A4 R B4 -S(=O)(=NR) E4)NR A4 R B4 -NR A4 S(=O)2NR A4 R B4 -NR A4 S(=O)(=NR E4 )NR A4 R B4 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X4 Substituents of the substituents; R 5 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A5 R B5 -OR A5 -SR A5 -C(=O)R A5 -C(=O)OR A5 -OC(=O)R A5 -C(=O)NR A5 R B5 -NR A5 C(=O)R B5 -NR A5 C(=NR E5 )R B5 -OC(=O)NR A5 R B5 -NR A5 C(=O)OR B5 -NR A5 C(=O)NR A5 R B5 -NR A5 C(=S)NR A5 R B5 -NR A5 C(=NR E5 )NR A5 R B5 -S (=O) r R A5 -S(=O)(=NR)E5 )R B5 -N = S(=O)R A5 R B5 -S(=O)2OR A5 -OS(=O)2R A5 -NR A5 S(=O) r R B5 -NR A5 S(=O)(=NR E5 )R B5 -S (=O) r NR A5 R B5 -S(=O)(=NR) E5 )NR A5 R B5 -NR A5 S(=O)2NR A5 R B5 -NR A5 S(=O)(=NR E5 )NR A5 R B5 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X5 Substituents of the substituents; R 6 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A6 R B6 -OR A6 -SR A6 -C(=O)R A6 -C(=O)OR A6 -OC(=O)R A6 -C(=O)NR A6 R B6 -NR A6 C(=O)R B6 -NR A6 C(=NR E6 )R B6-OC(=O)NR A6 R B6 -NR A6 C(=O)OR B6 -NR A6 C(=O)NR A6 R B6 -NR A6 C(=S)NR A6 R B6 -NR A6 C(=NR E6 )NR A6 R B6 -S (=O) r R A6 -S(=O)(=NR) E6 )R B6 -N = S(=O)R A6 R B6 -S(=O)2OR A6 -OS(=O)2R A6 -NR A6 S(=O) r R B6 -NR A6 S(=O)(=NR E6 )R B6 -S (=O) r NR A6 R B6 -S(=O)(=NR) E6 )NR A6 R B6 -NR A6 S(=O)2NR A6 R B6 -NR A6 S(=O)(=NR E6 )NR A6 R B6 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X6 Substituents of the substituents; Or "R" 2 and R 3 "or "R 3 and R 4 "or "R 4 and R 5 "or "R 5 and R 6Together with the carbon atoms attached to them, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2, or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or is composed of at least one heteroatom independently selected from R. X Substituents of the substituents; Each R 7 Independently selected from halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A7 R B7 -OR A7 -SR A7 -C(=O)R A7 -C(=O)OR A7 -OC(=O)R A7 -C(=O)NR A7 R B7 -NR A7 C(=O)R B7 -NR A7 C(=NR E7 )R B7 -OC(=O)NR A7 R B7 -NR A7 C(=O)OR B7 -NR A7 C(=O)NR A7 R B7 -NR A7 C(=S)NR A7 R B7 -NR A7 C(=NR E7 )NR A7 R B7 -S (=O) r R A7 -S(=O)(=NR) E7 )R B7 -N = S(=O)R A7 R B7 -S(=O)2OR A7 -OS(=O)2R A7 -NR A7 S(=O) r R B7 -NR A7 S(=O)(=NRE7 )R B7 -S (=O) r NR A7 R B7 -S(=O)(=NR) E7 )NR A7 R B7 -NR A7 S(=O)2NR A7 R B7 -NR A7 S(=O)(=NR E7 )NR A7 R B7 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X7 Substituents of the substituents; Or any two adjacent R 7 Together with the carbon atoms attached to them, they form a saturated or unsaturated 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or has at least one heteroatom independently selected from R. X7 Substituents of the substituents; L 1 Selected from chemical bonds, -(CR C1 R D1 ) u -O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=O)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=O)O-(CR C1 R D1 ) t -、-(CRC1 R D1 ) u -C(=O)NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -OC(=O)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 C(=O)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=S)O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=S)NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -OC(=S)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 C(=S)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S(=O) r O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S(=O) r NR 8 -(CR C1 R D1 ) t -、-(CR C1 RD1 ) u -OS(=O) r -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 S(=O) r -(CR C1 R D1 ) t -、C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group, wherein each alkylene group, alkenylene group, or alynyl group is unsubstituted or is independently selected from R X Substituents of the substituents; R 8 Selected from hydrogen and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X8 Substituents of the substituents; U 0 For O or S; Y 1 For C(R) 9a R 9a’ ); Y 2 For C(R) 9b R 9b’ ); Y 3 For C(R) 9c R 9c’ ); Y 4 For C(R) 9d R 9d’ ); R 9a R 9a’ R 9b R 9b’ R 9c R 9c’ R 9d and R 9d’ Each is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C1-4 Alkylene-heteroaryl, CN, NO2, -NR A9 R B9 -OR A9 -SR A9 -C(=O)R A9 -C(=O)OR A9 -OC(=O)R A9 -C(=O)NR A9 R B9 -NR A9 C(=O)R B9 -NR A9 C(=NR E9 )R B9 -OC(=O)NR A9 R B9 -NR A9 C(=O)OR B9 -NR A9 C(=O)NR A9 R B9 -NR A9 C(=S)NR A9 R B9 -NR A9 C(=NR E9 )NR A9 R B9 -OS(=O)2R A9 -NR A9 S(=O) r R B9 -NR A9 S(=O)(=NR E9 )R B9 -NR A9 S(=O)2NR A9 R B9 -NR A9 S(=O)(=NR E9 )NR A9 R B9 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X9 Substituents of the substituents; Each R A2 R A3 R A4 R A5 R A6 R A7 R A9 R B2 R B3 RB4 R B5 R B6 R B7 and R B9 Independently selected from hydrogen and C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X Substituents of the substituents; Or "R" A2 and R B2 "or "R A3 and R B3 "or "R A4 and R B4 "or "R A5 and R B5 "or "R A6 and R B6 "or "R A7 and R B7 "or "R A9 and R B9 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms selected from R. X Substituents of the substituents; Each R C1 and R D1 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X Substituents of the substituents; Or each "R" C1 and R D1 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms independently selected from R. X Substituents of the substituents; Each R E2 R E3 R E4 R E5 R E6 R E7 and R E9 Independently selected from hydrogen and C 1-10 Alkyl group, CN, NO2, -S (=O) r R a1 -C(=O)R a1 -C(=O)OR a1 -C(=O)NR a1 R b1 -S (=O) r NR a1 R b1 and Wherein the alkyl group is unsubstituted or is selected independently from R X Substituents of the substituents; Each L is independently selected from chemical bonds, -(CR) c R d ) u -O-(CR c R d ) t -、-(CR c R d ) u -S-(CR c R d ) t -、-(CR c R d ) u -NR 8 -(CR c R d ) t -、-(CR c R d ) u -C(=O)-(CR c R d ) t -、-(CR c R d ) u -C(=O)O-(CR c R d) t -、-(CR c R d ) u -C(=O)NR 8 -(CR c R d ) t -、-(CR c R d ) u -OC(=O)-(CR c R d ) t -、-(CR c R d ) u -NR 8 C(=O)-(CR c R d ) t -、-(CR c R d ) u -C(=S)-(CR c R d ) t -、-(CR c R d ) u -C(=S)O-(CR c R d ) t -、-(CR c R d ) u -C(=S)NR 8 -(CR c R d ) t -、-(CR c R d ) u -OC(=S)-(CR c R d ) t -、-(CR c R d ) u -NR 8 C(=S)-(CR c R d ) t -、-(CR c R d ) u -S(=O) r -(CR c R d ) t -、-(CR c Rd ) u -S(=O) r O-(CR c R d ) t -、-(CR c R d ) u -S(=O) r NR 8 -(CR c R d ) t -、-(CR c R d ) u -OS(=O) r -(CR c R d ) t -、-(CR c R d ) u -NR 8 S(=O) r -(CR c R d ) t -、C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group, wherein the alkylene group, alkenyl group, or alynyl group is unsubstituted or is selected independently from R. Y Substituents of the substituents; Each R c and R d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic groups, M, -C 1-4 Alkylene-M, wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. Y Substituents of the substituents; Each M is independently selected from a NO donor; Each R X R X1 R X2 R X3 R X4 R X5 R X6 R X7 RX8 and R X9 Independently selected from halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR) c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CR c1 R d1 ) u C(=NR e1 )R a1 、-(CR c1 R d1 ) u C(=O)OR b1 、-(CR c1 R d1 ) u OC(=O)R b1 、-(CR c1 R d1 ) u C(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=O)R b1 、-(CR c1 R d1 ) u C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=NR e1 )R b1 、-(CR c1R d1 ) u OC(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=O)OR b1 、-(CR c1 R d1 ) u NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=S)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u S(=O) r R b1 、-(CR c1 R d1 ) u S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) u N=S(=O)R a1 R b1 、-(CR c1 R d1 ) u S(=O)2OR b1 、-(CR c1 R d1 ) u OS(=O)2R b1 、-(CR c1 R d1 ) u NR a1 S(=O) r R b1 、-(CR c1 R d1 ) u NR a1 S(=O)(=NR e1 )Rb1 、-(CR c1 R d1 ) u S(=O) r NR a1 R b1 、-(CR c1 R d1 ) u S(=O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u NR a1 S(=O)2NR a1 R b1 、-(CR c1 R d1 ) u NR a1 S(=O)(=NR e1 )NR a1 R b1 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. Y Substituents of the substituents; Each R a1 and R b1 Independently selected from hydrogen and C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. Y Substituents of the substituents; Or R a1 and R b1 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms selected independently from oxygen, sulfur, nitrogen, and phosphorus. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms selected from R. Y Substituents of the substituents; Each R c1 and R d1Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. Y Substituents of the substituents; Or each R c1 and R d1 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms independently selected from R. Y Substituents of the substituents; Each R e1 Independently selected from hydrogen and C 1-10 Alkyl group, CN, NO2, -S (=O) r R a1 -C(=O)R a1 -C(=O)OR a1 -C(=O)NR a1 R b1 -S (=O) r NR a1 R b1 and Wherein the alkyl group is unsubstituted or is selected independently from R Y Substituents of the substituents; Each R Y Independently selected from halogens, NO2, -CN, C 1-10 Alkyl, -OH, -O(C) 1-10 alkyl), -O(C) 3-10 cycloalkyl), -O(C 1-4 Alkylene-C 3-10 cycloalkyl), -O (heterocyclic), -O (C 1-4 alkylene-heterocyclic groups), -SH, -S(C 1-10 alkyl), -S(C 3-10 cycloalkyl), -S(C 1-4 Alkylene-C 3-10 cycloalkyl), -S (heterocyclic), -S (C 1-4 alkylene-heterocyclic groups), -NH2, -NH(C1-10 alkyl), -N(C) 1-10 alkyl)2、-NH(C 3-10 cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 cycloalkyl), -NH (heterocyclic) and -NH (C 1-4 (alkylene-heterocyclic group); m is 0 or 1; p is 0, 1, 2 or 3; Each r is independently selected from 1 and 2; Each t is independently selected from integers between 0 and 10; Each u is independently selected from integers between 0 and 10; Each k is independently selected from 1, 2, 3, and 4; Each q is independently selected from 0, 1, 2, and 3; The total number of M molecules is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0010] In another aspect, a pharmaceutical composition is provided comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0011] In another aspect, the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of medicaments for treating diseases, symptoms or conditions selected from intraocular pressure-related diseases and optic nerve damage-related diseases is provided. Attached Figure Description

[0012] Figures 1 to 5 The protective effects of compounds 001, 002, 003, 004, and 005 against NMDA-induced retinal nerve cell damage are shown.

[0013] Figure 6 The IOP response of normal-toning beagle dogs to solvent, timolol maleate, and compounds 001, 002, 003, 004, and 005 is shown. The vertical axis represents the change in intraocular pressure relative to baseline (ΔIOP%). Among the curves in each group, the curve of the solvent group is closest to the baseline.

[0014] Figure 7 The IOP response of a rat model of high intraocular pressure to solvent, timolol maleate, and compounds 001 and 003 is shown.

[0015] Figure 8 The IOP response of a rat model of high intraocular pressure to solvent, timolol maleate, and compounds 001 and 003 is shown. The vertical axis represents the change in intraocular pressure relative to baseline (ΔIOP%). Detailed Implementation

[0016] The following specific embodiments illustrate the technical content of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention through the content disclosed in the specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention. definition

[0017] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The term "technique" as used herein refers to techniques commonly understood in the art, including variations and equivalent substitutions that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be readily understood by one of ordinary skill in the art, the following definitions are set forth to better illustrate the invention. When a trade name appears herein, it refers to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0018] When a quantity, concentration, or other numerical value or parameter is described as a range, preferred range, or preferred upper or lower limit, it should be understood as equivalent to specifically disclosing any range formed by combining any upper or preferred value with any lower or preferred value, whether or not the range is explicitly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range as well as all integers and fractions (decimals) within the range. For example, the expression "C1-C 10 "or "C 1-10 "Covering the range of 1-10 carbon atoms, and should be understood to also cover any subrange within that range and each point value, such as C." 2-3 C 2-4 C 2-5 C 3-4 C 3-5 C 3-6 C 3-7 C 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C1-9, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 etc. The expression "C3-C" is used. 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover C." 3-4 C 3-5 C 3-6 C 3-7 C 3-8 C4-5 C 4-6 C4-C7, C5-C6, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "3-14 yuan" should be understood as encompassing any sub-range and each point value, such as 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6, or 7 yuan, etc. The expressions "3-12 yuan," "3-7 yuan," and "4-8 yuan" should also be understood in a similar way.

[0019] When any variable (e.g., R) X When an element appears more than once in the composition or structure of a compound, its definition is independent for each occurrence in each case. For example, the statement "each R..." X "Independently selected" indicates that if it contains multiple R X In each case, each R X The options for substituents are all independent of each other. Other variables or expressions should be understood in a similar way.

[0020] Unless the context clearly specifies otherwise, the singular forms such as “a kind” and “the kind” include the plural forms. The expressions “a kind or more” or “at least one” can mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more. In one embodiment, “at least one” means 1, 2, 3, or 4.

[0021] The terms “optional” or “optional” mean that the events described below may occur but are not guaranteed to occur, and the description includes the possibility that the events or situations described therein may or may not occur.

[0022] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state.

[0023] Unless otherwise specified, as used herein, the connection point of a substituent may be any suitable location of the substituent. When the bond of a substituent is such that it is a bond that passes through the ring and connects two atoms, such a substituent may be bonded to either cyclic atom in the substituted ring.

[0024] The expressions “comprising,” “including,” “containing,” and “having” are open-ended and do not exclude additional unlisted elements, steps, or components. The expression “consisting of…” does not include any unspecified elements, steps, or components. The expression “substantially consisting of…” means that the scope is limited to the specified elements, steps, or components, as well as optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression “comprising” includes both the expressions “substantially consisting of…” and “consisting of…”.

[0025] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0026] The term "hydrocarbon group" refers to a monovalent group derived from a hydrocarbon. Examples of hydrocarbon groups include, but are not limited to, alkyl, alkenyl, alkynyl, cyclic hydrocarbon, and aryl groups.

[0027] The term "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by a single bond. Alkyl groups include straight-chain alkyl groups and branched-chain alkyl groups. Alkyl groups can contain 1-10 carbon atoms, referred to as C1. 1-10 Alkyl, such as C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 3-6 Alkyl groups. Non-limiting examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. Non-limiting examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc.

[0028] A divalent group is a group obtained by removing a hydrogen atom from an atom with free valence electrons in a corresponding monovalent group. A divalent group has two connection sites that attach to the rest of the molecule, and these two connection sites can be located on the same atom or two different atoms of the divalent group.

[0029] "alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon group. Alkylenes include straight-chain or branched alkylenes. Examples of straight-chain alkylenes include, but are not limited to, methylene (-CH2-), -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, etc. Examples of branched alkylenes include, but are not limited to, -CH(CH3)-, -CH(C2H5)-, -CH(CH3)-CH2-, -CH(C3H7)-, -CH(C2H5)-CH2-, -C(CH3)2-CH2-, -(CH(CH3))2-, -CH(CH3)-(CH2)2-, -CH2-CH(CH3)-CH2-, -CH(C4H9)-, -C(CH3)(C3H7)- , -C(C2H5)2-, -CH(C3H7)-CH2-, -CH(C2H5)-CH(CH3)-, -CH(C2H5)-(CH2)2-, -CH2-CH(C2H5)-CH2 -, -C(CH3)2-(CH2)2-, -CH2-C(CH3)2-CH2-, -CH(CH3)-(CH2)3-, -CH2-CH(CH3)-(CH2)2-, -CH(C5H 11 )-, -C(C2H5)(C3H7)-, -C(CH3)(C4H9)-, -CH(C4H9)-CH2-, -C(C2H5)2-CH2-, -C (CH3)(C3H7)-CH2-, -CH(C2H5)-CH(C2H5)-, -CH(CH3)-CH(C3H7)-, -C(CH3)2-C( CH3)2-, -CH(C3H7)-(CH2)2-, -CH2-CH(C3H7)-CH2-, -CH(C2H5)-C(CH3)2-, -C(CH3)2-CH(CH3)-CH2-, -CH(CH3)-C(CH3)2-CH2-, -CH(C2H5)-CH(CH3)-CH2-, -CH( CH3)-CH(C2H5)-CH2-, -CH(CH3)-CH2-CH(C2H5)-, -CH(CH3)-C(CH3)2-CH2-, -(CH(CH3))3-, -C(CH3)2-(CH2)3-, -CH(C2H5)-(CH2)3-, -CH2-CH(C2H5)-(CH2)2-, -CH2-CH(CH3)-CH(CH3)-CH2-, -(CH(CH3))2-(CH2)2-, -CH(CH3)-(CH2)2-CH(CH3)-, -(CH2)2-CH(CH3)-(CH2)2-, -CH2-CH(CH3)-(CH2)3-, -CH(CH3)-(CH2)4-, etc.

[0030] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, with at least one double bond. Alkenyl groups can have 2-8 carbon atoms, i.e., "C6H ... 2-8 "Alkenyl", for example, C 2-4 alkenyl, C 3-4 Alkenyl. Non-limiting examples of alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.

[0031] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, with at least one triple bond. Alkynyl groups can have 2-8 carbon atoms, i.e., "C6H ... 2-8 "Alkyne group", such as C 2-4 alkynyl group, C 3-4 Alkynyl. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, etc.

[0032] "Imyynyl" refers to an unsaturated divalent hydrocarbon group having at least one triple bond. Imyynyl groups include straight-chain or branched-chain ynylyl groups. Examples of straight-chain ynylyl groups include, but are not limited to, -C≡C-, -CH2-C≡C-, -(CH2)2-C≡C-, -(CH2)3-C≡C-, and -CH(CH3)-C≡C-.

[0033] The term "cyclic hydrocarbon group" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon and hydrogen atoms, preferably containing one or two rings. The cyclic hydrocarbon group can be a monocyclic, fused polycyclic, bridged, or spirocyclic structure. The cyclic hydrocarbon group can have 3-10 carbon atoms, i.e., "C 3-10 "Cyclic hydrocarbon group", such as C 3-8 Cyclic hydrocarbon groups, C5 cyclic hydrocarbon groups, C6 cyclic hydrocarbon groups, and C7 cyclic hydrocarbon groups. Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl. In some embodiments, the C atom in the cyclic hydrocarbon group is optionally substituted with an oxo group. In some embodiments, the C atom in the cyclic hydrocarbon group is optionally substituted with an imino group. In some embodiments, the imino group is unsubstituted (=NH) or substituted with a group described in the context. In some embodiments, the imino group is substituted with -OR, where R is H or C. 1-10 alkyl.

[0034] The terms "cycloalkyl" and "cycloalkyl group" have the same meaning herein and are used interchangeably. A cycloalkyl group refers to a saturated cyclic hydrocarbon group. A cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbon atoms (C1, C2, C3). 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.1.1]hexyl. In some embodiments, the cycloalkyl group is C10. 3-7 Monocyclic or bicyclic cycloalkyl, preferably C 3-6 Monocyclic cycloalkyl groups, especially cyclopropyl groups.

[0035] The term "heterocyclic group" or "heterocyclic hydrocarbon group" refers to a monocyclic or bicyclic cyclic system (3-14-membered, 7-14-membered, 3-8-membered, 3-7-membered, 4-6-membered, 5-6-membered) having, for example, 3-14 (e.g., 7-14, 3-8, 3-7, 4-6-membered, or 5-6-membered) ring atoms, wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are carbon atoms. The cyclic system can be saturated (also understood as the corresponding "heterocyclic alkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring). Optionally, the heterocyclic group can be benzofused. The "heterocyclic group" or "heterocyclic hydrocarbon group" is not aromatic. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted with oxygen. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino groups. In some embodiments, the imino group is unsubstituted (=NH) or substituted with a group as described in the context. In some embodiments, the imino group is substituted with -OR, where R is H or C. 1-10 alkyl.

[0036] The heterocyclic group can be, for example, a four-membered ring, such as azahexacyclobutane or oxacyclobutane; or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, oxopyrrolyl, or 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, 1,1-dioxo-1,2-thiazin-2-yl, or trithiaalkyl; or a seven-membered ring, such as diazacyclobutane. Base ring.

[0037] Heterocyclic groups can be bicyclic, without limitation, such as five-membered fused five-membered rings, like octahydrocyclopentane[c]pyrrolithyl; or five-membered fused six-membered bicyclic rings, like octahydropyrrolo[1,2-b]pyrazinyl.

[0038] As mentioned above, heterocycles can be unsaturated, meaning they can contain one or more double bonds without limitation. For example, unsaturated heterocycles containing nitrogen atoms can be 1,6-dihydropyrimidine, 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl rings. Unsaturated heterocycles containing oxygen atoms can be 2H-pyran, 4H-pyran, or 2,3-dihydrofuran. Unsaturated heterocycles containing sulfur atoms can be 2H-thiaran or 4H-thiaran. Heterocycles can be benzofused without limitation, such as dihydroisoquinoline rings.

[0039] Exemplary bicyclic heterocyclic rings also include:

[0040] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) ring with a conjugated π-electron system. For example, an aryl group can have 6-14 carbon atoms, suitably 6-10, and more preferably 6 or 10. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.

[0041] The term "heteroaryl" should be understood to preferably refer to a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms ("5-10 heteroaryl"), particularly 5, 6, 9, or 10 ring atoms, and the ring atoms contain at least one (suitably 1-4, more preferably 1, 2, or 3) heteroatoms that may be the same or different, said heteroatoms being, for example, oxygen, nitrogen, or sulfur. Furthermore, in each case, the heteroaryl group may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, inazinyl, purinyl, etc., and their benzo[derivatives]; or cyclophosphinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, carbazole, acridinyl, etc.

[0042] The term "nitric oxide donor" refers to a chemical structure that produces or releases NO in vivo. Preferably, the NO donor releases NO stably via a chemical process. This document does not limit the mechanism by which the NO donor releases NO. For example, the NO donor may have a functional group capable of releasing NO, such as a nitroso or nitrosyl group; or, the NO donor may release NO under the catalysis of an enzyme; or, the NO donor may release NO through an oxidation or reduction reaction.

[0043] In one embodiment, the NO donor contains a nitrate ester structure. In one embodiment, the nitrate ester is an alkyl nitrate ester. In one embodiment, the NO donor contains an azooxide structure. In one embodiment, the azooxide structure comprises... In one embodiment, the NO donor contains a furazan oxynitride structure. In another embodiment, the furazan oxynitride structure comprises... R can be, for example, CN or benzenesulfonyl.

[0044] Endogenous NO is primarily synthesized in vivo by nitric oxide synthase. Three isoforms of this enzyme have been identified: endothelial NOS (eNOS) and neuronal NOS (nNOS), which are structurally expressed and whose NO production is highly regulated; and inducible NOS (iNOS), which is expressed in damaged tissues and whose NO production is largely uncontrolled, leading to higher local NO concentrations and thus cytotoxicity. iNOS expression is often associated with inflammatory responses.

[0045] NO plays important and complex physiological roles. Most known NO donor drugs suffer from drug resistance issues, limiting their clinical use; this is related to the reactive properties of NO. Under most conditions, NO acts directly as an antioxidant. The main exception is when NO production and superoxide production exhibit similar fluctuations, with NO reacting with superoxide anions (O2). ·- The reaction produces peroxynitrite (ONOO). - NO donor resistance may also lead to cross-resistance to endothelial-derived NO. The mechanism of peroxynitrite production is complex; for example, the increase of peroxynitrite in blood vessels is related to NAD(P)H oxidase and angiotensin-converting enzyme.

[0046] Flavonoids are a class of compounds with a 2-phenylchromone skeleton. Flavonoid glycosides are compounds formed by covalently linking flavonoids with sugars or sugar derivatives. Literature reports various activities of some natural products of flavonoids and flavonoid glycosides, including antioxidant, anti-inflammatory, vascular endothelial protection, and anti-angiogenic effects. Antioxidant effects include scavenging reactive oxygen species (ROS) or inhibiting ROS production.

[0047] Carbohydrates are a class of compounds with polyhydroxy aldehyde or polyhydroxy ketone structures; the oxygen atom in the hydroxyl, aldehyde carbonyl, and ketone carbonyl groups can be optionally replaced by an sulfur atom, in which case they are called thioglycoses; in addition, one or more of the oxygen atoms in the hydroxyl groups of the molecule can be missing, i.e., the position is H, in which case they are called deoxyglycans. Monosaccharides are sugars that cannot be simply broken down into more than one smaller sugar molecule. Monosaccharides can have 5, 6, or 7 carbon atoms, i.e., pentose, hexose, or heptaoses. The aldehyde, ketone carbonyl, or thiocarbonyl group of a monosaccharide can form a cyclic hemiacetal or thiohemiacetal structure with a hydroxyl or mercapto group in the molecule; among them, those forming a furan ring are called furanoses, and those forming a pyran ring are called pyranoses.

[0048] The term "intraocular pressure-related diseases" refers to ophthalmic diseases associated with or responding to intraocular pressure levels; it is a group of clinically heterogeneous diseases. Their sites of onset are not limited to the eye.

[0049] "Normal intraocular pressure" refers to intraocular pressure under normal physiological conditions. In contrast, "high intraocular pressure" refers to intraocular pressure that is higher than normal. For example, "high intraocular pressure" refers to intraocular pressure of approximately 8 mmHg or higher, approximately 9 mmHg or higher, approximately 10 mmHg or higher, approximately 11 mmHg or higher, approximately 12 mmHg or higher, approximately 13 mmHg or higher, approximately 14 mmHg or higher, approximately 15 mmHg or higher, approximately 16 mmHg or higher, approximately 17 mmHg or higher, approximately 18 mmHg or higher, approximately 19 mmHg or higher, approximately 20 mmHg or higher, approximately 21 mmHg or higher, approximately 22 mmHg or higher, approximately 23 mmHg or higher, approximately 24 mmHg or higher, approximately 25 mmHg or higher, approximately 26 mmHg or higher, approximately 27 mmHg or higher, approximately 28 mmHg or higher, approximately 29 mmHg or higher, or approximately 30 mmHg or higher. In one particular implementation, the individual is a person, and "high intraocular pressure" refers to an intraocular pressure, for example, above approximately 20 mmHg. Intraocular pressure can be measured using a tonometer. High intraocular pressure can cause compression and ischemia of the retina and optic nerve, leading to retinal and optic nerve damage.

[0050] As examples, diseases associated with high intraocular pressure include, but are not limited to, glaucoma and optic nerve damage.

[0051] The term "optic nerve injury-related diseases" refers to diseases that present with or are caused by optic nerve injury.

[0052] As examples, optic nerve injury-related diseases include, but are not limited to, neurodegenerative eye diseases, injuries caused by trauma or surgery, and eye diseases caused by diabetes, inflammation, or tumors.

[0053] The terms "small organic molecule" or "low molecular weight compound" refer to molecules whose size is comparable to that of organic molecules commonly used in pharmaceuticals. In one specific embodiment, the small organic molecule has a size of about 100 to about 2000 Da, preferably about 200 to about 1000 Da, for example about 200 to about 900 Da, about 200 to about 800 Da, about 200 to about 700 Da, about 200 to about 600 Da, or about 200 to about 500 Da.

[0054] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0055] The compounds of this invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites, or prodrugs.

[0056] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds are contemplated. For example, the compounds of this invention may contain E or Z configurations of carbon-carbon or carbon-nitrogen double bonds, where “E” indicates that, according to the Cahn-Ingold-Prelog preference rule, the preferred substituent is on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and “Z” indicates that the preferred substituent is on the same side of the carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as mixtures of “E” and “Z” isomers. Isomeric forms also include cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0057] Optically pure enantiomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts using optically active acids or bases, or by forming covalent diastereomers. Mixtures of diastereomers can be separated into individual diastereomers based on their physical and / or chemical differences using methods known in the art (e.g., by chromatography or fractional crystallization). An optically active enantiomer base or acid is then released from the separated diastereomer salt. Another method for separating racemic enantiomers uses chiral chromatography (e.g., chiral HPLC columns), where the separated chiral isomers may be conventionally derivatized or not derivatized prior to separation, depending on which method allows for more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers. Similarly, optically pure compounds of the present invention can be obtained via chiral synthesis using optically active starting materials.

[0058] The compounds of the present invention can exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric proportions.

[0059] This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0060] The compounds of this invention can exist in isotopically labeled or enriched form, comprising one or more atoms with masses and mass numbers different from the most common atomic masses and mass numbers found in nature. The isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine are included, but not limited to, these isotopes. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I.

[0061] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compounds.

[0062] The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity.

[0063] The term “polymorph” or “polymorphic material” refers to a single polymorph or a mixture of more than one polymorph in any proportion.

[0064] The term "crystal form" or "crystal" refers to any solid substance that exhibits a three-dimensional arrangement, as opposed to amorphous solid substances, and produces characteristic X-ray powder diffraction patterns with clearly defined peaks.

[0065] The term "amorphous" refers to any solid substance that is not ordered in three dimensions.

[0066] The term "pharmaceutically acceptable" means that, within the normal range of medical judgment, contact with a patient's tissues will not cause inappropriate toxicity, irritation, allergic reactions, etc.

[0067] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0068] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

[0069] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0070] The term "individual" includes humans or non-human animals. Exemplary human individuals include individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, "non-human animals" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Compound of formula (I)

[0071] In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I): D1 a —G1 g —F1—D2 b (I) in, "―" indicates covalent connection; Each D1 and D2 is independently a portion containing a nitric oxide donor; F1 is the portion containing flavonoid structures; Each G1 is independently a monosaccharide or a derivative of a monosaccharide; g is any integer from 1 to 10; a is any integer from 0 to 10, and b is any integer from 0 to 10, provided that a and b are not both 0.

[0072] In one embodiment, the compound of formula (I) does not include the following structures: Where R is substituted or unsubstituted C 1-12 Alkyl, substituted or unsubstituted benzyl; the substituent is: C1-4 alkyl, ... 1-4 Alkoxy group; n is an integer from 2 to 8.

[0073] In one embodiment, g is 1. In one embodiment, a is 1, 2, or 3, preferably 1 or 2, particularly 1. In one embodiment, b is 0. In one embodiment, F1 is 5,6,7-trihydroxy-4-oxo-2-phenyl-4H-chromene. In one embodiment, G1 is β-D-glucuronic acid, or an amide formed from the carboxyl group of β-D-glucuronic acid. In one embodiment, F1 and G1 are linked by a glycosidic bond.

[0074] In one embodiment, equation (I) has the structure of equation (I-1): in, R 1 Selected from hydrogen, -OH, -OC 1-10 Alkyl and Each alkyl group is unsubstituted or is selected independently from R. X1 Substituents of the substituents; R 2 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A2 R B2 -OR A2 -SR A2 -C(=O)R A2 -C(=O)OR A2 -OC(=O)R A2 -C(=O)NR A2 R B2 -NR A2 C(=O)R B2 -NR A2 C(=NR E2 )R B2 -OC(=O)NR A2 R B2 -NR A2 C(=O)OR B2 -NR A2 C(=O)NR A2 R B2 -NR A2 C(=S)NR A2 R B2 -NR A2 C(=NR E2 )NR A2 R B2 -S (=O) r R A2 -S(=O)(=NR) E2 )R B2 -N = S(=O)R A2 R B2 -S(=O)2OR A2 -OS(=O)2R A2 -NR A2 S(=O) r R B2 -NR A2 S(=O)(=NR E2 )R B2 -S (=O) r NR A2 R B2 -S(=O)(=NR) E2 )NR A2 R B2 -NR A2 S(=O)2NR A2 RB2 -NR A2 S(=O)(=NR E2 )NR A2 R B2 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X2 Substituents of the substituents; R 3 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A3 R B3 -OR A3 -SR A3 -C(=O)R A3 -C(=O)OR A3 -OC(=O)R A3 -C(=O)NR A3 R B3 -NR A3 C(=O)R B3 -NR A3 C(=NR E3 )R B3 -OC(=O)NR A3 R B3 -NR A3 C(=O)OR B3 -NR A3 C(=O)NR A3 R B3 -NR A3 C(=S)NR A3 R B3 -NR A3 C(=NR E3 )NR A3 R B3 -S (=O) r R A3 -S(=O)(=NR) E3 )R B3 -N = S(=O)R A3 R B3 -S(=O)2ORA3 -OS(=O)2R A3 -NR A3 S(=O) r R B3 -NR A3 S(=O)(=NR E3 )R B3 -S (=O) r NR A3 R B3 -S(=O)(=NR) E3 )NR A3 R B3 -NR A3 S(=O)2NR A3 R B3 -NR A3 S(=O)(=NR E3 )NR A3 R B3 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X3 Substituents of the substituents; R 4 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A4 R B4 -OR A4 -SR A4 -C(=O)R A4 -C(=O)OR A4 -OC(=O)R A4 -C(=O)NR A4 R B4 -NR A4 C(=O)R B4 -NR A4 C(=NR E4 )R B4 -OC(=O)NR A4 R B4 -NR A4 C(=O)OR B4 -NRA4 C(=O)NR A4 R B4 -NR A4 C(=S)NR A4 R B4 -NR A4 C(=NR E4 )NR A4 R B4 -S (=O) r R A4 -S(=O)(=NR) E4 )R B4 -N = S(=O)R A4 R B4 -S(=O)2OR A4 -OS(=O)2R A4 -NR A4 S(=O) r R B4 -NR A4 S(=O)(=NR E4 )R B4 -S (=O) r NR A4 R B4 -S(=O)(=NR) E4 )NR A4 R B4 -NR A4 S(=O)2NR A4 R B4 -NR A4 S(=O)(=NR E4 )NR A4 R B4 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X4 Substituents of the substituents; R 5 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A5 R B5 -OR A5-SR A5 -C(=O)R A5 -C(=O)OR A5 -OC(=O)R A5 -C(=O)NR A5 R B5 -NR A5 C(=O)R B5 -NR A5 C(=NR E5 )R B5 -OC(=O)NR A5 R B5 -NR A5 C(=O)OR B5 -NR A5 C(=O)NR A5 R B5 -NR A5 C(=S)NR A5 R B5 -NR A5 C(=NR E5 )NR A5 R B5 -S (=O) r R A5 -S(=O)(=NR) E5 )R B5 -N = S(=O)R A5 R B5 -S(=O)2OR A5 -OS(=O)2R A5 -NR A5 S(=O) r R B5 -NR A5 S(=O)(=NR E5 )R B5 -S (=O) r NR A5 R B5 -S(=O)(=NR) E5 )NR A5 R B5 -NR A5 S(=O)2NR A5 R B5 -NR A5 S(=O)(=NR E5 )NR A5 R B5 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X5Substituents of the substituents; R 6 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A6 R B6 -OR A6 -SR A6 -C(=O)R A6 -C(=O)OR A6 -OC(=O)R A6 -C(=O)NR A6 R B6 -NR A6 C(=O)R B6 -NR A6 C(=NR E6 )R B6 -OC(=O)NR A6 R B6 -NR A6 C(=O)OR B6 -NR A6 C(=O)NR A6 R B6 -NR A6 C(=S)NR A6 R B6 -NR A6 C(=NR E6 )NR A6 R B6 -S (=O) r R A6 -S(=O)(=NR) E6 )R B6 -N = S(=O)R A6 R B6 -S(=O)2OR A6 -OS(=O)2R A6 -NR A6 S(=O) r R B6 -NR A6 S(=O)(=NR E6 )R B6 -S (=O)r NR A6 R B6 -S(=O)(=NR) E6 )NR A6 R B6 -NR A6 S(=O)2NR A6 R B6 -NR A6 S(=O)(=NR E6 )NR A6 R B6 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X6 Substituents of the substituents; Or "R" 2 and R 3 "or "R 3 and R 4 "or "R 4 and R 5 "or "R 5 and R 6 Together with the carbon atoms attached to them, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2, or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or is composed of at least one heteroatom independently selected from R. X Substituents of the substituents; Each R 7 Independently selected from halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A7 R B7 -OR A7 -SR A7 -C(=O)R A7 -C(=O)OR A7 -OC(=O)R A7 -C(=O)NR A7 R B7 -NR A7 C(=O)R B7 -NR A7 C(=NR E7 )R B7 -OC(=O)NR A7 R B7-NR A7 C(=O)OR B7 -NR A7 C(=O)NR A7 R B7 -NR A7 C(=S)NR A7 R B7 -NR A7 C(=NR E7 )NR A7 R B7 -S (=O) r R A7 -S(=O)(=NR) E7 )R B7 -N = S(=O)R A7 R B7 -S(=O)2OR A7 -OS(=O)2R A7 -NR A7 S(=O) r R B7 -NR A7 S(=O)(=NR E7 )R B7 -S (=O) r NR A7 R B7 -S(=O)(=NR) E7 )NR A7 R B7 -NR A7 S(=O)2NR A7 R B7 -NR A7 S(=O)(=NR E7 )NR A7 R B7 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X7 Substituents of the substituents; Or any two adjacent R 7 Together with the carbon atoms attached to them, they form a saturated or unsaturated 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or has at least one heteroatom independently selected from R. X7 Substituents of the substituents; L 1 Selected from chemical bonds, -(CR C1 R D1 ) u -O-(CR C1 RD1 ) t -、-(CR C1 R D1 ) u -S-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=O)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=O)O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=O)NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -OC(=O)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 C(=O)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=S)O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -C(=S)NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 )u -OC(=S)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 C(=S)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S(=O) r O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S(=O) r NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -OS(=O) r -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 S(=O) r -(CR C1 R D1 ) t -、C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group, wherein each alkylene group, alkenylene group, or alynyl group is unsubstituted or is independently selected from R X Substituents of the substituents; R 8 Selected from hydrogen and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X8 Substituents of the substituents; U 0 For O or S; Y 1 For C(R) 9a R 9a’ ); Y 2 For C(R) 9b R 9b’ ); Y 3 For C(R) 9c R 9c’ ); Y 4 For C(R) 9d R 9d’ ); R 9a R 9a’ R 9b R 9b’ R 9c R 9c’ R 9d and R 9d’ Each is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A9 R B9 -OR A9 -SR A9 -C(=O)R A9 -C(=O)OR A9 -OC(=O)R A9 -C(=O)NR A9 R B9 -NR A9 C(=O)R B9 -NR A9 C(=NR E9 )R B9 -OC(=O)NR A9 R B9 -NR A9 C(=O)OR B9 -NR A9 C(=O)NR A9 R B9 -NR A9 C(=S)NR A9 R B9 -NR A9 C(=NR E9 )NR A9 R B9 -OS(=O)2R A9 -NR A9 S(=O)r R B9 -NR A9 S(=O)(=NR E9 )R B9 -NR A9 S(=O)2NR A9 R B9 -NR A9 S(=O)(=NR E9 )NR A9 R B9 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X9 Substituents of the substituents; Each R A2 R A3 R A4 R A5 R A6 R A7 R A9 R B2 R B3 R B4 R B5 R B6 R B7 and R B9 Independently selected from hydrogen and C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X Substituents of the substituents; Or "R" A2 and R B2 "or "R A3 and R B3 "or "R A4 and R B4 "or "R A5 and R B5 "or "R A6 and R B6 "or "R A7 and R B7 "or "R A9and R B9 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms selected from R. X Substituents of the substituents; Each R C1 and R D1 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X Substituents of the substituents; Or each "R" C1 and R D1 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms independently selected from R. X Substituents of the substituents; Each R E2 R E3 R E4 R E5 R E6 R E7 and R E9 Independently selected from hydrogen and C 1-10 Alkyl group, CN, NO2, -S (=O) r R a1 -C(=O)R a1 -C(=O)OR a1 -C(=O)NR a1 R b1 -S (=O) r NR a1 R b1 and Wherein the alkyl group is unsubstituted or is selected independently from R X Substituents of the substituents; Each L is independently selected from chemical bonds, -(CR) c R d )u -O-(CR c R d ) t -、-(CR c R d ) u -S-(CR c R d ) t -、-(CR c R d ) u -NR 8 -(CR c R d ) t -、-(CR c R d ) u -C(=O)-(CR c R d ) t -、-(CR c R d ) u -C(=O)O-(CR c R d ) t -、-(CR c R d ) u -C(=O)NR 8 -(CR c R d ) t -、-(CR c R d ) u -OC(=O)-(CR c R d ) t -、-(CR c R d ) u -NR 8 C(=O)-(CR c R d ) t -、-(CR c R d ) u -C(=S)-(CR c R d ) t -、-(CR c R d ) u -C(=S)O-(CR c R d ) t -、-(CR c Rd ) u -C(=S)NR 8 -(CR c R d ) t -、-(CR c R d ) u -OC(=S)-(CR c R d ) t -、-(CR c R d ) u -NR 8 C(=S)-(CR c R d ) t -、-(CR c R d ) u -S(=O) r -(CR c R d ) t -、-(CR c R d ) u -S(=O) r O-(CR c R d ) t -、-(CR c R d ) u -S(=O) r NR 8 -(CR c R d ) t -、-(CR c R d ) u -OS(=O) r -(CR c R d ) t -、-(CR c R d ) u -NR 8 S(=O) r -(CR c R d ) t -、C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group, wherein the alkylene group, alkenyl group, or alynyl group is unsubstituted or is selected independently from R. Y Substituents of the substituents; Each R c and R d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic groups, M, -C 1-4 Alkylene-M, wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. Y Substituents of the substituents; Each M is independently selected from the NO donor; NO represents nitric oxide. Each R X R X1 R X2 R X3 R X4 R X5 R X6 R X7 R X8 and R X9 Independently selected from halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR) c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CR c1 R d1 ) u C(=NR e1 )R a1 、-(CR c1 R d1 ) u C(=O)ORb1 、-(CR c1 R d1 ) u OC(=O)R b1 、-(CR c1 R d1 ) u C(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=O)R b1 、-(CR c1 R d1 ) u C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) u OC(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=O)OR b1 、-(CR c1 R d1 ) u NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=S)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u S(=O) r R b1 、-(CR c1 R d1 )u S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) u N = S(=O)R a1 R b1 、-(CR c1 R d1 ) u S(=O)2OR b1 、-(CR c1 R d1 ) u OS(=O)2R b1 、-(CR c1 R d1 ) u NR a1 S(=O) r R b1 、-(CR c1 R d1 ) u NR a1 S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) u S(=O) r NR a1 R b1 、-(CR c1 R d1 ) u S(=O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u NR a1 S(=O)2NR a1 R b1 、-(CR c1 R d1 ) u NR a1 S(=O)(=NR e1 )NR a1 R b1 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. Y Substituents of the substituents; Each R a1 and R b1 Independently selected from hydrogen and C 1-10Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. Y Substituents of the substituents; Or R a1 and R b1 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms selected independently from oxygen, sulfur, nitrogen, and phosphorus. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms selected from R. Y Substituents of the substituents; Each R c1 and R d1 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. Y Substituents of the substituents; Or each R c1 and R d1 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring is either unsubstituted or surrounded by 1, 2, or 3 heteroatoms independently selected from R. Y Substituents of the substituents; Each R e1 Independently selected from hydrogen and C 1-10 Alkyl group, CN, NO2, -S (=O) r R a1 -C(=O)R a1 -C(=O)OR a1 -C(=O)NRa1 R b1 -S (=O) r NR a1 R b1 and Wherein the alkyl group is unsubstituted or is selected independently from R Y Substituents of the substituents; Each R Y Independently selected from halogens, NO2, -CN, C 1-10 Alkyl, -OH, -O(C) 1-10 alkyl), -O(C) 3-10 cycloalkyl), -O(C 1-4 Alkylene-C 3-10 cycloalkyl), -O (heterocyclic), -O (C 1-4 alkylene-heterocyclic groups), -SH, -S(C 1-10 alkyl), -S(C 3-10 cycloalkyl), -S(C 1-4 Alkylene-C 3-10 cycloalkyl), -S (heterocyclic), -S (C 1-4 alkylene-heterocyclic groups), -NH2, -NH(C 1-10 alkyl), -N(C) 1-10 alkyl)2、-NH(C 3-10 cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 cycloalkyl), -NH (heterocyclic) and -NH (C 1-4 (alkylene-heterocyclic group); m is 0 or 1; p is 0, 1, 2 or 3; Each r is independently selected from 1 and 2; Each t is independently selected from integers between 0 and 10; Each u is independently selected from integers between 0 and 10; Each k is independently selected from 1, 2, 3, and 4; Each q is independently selected from 0, 1, 2, and 3; The total number of M molecules is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0075] In one implementation scheme, each R A2 R A3 R A4 R A5 R A6 R A7 R A9 R B2 R B3 R B4 R B5R B6 R B7 and R B9 Independently selected from hydrogen and C 1-10 Alkyl and Each alkyl group is unsubstituted or is selected independently from R. X Substituents are substituted. In one embodiment, each R... A2 R A3 R A4 R A5 R A6 R A7 R A9 R B2 R B3 R B4 R B5 R B6 R B7 and R B9 Independently selected from hydrogen, methyl and

[0076] In one implementation scheme, each R X R X1 R X2 R X3 R X4 R X5 R X6 R X7 R X8 and R X9 Independently selected from halogens, C 1-10 Alkyl, CN, NO2, -(CR) c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CR c1 R d1 ) u C(=O)OR b1 、-(CR c1 R d1 ) u OC(=O)R b1 、-(CR c1 R d1 ) u C(=O)NR a1 R b1 、-(CRc1 R d1 ) u NR a1 C(=O)R b1 、-(CR c1 R d1 ) u OC(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=O)OR b1 、-(CR c1 R d1 ) u NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) u S(=O) r R b1 、-(CR c1 R d1 ) u S(=O)2OR b1 、-(CR c1 R d1 ) u OS(=O)2R b1 、-(CR c1 R d1 ) u NR a1 S(=O) r R b1 、-(CR c1 R d1 ) u S(=O) r NR a1 R b1 and is preferably selected from halogen, C 1-10 alkyl, CN, NO2, -(CR c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CR c1 Rd1 ) u C(=O)OR b1 、-(CR c1 R d1 ) u OC(=O)R b1 、-(CR c1 R d1 ) u C(=O)NR a1 R b1 、-(CR c1 R d1 ) u NR a1 C(=O)R b1 and Each alkyl group is unsubstituted or is selected independently from R. Y Substituents are substituted.

[0077] In one implementation scheme, each R Y Independently selected from halogens, NO2, -CN, C 1-10 Alkyl, -OH, -O(C) 1-10 Alkyl), -SH, -S(C 1-10 Alkyl groups), -NH2 and -NH(C 1-10 Alkyl groups, preferably selected from halogens, NO2, -CN and C. 1-10 alkyl.

[0078] In one implementation, u is 0. In another implementation, t is 0.

[0079] In one implementation scheme, R 1 It is hydrogen.

[0080] In one implementation scheme, R 2 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A2 R B2 -OR A2 -SR A2 -C(=O)R A2 -C(=O)OR A2 -OC(=O)R A2 -C(=O)NR A2 R B2 -NR A2 C(=O)R B2 -OC(=O)NRA2 R B2 -NR A2 C(=O)OR B2 -NR A2 C(=O)NR A2 R B2 -S (=O) r R A2 -S(=O)2OR A2 -OS(=O)2R A2 -NR A2 S(=O) r R B2 -S (=O) r NR A2 R B2 and Preferably selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A2 R B2 -OR A2 -OC(=O)R A2 -OS(=O)2R A2 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X2 Substituents are substituted. In one embodiment, R 2 It is hydrogen.

[0081] In one implementation scheme, R 3 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A3 R B3 -OR A3 -SR A3 -C(=O)R A3 -C(=O)OR A3 -OC(=O)R A3 -C(=O)NR A3 R B3 -NR A3 C(=O)R B3 -OC(=O)NR A3 R B3 -NR A3 C(=O)OR B3 -NR A3 C(=O)NR A3R B3 -S (=O) r R A3 -S(=O)2OR A3 -OS(=O)2R A3 -NR A3 S(=O) r R B3 -S (=O) r NR A3 R B3 and Preferably selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A3 R B3 -OR A3 -OC(=O)R A3 -OS(=O)2R A3 and More preferably selected from hydrogen, -OR A3 -OC(=O)R A3 -OS(=O)2R A3 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X3 Substituents are substituted. In one embodiment, R 3 It is hydrogen.

[0082] In one implementation scheme, R 4 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A4 R B4 -OR A4 -SR A4 -C(=O)R A4 -C(=O)OR A4 -OC(=O)R A4 -C(=O)NR A4 R B4 -NR A4 C(=O)R B4 -OC(=O)NR A4 R B4 -NR A4 C(=O)OR B4 -NR A4 C(=O)NR A4 R B4-S (=O) r R A4 -S(=O)2OR A4 -OS(=O)2R A4 -NR A4 S(=O) r R B4 -S (=O) r NR A4 R B4 and Preferably selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A4 R B4 -OR A4 -OC(=O)R A4 -OS(=O)2R A4 and More preferably selected from hydrogen, -OR A4 -OC(=O)R A4 -OS(=O)2R A4 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X4 Substituents are substituted. In one embodiment, R 4 It is hydrogen.

[0083] In one implementation scheme, R 5 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A5 R B5 -OR A5 -SR A5 -C(=O)R A5 -C(=O)OR A5 -OC(=O)R A5 -C(=O)NR A5 R B5 -NR A5 C(=O)R B5 -OC(=O)NR A5 R B5 -NR A5 C(=O)OR B5 -NR A5 C(=O)NR A5 R B5 -S (=O)r R A5 -S(=O)2OR A5 -OS(=O)2R A5 -NR A5 S(=O) r R B5 -S (=O) r NR A5 R B5 and Preferably selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A5 R B5 -OR A5 -OC(=O)R A5 -OS(=O)2R A5 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X5 Substituents are substituted. In one embodiment, R 5 It is hydrogen.

[0084] In one implementation scheme, R 6 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A6 R B6 -OR A6 -SR A6 -C(=O)R A6 -C(=O)OR A6 -OC(=O)R A6 -C(=O)NR A6 R B6 -NR A6 C(=O)R B6 -OC(=O)NR A6 R B6 -NR A6 C(=O)OR B6 -NR A6 C(=O)NR A6 R B6 -S (=O) r R A6 -S(=O)2OR A6 -OS(=O)2R A6 -NR A6 S(=O)r R B6 -S (=O) r NR A6 R B6 and Preferably selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A6 R B6 -OR A6 -OC(=O)R A6 -OS(=O)2R A6 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X6 Substituents are substituted. In one embodiment, R 6 It is hydrogen.

[0085] In one implementation scheme, R 2 R 3 R 4 R 5 and R 6 At least two of them are hydrogen. In one embodiment, R 2 R 3 R 4 R 5 R 6 It is hydrogen.

[0086] In one implementation scheme, each R 7 Independently selected from halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A7 R B7 -OR A7 -SR A7 -C(=O)R A7 -C(=O)OR A7 -OC(=O)R A7 -C(=O)NR A7 R B7 -NR A7 C(=O)R B7 -OC(=O)NR A7 R B7 -NR A7 C(=O)OR B7 -NR A7 C(=O)NR A7 RB7 -S (=O) r R A7 -S(=O)2OR A7 -OS(=O)2R A7 -NR A7 S(=O) r R B7 -S (=O) r NR A7 R B7 and Preferred selections are hydrogen, -OR A7 -OC(=O)R A7 -OS(=O)2R A7 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X7 Substituents are substituted. In one embodiment, each R... 7 Independent selection from -OR A7 and In one implementation scheme, each R A7 For hydrogen. In one embodiment, each R A7 It is a methyl group.

[0087] In one embodiment, p is 2. In one embodiment, p is 2; and, (1) two R 7 For -OH, or (2) an R 7 For -OH, another R 7 for

[0088] In one implementation scheme, U 0 It is O.

[0089] In one implementation scheme, R 9a R 9a’ R 9b R 9b’ R 9c (if it exists), R 9c’ (if it exists), R 9d and R 9d’ Each is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A9 R B9 -OR A9 -SR A9 -C(=O)RA9 -C(=O)OR A9 -OC(=O)R A9 -C(=O)NR A9 R B9 -NR A9 C(=O)R B9 -OC(=O)NR A9 R B9 -NR A9 C(=O)OR B9 -NR A9 C(=O)NR A9 R B9 -S (=O) r R A9 -S(=O)2OR A9 -OS(=O)2R A9 -NR A9 S(=O) r R B9 -S (=O) r NR A9 R B9 and Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. X9 Substituents are substituted.

[0090] In one implementation scheme, R 9a -C(=O)R A9 R 9a’ It is hydrogen. In one embodiment, R A9 for

[0091] In one implementation, m is 1.

[0092] In one implementation scheme, R 9b R 9b’ R 9c (if it exists), R 9c’ (if it exists), R 9d and R 9d’ Each is independently selected from hydrogen, -OR A9 and In one implementation scheme, each R A9 It is hydrogen or methyl, especially hydrogen.

[0093] In one implementation scheme, R 9b R 9c (if it exists) and R 9d For -OH, R 9b’ R 9c’ (if it exists), R9d’ It is hydrogen. In one embodiment, R 9b and R 9c (If present) is -OH, R 9d for R 9b’ R 9c’ (if it exists) and R 9d’ It is hydrogen.

[0094] In one implementation scheme, L 1 Selected from chemical bonds, -(CR C1 R D1 ) u -O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S-(CR C1 R D1 ) t - and -(CR C1 R D1 ) u -NR 8 -(CR C1 R D1 ) t -

[0095] In one implementation scheme, R 8 For hydrogen. In one embodiment, each R C1 and R D1 Independently selected from hydrogen, halogen, C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0096] In one implementation scheme, L 1 It can be -O- or -S-, especially -O-.

[0097] In one embodiment, each L is independently selected from chemical bonds, -(CR) c R d ) u -O-(CR c R d ) t -、-(CR c R d ) u -S-(CR c R d ) t -、-(CR c R d ) u -NR8 -(CR c R d ) t -、-(CR c R d ) u -C(=O)-(CR c R d ) t -、-(CR c R d ) u -C(=O)O-(CR c R d ) t -、-(CR c R d ) u -C(=O)NR 8 -(CR c R d ) t -、-(CR c R d ) u -OC(=O)-(CR c R d ) t -、-(CR c R d ) u -NR 8 C(=O)-(CR c R d ) t -and C 1-4 Alkylene, wherein the alkylene is unsubstituted or is selected independently from R Y Substituents are substituted. In one embodiment, each L is independently selected from chemical bonds, -(CR) c R d ) u -O-(CR c R d ) t -、-(CR c R d ) u -S-(CR c R d ) t - and -(CR c R d ) u -C(=O)-(CR c R d ) t -

[0098] In one implementation, k is 1, 2, or 3. In one implementation, each Rc and R d Independently selected from hydrogen, halogens and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. Y Substituents are substituted.

[0099] In one implementation scheme, This indicates that the NO donor is linked to other parts of the molecule via a linking group; where -(L) k - represents a linking group, which is connected to one M and q M's; square brackets indicate that M can be connected to any position of the linking group, as long as a stable chemical structure can be formed. It can be linked to other parts of the molecule through, for example, C-C bonds, amide bonds, ester bonds or ether bonds, especially through ester bonds.

[0100] When calculating the value of q, R is included. c Or R d For M or -C 1-4 The amount of M in alkylene-M. In one embodiment, q is 0. The structure can be represented as -(L) k —M.

[0101] In one implementation scheme, -(L) k The structure of ― is selected from -(CH2). j -、-(CH2) j1 -O-(CH2) j2 -、-(CH2) j1 -OC(=O)-(CH2) j2 -、-(CH2) j1 -C(=O)-(CH2) j2 -、-(CH2) j1 -OC(=O)-(CH2) i -O-(CH2) j2 -、-(CH2) j1 -C(=O)-(CH2) i -O-(CH2) j2 -、-(CH2) j1 -OC(=O)-(CH2) i1 -O-(CH2) i2 -O-(CH2) j2 - and -(CH2) j1 -C(=O)-(CH2) i1 -O-(CH2) i2 -O-(CH2) j2-; where i, i1, and i2 are integers from 1 to 10, especially 1; j, j1, and j2 are each independent integers from 0 to 10.

[0102] In one implementation scheme, -(L) k The structure of ― is selected from -(CH2). j -、-O-、-O-CH2-、 Where j is an integer between 0 and 10.

[0103] In one implementation scheme, -(L) k The structure of ― is selected from -(CH2). j -、-O-、-O-CH2-、 Where j is an integer between 0 and 10.

[0104] In one embodiment, each NO donor is independently selected from nitrates, furazolidone oxides, azooxides, thionitrites, and sydnone imines. In one embodiment, the azooxide is an azomonium glycol salt.

[0105] In one implementation scheme, M is in R 10 For -NR A10 R B10 ;R B10 and R B10 Independently selected from hydrogen and C 1-10 Alkyl and C 2-10 Alkenyl groups, wherein each alkyl and alkenyl group is unsubstituted or is independently selected from R. X Substituents of the substituents; Or "R" A10 and R B10 Together with the N atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms selected independently from oxygen, sulfur, nitrogen, and phosphorus. This ring is either unsubstituted or surrounded by 1, 2, or 3 atoms selected from R. X Substituents are substituted.

[0106] In one implementation scheme, each R X Independently selected from halogens, C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl groups and -C(=O)O(C 1-10 alkyl).

[0107] In one implementation scheme, M is Where R 11 Selected from hydrogen, halogens, C 1-10Alkyl, -OH and -O(C 1-10 alkyl).

[0108] In one implementation scheme, M is Where R 12 and R 13 Independently selected from C 1-10 Alkyl, R 14 Selected from C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl group, -C(=O)O(C 1-10 Alkyl), -C(=O)NH(C 1-10 Alkyl) and -C(=O)S(C 1-10 alkyl).

[0109] In one implementation, each M is independently selected from -ONO2, Preferred ingredients are selected from -ONO2, Where R is CN or benzenesulfonyl, wherein the benzene ring of the benzenesulfonyl group is unsubstituted or is composed of 1, 2 or 3 independently selected from R. Y Substituents are substituted.

[0110] In one implementation, when there are multiple M's, each M is identical. In another implementation, when there are multiple M's, each M may be identical or different.

[0111] In one implementation scheme, The structure is selected from -(CH2). j -ONO2、 Preferred selection Where j is an integer between 0 and 10.

[0112] In one implementation scheme, It is attached to other parts of the molecule via amide, ester, or ether bonds, especially via ester bonds.

[0113] In one embodiment, formula (I-1) has the structure of formula (I-2-1): in, L 2 Selected from L; M 1 Selected from M; R 1 R 2 R 3 R 4 R 5 R 6 R 7p, L 1 U 0 Y 2 Y 3 Y 4 , m, L, M are defined as in equation (I-1).

[0114] In one implementation scheme, R 9d Selected from hydrogen and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X9 Substituents are substituted.

[0115] In another embodiment, equation (I-1) has the structure of equation (I-2-2): in, L 2 and L 3 Independently selected from L; M 1 and M 2 Independently selected from M; R 1 R 2 R 3 R 4 R 5 R 6 R 7 p, L 1 U 0 Y 2 Y 3 , m, L, M are defined as in equation (I-1).

[0116] In another embodiment, equation (I-1) has the structure of equation (I-2-3): in, L 2 and L 4 Independently selected from L; M 1 and M 3 Independently selected from M; R 1 R 2 R 3 R 4 R 5 R 6 R 7 p, L 1 U 0 Y 3 Y 4 , m, L, M are defined as in equation (I-1).

[0117] In another embodiment, equation (I-1) has the structure of equation (I-2-4): in, L 2 and L 5 Independently selected from L; M 1 and M 4 Independently selected from M; R 1 R 2 R 3 R 4 R 5 R 6 R 7 p, L 1 U 0 Y 2 Y 4 , m, L, M are defined as in equation (I-1).

[0118] In one embodiment, in equations (I-2-1) and (I-2-2), -L 2 -M 1 The structure is selected from

[0119] In one embodiment, in equations (I-2-1) and (I-2-2), -L 3 -M 2 The structure is

[0120] In one embodiment, formula (I-2-1) has the structure of formula (I-3-1): in, L 2 and M 1 As defined in equation (I-2-1).

[0121] In one embodiment, formula (I-2-2) has the structure of formula (I-3-2): in, L 2 M 1 and M 2 As defined in equation (I-2-2).

[0122] In one embodiment, formula (I-2-3) has the structure of formula (I-3-3): in, L 2 M 1 and M 3 As defined in equation (I-2-3).

[0123] In one embodiment, formula (I-2-4) has the structure of formula (I-3-4): in, L 2 M 1 and M 4 As defined in equation (I-2-4).

[0124] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: Pharmaceutical compositions and pharmaceutical preparations

[0125] Another object of the present invention is to provide a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug, and at least one pharmaceutically acceptable carrier.

[0126] The pharmaceutical compositions of the present invention can be administered in any manner, provided they achieve the effect of preventing, alleviating, preventing, or treating symptoms in humans or animals. For example, various suitable dosage forms can be prepared depending on the route of administration. For example, they can be administered to patients orally or parenterally in conventional formulations. These conventional formulations include, for example, capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. The routes of administration are particularly ocular, such as ocular surface administration, intraocular administration, or periocular administration. The formulations are particularly eye drops and eye ointments.

[0127] The dosage of the compound administered to the subject can be adjusted to a considerable extent. The dosage can be varied depending on the specific route of administration and the subject's needs, and can be determined by a healthcare professional. Treatment methods and uses

[0128] According to certain embodiments of the present invention, the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs, or pharmaceutical compositions thereof, can be used to treat or prevent ocular hypertension-related diseases and optic nerve damage-related diseases.

[0129] Therefore, in another aspect, the present invention also provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of medicaments for the treatment or prevention of diseases, symptoms or conditions selected from intraocular pressure-related diseases and optic nerve damage-related diseases, wherein the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof are optionally used in combination with a second therapeutic agent.

[0130] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof, optionally in combination with a second therapeutic agent, for the treatment of diseases related to high intraocular pressure or optic nerve damage.

[0131] In a further aspect, the present invention provides a method for treating ocular hypertension-related diseases or optic nerve injury-related diseases, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof is optionally used in combination with a second therapeutic agent.

[0132] In one implementation, the disease, condition, or symptom is selected from: glaucoma, neurodegenerative eye disease, and optic nerve injury.

[0133] In one implementation, the disease, condition, or symptom is selected from: glaucoma, age-related macular degeneration, diabetic retinopathy, cataracts, high intraocular pressure caused by retinal vascular occlusion, and optic nerve damage.

[0134] combination therapy

[0135] The compounds of the present invention or their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention, may be used alone or in combination with other therapeutic agents.

[0136] For example, the use of adjuvants can enhance the therapeutic effect of the compounds of this invention (e.g., the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, it can enhance the individual's therapeutic benefit), or, for example, the combination of the compounds of this invention with another equally effective therapeutic agent can enhance the individual's therapeutic benefit. For example, in the treatment of glaucoma, using the compounds of this invention in combination with another drug for treating glaucoma may enhance clinical benefit. Combined therapies include, but are not limited to, physical therapy, psychotherapy, small molecule targeted therapeutic agents (e.g., kinase inhibitors), etc. Regardless of the disease, symptom, or condition, the two therapies should have an additive or synergistic effect on the individual's therapeutic benefit. Beneficial effects

[0137] The novel small molecule compound containing a nitric oxide (NO) donor provided by this invention exhibits outstanding intraocular pressure-lowering activity and protective effect on optic nerve cells.

[0138] Therefore, the compounds of the present invention can treat or prevent diseases related to high intraocular pressure and optic nerve damage, such as glaucoma, age-related macular degeneration, diabetic retinopathy, cataracts, high intraocular pressure caused by retinal vascular occlusion, and optic nerve damage, and have good prospects for development into drugs.

[0139] The compounds of the present invention achieve at least one of the following technical effects: (1) It has a high activity or strong protective effect on target cells or tissues. (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability). (3) Excellent pharmacokinetic properties (e.g., good corneal absorption and / or other pathways of absorption, good stability in plasma, cornea and / or aqueous humor, suitable half-life and duration of action). (4) Excellent safety (few side effects, wide therapeutic window), etc. (5) Lower risk of drug resistance (less likely to develop drug resistance), etc. Example

[0140] To more clearly illustrate the objectives and technical solutions of this invention, the invention will be further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Specific experimental methods not mentioned in the following embodiments were performed according to conventional experimental methods. Instruments, materials and reagents

[0141] Unless otherwise specified, all instruments and reagents used in the examples are commercially available. Reagents may be used directly without further purification. Compound A: CAS No.: 21967-41-9, available from companies such as Merck. Its structure is... LCMS: Shimadzu LC20 Semi-preparative HPLC: Column: F-Prepulite XP tC 18 40*200mm*7mm; Mobile phase: [water (0.225% FA)-ACN] NMR: BRUKER_400MHZ

[0142] Intraocular pressure was measured using the Icare TONOVET Plus tonometer. Synthesis scheme

[0143] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be synthesized by various methods, some exemplary methods of which are provided below and in examples. Other synthetic methods can be readily devised by those skilled in the art based on the information disclosed herein.

[0144] In the reactions described below, it may be necessary to protect the active groups to prevent them from participating in other undesirable reactions. These groups include hydroxyl, amino, imine, thiol-containing, or carboxyl groups, which may be present in the final product. Commonly used protecting groups can be found in TW Greene and PGM Uts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991.

[0145] The synthetic schemes for all compounds of this invention are illustrated by the following schemes and examples. The raw materials used are derived from commercially available products or can be prepared according to existing processes or the methods exemplified herein.

[0146] As shown in Synthesis Scheme 1, the compound of formula (I-1) can be prepared and synthesized by various methods from compound Z1 containing active group 1 and compound Z2 containing active group 2, which are known in the literature or are well known to those skilled in the art.

[0147] In synthetic scheme 1, active group 1 and active group 2 are independently active groups (e.g., active C=O moiety, active C=CC=O moiety, amino, amine, hydroxyl, or thiol group) for condensation reactions, nucleophilic addition, or electrophilic addition, or active groups (e.g., leaving groups attached to O, C, N, or S atoms) for substitution reactions. For example, one of active group 1 and active group 2 is a carboxyl group, a sulfonic acid group, a phosphoryl group with a free -OH terminus, an active ester, an acyl chloride, or an isocyanate, and the other is an amino group, an amine group, a hydroxyl group, or a halogen group; or, one of active group 1 and active group 2 is an amino group, a hydroxyl group, or a thiol group, and the other is a halogen group, a hydroxyl group, or an aldehyde group. In a particular embodiment, one of active group 1 and active group 2 is a carboxyl group, and the other is a hydroxyl group or a halogen group, and active group 1 and active group 2 react to form an ester bond.

[0148] The following embodiments are provided to provide a fuller understanding of the invention. These embodiments are merely illustrative and should not be construed as limiting the invention in any way. Example 1 4-(nitrooxy)butyl(2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-benzene) 4H-chromene-7-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (Compound 001)

[0149] 1.1 Synthesis of intermediate L1-2

[0150] Concentrated nitric acid (2.02 eq) and concentrated sulfuric acid (2.0 eq) were added to a solution of 4-bromobutanol (50 g, 326.8 mmol) in dichloromethane, and the reaction was carried out in an ice-water bath for 2 hours. The reaction system was purified to give a colorless or yellow oily intermediate L1-2 (15.3 g, 77.3 mmol). Yield: 23.65%, purity: 90%.

[0151] 1.2 Synthesis of Compound 001

[0152] Intermediate L1-2 (5 g, 32.7 mmol) was dissolved in DMF, and compound A (1.2 eq) and DBU (1.2 eq) were added. The mixture was reacted at room temperature for 12 hours. The product was post-processed and purified by HPLC to give a yellow or green solid compound 001 (570 mg, 1.01 mmol). Yield: 2.55%, purity: 95.9%. LCMS: ESI-MS m / z 564.1 [M+H] + . 1 H NMR (DMSO-d6, 400M Hz): δ (ppm) 12.58 (br s, 1H), 8.67 (br s,1H),8.07(dd,J=8.0,1.6Hz,2H),7.52-7.67(m,3H),7.04(s,1H),7.00(s,1H),5.33-5.90(m,2H),5.28(d,J=7 .2Hz,1H),4.45(t,J=6.0Hz,2H),4.20(d,J=9.6Hz,1H),4.09-4.18(m,2H),3.41-3.47(m,4H),1.56-1.91(m,4H). Example 2 4-(nitrooxy)butyl(2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-benzene) 4H-chromene-7-yl)oxy)-3,4-dihydroxy-5-((6-(nitrooxy)hexanoyl)oxy)tetrahydro-2H-pyran-2- Formate (compound 002)

[0153] 2.1 Synthesis of intermediate L2-2

[0154] Concentrated nitric acid (4.1 eq) and concentrated sulfuric acid (3.1 eq) were added to a dichloromethane solution of methyl 6-hydroxyhexanoate (500 mg, 3.42 mmol), and the reaction was carried out in an ice-water bath for 2 hours. The reaction system was purified to give intermediate L2-2 (530 mg, 7.75 mmol).

[0155] 2.2 Synthesis of intermediate L2-3

[0156] Intermediate L2-2 (500 mg, 2.62 mmol) was dissolved in a mixture of tetrahydrofuran and water, and LiOH (5.0 eq) was added. The mixture was reacted at room temperature for 12 h. After purification, intermediate L2-3 (300 mg, 7.34 mmol) was obtained.

[0157] 2.3 Synthesis of Compound 002

[0158] Intermediate L2-3 (300 mg, 7.34 mmol) was reacted with compound 001 (4.0 eq), EDCI (3.5 eq), and DMAP (1.0 eq) in DMF at room temperature for 12 hours. The reaction was purified by column chromatography to give compound 002 (12 mg, 0.017 mmol). Yield: 0.2%, purity: 95%. LCMS: ESI-MS m / z 723.2 [M+H] + . 1 H NMR(DMSO-d6,400M Hz): δ(ppm)12.92–12.88(s,1H),8.15–8.08(m,2H),7.68–7.58(m,3H),7.20–7.15(s,1H),7.13–7. 09(s,1H),5.54–5.47(t,J=4.9Hz,2H),5.39–5.34(d,J=4.9Hz,1H),5.34–5.29(d,J=7.2Hz,1H),4. 60–4.50(t,J=6.6Hz,2H),4.49–4.42(t,J=6.0Hz,2H),4.24–4.17(d,J=9.6Hz,1H),4.17–4.11(m,2 H),3.68-3.41(m,2H),2.69–2.61(t,J=7.3Hz,2H),1.80–1.66(m,8H),1.55–1.43(q,J=8.1Hz,2H). Example 3 4-(2-(((2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromene-) 7-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carbonyl)oxy)ethoxy)-3-(benzenesulfonyl)-1,2,5-ox Diazole 2-oxide (Compound 003)

[0159] 3.1 Synthesis of intermediate L3-2

[0160] 3,4-bis(benzenesulfonyl)-1,2,5-oxadiazole-2-oxide (2.0 g, 5.26 mmol) was dissolved in THF / H₂O and reacted with tert-butyldimethylhydroxyethoxysilane (1.0 eq) and 50% NaOH (2.0 eq) at room temperature for 2 h. After extraction and drying, it was dissolved in methanol, and camphor-10-sulfonic acid (1.7 eq) was added. The mixture was stirred at room temperature for 0.5 h. After purification by column chromatography, intermediate L3-2-2 (1.02 g, 3.57 mmol) was obtained.

[0161] 3.2 Synthesis of intermediate L3-3-2

[0162] Intermediate L3-2-2 (1.02 g, 3.57 mmol) was reacted with NBS (2.0 eq) and PPh3 (2.0 eq) in dichloromethane in an ice-water bath for 0.5 h. The intermediate L3-3-2 was purified.

[0163] 3.3 Synthesis of Compound 003

[0164] Intermediate L3-3-2 (500 mg, 1.43 mmol) was dissolved in DMF and reacted with compound A (1.2 eq) and DBU (2.0 eq) at 50 °C for 12 h. The product was purified by HPLC to give compound 003 (55 mg, 0.077 mmol), with a yield of 5.38% and a purity of 92%. LCMS: ESI-MS m / z 715.0 [M+H] + . 1 H NMR(DMSO-d6,400M Hz): δ(ppm)12.57(s,1H),8.68(s,1H),8.05-7.98(m,2H),7.97-7.93(m ,2H),7.85-7.76(m,1H),7.73-7.64(m,2H),7.63-7.51(m,3H),7.08(s, 1H),6.97(s,1H),5.56(d,J=5.2Hz,2H),5.44-5.30(m,2H),4.67-4.56( m,2H),4.44(q,J=3.6Hz,2H),4.32(d,J=9.2Hz,1H),3.54-3.41(m,3H). Example 4 (Z)-2-(((2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromene- 7-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carbonyl)oxy)-1-(pyrrolidine-1-yl)azo-1-oxide (Compound 004)

[0165] 4.1 Synthesis of intermediate L4-2

[0166] 10 g of tetrahydropyrrole (10 g, 140.8 mmol) was dissolved in 100 mL of methanol, and sodium methoxide (1.0 eq) was added. After complete dissolution, the solution was transferred to a stainless steel high-pressure reactor, and argon gas was continuously bubbled in to replace the air. The reaction was carried out under NO (0.5 mPa) for 3 days. After the reaction was complete, argon gas was bubbled in to quench the reaction. After purification by column chromatography, intermediate L4-2 (1.53 g, 10 mmol) was obtained.

[0167] 4.2 Synthesis of Compound 004

[0168] Intermediate L4-2 (1.53 g, 10 mmol) was reacted with compound A (1.2 eq) and DBU (1.2 eq) at room temperature for 12 hours. The product was post-processed and purified by HPLC to give compound 004 (1.29 g, 2.3 mmol). Yield: 23.2%, purity: 98.7%. LCMS: ESI-MS m / z 560.1 [M+H] + . 1 H NMR(DMSO-d6,400M Hz): δ(ppm)9.37(s,1H),8.09–7.98(m,2H),7.58–7.46(m,3H),7.00(s, 1H),6.71(s,1H),5.15(d,J=6.3Hz,1H),5.07(dt,J=7.2,2.6Hz,1H),4. 95(d,J=6.2Hz,1H),4.71(d,J=6.0Hz,1H),4.31(dt,J=8.5,2.4Hz,1H), 3.81(tdd,J=8.6,6.5,2.2Hz,1H),3.70–3.46(m,6H),2.01–1.84(m,4H). Example 5 3-Cyano-4-((((2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H- Chromene-7-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carbonyl)oxy)methyl)-1,2,5-oxadiazole 2-oxidation (Compound 005)

[0169] 5.1 Synthesis of intermediate L5-1

[0170] NaNO2 (1.0 eq) and a suitable amount of 3N hydrochloric acid were added to 15 g (150 mmol) of 3-carbonylbutyrate lactone. Then, hydroxylamine hydrochloride (1.0 eq) was added, and the mixture was reacted in an ice-water bath for 30 min. After post-treatment, intermediate L5-1 (14.5 g, 100.7 mmol) was obtained.

[0171] 5.2 Synthesis of intermediate L5-2

[0172] Intermediate L5-1 (14.5 g, 100.7 mmol) was dissolved in dichloromethane and reacted with Pb(OAc)4 (1.0 eq) and TEA (1.0 eq) in an ice-water bath for 2 hours. The reaction solution was evaporated to dryness to obtain crude intermediate L5-2.

[0173] 5.3 Synthesis of intermediate L5-3

[0174] The crude intermediate L5-2 obtained in step 5.2 was dissolved in methanol, and ammonia gas was continuously introduced under reflux in an oil bath. After the reaction was complete, the mixture was used directly in the next step.

[0175] 5.4 Synthesis of intermediate L5-4

[0176] The mixture obtained in step 5.3 was evaporated to dryness and then dissolved in an appropriate amount of tetrahydrofuran. Carbon tetrabromide (1.2 eq) and triphenylphosphine (1.2 eq) were added, and the mixture was reacted at room temperature. Post-treatment yielded crude intermediate L5-4.

[0177] 5.5 Synthesis of intermediate L5-5

[0178] The crude intermediate L5-4 obtained in step 5.4 was dissolved in dichloromethane and reacted with TFAA (1.2 eq) and DIEA (1.5 eq) in an ice-water bath for 1 h to obtain intermediate L5-5.

[0179] 5.6 Synthesis of Compound 005

[0180] Intermediate L5-5 obtained from step 5.5 was dissolved in DMF with compound A (1.2 eq), NaHCO3 (2.0 eq), and NaI, and the mixture was heated to 90 °C and reacted for 1 h. After purification, compound 005 (147.7 mg, 0.26 mmol) was obtained, with a yield of 25.8% and a purity of 96.3%. LCMS: ESI-MS m / z: [M+H] +=570.10. 1 H NMR(DMSO-d6,400M Hz): δ (ppm) 12.59 (s, 1H), 8.69 (s, 1H), 8.01-8.17 (m, 2H), 7.50-7.69 (m, 3H), 7.03 (d, J = 8.94Hz, 2H), 5.62 (d, J = 5.36 Hz,1H),5.57(d,J=3.93Hz,1H),5.36-5.53(m,3H),5.30(d,J=7.15Hz,1H),4.36(d,J=9.18Hz,1H),3.40-3.50(m,3H). Example 1: Protective effect of compound against NMDA-induced retinal nerve cell damage

[0181] To verify the protective effect of the compound on optic nerve cells, retinal ganglion cells (RGCs) were used for the following tests.

[0182] The accumulation of large amounts of N-methyl-D-aspartate (NMDA) activates numerous NMDA receptors on the RGC cell membrane, causing extracellular calcium... 2+ Influx of calcium into the intracellular calcium pool 2+ Mobilization, leading to intracellular Ca2+ mobilization 2+ Overload, excessive Ca 2+ Activation of intracellular Ca 2+ The signaling cascade pathway induces cellular glutamate excitotoxicity and oxidative stress responses, ultimately leading to neuronal apoptosis. NMDA is commonly used to induce animal glaucoma models or RGC damage models.

[0183] 1.1 Cell Culture: RGC-5 cells (Guangzhou Genio Biotechnology Co., Ltd.) were placed in DMEM medium containing 10% fetal bovine serum and cultured in an incubator at 37°C with 5% CO2. The cells were passaged every 2-3 days by digestion with 0.25% trypsin.

[0184] 1.2 MTT assay for cell viability:

[0185] (1) RGC-5 cells (1×10 5 Cells were seeded at a density of 10 cells / mL into 96-well culture plates and, after adhesion, divided into 8 groups: NMDA damage group (negative control group), blank control group, positive control group, and treatment groups with compounds 001, 002, 003, 004, and 005. Each group had 6 replicates.

[0186] (2) For treatment groups of compounds 001, 002, 003, 004, and 005, each group was divided into three subgroups, which were treated with the following concentrations of the compounds: 0.5 μM, 5 μM, and 10 μM, respectively. The positive control group was treated with dizoxipine (Sigma-Aldrich) to reach the test concentration of 10 μM. The negative control group and the blank control group were treated with an equal volume of DMEM (Adamas Life) complete medium.

[0187] (3) Place the culture plate in a cell culture incubator at 37°C and 5% CO2 for 12 hours.

[0188] (4) Discard the culture medium and wash three times with phosphate-buffered saline (PBS) (Adamas Life). Except for the blank control group, all other groups were treated with 10 μM glycine and 10 μM NMDA (Adamas Life) for 30 min, washed three times with PBS, and then returned to the original culture medium environment.

[0189] (5) After 36 hours, add 20 μL of freshly prepared MTT (Sigma-Aldrich) (5 mg / mL) to each well and measure the absorbance (OD value) at a wavelength of 490 nm to calculate the cell viability.

[0190] 1.3 Hoechst staining:

[0191] (1) The cells were grouped and treated in a similar manner to steps (1) to (4) of 1.2 above, but RGC-5 cells were cultured on coverslips, and the treatment groups of compounds 001, 002, 003, 004, and 005 were treated with 5 μM of the compounds instead of the three concentrations described in 1.2 above.

[0192] (2) Fix with paraformaldehyde (4%), wash three times with PBS, then stain with Hoechst 33258 (Sigma-Aldrich) working solution for 5 min, rinse three times, mount, and observe the results under a fluorescence microscope. Under the fluorescence microscope, live cells are stained with homogeneous blue fluorescence and appear elliptical, while the nuclei of apoptotic cells appear as densely stained bright blue granular blocks, with nuclear condensation. The apoptosis percentage was calculated from six randomly selected fields of view (apoptosis percentage = number of apoptotic cell nuclei / total number of cell nuclei × 100%).

[0193] 1.4 Data Analysis:

[0194] MTT colorimetric assay results showed that, compared with the negative control group, the cell viability of each subgroup in the positive control group and the treatment groups of compounds 001, 002, 003, 004, and 005 was significantly increased (* indicates P < 0.05, ** indicates P < 0.01), see [link to MTT assay]. Figures 1 to 5 .

[0195] Hoechst staining results showed that the percentage of apoptotic cells in the negative control group was (38.6±0.76)%, while that in the blank control group was (4.15±0.62)%, with a statistically significant difference (P<0.01). The percentages of apoptotic cells in the treatment groups of compounds 001, 002, 003, 004, and 005 and the positive control group were (5.6±1.33)%, (5.8±1.35)%, (6.2±0.93)%, (6.0±1.51)%, (5.9±1.05)%, and (6.3±1.13)%, respectively, all significantly lower than those in the negative control group (P<0.01). See Table 1. Table 1. Effects of compounds on the percentage of retinal neuronal apoptosis induced by NMDA (X±SD) Example 2: Effect of compound on intraocular pressure in a dog.

[0196] 1. Dissolve compounds 001, 002, 003, 004, and 005 in a solvent (10 mM disodium hydrogen phosphate buffer solution of 0.5% Tween 80 and 0.02% benzalkonium chloride (pH = 7.0)) to prepare a 0.25% solution. 2. Select Beagles weighing approximately 10–14 kg and aged approximately 9–21 months (3 dogs per group).

[0197] 3. All animals underwent a physical examination before the start of the experiment, and no obvious abnormalities were found in the anterior segment and fundus of the eye to confirm that the animals were healthy and could be used for this study. Animals that failed the physical examination were excluded or replaced before the start of the experiment.

[0198] 4. At least 4 weeks of behavioral and conscious intraocular pressure training is required before the trial until a stable IOP value is obtained.

[0199] 5. During the experimental drug administration phase, the following groups were formed: negative control group (solvent group), positive control group (administered with timolol maleate eye drops (Bausch & Lomb, specification: 0.5%) (Shandong Bausch & Lomb Freda Pharmaceutical Co., Ltd.), and treatment groups for compounds 001, 002, 003, 004, and 005 (administered with 0.25% compound solution). The administration route was intraconjunctival instillation, with a volume of 50 μL / eye / time, administered twice daily at approximately 10:00 AM and 5:00 PM for 15 consecutive days. The first day of administration was recorded as Day 1. During administration, the eyelids were gently pulled open to avoid contact with the ocular surface. 50 μL of solvent or test sample was pipetted into the conjunctival sac, and the eyelids were gently closed several times.

[0200] 6. Intraocular pressure (IOP) measurement: IOP was measured once before the first dose on Day 1, and again 2 and 4 hours after the first dose on Day 1. IOP was also measured once before the first dose on Day 2, Day 4, Day 7, Day 13, Day 15, and Day 16. Detailed data are shown in Table 2 and... Figure 6 .

[0201] Calculate the change in IOP (%) using the following formula: The percentage reduction in IOP (ΔIOP%) = [IOP(treatment group) - IOP(baseline)] / IOP(baseline) * 100 Table 2. Effects of compounds on intraocular pressure in dogs. compound concentration(%) Mean baseline (mmHg) ΔIOP (mmHg) ΔIOP(%) Timolol maleate 0.5 17.6 3.1 -17.6*** Compound 001 0.25 17.7 4.3 -24.5*** Compound 002 0.25 18.2 4.4 -24.2*** Compound 003 0.25 17.4 4.7 -27.0*** Compound 004 0.25 17.8 4.3 -24.2*** Compound 005 0.25 17.6 4.0 -22.7*** T.Test: Compared with the solvent group, *** indicates p≤0.001.

[0202] Results: Compared with the average intraocular pressure at each measurement point from the start of the experiment, the intraocular pressure data shown in Table 2 show that the control group did not show significant changes in intraocular pressure, while the average intraocular pressure of the positive group and the groups treated with compounds 001, 002, 003, 004, and 005 were significantly different from that of the control group. Effect of Compound 3 on Intraocular Pressure in Rats

[0203] 1. Dissolve compounds 001 and 003 in a solvent (10 mM disodium hydrogen phosphate buffer solution of 0.5% Tween 80 and 0.02% benzalkonium chloride (pH=7.0)) to prepare a 0.25% solution.

[0204] 2. Eighty SD rats (Zhejiang Vital River Experimental Animal Technology Co., Ltd.) weighing approximately 160-180g and aged approximately 35 days were selected for the modeling experiment. The rats were randomly divided into a blank control group (n=16), a dexamethasone group (n=48), and a solvent group (n=16) using a random number table.

[0205] 3. All animals underwent a physical examination before the start of the experiment, and no obvious abnormalities were found in the anterior segment and fundus of the eye to confirm that the animals were healthy and could be used for this study. Animals that failed the physical examination were excluded or replaced before the start of the experiment.

[0206] 4. The normal range of intraocular pressure (IOP) in the right eye was measured 7 days, 3 days, and 1 day before model initiation in rats, and this was used as the baseline IOP. After the IOP of the SD rats stabilized, dexamethasone sodium phosphate eye drops (Xinxiang Huaqing Pharmaceutical Co., Ltd.) were instilled into the right eye of the dexamethasone group rats twice daily at 8:30 AM and 1:30 PM, 5 hours apart. The solvent group rats received 0.02 ml of the solution instilled into their right eye. The blank control group served as a simple control. IOP was measured every 2 days, and the systemic and local ocular reactions of the rats were observed. Model initiation was considered successful when the IOP in the right eye of the rat increased to above 20 mmHg, approximately 7-10 days later.

[0207] 5. During the experimental drug administration phase, 40 successfully modeled rats were randomly divided into three groups according to the following scheme: negative control group (high intraocular pressure solvent group), positive control group (administered with timolol maleate eye drops (Bausch & Lomb, specification: 0.5%)), and compound 001 and 003 treatment groups (administered with 0.25% compound solution). Additionally, 10 rats were randomly selected from the solvent group described in section 4 above as a non-model blank control group for the efficacy test phase, using the same method. The administration route was intraconjunctival instillation of 20 μL / eye / time, twice daily at 10:00 AM and 5:00 PM for 15 consecutive days. The first day of administration was recorded as Day 1. During administration, the eyelid was gently pulled open to avoid contact with the ocular surface. 20 μL of solvent or test sample was gently instilled into the conjunctival sac using a pipette, and the eyelid was gently closed several times. In this experiment, dexamethasone sodium phosphate eye drops will continue to be administered twice daily at the same time as during modeling to maintain the intraocular pressure in the right eye of rats in the negative control group (high intraocular pressure solvent group), positive control group (administered timolol maleate eye drops (Bausch & Lomb, specification: 0.5%)), and compound 001 and 003 treatment groups (administered 0.25% compound solution).

[0208] 6. Intraocular pressure measurement: Intraocular pressure was measured once on Day 1 before the first dose, once on Day 2 before the first dose, once on Day 4 before the first dose, once on Day 6 before the first dose, once on Day 8 before the first dose, once on Day 10 before the first dose, once on Day 13 before the first dose, once on Day 15 before the first dose, and once on Day 16. Detailed test data for the efficacy trial phase are shown in Table 3 and... Figure 7 , Figure 8 . Table 3 Effects of compounds on intraocular pressure in rats T.Test: Compared with the solvent group, *** indicates p≤0.001.

Claims

1. A compound of formula (I-1): wherein, each M is independently selected from a NO donor; R 1 selected from the group consisting of hydrogen, -OH, -O-C 1-10 alkyl and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 ; R 2 selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A2 R B2 , -OR A2 , -SR A2 , -C(=O)R A2 , -C(=O)OR A2 , -OC(=O)R A2 , -C(=O)NR A2 R B2 , -NR A2 C(=O)R B2 , -NR A2 C(=NR E2 )R B2 , -OC(=O)NR A2 R B2 , -NR A2 C(=O)OR B2 , -NR A2 C(=O)NR A2 R B2 , -NR A2 C(=S)NR A2 R B2 , -NR A2 C(=NR E2 )NR A2 R B2 , -S(=O) r R A2 , -S(=O)(=NR E2 )R B2 , -N=S(=O)R A2 R B2 , -S(=O)2OR A2 , -OS(=O)2R A2 , -NR A2 S(=O) r R B2 , -NR A2 S(=O)(=NR E2 )R B2 , -S(=O) r NR A2 R B2 , -S(=O)(=NR E2 )NR A2 R B2 , -NR A2 S(=O)2NR A2 R B2 , -NR A2 S(=O)(=NR E2 )NR A2 R B2 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R X2 ; R 3 selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A3 R B3 , -OR A3 , -SR A3 , -C(=O)R A3 , -C(=O)OR A3 , -OC(=O)R A3 , -C(=O)NR A3 R B3 , -NR A3 C(=O)R B3 , -NR A3 C(=NR E3 )R B3 , -OC(=O)NR A3 R B3 , -NR A3 C(=O)OR B3 , -NR A3 C(=O)NR A3 R B3 , -NR A3 C(=S)NR A3 R B3 , -NR A3 C(=NR E3 )NR A3 R B3 , -S(=O) r R A3 , -S(=O)(=NR E3 )R B3 , -N=S(=O)R A3 R B3 , -S(=O)2OR A3 , -OS(=O)2R A3 , -NR A3 S(=O) r R B3 , -NR A3 S(=O)(=NR E3 )R B3 , -S(=O) r NR A3 R B3 , -S(=O)(=NR E3 )NR A3 R B3 , -NR A3 S(=O)2NR A3 R B3 , -NR A3 S(=O)(=NR E3 )NR A3 R B3 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X3 ; R 4 selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A4 R B4 , -OR A4 , -SR A4 , -C(=O)R A4 , -C(=O)OR A4 , -OC(=O)R A4 , -C(=O)NR A4 R B4 , -NR A4 C(=O)R B4 , -NR A4 C(=NR E4 )R B4 , -OC(=O)NR A4 R B4 , -NR A4 C(=O)OR B4 , -NR A4 C(=O)NR A4 R B4 , -NR A4 C(=S)NR A4 R B4 , -NR A4 C(=NR E4 )NR A4 R B4 , -S(=O) r R A4 , -S(=O)(=NR E4 )R B4 , -N=S(=O)R A4 R B4 , -S(=O)2OR A4 , -OS(=O)2R A4 , -NR A4 S(=O) r R B4 , -NR A4 S(=O)(=NR E4 )R B4 , -S(=O) r NR A4 R B4 , -S(=O)(=NR E4 )NR A4 R B4 , -NR A4 S(=O)2NR A4 R B4 , -NR A4 S(=O)(=NR E4 )NR A4 R B4 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R X4 ; R 5 selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A5 R B5 , -OR A5 , -SR A5 , -C(=O)R A5 , -C(=O)OR A5 , -OC(=O)R A5 , -C(=O)NR A5 R B5 , -NR A5 C(=O)R B5 , -NR A5 C(=NR E5 )R B5 , -OC(=O)NR A5 R B5 , -NR A5 C(=O)OR B5 , -NR A5 C(=O)NR A5 R B5 , -NR A5 C(=S)NR A5 R B5 , -NR A5 C(=NR E5 )NR A5 R B5 , -S(=O) r R A5 , -S(=O)(=NR E5 )R B5 , -N=S(=O)R A5 R B5 , -S(=O)2OR A5 , -OS(=O)2R A5 , -NR A5 S(=O) r R B5 , -NR A5 S(=O)(=NR E5 )R B5 , -S(=O) r NR A5 R B5 , -S(=O)(=NR E5 )NR A5 R B5 , -NR A5 S(=O)2NR A5 R B5 , -NR A5 S(=O)(=NR E5 )NR A5 R B5 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X5 ; R 6 selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A6 R B6 , -OR A6 , -SR A6 , -C(=O)R A6 , -C(=O)OR A6 , -OC(=O)R A6 , -C(=O)NR A6 R B6 , -NR A6 C(=O)R B6 , -NR A6 C(=NR E6 )R B6 , -OC(=O)NR A6 R B6 , -NR A6 C(=O)OR B6 , -NR A6 C(=O)NR A6 R B6 , -NR A6 C(=S)NR A6 R B6 , -NR A6 C(=NR E6 )NR A6 R B6 , -S(=O) r R A6 , -S(=O)(=NR E6 )R B6 , -N=S(=O)R A6 R B6 , -S(=O)2OR A6 , -OS(=O)2R A6 , -NR A6 S(=O) r R B6 , -NR A6 S(=O)(=NR E6 )R B6 , -S(=O) r NR A6 R B6 , -S(=O)(=NR E6 )NR A6 R B6 , -NR A6 S(=O)2NR A6 R B6 , -NR A6 S(=O)(=NR E6 )NR A6 R B6 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R X6 ; or "R 2 and R 3 " or "R 3 and R 4 " or "R 4 and R 5 " or "R 5 and R 6 " together with the carbon atom to which they are attached form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, which ring is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X ; each R 7 is independently selected from the group consisting of halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -NR A7 R B7 , -OR A7 , -SR A7 , -C(=O)R A7 , -C(=O)OR A7 , -OC(=O)R A7 , -C(=O)NR A7 R B7 , -NR A7 C(=O)R B7 , -NR A7 C(=NR E7 )R B7 , -OC(=O)NR A7 R B7 , -NR A7 C(=O)OR B7 , -NR A7 C(=O)NR A7 R B7 , -NR A7 C(=S)NR A7 R B7 , -NR A7 C(=NR E7 )NR A7 R B7 , -S(=O) r R A7 , -S(=O)(=NR E7 )R B7 , -N=S(=O)R A7 R B7 , -S(=O)2OR A7 , -OS(=O)2R A7 , -NR A7 S(=O) r R B7 , -NR A7 S(=O)(=NR E7 )R B7 , -S(=O) r NR A7 R B7 , -S(=O)(=NR E7 )NR A7 R B7 , -NR A7 S(=O)2NR A7 R B7 , -NR A7 S(=O)(=NR E7 )NR A7 R B7 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X7 ; or any two adjacent R 7 together with the carbon atom to which they are attached form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, which ring is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X7 together with the carbon atom to which they are attached form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, which ring is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R L 1 selected from a chemical bond, -(CR C1 R D1 ) u -O-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -S-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -NR 8 -(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -C(=O)-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -C(=O)O-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -C(=O)NR 8 -(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -OC(=O)-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -NR 8 C(=O)-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -C(=S)O-(CR C1 R D1 ) t -, -(CR C1 R D1 ) u -C(=S)NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -OC(=S)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 C(=S)-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S(=O) r O-(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -S(=O) r NR 8 -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -OS(=O) r -(CR C1 R D1 ) t -、-(CR C1 R D1 ) u -NR 8 S(=O) r -(CR C1 R D1 ) t -、C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group, wherein each alkylene group, alkenylene group, or alynyl group is unsubstituted or is independently selected from R X Substituents of the substituents; R 8 selected from hydrogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X8 . U 0 is O or S; Y 1 is C(R 9a R 9a’ ); Y 2 is C(R 9b R 9b’ ); Y 3 is C(R 9c R 9c’ ); Y 4 is C(R 9d R 9d’ ); R 9a , R 9a’ , R 9b , R 9b’ , R 9c , R 9c’ , R 9d and R 9d’ are each independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A9 R B9 , -OR A9 , -SR A9 , -C(=O)R A9 , -C(=O)OR A9 , -OC(=O)R A9 , -C(=O)NR A9 R B9 , -NR A9 C(=O)R B9 , -NR A9 C(=NR E9 )R B9 , -OC(=O)NR A9 R B9 , -NR A9 C(=O)OR B9 , -NR A9 C(=O)NR A9 R B9 , -NR A9 C(=S)NR A9 R B9 , -NR A9 C(=NR E9 )NR A9 R B9 , -OS(=O)2R A9 , -NR A9 S(=O) r R B9 , -NR A9 S(=O)(=NR E9 )R B9 , -NR A9 S(=O)2NR A9 R B9 , -NR A9 S(=O)(=NR E9 )NR A9 R B9 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X9 ; each R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A9 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 and R B9 are independently selected from hydrogen, C 1-10 1-6alkyl, C 2-10 1-6alkenyl, C 2-10 1-6alkynyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 1-6alkylene-heterocyclyl, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl, -C 1-4 1-6alkylene-heteroaryl and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X ; or "R A2 and R B2 " or "R A3 and R B3 " or "R A4 and R B4 " or "R A5 and R B5 " or "R A6 and R B6 " or "R A7 and R B7 " or "R A9 and R B9 " together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from R X ; each R C1 and R D1 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X ; or each "R C1 and R D1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, which ring is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from R X ; Each R E2 R E3 R E4 R E5 R E6 R E7 and R E9 Independently selected from hydrogen and C 1-10 Alkyl group, CN, NO2, -S (=O) r R a1 -C(=O)R a1 -C(=O)OR a1 -C(=O)NR a1 R b1 -S (=O) r NR a1 R b1 and Wherein the alkyl group is unsubstituted or is selected independently from R X Substituents of the substituents; each L is independently selected from a chemical bond, -(CR c R d ) u -O-(CR c R d ) t -, -(CR c R d ) u -S-(CR c R d ) t -, -(CR c R d ) u -NR 8 -(CR c R d ) t -, -(CR c R d ) u -C(=O)-(CR c R d ) t -, -(CR c R d ) u -C(=O)O-(CR c R d ) t -, -(CR c R d ) u -C(=O)NR 8 -(CR c R d ) t -, -(CR c R d ) u -OC(=O)-(CR c R d ) t -, -(CR c R d ) u -NR 8 C(=O)-(CR c R d ) t -, -(CR c R d ) u -C(=S)-(CR c R d ) t -, -(CR c R d ) u -C(=S)O-(CR c R d ) t -, -(CR c R d ) u - C(=S)NR 8 -, -(CR c R d ) t -, -(CR c R d ) u - OC(=S)-(CR c R d ) t -, -(CR c R d ) u - NR 8 C(=S)-(CR c R d ) t -, -(CR c R d ) u - S(=O) r -, -(CR c R d ) t -, -(CR c R d ) u - S(=O) r O-(CR c R d ) t -, -(CR c R d ) u - S(=O) r NR 8 -, -(CR c R d ) t -, -(CR c R d ) u - OS(=O) r -, -(CR c R d ) t -, -(CR c R d ) u - NR 8 S(=O) r -, -(CR c R d ) t -, C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene, is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxy, hydroxyalkyl, alkylcarb Each R c and R d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic groups, M, -C 1-4 Alkylene-M, wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R. Y Substituents of the substituents; m is 0 or 1 ; each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , and R X9 are independently selected from halo, C 1-10 1-6alkyl, C 2-10 1-6alkenyl, C 2-10 1-6alkynyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 1-6alkylene-heterocyclyl, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl, -C 1-4 1-6alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 ) u NR a1 R b1 , -(CR c1 R d1 ) u OR b1 , -(CR c1 R d1 ) u C(=O)R a1 , -(CR c1 R d1 ) u C(=NR e1 )R a1 , -(CR c1 R d1 ) u C(=O)OR b1 , -(CR c1 R d1 ) u OC(=O)R b1 , -(CR c1 R d1 ) u C(=O)NR a1 R b1 , -(CR c1 R d1 ) u NR a1 C(=O)R b1 , -(CR c1 R d1 ) u C(=NR e1 )NR a1 R b1 , -(CR c1 R d1 ) u NR a1 C(=NR e1 )R b1 , -(CR c1 R d1 ) u OC(=O)NR a1 R b1 , -(CR c1 R d1 ) u NR a1 C(=O)OR b1 , -(CR c1 R d1 ) u NR a1 C(=O)NR a1 R b1 , -(CR c1 R d1 ) u NR a1 C(=S)NR a1 R b1 , -(CR c1 R d1 ) u NR a1 C(=NR e1 )NR a1 R b1 , -(CR c1 R d1 ) u S(=O) r R b1 , -(CR c1 R d1 ) u S(=O)(=NR e1 )R b1 , -(CR c1 R d1 ) u N=S(=O)R a1 R b1 , -(CR c1 R d1 ) u S(=O)2OR b1 , -(CR c1 R d1 ) u OS(=O)2R b1 , -(CR c1 R d1 ) u NR a1 S(=O) r R b1 , -(CR c1 R d1 ) u NR a1 S(=O)(=NR e1 )R b1 , -(CR c1 R d1 ) u S(=O) r NR a1 R b1 , -(CR c1 R d1 ) u S(=O)(=NR e1 )NR a1 R b1 , -(CR c1 R d1 ) u NR a1 S(=O)2NR a1 R b1 , -(CR c1 R d1 ) u NR a1 S(=O)(=NR e1 )NR a1 R b1 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R Y ; each R a1 and R b1 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; or R a1 and R b1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring is unsubstituted or substituted with 1, 2, or 3 substituents selected from R Y ; each R c1 and R d1 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R Y ; or each R c1 and R d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, which ring is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from R Y ; each R is independently selected from the group consisting of hydrogen, C e1 alkyl, CN, NO2, -S(=O) 1-10 alkyl, CN, NO2, -S(=O) r R a1 , -C(=O)R a1 , -C(=O)OR a1 , -C(=O)NR a1 R b1 , -S(=O) r NR a1 R b1 and wherein alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R Y ; each R is independently selected from the group consisting of halogen, NO2, -CN, C 1-10 alkyl, -OH, -0(C 1-10 alkyl), -0(C 3-10 cycloalkyl), -0(C 1-4 alkylene-C 3-10 cycloalkyl), -0(C 1-4 alkylene-heterocyclyl), -SH, -S(C 1-10 alkyl), -S(C 3-10 cycloalkyl), -S(C 1-4 alkylene-C 3-10 cycloalkyl), -S(C 1-4 heterocyclyl), -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, -NH(C 3-10 cycloalkyl), -NH(C 1-4 alkylene-C 3-10 cycloalkyl), -NH(C 1-4 heterocyclyl), and -NH(C k alkylene-heterocyclyl); p is 0, 1, 2 or 3; each r is independently selected from 1 and 2; each t is independently selected from an integer from 0 to 10; each u is independently selected from an integer from 0 to 10; each k is independently selected from 1, 2, 3 and 4; each q is independently selected from 0, 1, 2 and 3; the total number of M in the molecule is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

2. The compound of claim 1, wherein 3. The compound of claim 1 or 2, wherein -(L) k the structure of - is selected from -(CH2) j - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - -(CH2) i - -(CH2) j2 - -(CH2) j1 - -(CH2) i1 - -(CH2) i2 - -(CH2) j2 - -(CH2) wherein i, i1and i2are integers from 1 to 10; j, j1and j2are each independently integers from 0 to 10; Preferably, -(L) k the structure of -(CH2) j -, -O-, -O-CH2-, 4. The compound of any one of claims 1 to 5, wherein each M is independently selected from -ONO2, wherein R is CN or phenylsulfonyl, wherein the phenyl ring of the phenylsulfonyl group is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from R Y . the total number of M in the molecule is 1, 2, 3 or 4, preferably 1 or 2; and / or when multiple M are present, each M is the same.

5. The compound of any one of claims 1 to 3, wherein 7. The compound of any one of claims 1 to 6, wherein the structure is selected from -(CH2) j -ONO2, wherein j is an integer from 0 to 10.

6. The compound of any one of claims 1-5, wherein R 1 is hydrogen.

8. The compound of claim 7, wherein R 2 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A2 R B2 , -OR A2 , -OC(=O)R A2 , -OS(=O)2R A2 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X2 ; and / or R 3 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A3 R B3 , -OR A3 , -OC(=O)R A3 , -OS(=O)2R A3 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X3 ; and / or R 4 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A4 R B4 , -OR A4 , -OC(=O)R A4 , -OS(=O)2R A4 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X4 ; and / or R 5 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A5 R B5 , -OR A5 , -OC(=O)R A5 , -OS(=O)2R A5 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X5 ; and / or R 6 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A6 R B6 , -OR A6 , -OC(=O)R A6 , -OS(=O)2R A6 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X6 .

9. The compound of any one of claims 1 to 8, wherein R 2 is hydrogen; and / or R 3 is hydrogen; and / or R 4 is hydrogen; and / or R 5 is hydrogen; and / or R 6 is hydrogen. preferably: each R is independently selected from the group consisting of hydrogen, -OR 7 A7 A7 A7 and ​​​ p is 2; and 10. The compound of any one of claims 1 to 9, wherein two R 7 is -OH, or one R 7 is -OH, the other R 7 is 11. The compound of any one of claims 1 to 10, wherein R 9a -C(=O)R A9 , R 9a’ is hydrogen; preferably, R A9 is m is 1 ; and / or 12. The compound of any one of claims 1 to 11, wherein R 9b , R 9c , and R 9d are -OH, R 9b’ , R 9c’ , R 9d’ is hydrogen; or R 9b and R 9c is -OH, R 9d is R 9b’ , R 9c’ and R 9d’ are hydrogen.

13. The compound of any one of claims 1 to 12, wherein L 1 selected from a chemical bond, -(CR C1 R D1 ) u -O-(CR C1 R D1 ) t -, C1 R D1 ) u -S-(CR C1 R D1 ) t - and -(CR C1 R D1 ) u -NR 8 -(CR C1 R D1 ) t -; Preferably, wherein R 8 is hydrogen; More preferably, L 1 is -O. formula (I-1) has the structure of formula (I-2-1), formula (I-2-2), formula (I-2-3) or formula (I-2-4): wherein, 14. The compound of claim 13, wherein L 2 , L 3 , L 4 and L 5 are independently selected from L; M 1 , M 2 , M 3 and M 4 are independently selected from M.

15. The compound of claim 13 or 14, having the structure of formula (I-3-1), formula (I-3-2), formula (I-3-3) or formula (I-3-4): - L 2 - M 1 the structure is selected from and / or; - L 3 - M 2 the structure of 16. A compound selected from:

17. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

18. Use of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17, in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from the group consisting of a high intraocular pressure related disease and an optic nerve damage related disease.

19. The use of claim 18, wherein the disease, disorder or condition is selected from the group consisting of: glaucoma, age-related macular degeneration, diabetic retinopathy, cataract, high intraocular pressure induced by retinal vascular occlusion, and optic nerve damage. ​

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