Nitric oxide donor-containing compounds

Abstract

The present invention relates to the technical field of pharmaceuticals, and in particular to a class of nitric oxide (NO) donor-containing compounds or pharmaceutically acceptable salts, a preparation method therefor, a pharmaceutical composition, and a use thereof in the treatment or prevention of an ocular hypertension-related ophthalmic disease and an optic nerve injury-related disease.

Description

Compounds containing a nitric oxide donor TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a class of compounds containing a nitric oxide (NO) donor or a pharmaceutically acceptable salt, a preparation method thereof, a pharmaceutical composition and the use thereof in treating or preventing ophthalmic high intraocular pressure related diseases and optic nerve injury related diseases. BACKGROUND

[0002] Glaucoma is a group of eye diseases characterized by degeneration of retinal ganglion cells, specific optic atrophy and progressive visual field loss, mainly associated with the increase of intraocular pressure, and is the most common cause of irreversible blindness. The signal pathways related to the pathogenesis of glaucoma are very complex, and the downstream signal factors often cross each other. The main pathological mechanism involves the up-regulation of pro-apoptotic gene expression, the down-regulation of neuroprotective and regenerative factors, and the promotion of the production and action of optic nerve injury factors. A series of changes at the molecular and cellular levels cause aqueous humor outflow obstruction and optic nerve injury, eventually leading to blindness.

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

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

[0005] In the optic nerve head, NO donors reduce vascular resistance by relaxing smooth muscle, leading to local vasodilation and increased optic nerve head blood flow. Conversely, impairment of the NO pathway reduces blood flow to the optic nerve head, leading to ischemia.

[0006] Structural nitric oxide synthase (cNOS) exists in the trabecular meshwork, Schlemm's canal, hyaloid canal and ciliary muscle annular fiber, radial fiber and longitudinal fiber. Various evidence has shown that NO can reduce IOP. NO can increase the aqueous outflow of the anterior segment of the human eye trabecular meshwork (TM). NO donors can reduce IOP in animal models. Mice overexpressing endothelial nitric oxide synthase (eNOS) have lower IOP; in contrast, eNOS knockout mice (mice without functional eNOS gene, thus without endogenous eNOS) have elevated IOP. In addition, sGC knockout mice have elevated IOP and optic nerve degeneration. The mechanism by which NO reduces IOP appears to be through inhibition of actin-myosin interaction, thereby relaxing cells in the TM and Schlemm's canal, leading to increased aqueous outflow and reduced IOP.

[0007] There are various challenges in the treatment of glaucoma. For example, primary open angle glaucoma is a chronic progressive optic neuropathy in which the optic nerve of a patient is damaged and the outflow of aqueous humor from the trabecular meshwork is blocked. There is a lack of drugs in the clinic that treat the pathological mechanism of glaucoma.

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

[0009] In one aspect, a compound of Formula (I-1) is provided:

[0010] wherein,

[0011] R 1 is 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 ;

[0012] R 2 is 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 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 , -NRA2 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 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;

[0013] 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 RB3 , -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 with at least one substituent independently selected from the group consisting of R X3 ;

[0014] R 4 is selected from the group consisting of hydrogen, halogen, C 1-10 1-6alkyl, C 2-10 1-6alkenyl, C 2-10 1-6alkynyl, C 3-10 1-6cycloalkyl, -C 1-4 1-6alkylene-C 3- 10 1-6alkylene-C 1-4 1-6alkylene-heterocyclyl, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl, -C 1-4 1-6alkylene-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;

[0015] 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 RB5 -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 with at least one substituent independently selected from the group consisting of R X5 ;

[0016] R 6 is 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 A6 R B6 , -OR A6 , -SRA6 -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 independently selected from R X6substituted by 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of R

[0017] 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 by 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of R X

[0018] 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 the group consisting of R X7 ;

[0019] 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 ;

[0020] L 1 is selected from the group consisting of a 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 -, -(CRC1 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 alkynyl groups, wherein each alkylene group, alkenyl group, and alkynyl group is unsubstituted or is independently selected from R. X Substituents of the substituents;

[0021] 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;

[0022] U 0 For O or S;

[0023] Y 1 For C(R) 9a R 9a’ );

[0024] Y 2 For C(R) 9b R 9b’ );

[0025] Y 3 For C(R) 9c R 9c’ );

[0026] Y 4 For C(R) 9d R 9d’ );

[0027] R9a , 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 , -NRA9 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 the group consisting of R X9 ;

[0028] 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 the group consisting of hydrogen, C 1-10 1-6 alkyl, C 2-10 2-6 alkenyl, C 2-10 2-6 alkynyl, C 3-10 3-6 cycloalkyl, -C 1-4 1-6 alkylene-C 3-10 3-6 cycloalkyl, heterocyclyl, -C 1-4 1-6 alkylene-heterocyclyl, aryl, -C 1-4 1-6 alkylene-aryl, heteroaryl, -C 1-4 1-6 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 X ;

[0029] 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 ", taken 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 the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of R XSubstituents of the substituents;

[0030] 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;

[0031] 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;

[0032] 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;

[0033] 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 -(CRc 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;

[0034] Each R c and R dindependently 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, M, -C 1-4 alkylene-M, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R Y ;

[0035] each M is independently selected from NO donors;

[0036] each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , and R X9 is independently selected from 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, -(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 c1R 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;

[0037] Each R a1 and R b1 Independently selected from hydrogen and C 1-10 Alkyl, C 2-10alkenyl, 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 ;

[0038] 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 independently selected from R Y ;

[0039] each R c1 and R d1 is independently 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 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 ;

[0040] 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 ;

[0041] each R e1 is independently selected from hydrogen, C 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 with at least one substituent independently selected from R Y ;

[0042] each R Y is independently selected from the group consisting of halogen, 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(heterocyclyl), -O(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(heterocyclyl), -S(C 1-4 alkylene-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(heterocyclyl), and -NH(C 1-4 alkylene-heterocyclyl);

[0043] m is 0 or 1 ;

[0044] p is 0, 1, 2, or 3;

[0045] each r is independently selected from the group consisting of 1 and 2;

[0046] each t is independently selected from an integer from 0 to 10;

[0047] each u is independently selected from an integer from 0 to 10;

[0048] each k is independently selected from the group consisting of 1, 2, 3, and 4;

[0049] each q is independently selected from the group consisting of 0, 1, 2, and 3;

[0050] the total number of M in the molecule is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0051] In another aspect, there is provided a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the application, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0052] In another aspect, there is provided the use of a compound of the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from the group consisting of ocular hypertension-related diseases and optic nerve damage-related diseases. BRIEF DESCRIPTION OF DRAWINGS

[0053] Figures 1 to 5 show the protective effect of compounds 001, 002, 003, 004, 005, respectively, on NMDA-induced retinal neuronal cell damage.

[0054] Figure 6 shows the IOP response of normotensive beagle dogs to vehicle, timolol maleate and compounds 001, 002, 003, 004, 005. The ordinate is the change in intraocular pressure from baseline (ΔIOP %). The curve closest to the baseline in each group is the vehicle group.

[0055] Figure 7 shows the IOP response of a rat model of ocular hypertension to vehicle, timolol maleate and compounds 001, 003.

[0056] Figure 8 shows the IOP response of a rat model of ocular hypertension to vehicle, timolol maleate and compounds 001, 003. The ordinate is the change in intraocular pressure from baseline (ΔIOP %). DETAILED DESCRIPTION

[0057] The specific embodiments provided below are illustrative of the technical content of the present application. Other advantages and effects of the present application can be easily understood by those skilled in the art from the content disclosed in the specification. The present application can also be implemented or applied by other different specific embodiments. Various modifications and changes can be made by those skilled in the art without departing from the spirit of the present application.

[0058] DEFINITIONS

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Technical terms used herein refer to the technology commonly understood by those skilled in the art, including variants and equivalent replacements obvious to those skilled in the art. Although the following terms are believed to be readily understood by those skilled in the art, the following definitions are set forth to better illustrate the present application. When a trade name appears herein, it refers to the corresponding product or active ingredient thereof. All patents, published patent applications and publications cited herein are incorporated by reference herein.

[0060] When a range, preferably range or preferred upper or lower limit, is recited in the form of a process, preferred process, or process of claim, it is to be understood that unless otherwise explicitly indicated, it is meant to include any and every set of values not 10 ” or “C 1-10 ” encompasses a range of 1-10 carbon atoms, and is to be understood to also encompass any sub-range within that range, as well as each individual number in that range, e.g., 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, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , etc. The expressions “C3-C 10 ” or “C 3-10 ” should also be understood in a like manner, e.g., can encompass C 3-4 , C 3-5 , C 3-6 , C 3-7 , C 3-8 , C 4-5 , C 4-6 , C4-C7, C5-C6, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 , etc. Yet further, for example, the expression “3-14 membered” is to be understood as encompassing any sub-range therein, as well as each individual number, e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6, or 7 membered, etc. The expressions “3-12 membered,” “3-7 membered,” “4-8 membered” should also be understood in a like manner.

[0061] When any variable (e.g., R X ) occurs more than one time in a constituent or X , then each occurrence of such variable is to be understood as being independent of the other. For example, the expression “a group chosen from R X , each occurrence of which is independent of the other” means that if there are multiple R XThe options for substituents are all independent of each other. Other variables or expressions should also be understood in a similar manner.

[0062] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The expressions "one or more" or "at least one" can mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more. In an embodiment, "at least one" means 1, 2, 3, or 4.

[0063] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance can occur but does not necessarily occur and that the description includes situations in which the event or circumstance occurs and situations in which it does not.

[0064] The terms "substituted" and "substitution" mean that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When describing the absence of a substituent, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to be in a stable state.

[0065] Unless indicated otherwise, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent. When the bond of a substituent is shown as going through a bond connecting two atoms in a ring, then such substituent can be bonded to either atom in the ring that can be substituted.

[0066] The expressions "comprising," "including," "containing," and "having" are open-ended, and do not exclude additional, unrecited elements, steps, or ingredients. The expression "consisting of" excludes any element, step, or ingredient not specified. The expression "consisting essentially of" limits the scope of a composition or process to the specified materials or procedures and those that do not materially affect the basic and novel characteristic(s). It is understood that the expression "comprising" includes the expressions "consisting of" and "consisting essentially of."

[0067] The term "halo" or "halogen" or "halogenated" is understood to mean a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) atom, preferably a fluorine, chlorine, or bromine atom.

[0068] The term "hydrocarbyl" refers to a monovalent radical derived from a hydrocarbon. Examples of hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups.

[0069] 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.

[0070] 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.

[0071] "Alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon radical. Alkylene groups include straight chain or branched chain alkylene groups. Examples of straight chain alkylene groups include, but are not limited to, methylene (-CH2-), -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, and the like. Examples of branched chain alkylene groups 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)-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-, and the like.

[0072] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon and hydrogen atoms. Alkenyl groups can have 2-8 carbon atoms, i.e., "C 2-8 alkenyl," such as C 2-4 alkenyl, C 3-4 alkenyl. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, and the like.

[0073] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one triple bond, consisting of carbon and hydrogen atoms. Alkynyl groups can have 2-8 carbon atoms, i.e., "C 2-8 alkynyl," such as C 2-4 alkynyl, C 3-4 alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0074] "Alkynylene" refers to an unsaturated divalent hydrocarbon group having at least one triple bond. Alkynylene groups include straight-chain or branched-chain alkynylene groups. Examples of straight-chain alkynylene 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-.

[0075] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably comprising 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. Cycloalkyl groups can have 3-10 carbon atoms, i.e., "C 3-10 cycloalkyl," such as C 3-8 cycloalkyl, C5cycloalkyl, C6cycloalkyl, C7cycloalkyl. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl, and the like. In some embodiments, a C atom in a cycloalkyl group is optionally substituted with oxo. In some embodiments, a C atom in a cycloalkyl group is optionally substituted with imino. In some embodiments, the imino is unsubstituted (=NH), or is substituted with a group as described in context. In some embodiments, the imino is substituted with -OR, wherein R is H or C 1-10 alkyl.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] As mentioned above, the heterocycle can be unsaturated, i.e. it can contain one or more double bonds, without restricting it, for example an unsaturated heterocycle containing a nitrogen atom can be a 1,6-dihydropyrimidine, 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1 H-pyrrolyl, 3,4-dihydro-1 H-pyrrolyl, 2,5-dihydro-1 H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom can be a 2H-pyran, 4H-pyran, 2,3-dihydrofuran, an unsaturated heterocycle containing a sulfur atom can be a 2H-thiopyran, 4H-thiopyran. The heterocycle can be benzo-fused, without restricting it, for example a dihydroisoquinolinyl ring.

[0081] Exemplary bicyclic heterocycles also include:

[0082] The term "aryl" means a fully carbon monovalent monocyclic or fused polycyclic (such as bicyclic) aromatic ring group having a conjugated pi-electron system. For example, aryl groups can have 6 to 14 carbon atoms, suitably 6 to 10, more suitably 6 or 10. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthryl groups, and the like.

[0083] The term "heteroaryl" is to be understood as preferably meaning a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5-10 heteroaryl"), in particular 5 or 6 or 9 or 10 ring atoms, and of the ring atoms at least one, suitably 1 to 4, more suitably 1, 2 or 3, can be the same or different heteroatom, such as oxygen, nitrogen or sulfur. Furthermore, the heteroaryl group can in each case be benzo-fused. In particular, the heteroaryl group is selected from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and their benzo derivatives, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like, and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, acridinyl and the like.

[0084] The term "nitric oxide donor" refers to a chemical structure that generates or releases NO in vivo. Preferably, the NO donor releases NO chemically and stably. The mechanism by which the NO donor releases NO is not limited herein. For example, the NO donor can have a functional group capable of releasing NO, such as a nitroso group or a nitrosyl group; or, the NO donor can release NO under the catalysis of an enzyme; or, the NO donor can release NO through an oxidation reaction or a reduction reaction.

[0085] 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 azoxy structure. In one embodiment, the azoxy structure comprises In one embodiment, the NO donor contains a furazan nitroxide structure. In one embodiment, the furazan nitroxide structure comprises wherein R is, for example, CN or phenylsulfonyl.

[0086] Endogenous NO is mainly synthesized in vivo by nitric oxide synthase. Three isoforms of the enzyme have been identified: endothelial NOS (eNOS) and neuronal NOS (nNOS) are constitutively expressed and their behavior to produce NO is highly regulated; inducible NOS (iNOS) is expressed in damaged tissues and its behavior to produce NO is largely uncontrolled, leading to high local NO concentrations and thus to cytotoxicity. Expression of iNOS is often associated with inflammatory responses.

[0087] NO has important and complex physiological roles. Most of the currently known NO donor drugs have the problem of drug resistance, which limits their clinical use; this is related to the reactive nature of NO. Under most conditions, NO acts directly as an antioxidant. The main exception is when NO production and superoxide production occur together with the same fluctuations, the reaction of NO with superoxide anion (O2 ·- ) generates peroxynitrite (ONOO - ). NO donor drug resistance can also cause cross-resistance to endothelium-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.

[0088] Flavonoids are a class of compounds with a 2-phenyl chromone skeleton. Flavonoid glycosides are compounds formed by the covalent linkage of flavonoids and sugars or derivatives of sugars. For some natural products in flavonoids and flavonoid glycosides, the literature reports antioxidant, anti-inflammatory, protection of vascular endothelium, anti-neovascularization, etc. Among them, the antioxidant effect such as scavenging reactive oxygen species (ROS) or inhibiting the production of ROS.

[0089] Carbohydrates are a class of compounds with polyhydroxy aldehyde or polyhydroxy ketone structures; the O atoms in the hydroxyl, aldehyde carbonyl and ketone carbonyl groups can optionally be replaced by S atoms, in which case the compounds are referred to as thio sugars; in addition, one or some of the O atoms of the hydroxyl groups in the molecule can be missing, i.e., the position is H, in which case the compounds are referred to as deoxy sugars. 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., pentoses, hexoses or heptoses. The aldehyde or ketone carbonyl or thiocarbonyl group of a monosaccharide can form a cyclic hemiacetal or hemithioacetal structure with one of the hydroxyl or thiol groups within the molecule; in which the ring formed (of the cyclic hemiacetal) is furanose if the ring is furan, or pyranose if the ring is pyran.

[0090] The term "high intraocular pressure related disease" refers to an ophthalmic disease associated with high intraocular pressure, or a disease responsive to the level of intraocular pressure, which is a group of clinically heterogeneous diseases. The site of onset thereof is not limited to the eye.

[0091] "Normal intraocular pressure" refers to the intraocular pressure under normal physiological conditions. Correspondingly, "high intraocular pressure" refers to an intraocular pressure higher than normal, for example, "high intraocular pressure" refers to an intraocular pressure of about 8 mmHg or more, about 9 mmHg or more, about 10 mmHg or more, about 11 mmHg or more, about 12 mmHg or more, about 13 mmHg or more, about 14 mmHg or more, about 15 mmHg or more, about 16 mmHg or more, about 17 mmHg or more, about 18 mmHg or more, about 19 mmHg or more, about 20 mmHg or more, about 21 mmHg or more, about 22 mmHg or more, about 23 mmHg or more, about 24 mmHg or more, about 25 mmHg or more, about 26 mmHg or more, about 27 mmHg or more, about 28 mmHg or more, about 29 mmHg or more, or about 30 mmHg or more. In a particular embodiment, the subject is a human, and "high intraocular pressure" refers to an intraocular pressure of, for example, about 20 mmHg or more. Intraocular pressure can be measured using a tonometer. High intraocular pressure can cause compression, ischemia of the retina and optic nerve, leading to retinal and optic nerve damage.

[0092] As an example, high intraocular pressure related diseases include, but are not limited to, glaucoma, optic nerve damage.

[0093] The term "optic nerve damage related disease" refers to a disease that is symptomatic of or caused by optic nerve damage.

[0094] As an example, optic nerve damage related diseases include, but are not limited to, neurodegenerative eye diseases, damage caused by trauma or surgery, and ocular lesions caused by diabetes, inflammation or tumors, etc.

[0095] The term "small organic molecule" or "low molecular weight compound" refers to a molecule of a size comparable to organic molecules typically used in pharmaceuticals. In a particular embodiment, the small organic molecule has a size of from about 100 to about 2000 Da, preferably from about 200 to about 1000 Da, such as from about 200 to about 900 Da, from about 200 to about 800 Da, from about 200 to about 700 Da, from about 200 to about 600 Da, from about 200 to about 500 Da.

[0096] Pharmaceutically acceptable salts of the compounds of the present application include both acid and base addition salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present application are known to those of skill in the art.

[0097] The compounds of the present application encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopically enriched compounds, metabolites, or prodrugs thereof.

[0098] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds. For example, the compounds of the present application can exist in E or Z configurations about carbon-carbon double bonds or carbon-nitrogen double bonds, where "E" represents the less substituted side of the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z" represents the more substituted side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present application can also exist as mixtures of the "E" and "Z" isomers. Isomeric forms also include cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, such as those that are enriched in an enantiomeric or diastereomeric form, all of which are intended to be within the scope of the present application. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0099] Optically pure enantiomers can be obtained from racemic mixtures according to conventional procedures by resolution of the racemic mixture, for example, by the formation of diastereomeric salts using an optically active acid or base, or by the formation of covalent diastereomers. Mixtures of diastereomers can be separated into the single diastereomers by methods known in the art, for example, by chromatography or fractional crystallization based on the differing solubilities of the compounds. The optically active base or acid addition salt of the separated diastereomer is then liberated from the salt by treatment with an appropriate hydride base or acid. Another method of separating racemic enantiomers uses chiral chromatography (e.g., chiral HPLC columns), and the separated chiral isomers can or can not be derivatized prior to separation, depending on which method allows for the more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or non-derivatized chiral isomers. Likewise, optically pure compounds of the present application can be obtained by chiral synthesis using optically pure starting materials.

[0100] The compounds of the present application can exist in solvated (e.g., hydrated) forms. In particular, the compounds of the present application can contain solvent, e.g., water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0101] The present application also encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0102] The compounds of the present application can exist in isotopically-labeled or enriched forms, containing one or more atoms which differ from the most abundant or naturally occurring isotopic form, due to the addition of neutrons or electrons. The isotopes can be radioactive or non-radioactive. Isotopes of atoms commonly occurring in the compounds of the present application, such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine and iodine, include but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.

[0103] Metabolites of the compounds of the present application, i.e., species derived from the compounds of the present application in vivo, are also within the scope of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, amide formation, deamidation, ester formation, enzymatic cleavage, and the like, of an administered compound.

[0104] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that upon administration to the body are capable of being converted to the compounds of the application having the desired activity, for example, by hydrolytic cleavage.

[0105] The term "polymorph" or "polymorphic form" refers to a single polymorphic form or a mixture of more than one polymorphic form in any ratio.

[0106] The term "crystalline" or "crystal" refers to any solid material that exhibits three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0107] The term "amorphous" refers to any solid material that is not ordered in three dimensions.

[0108] The term "pharmaceutically acceptable" means, within the scope of normal medical judgment, that contact with the tissues of the patient will not be accompanied by undue toxicity, irritation, allergic response, or the like.

[0109] The term "pharmaceutically acceptable carrier" means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the active or inactive components of the composition. The carrier would be one that is nontoxic to the subject, biologically acceptable, and does not interact with the active ingredient in a deleterious manner.

[0110] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest.

[0111] The term "effective amount," "therapeutically effective amount," or "prophylactically effective amount" with respect to a drug, pharmaceutical unit, or active ingredient means a sufficient amount of the drug or agent to produce a desired effect, which is acceptable with respect to side effects. The determination of an effective amount is dependent on the age and general condition of the individual, as well as the particular active substance, and an effective amount in a given case can be determined by a person skilled in the art according to routine experiments.

[0112] The term "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) who has a disease, such as a disease described herein, or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, domestic animals, and / or laboratory animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0113] The compounds of formula (I)

[0114] In one aspect, the present application provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (I):

[0115] D1 a — G1 g — F1— D2 b (I)

[0116] wherein,

[0117] “—” represents a covalent linkage;

[0118] each D1and D2is independently a moiety comprising a nitric oxide donor;

[0119] F1is a moiety having a flavonoid structure;

[0120] each G1is independently a monosaccharide or a derivative of a monosaccharide;

[0121] g is any integer from 1 to 10;

[0122] a is any integer from 0 to 10, b is any integer from 0 to 10, provided that a and b are not simultaneously 0.

[0123] In one embodiment, the compound of Formula (I) does not include the following structure:

[0124] wherein, R is a substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted benzyl; said substituents are: C1-4alkyl, C 1-4 alkoxy; n is an integer from 2 to 8.

[0125] In one embodiment, g is 1. In one embodiment, a is 1, 2, or 3, preferably 1 or 2, especially 1. In one embodiment, b is 0. In one embodiment, F1is 5,6,7-trihydroxy-4-oxo-2-phenyl-4H-chromen. In one embodiment, G1is β-D-glucuronic acid, or an amide formed by carboxyl group of β-D-glucuronic acid. In one embodiment, F1is linked to G1by a glycosidic bond.

[0126] In one embodiment, Formula (I) has the structure of Formula (I-1) as follows:

[0127] wherein,

[0128] R 1 is 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 ​

[0129] 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 , -NR-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 independently selected from the group consisting of R X2 ;

[0130] R 3 is selected from the group consisting of hydrogen, halogen, 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, -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 A3C(=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 the group consisting of R X3 ;

[0131] R 4 is 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 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;

[0132] R 5 Selected from hydrogen, halogens, C 1-10 Alkyl, C2-10 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;

[0133] 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 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 X6 ;

[0134] 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 ;

[0135] 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 1-4alkylene-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 the group consisting of R X7 ;

[0136] 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 ;

[0137] L 1 is selected from the group consisting of a 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 RD1 ) 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 -、C1-4 alkylene, C 2-4 alkenylene and C 2- alkynylene, wherein each alkylene, alkenylene, alkynylene is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X ;

[0138] R 8 is selected from the group consisting of hydrogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ;

[0139] U 0 is O or S;

[0140] Y 1 is C(R 9a R 9a’ );

[0141] Y 2 is C(R 9b R 9b’ );

[0142] Y 3 is C(R 9c R 9c’ );

[0143] Y 4 is C(R 9d R 9d’ );

[0144] 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 -OC(=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 ;

[0145] 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 2-6alkenyl, C2-10 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;

[0146] 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;

[0147] 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;

[0148] Or each "R" C1 and R D1together 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 the group consisting of oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of R X ;

[0149] each R E2 , R E3 , R E4 , R E5 , R E6 , R E7 and R E9 are independently selected from the group consisting of hydrogen, C 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 X ;

[0150] each L is independently selected from the group consisting of a 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 -, c R d ) u -OC(=O)-(CR c R d ) t -, c R d ) u -NR 8 C(=O)-(CR c R d ) t -, c R d ) u -C(=S)-(CR c R d ) t -, c R d ) u -C(=S)O-(CR c R d ) t -, c R d ) u -C(=S)NR 8 -(CR c R d ) t -, c R d ) u -OC(=S)-(CR c R d ) t -, c R d ) u -NR 8 C(=S)-(CR c R d ) t -, c R d ) u -S(=O) r -(CR c R d ) t -, 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;

[0151] 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;

[0152] Each M is independently selected from the NO donor; NO represents nitric oxide.

[0153] Each R X R X1 R X2 R X3 R X4 R X5 RX6 , R X7 , R X8 and R X9 are independently selected from 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, -(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 )Rb1 -(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 a1S(=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 independently selected from the group consisting of R Y ;

[0154] 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 ;

[0155] 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 the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of R Ysubstituents independently selected from the group consisting of R

[0156] 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 the group consisting of R Y ;

[0157] or each R c1 and R d1 together with the single or multiple carbon atom(s) to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of R Y ;

[0158] each R e1 is independently selected from the group consisting of hydrogen, C 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 with at least one substituent independently selected from the group consisting of R Y ;

[0159] each R Y is independently selected from the group consisting of halogen, 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(heterocyclyl), -O(C 1-4 alkylene-heterocyclyl), -SH, -S(C 1-10alkyl), -S(C 3-10 cycloalkyl), -S(C 1-4 alkylene-C 3-10 cycloalkyl), -S(heterocyclyl), -S(C 1-4 alkylene-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(heterocyclyl), and -NH(C 1-4 alkylene-heterocyclyl);

[0160] m is 0 or 1 ;

[0161] p is 0, 1, 2, or 3;

[0162] each r is independently selected from the group consisting of 1 and 2;

[0163] each t is independently selected from the group consisting of an integer from 0 to 10;

[0164] each u is independently selected from the group consisting of an integer from 0 to 10;

[0165] each k is independently selected from the group consisting of 1, 2, 3, and 4;

[0166] each q is independently selected from the group consisting of 0, 1, 2, and 3;

[0167] the total number of M in the molecule is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0168] 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 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X In one embodiment, each R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , RA9 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 and R B9 are independently selected from hydrogen, methyl and

[0169] In one embodiment, 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 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 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 OC(=O)NR a1 R b1 , -(CR c1 R d1 ) u NR a1 C(=O)ORb1 -(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 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 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 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R Y .

[0170] In one embodiment, each R Y is independently selected from halogen, NO2, -CN, C 1-10 alkyl, -OH, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NH2and -NH(C 1-10 alkyl), preferably from halogen, NO2, -CN and C 1-10 alkyl.

[0171] In one embodiment, u is 0. In one embodiment, t is 0.

[0172] In one embodiment, R 1 is hydrogen.

[0173] In one embodiment, R 2 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, 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)NR A2 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 RB2 -S(=O) r NR A2 R B2 and preferably selected from the group consisting of 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, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X2 In one embodiment, R 2 is hydrogen.

[0174] In one embodiment, R 3 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, 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 A3 R 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 the group consisting of hydrogen, halogen, C1-10 alkyl, CN, NO2, -NR A3 R B3 , -OR A3 , -OC(=O)R A3 , -OS(=O)2R A3 and more preferably selected from the group consisting of hydrogen, -OR A3 , -OC(=O)R A3 , -OS(=O)2R A3 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X3 In one embodiment, R 3 is hydrogen.

[0175] In one embodiment, R 4 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, 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 the group consisting of hydrogen, halogen, C 1-10alkyl, CN, NO2, -NR A4 R B4 , -OR A4 , -OC(=O)R A4 , -OS(=O)2R A4 and more preferably selected from the group consisting of hydrogen, -OR A4 , -OC(=O)R A4 , -OS(=O)2R A4 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 In one embodiment, R 4 is hydrogen.

[0176] In one embodiment, R 5 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, 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 the group consisting of hydrogen, halogen, C 1-10alkyl, CN, NO2, -NR A5 R B5 , -OR A5 , -OC(=O)R A5 , -OS(=O)2R A5 , and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X5 In one embodiment, R 5 is hydrogen.

[0177] In one embodiment, R 6 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, 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)2RA6 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X6 In one embodiment, R 6 is hydrogen.

[0178] In one embodiment, at least two of R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen. In one embodiment, R 2 , R 3 , R 4 , R 5 , R 6 are hydrogen.

[0179] In one embodiment, each R 7 is independently selected from halogen, C 1-10 alkyl, 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 , -OC(=O)NR A7 R B7 , -NR A7 C(=O)OR B7 , -NR A7 C(=O)NR A7 R B7 , -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 preferably selected from the group consisting of hydrogen, -OR A7 , -OC(=O)R A7 , -OS(=O)2R A7 , and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X7 In one embodiment, each R 7 is independently selected from the group consisting of -OR A7 , and In one embodiment, each R A7 is hydrogen. In one embodiment, each R A7 is methyl.

[0180] In one embodiment, p is 2. In one embodiment, p is 2; and, (1) both R 7 are -OH, or (2) one R 7 is -OH and the other R 7 is

[0181] In one embodiment, U 0 is O.

[0182] In one embodiment, R 9a , R 9a’ , R 9b , R 9b’ , R 9c (if present), R 9c’ (if present), R 9d , and R 9d’ are each independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, 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 , -OC(=O)NR A9 R B9 , -NR A9 C(=O)ORB9 , -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 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X9 .

[0183] In one embodiment, Y 2 is -CH(OH)-. In one embodiment, m is 1 and Y 3 is -CH(OH)-. In one embodiment, Y 4 is -CH(OH)-.

[0184] In one embodiment, R 9a is -C(=O)R A9 , and R 9a’ is hydrogen. In one embodiment, R A9 is

[0185] In one embodiment, m is 1.

[0186] In one embodiment, R 9b , R 9b’ , R 9c (if present), R 9c’ (if present), R 9d and R 9d’ are each independently selected from hydrogen, -OR A9 and In one embodiment, each R A9 is hydrogen or methyl, in particular hydrogen.

[0187] In one embodiment, R 9b , R 9c (if present) and R 9d are -OH, R 9b’ , R 9c’ (if present), R 9d’ is hydrogen. In one embodiment, R 9b and R 9cR is -OH, R 9d is R 9b’ , R 9c’ , and R 9d’ is hydrogen.

[0188] In one embodiment, L 1 is selected from a bond, -(CR C1 R D1 ) u -O-(CR C1 R D1 ) t -, C1 R D1 ) u -S-(CR C1 R D1 ) t -, C1 R D1 ) u -NR 8 -(CR C1 R D1 ) t -.

[0189] In one embodiment, R 8 is hydrogen. In one embodiment, each R C1 and R D1 is independently selected from hydrogen, halogen, C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X .

[0190] In one embodiment, L 1 is -O- or -S-, in particular -O-.

[0191] In one embodiment, each L is independently selected from a bond, -(CR c R d ) u -O-(CR c R d ) t -, c R d ) u -S-(CR c R d ) t -, c R d ) u -NR 8 -(CR c R d ) t-, -(CR c R d ) u -C(=O)-(CR c R d ) t -, c R d ) u -C(=O)O-(CR c R d ) t -, c R d ) u -C(=O)NR 8 -(CR c R d ) t -, c R d ) u -OC(=O)-(CR c R d ) t -, c R d ) u -NR 8 C(=O)-(CR c R d ) t - and C 1-4 alkylene, wherein alkylene is unsubstituted or substituted with at least one substituent independently selected from R Y . In one embodiment, each L is independently selected from the group consisting of a bond, -(CR c R d ) u -O-(CR c R d ) t -, c R d ) u -S-(CR c R d ) t - and -(CR c R d ) u -C(=O)-(CR c R d ) t -.

[0192] In one embodiment, k is 1, 2, or 3. In one embodiment, each R c and R d is independently selected from the group consisting of hydrogen, halogen, and C 1-10Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. Y Substituents are substituted.

[0193] 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.

[0194] 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.

[0195] In one implementation scheme, -(L) k The structure of ― is selected from -(CH2). j -、-(CH2) j1 -O-(CH2) j2 -、-(CH2) j1 -O-(CH2) i1 -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; wherein i, i1and i2are integers from 1 to 10, in particular 1 ; j, j1and j2are each independently integers from 0 to 10.

[0196] In one embodiment, -(L) k is selected from -(CH2) j , -O-, -O-CH2-, wherein j is an integer from 0 to 10.

[0197] In one embodiment, -(L) k is selected from -(CH2) j , -O-, -O-CH2-, wherein j is an integer from 0 to 10.

[0198] In one embodiment, each NO donor is independently selected from nitrate, furazan nitroxides, azo oxides, sulfonitrites and sydnone imines. In one embodiment, the azo oxide is an azoium diol salt.

[0199] In one embodiment, M is wherein

[0200] R 10 is -NR A10 R B10 ; R B10 and R B10 are independently selected from hydrogen, C 1-10 alkyl and C 2-10 alkenyl, wherein each alkyl and alkenyl is unsubstituted or substituted with at least one substituent independently selected from R X ;

[0201] or "R A10 and R B10 " together with the N atom 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 .

[0202] In one embodiment, each R X is independently selected from halogen, C 1-10 alkyl, -C(=O)-C 1-10 alkyl and -C(=O)O(C 1- 10 alkyl).

[0203] In one embodiment, M is wherein R 11 is selected from hydrogen, halogen, C 1-10 alkyl, -OH and -0(C 1-10 alkyl).

[0204] In one embodiment, M is wherein R 12 and R 13 are independently selected from C 1-10 alkyl, R 14 is selected from C 1-10 alkyl, -C(=0)-C 1-10 alkyl, -C(=0)0(C 1-10 alkyl), -C(=0)NH(C 1-10 alkyl) and -C(=0)S(C 1- 10 alkyl).

[0205] In one embodiment, each M is independently selected from -ON02, preferably from -ON02, wherein R is CN or phenylsulfonyl, wherein the phenyl ring of the phenylsulfonyl group is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from R Y .

[0206] In one embodiment, when multiple M are present, each M is the same. In another embodiment, when multiple M are present, each M can be the same or not the same.

[0207] In one embodiment, the structure of -CH2) j -ON02, preferably from wherein j is an integer from 0 to 10.

[0208] In one embodiment, by an amide bond or an ester bond or an ether bond to other parts of the molecule, in particular by an ester bond.

[0209] In one embodiment, formula (I-1) has the structure of formula (I-2-1) as follows:

[0210] wherein,

[0211] L 2 is selected from L;

[0212] M 1 is selected from M;

[0213] R 1 R 2 R 3 R 4 R 5 R 6 R 7 p, L 1 U 0 Y 2 Y 3 Y 4 m, L, M are defined as in formula (I-1).

[0214] In one embodiment, R 9d is selected from hydrogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X9 .

[0215] In another embodiment, formula (I-1) has the structure of formula (I-2-2) as follows:

[0216] wherein,

[0217] L 2 and L 3 are independently selected from L;

[0218] M 1 and M 2 are independently selected from M;

[0219] 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 formula (I-1).

[0220] In another embodiment, formula (I-1) has the structure of formula (I-2-3) as follows:

[0221] wherein,

[0222] L 2 and L 4 are independently selected from L;

[0223] M 1 and M 3 are independently selected from M;

[0224] R1 , 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 formula (I-1).

[0225] In another embodiment, formula (I-1) has the structure of formula (I-2-4):

[0226] wherein,

[0227] L 2 and L 5 are independently selected from L;

[0228] M 1 and M 4 are independently selected from M;

[0229] 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 formula (I-1).

[0230] In an embodiment, in formula (I-2-1) and formula (I-2-2), -L 2 -M 1 has the structure selected from

[0231] In an embodiment, in formula (I-2-2), -L 3 -M 2 has the structure

[0232] In an embodiment, formula (I-2-1) has the structure of formula (I-3-1):

[0233] wherein,

[0234] L 2 and M 1 are defined as in formula (I-2-1).

[0235] In one embodiment, Formula (I-2-2) has the structure of Formula (I-3-2) as follows:

[0236] wherein,

[0237] L 2 , M 1 and M 2 are as defined in Formula (I-2-2).

[0238] In one embodiment, Formula (I-2-3) has the structure of Formula (I-3-3) as follows:

[0239] wherein,

[0240] L 2 , M 1 and M 3 are as defined in Formula (I-2-3).

[0241] In one embodiment, Formula (I-2-4) has the structure of Formula (I-3-4) as follows:

[0242] wherein,

[0243] L 2 , M 1 and M 4 are as defined in Formula (I-2-4).

[0244] In one embodiment, the present application provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0245] Pharmaceutical compositions and pharmaceutical formulations

[0246] It is another object of the present application to provide a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite, or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0247] The pharmaceutical composition of the present application can be administered in any manner that achieves the desired prophylactic, palliative, preventative or therapeutic effect on the symptoms of a human or animal. For example, various suitable dosage forms can be prepared depending on the route of administration. For example, the present application can be administered orally or parenterally to a patient in the form of conventional formulations. Such 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 route of administration is particularly ocular administration, for example, ocular surface administration, intraocular administration, or periocular administration. The formulations are particularly eye drops and eye ointments.

[0248] The dosage of the compound administered to a subject can be adjusted to a considerable extent. The dosage can vary depending on the specific route of administration and the needs of the subject, and can be judged by a health care professional.

[0249] Therapeutic methods and uses

[0250] According to certain embodiments of the present application, the high intraocular pressure-related diseases and optic nerve damage-related diseases can be treated or prevented using the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- enriched compound, metabolite, or prodrug thereof, or the pharmaceutical composition of the present application.

[0251] Accordingly, in yet another aspect, the present application also provides the use of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application in the manufacture of a medicament for the treatment or prevention of a disease, disorder, or condition selected from the group consisting of high intraocular pressure-related diseases and optic nerve damage-related diseases, the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition being optionally used in combination with a second therapeutic agent.

[0252] In another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application, optionally used in combination with a second therapeutic agent, for use in the treatment of a high intraocular pressure-related disease or an optic nerve damage-related disease.

[0253] In a further aspect, the present application provides a method of treating a high intraocular pressure-related disease or an optic nerve damage-related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application, the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition being optionally used in combination with a second therapeutic agent.

[0254] In an embodiment, the disease, disorder, or condition is selected from the group consisting of glaucoma, neurodegenerative ocular disease, and optic nerve damage.

[0255] 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.

[0256] combination therapy

[0257] 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.

[0258] 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

[0259] 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.

[0260] 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.

[0261] The compounds of the present invention achieve at least one of the following technical effects:

[0262] (1) It has a high activity or strong protective effect on target cells or tissues.

[0263] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0264] (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).

[0265] (4) Excellent safety (few side effects, wide therapeutic window), etc.

[0266] (5) lower risk of resistance (less likely to develop resistance), etc.

[0267] Examples

[0268] In order to more clearly illustrate the purpose and technical solutions of the present application, the present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not intended to limit the scope of the present application. The specific experimental methods not mentioned in the following examples are all carried out according to the conventional experimental methods.

[0269] Instruments, materials and reagents

[0270] Unless otherwise specified, the instruments and reagents used in the examples are commercially available. The reagents can be used directly without further purification.

[0271] Compound A: CAS No. 21967-41-9, available from companies such as Merck, etc. The structure is

[0272] LCMS: Shimadzu LC20

[0273] Semi-preparative HPLC: Column: F-Prepulite XP tC 18 40*200mm*7mm; Mobile phase: [water(0.225%FA)-ACN]

[0274] NMR: BRUKER 400 MHZ

[0275] Intraocular pressure measurement was performed using tonometer Icare TONOVET Plus.

[0276] Synthetic scheme

[0277] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be synthesized by different methods, some exemplary methods are provided below and in the examples. Other synthetic methods can be readily proposed by those skilled in the art based on the information disclosed in the present application.

[0278] In the reactions described below, it can be necessary to protect reactive groups to prevent them from undergoing undesired reactions. Groups that must be protected include, for example, hydroxyl, amino, imino, thiol, and carboxyl groups in the final product. Conventional protecting groups can be used in accordance with T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

[0279] The synthetic scheme for all compounds of the present application is illustrated by the following scheme and examples. The starting materials used are either commercially available or can be prepared according to known procedures or the procedures exemplified herein.

[0280] As shown in synthetic scheme 1, compounds of formula (I-1) can be prepared from compounds containing reactive group 1, Z1, and compounds containing reactive group 2, Z2, which are either known in the literature or well known to those skilled in the art, via a variety of methods.

[0281] In synthetic scheme 1, reactive group 1 and reactive group 2 are independently reactive groups for condensation, nucleophilic addition or electrophilic addition (e.g. active C=0 moiety, active C=C-C=0 moiety, amino, amine, hydroxyl or thiol), or reactive groups for substitution (e.g. leaving group attached to an O, C, N or S atom). For example, one of reactive group 1 and reactive group 2 is carboxyl, sulfonic acid, phosphoryl with free -OH end, active ester, acid chloride or isocyanate, and the other is amino, amine, hydroxyl or halogen; or, one of reactive group 1 and reactive group 2 is amino, hydroxyl or thiol, and the other is halogen, hydroxyl or aldehyde. In a particular embodiment, one of reactive group 1 and reactive group 2 is carboxyl, and the other is hydroxyl or halogen, and reactive group 1 and reactive group 2 react to form an ester linkage.

[0282] Synthetic scheme 1

[0283] The following examples are provided in order that the application might be more fully understood. These examples are illustrative only and should not be construed as limiting the application in any way.

[0284] Example 1 4-(Nitrooxy)butyl (2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7- yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (Compound 001)

[0285] 1.1 Synthesis of intermediate L1-2

[0286] To a solution of 4-bromobutanol (50 g, 326.8 mmol) in dichloromethane was added concentrated nitric acid (2.02 eq), concentrated sulfuric acid (2.0 eq) and the reaction was allowed to proceed for 2 hours in an ice water bath. The reaction mixture upon purification gave intermediate L1-2 (15.3 g, 77.3 mmol) as a colorless or yellowish oil. Yield 23.65%, purity 90%.

[0287] 1.2 Synthesis of Compound 001

[0288] Intermediate L1-2 (5 g, 32.7 mmol) was dissolved in DMF, compound A (1.2 eq), DBU (1.2 eq) was added and reacted at room temperature for 12 h. The product was obtained as a yellow or green solid (570 mg, 1.01 mmol) after work-up and HPLC purification. Yield 2.55%, purity 95.9%.

[0289] LCMS: ESI-MS m / z 564.1 [M+H] + .

[0290] 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.58 (br s, 1H), 8.67 (br s, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 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 = 7.2 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 4.20 (d, J = 9.6 Hz, 1H), 4.09-4.18 (m, 2H), 3.41-3.47 (m, 4H), 1.56-1.91 (m, 4H).

[0291] Example 2 4-(Nitrooxy)butyl (2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7- yl)oxy)-3,4-dihydroxy-5-((6-(nitrooxy)hexanoyl)oxy)tetrahydro-2H-pyran-2-carboxylate (Compound 002)

[0292] 2.1 Synthesis of intermediate L2-2

[0293] To a solution of methyl 6-hydroxyhexanoate (500 mg, 3.42 mmol) in dichloromethane was added concentrated nitric acid (4.1 eq), concentrated sulfuric acid (3.1 eq) and the reaction was carried out in an ice water bath for 2 h. The reaction system was purified to obtain intermediate L2-2 (530 mg, 7.75 mmol).

[0294] 2.2 Synthesis of intermediate L2-3

[0295] Intermediate L2-2 (500 mg, 2.62 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water, and LiOH (5.0 eq) was added and reacted at room temperature for 12 h. Purification obtained intermediate L2-3 (300 mg, 7.34 mmol).

[0296] 2.3 Synthesis of compound 002

[0297] Intermediate L2-3 (300 mg, 7.34 mmol) was reacted with compound 001 (4.0 eq), EDCI (3.5 eq), DMAP (1.0 eq) in DMF at room temperature for 12 h. Compound 002 (12 mg, 0.017 mmol) was obtained after purification by column chromatography. Yield 0.2%, purity 95%.

[0298] LCMS: ESI-MS m / z 723.2 [M+H] + .

[0299] 1 H NMR (DMSO-d6, 400 MHz): 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 = 4.9 Hz, 2H), 5.39-5.34 (d, J = 4.9 Hz, 1H), 5.34-5.29 (d, J = 7.2 Hz, 1H), 4.60-4.50 (t, J = 6.6 Hz, 2H), 4.49-4.42 (t, J = 6.0 Hz, 2H), 4.24-4.17 (d, J = 9.6 Hz, 1H), 4.17-4.11 (m, 2H), 3.68-3.41 (m, 2H), 2.69-2.61 (t, J = 7.3 Hz, 2H), 1.80-1.66 (m, 8H), 1.55-1.43 (q, J = 8.1 Hz, 2H).

[0300] Example 3 4-(2-(((2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carbonyl)oxy)ethoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide (compound 003)

[0301] 3.1 Synthesis of intermediate L3-2

[0302] Intermediate L3-2-2 (1.02 g, 3.57 mmol) was dissolved in DMF and reacted with compound A (1.2 eq), 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%.

[0303] 3.2 Synthesis of intermediate L3-3-2

[0304] Intermediate L3-2-2 (1.02 g, 3.57 mmol) was dissolved in DMF and reacted with compound A (1.2 eq), 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%.

[0305] 3.3 Synthesis of compound 003

[0306] Intermediate L3-2-2 (1.02 g, 3.57 mmol) was dissolved in DMF and reacted with compound A (1.2 eq), 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%.

[0307] LCMS: ESI-MS m / z 715.0 [M+H] + .

[0308] 1 H NMR (DMSO-d6, 400 MHz): 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 = 5.2 Hz, 2H), 5.44-5.30 (m, 2H), 4.67-4.56 (m, 2H), 4.44 (q, J = 3.6 Hz, 2H), 4.32 (d, J = 9.2 Hz, 1H), 3.54-3.41 (m, 3H).

[0309] Example 4 (Z)-2-(((2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7- yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)carbonyl)oxy)-1-(pyrrolidin-1- yl)azene 1-oxide (Compound 004)

[0310] 4.1 Synthesis of intermediate L4-2

[0311] Dissolve 10 g of tetrahydropyrrole (10 g, 140.8 mmol) in 100 mL of methanol, add sodium methoxide (1.0 eq) to it, after fully dissolving, transfer it to a stainless steel high-pressure reaction kettle, continuously blow in argon to replace air, finally react under NO (0.5 mPa) for 3 days, after sufficient reaction, blow in argon to quench the reaction. Purify by column chromatography to obtain intermediate L4-2 (1.53 g, 10 mmol).

[0312] 4.2 Synthesis of Compound 004

[0313] React intermediate L4-2 (1.53 g, 10 mmol) with compound A (1.2 eq), DBU (1.2 eq) at room temperature for 12 hours. The product is obtained by post-treatment and HPLC purification to obtain compound 004 (1.29 g, 2.3 mmol). Yield 23.2%, purity 98.7%.

[0314] LCMS: ESI-MS m / z 560.1 [M+H] + .

[0315] 1 H NMR (DMSO-d6, 400 MHz): 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 = 6.3 Hz, 1H), 5.07 (dt, J = 7.2, 2.6 Hz, 1H), 4.95 (d, J = 6.2 Hz, 1H), 4.71 (d, J = 6.0 Hz, 1H), 4.31 (dt, J = 8.5, 2.4 Hz, 1H), 3.81 (tdd, J = 8.6, 6.5, 2.2 Hz, 1H), 3.70-3.46 (m, 6H), 2.01-1.84 (m, 4H).

[0316] Example 5 3-cyano-4-((((2S,3S,4S,5R,6S)-6-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7- yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carbonyl)oxy)methyl)-1,2,5-oxadiazole 2-oxide (Compound 005)

[0317] 5.1 Synthesis of intermediate L5-1

[0318] To 3-oxobutyric acid lactone (15 g, 150 mmol) was added NaNCte (1.0 eq) and appropriate amount of 3N HCl. Then hydroxylamine hydrochloride (1.0 eq) was added and the reaction was carried out in ice water bath for 30 min. After work-up, intermediate L5-1 (14.5 g, 100.7 mmol) was obtained.

[0319] 5.2 Synthesis of intermediate L5-2

[0320] 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 ice water bath for 2 h. After the reaction mixture was spin-dried, crude intermediate L5-2 was obtained.

[0321] 5.3 Synthesis of intermediate L5-3

[0322] The crude intermediate L5-2 from 5.2 was dissolved in methanol and the reaction was carried out under continuous ammonia gas flow in oil bath. After the reaction was completed, the mixture was used directly in the next step.

[0323] 5.4 Synthesis of intermediate L5-4

[0324] The mixture from 5.3 was spin-dried and dissolved in appropriate amount of tetrahydrofuran. Carbon tetrabromide (1.2 eq) and triphenylphosphine (1.2 eq) were added and the reaction was carried out at room temperature. After work-up, crude intermediate L5-4 was obtained.

[0325] 5.5 Synthesis of intermediate L5-5

[0326] Crude intermediate L5-4 from 5.4 was dissolved in dichloromethane and reacted with TFAA (1.2 eq) and DIEA (1.5 eq) in ice water bath for 1 h. Intermediate L5-5 was obtained.

[0327] 5.6 Synthesis of Compound 005

[0328] The intermediate L5-5 obtained in 5.5 was dissolved in DMF with compound A (1.2 eq), NaHCO3(2.0 eq) and NaI, heated to 90°C for 1 h. Compound 005 (147.7 mg, 0.26 mmol) was obtained after purification with a yield of 25.8% and a purity of 96.3%.

[0329] LCMS: ESI-MS m / z: [M+H] + = 570.10.

[0330] 1 H NMR (DMSO-d6, 400 MHz): 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 = 8.94 Hz, 2H), 5.62 (d, J = 5.36 Hz, 1H), 5.57 (d, J = 3.93 Hz, 1H), 5.36-5.53 (m, 3H), 5.30 (d, J = 7.15 Hz, 1H), 4.36 (d, J = 9.18 Hz, 1H), 3.40-3.50 (m, 3H).

[0331] Protective effect of the compound of Example 1 on NMDA-induced retinal nerve cell damage

[0332] To verify the protective effect of the compound on the optic nerve cells, the following test was performed using retinal ganglion cells (RGC).

[0333] After a large amount of N-methyl-D-aspartate (NMDA) is aggregated, a large number of NMDA receptors on the cell membrane of RGC are activated, causing extracellular Ca 2+ inflow and intracellular calcium store Ca 2+ mobilization, leading to intracellular Ca 2+ overload, excessive Ca 2+ activating intracellular Ca 2+ dependent signal cascade pathway, inducing cell glutamate excitotoxicity and oxidative stress, and ultimately leading to nerve cell apoptosis. NMDA is commonly used to induce animal glaucoma models or RGC damage models.

[0334] 1.1 Cell culture: RGC-5 cells (Guangzhou Jinnyou Biological Technology Co., Ltd.) were placed in DMEM culture medium containing 10% fetal bovine serum, cultured in a 5% CO2, 37°C incubator, and subcultured once every 2-3 days using 0.25% trypsin.

[0335] 1.2 MTT colorimetric method for determining cell survival rate:

[0336] (1) RGC-5 cells (1 x 10 5 were seeded into 96-well plates and adhered, and then the cells were divided into 8 groups: NMDA injury group (negative control group), blank control group, positive control group, and compound 001, 002, 003, 004, 005 treatment groups. Each group had 6 replicates.

[0337] (2) For the compound 001, 002, 003, 004, 005 treatment groups, each group was divided into 3 subgroups, and treated with the following concentrations of compounds: 0.5 μM, 5 μM and 10 μM. The positive control group was added with diazoxide (Sigma-Aldrich) to reach the test concentration of 10 μM. The negative control group and the blank control group were added with the same volume of DMEM (Adamas life) complete medium.

[0338] (3) The plates were placed in a cell incubator at 37°C with 5% CO2for 12 h.

[0339] (4) The culture medium was discarded, and the cells were washed 3 times with phosphate buffered saline (PBS) (Adamas life). Except for the blank control group, 10 μM glycine and 10 μM NMDA (Adamas life) were added to the rest of the groups, and after 30 min, the cells were washed 3 times with PBS and returned to the original culture medium environment.

[0340] (5) After 36 h, 20 μL of freshly prepared MTT (Sigma-Aldrich) (5 mg / mL) was added to each well, and the absorbance (OD value) was measured at a wavelength of 490 nm using an enzyme-labeled instrument to calculate the cell survival rate.

[0341] 1.3 Hoechst staining:

[0342] (1) The cells were grouped and treated according to the method similar to steps (1) to (4) of 1.2 above, but the RGC-5 cells were cultured on cover slips, and the compound 001, 002, 003, 004, 005 treatment groups were treated with 5 μM of the compounds, instead of the three concentrations described in 1.2 above.

[0343] (2) Fixed with paraformaldehyde (4%), washed 3 times with PBS, then added with hoechst 33258 (Sigma-Aldrich) working solution for staining for 5 min, washed 3 times, then mounted, and the results were observed under a fluorescence microscope. Under the fluorescence microscope, the living cells were stained with homogeneous blue fluorescence, and the apoptotic cell nuclei were bright blue granular blocks, and the nuclei were pyknosis. Six fields were randomly selected to calculate the percentage of apoptosis (percentage of apoptosis = number of apoptotic nuclei / total number of nuclei x 100%).

[0344] 1.4 Data analysis:

[0345] The results of MTT colorimetric assay showed that the cell survival rate of each subgroup in the positive control group and the compound 001, 002, 003, 004, 005 treatment groups was significantly improved compared with the negative control group (* represents P<0.05, ** represents P<0.01), as shown in Figures 1 to 5.

[0346] The results of Hoechst staining 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)%, and the difference was statistically significant (P<0.01); the percentage of cell apoptosis in the compound 001, 002, 003, 004, 005 treatment groups and the positive control group was (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, which were significantly lower than that in the negative control group (P<0.01). See Table 1.

[0347] Table 1 Effect of compounds on the percentage of retinal nerve cell apoptosis caused by NMDA

[0348] Example 2 Effect of compounds on the intraocular pressure of beagle dogs

[0349] 1. Compound 001, 002, 003, 004, 005 were dissolved in solvent (0.5% Tween 80 and 0.02% benzalkonium chloride in 10 mM sodium phosphate buffer solution (pH = 7.0)) to prepare 0.25% solution.

[0350] 2. Beagle dogs with body weight of about 10-14 kg and age of about 9-21 months (Jiangsu Yadong Experimental Animal Research Institute Co., Ltd.) were selected (3 in each group).

[0351] 3. All animals were examined before the start of the test, and there was no obvious abnormality in the anterior segment and fundus of the eye, so as to confirm the health of the animals and their suitability for use in this study. Animals that failed the physical examination will be excluded or replaced before the start of the test.

[0352] 4. At least 4 weeks of behavior and consciousness measurement of intraocular pressure training are required before the test, until stable IOP values are obtained.

[0353] 5. In the experimental administration phase, the following groups were set up according to the following scheme: negative control group (vehicle group), positive control group (administered Timolol Maleate Eye Drops (Bausch & Lomb), specification: 0.5%) (Shandong Bausch & Lomb Furuida Pharmaceutical Co., Ltd.), compound 001, 002, 003, 004, 005 treatment groups (administered 0.25% compound solution). The administration route was conjunctival sac instillation, the administration volume was 50 μL / eye / time, and each eye was instilled twice a day at about 10:00 and 17:00, for 15 consecutive days. The first day of administration was recorded as Day 1. When administering, the eyelids were gently pried open to avoid touching the eyeball surface, 50 μL of vehicle or test product was gently instilled into the conjunctival sac with a pipette, and the eyelids were gently closed several times.

[0354] 6. Intraocular pressure measurement: once before the first administration on Day 1, 2h and 4h after the first administration on Day 1, once before the first administration on Day 2, Day 4, Day 7, Day 13, Day 15, and Day 16, respectively; see Table 2 and Figure 6 for detailed test data.

[0355] The change (%) in IOP was calculated using the following formula:

[0356] The percentage change in IOP (ΔIOP%) = [IOP (treatment group) - IOP (baseline)] / IOP (baseline) * 100

[0357] Table 2 Effect of compounds on the intraocular pressure of beagle dogs

[0358] T. Test: compared with the vehicle group, *** indicates p≤0.001.

[0359] Test results: compared with the average value of the intraocular pressure at each measurement point from the start of the test, it can be seen from the intraocular pressure data shown in Table 2 that the intraocular pressure of the control group did not change significantly, and the average intraocular pressure of the positive group and the compound 001, 002, 003, 004, 005 treatment groups was significantly different from that of the control group.

[0360] Effect Example 3 Effect of compounds on the intraocular pressure of rats

[0361] 1. Compound 001, 003 was dissolved in the vehicle (0.5% Tween 80 and 0.02% benzalkonium chloride in 10 mM sodium phosphate buffer solution (pH = 7.0)) to prepare a 0.25% solution.

[0362] 2. Select 80 SD rats weighing about 160-180 g and about 35 days old (Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) for modeling test grouping, and use random number table method to randomly divide the experimental rats into blank control group 16, dexamethasone group 48, and solvent group 16.

[0363] 3. Before the start of the test, all animals are subjected to physical examination, and there is no obvious abnormality in the anterior segment and fundus of the eye, so as to confirm the health of the animals and can be used for this study. The unqualified animals will be excluded or replaced before the start of the test.

[0364] 4. Before the rats start modeling, the normal range of intraocular pressure value of the right eye is measured at 7 days, 3 days, and 1 day, as the baseline intraocular pressure value of the rats. After the intraocular pressure of the SD rats is stable, dexamethasone sodium phosphate eye drops (Xinxiang Huaqing Pharmaceutical Co., Ltd.) are quantitatively (0.02 ml) dropped into the right eyes of the dexamethasone group rats at 8:30 and 13:30 twice a day with an interval of 5 hours, and the solvent (0.02 ml) is dropped into the right eyes of the solvent group rats. The blank control group is simply used as a control. The intraocular pressure is measured every 2 days, and the systemic and local reactions of the rats are observed. The right eye of the rat is considered to be successfully modeled when the intraocular pressure value is greater than 20 mmHg, and it takes about 7-10 days.

[0365] 5. In the experimental administration stage, select the successfully modeled rats (40) and divide them into the following groups according to the following scheme: negative control group (high intraocular pressure solvent group), positive control group (administered Timolol Maleate Eye Drops (Bausch & Lomb), specification: 0.5%), compound 001, 003 treatment groups (administered 0.25% compound solution). In addition, 10 rats are randomly selected from the above-mentioned 4 modeling test solvent groups as non-model blank control groups in the pharmacodynamic test stage. The administration route is conjunctival sac instillation of the right eye of the rats, and the administration volume is 20 μL / eye / time. Each eye is instilled twice a day at 10:00 am and 17:00 pm, and the instillation is continued for 15 days. The first day of administration is recorded as Day 1. When administering, the eyelids are gently pried open to avoid touching the surface of the eyeball, 20 μL of solvent or test product is gently instilled into the conjunctival sac with a pipette, and the eyelids are gently closed several times. In this experiment, dexamethasone sodium phosphate eye drops will continue to be used at the same time every day as in the modeling stage to maintain the intraocular pressure of the right eye of the rats in the negative control group (high intraocular pressure solvent group), the positive control group (administered Timolol Maleate Eye Drops (Bausch & Lomb), specification: 0.5%), and the compound 001, 003 treatment groups (administered 0.25% compound solution).

[0366] 6. Intraocular pressure measurement: once before the first administration on Day 1, before the first administration on Day 2, before the first administration on Day 4, before the first administration on Day 6, before the first administration on Day 8, before the first administration on Day 10, before the first administration on Day 13, before the first administration on Day 15, and before the first administration on Day 16; the detailed test data of the efficacy test stage are shown in Table 3 and Figures 7 and 8.

[0367] Table 3 Influence of the compound on the intraocular pressure of rats

[0368] T. Test: *** means p < 0.001 compared with the vehicle group.

Claims

Compounds of formula (I-1): wherein R 1 selected from hydrogen, -OH, -O-C 1-10 alkyl and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X1 ; and each R is independently selected from the group consisting of H, F, Cl, Br, I, CN, N02, CF3, CH3, CH2CH3, CH2CH 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 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 with at least one substituent selected independently from R X3 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 ; and each R is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR, -C(O)R, -C(O)OR, -C(O) 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 with at least one substituent selected independently from R X5 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 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 selected independently 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 ; 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 alkynyl groups, wherein each alkylene group, alkenyl group, and alkynyl 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 selected independently from R X9 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 2-6alkenyl, C 2-10 2-6alkynyl, 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 selected independently from R X ; and each R is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR, -C(O)R, -C(O)OR, -C(O) 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 is independently selected from hydrogen, halogen, C C1 and R D1 is independently 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 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 X ; and each R is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR, -C(O)R, -C(O)OR, -C(O) 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 are independently selected from hydrogen, C 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 with at least one substituent independently selected from R X ; and the like. 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 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, M, -C 1-4 alkylene-M, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; 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 , R X8 and R X9 are independently selected from halo, 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, -(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 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C each R is independently selected from the group consisting of hydrogen, C 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 selected independently from R Y ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 is independently selected from hydrogen, halogen, C c1 and R d1 is independently 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 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 ; and each R is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C 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 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 with at least one substituent independently selected from R Y ; and the like. 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 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. The compound of claim 1, wherein -(L) k the structure of - is selected from -(CH2) j - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - -(CH2) i1 - -(CH2) j2 - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - -(CH2) i - -(CH2) j2 - -(CH2) j1 - -(CH2) i1 - -(CH2) i2 - -(CH2) j2 - ; 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-, The compound of claim 1 or 2, 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 by 1, 2 or 3 substituents independently selected from R Y . The compound of any one of claims 1 -5, wherein 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. The compound of any one of claims 1 -3, wherein The structure is selected from -(CH2). j -ONO2、 wherein j is an integer from 0 to 10. The compound of any one of claims 1-5, wherein R 1 is hydrogen. The compound of any one of claims 1 -6, 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 . The compound of claim 7, 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. The compound of any one of claims 1 -8, wherein each R is independently selected from the group consisting of hydrogen, -OR 7 A7 A7 A7 and ​​​ preferably: p is 2; and two R 7 is -OH, or one R 7 is -OH, the other R 7 is The compound of any one of claims 1 -9, wherein R 9a -C(=O)R A9 , R 9a’ is hydrogen; preferably, R A9 is The compound of any one of claims 1 -10, wherein m is 1 ; and / or 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. The compound of any one of claims 1 -1 1, 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. The compound of any one of claims 1 -12, wherein Formula (I-1) has the structure of Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), or Formula (I-2-4) as follows: 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. The compound of claim 13, wherein - L 2 - M 1 the structure is selected from and / or; - L 3 - M 2 the structure of 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): A compound, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from: A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1 -16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Use of a compound of any one of claims 1 -16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, in the manufacture of a medicament for treating a disease, disorder, or condition selected from the group consisting of a high ocular pressure related disease and an optic nerve damage related disease. 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 ocular pressure induced by retinal vascular occlusion, and optic nerve damage. 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 ocular pressure induced by retinal vascular occlusion, and optic nerve damage.

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