Flavonoid derivative containing nitric oxide donor

Abstract

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

Description

Flavonoid derivatives containing nitric oxide donors TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a class of flavonoid derivatives containing nitric oxide donors or pharmaceutically acceptable salts, a preparation method thereof, a pharmaceutical composition and the use thereof in treating ophthalmic high intraocular pressure 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 elevated 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 up-regulation of pro-apoptotic gene expression, down-regulation of neuroprotective and regenerative factors, and 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 damage, ultimately 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 fibers, radial fibers and longitudinal fibers. Various evidence has shown that NO can reduce IOP. NO can increase the aqueous outflow of the human anterior segment 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 a 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 occurrence and 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 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 A1 R B1 , -OR A1 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -OC(=O)R A1 , -C(=O)NR A1 R B1 , -NR A1 C(=O)R B1 , -NR A1 C(=NR E1 )R B1 , -OC(=O)NR A1 R B1 , -NR A1 C(=O)OR B1 , -NR A1 C(=O)NR A1 R B1 , -NR A1 C(=S)NR A1 R B1 , -NR A1 C(=NR E1 )NRA1 R B1 -S (=O) r R A1 -S(=O)(=NR) E1 )R B1 -N = S(=O)R A1 R B1 -S(=O)2OR A1 -OS(=O)2R A1 -NR A1 S(=O) r R B1 -NR A1 S(=O)(=NR E1 )R B1 -S (=O) r NR A1 R B1 -S(=O)(=NR) E1 )NR A1 R B1 -NR A1 S(=O)2NR A1 R B1 -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. X1 Substituents of the substituents;

[0012] R 2 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A2 R B2 -OR A2 -SR A2 -C(=O)R A2 -C(=O)OR A2 -OC(=O)R A2 -C(=O)NR A2 RB2 , -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 ;

[0013] R 3 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10alkynyl, 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 RB3 -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 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;

[0015] R 5 Selected from hydrogen, -OH, -OC 1-10 Alkyl and Each alkyl group is unsubstituted or is selected independently from R. X5 Substituents of the substituents;

[0016] 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 -C(=O)OR A6 -C(=O)OR A6 R B6 -C(=O)OR A6 -C(=O)OR B6 -C(=O)OR A6 -C(=O)OR E6 -C(=O)OR B6 -C(=O)OR A6 -C(=O)OR B6 -C(=O)OR A6 -C(=O)OR B6 -C(=O)OR A6 -C(=O)OR A6 -C(=O)OR B6 -C(=O)OR A6 -C(=O)OR A6 -C(=O)OR B6 -C(=O)OR A6 -C(=O)OR E6 -C(=O)OR A6 -S(=O)R B6 -S(=O)R r -S(=O)R A6 -S(=O)R E6 -S(=O)R B6 -S(=O)R A6 -S(=O)R B6 -S(=O)R A6 -S(=O)R A6 -S(=O)R A6 -S(=O)R r -S(=O)R B6 -S(=O)R A6 -S(=O)R E6 -S(=O)R B6 -S(=O)R r -S(=O)R A6 -S(=O)R B6 -S(=O)R E6 -S(=O)R A6 -S(=O)R B6 -S(=O)R A6 -S(=O)R A6 -S(=O)R B6 -S(=O)R A6 -S(=O)R E6 -S(=O)R A6 -S(=O)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 X6

[0017] R​7 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 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 NRA7 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, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X7 ;

[0018] R 8 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 A8 R B8 , -OR A8 , -SR A8 , -C(=O)R A8 , -C(=O)OR A8 , -OC(=O)R A8 , -C(=O)NR A8 R B8 , -NR A8 C(=O)R B8 , -NR A8 C(=NR E8 )R B8 , -OC(=O)NR A8 R B8 , -NR A8 C(=O)OR B8 , -NR A8 C(=O)NR A8 R B8 , -NR A8 C(=S)NR A8 R B8 , -NR A8 C(=NR E8 )NRA8 R B8 , -S(=O) r R A8 , -S(=O)(=NR E8 )R B8 , -N=S(=O)R A8 R B8 , -S(=O)2OR A8 , -OS(=O)2R A8 , -NR A8 S(=O) r R B8 , -NR A8 S(=O)(=NR E8 )R B8 , -S(=O) r NR A8 R B8 , -S(=O)(=NR E8 )NR A8 R B8 , -NR A8 S(=O)2NR A8 R B8 , -NR A8 S(=O)(=NR E8 )NR A8 R B8 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 X8 ;

[0019] R 9 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 A9 R B9 , -OR A9 , -SR A9 , -C(=O)R A9 , -C(=O)OR A9 , -OC(=O)R A9 , -C(=O)NR A9 RB9 -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 -S(=O) r R A9 -S(=O)(=NR E9 )R B9 -N=S(=O)R A9 R B9 -S(=O)2OR A9 -OS(=O)2R A9 -NR A9 S(=O) r R B9 -NR A9 S(=O)(=NR E9 )R B9 -S(=O) r NR A9 R B9 -S(=O)(=NR E9 )NR A9 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 ;

[0020] R 10 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;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 A10 R B10 , -OR A10 , -SR A10 , -C(=O)R A10 , -C(=O)OR A10 , -OC(=O)R A10 , -C(=O)NR A10 R B10 , -NR A10 C(=O)R B10 , -NR A10 C(=NR E10 )R B10 , -OC(=O)NR A10 R B10 , -NR A10 C(=O)OR B10 , -NR A10 C(=O)NR A10 R B10 , -NR A10 C(=S)NR A10 R B10 , -NR A10 C(=NR E10 )NR A10 R B10 , -S(=O) r R A10 , -S(=O)(=NR E10 )R B10 , -N=S(=O)R A10 R B10 , -S(=O)2OR A10 , -OS(=O)2R A10 , -NR A10 S(=O) r R B10 , -NR A10 S(=O)(=NR E10 )R B10 , -S(=O) r NR A10 R B10 , -S(=O)(=NR E10 )NR A10 RB10 , -NR A10 S(=O)2NR A10 R B10 , -NR A10 S(=O)(=NR E10 )NR A10 R B10 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 X10 ;

[0021] or "R 1 and R 2 " or "R 1 and R 4 " or "R 2 and R 3 " or "R 6 and R 7 " or "R 7 and R 8 " or "R 8 and R 9 " or "R 9 and R 10 " 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 ;

[0022] each R A1 , R A2 , R A3 , R A4 , R A6 , R A7 , R A8 , R A9 , R A10 , R B1 , R B2 , R B3 , R B4 , R B6 , R B7 , R B8 , R B9 and R B10 are 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- 4alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4alkylene-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 X ;

[0023] or "R A1 and R B1 " or "R A2 and R B2 " or "R A3 and R B3 " or "R A4 and R B4 " or "R A6 and R B6 " or "R A7 and R B7 " or "R A8 and R B8 or "R A9 and R B9 " or "R A10 and R B10 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 X ;

[0024] each R E1 , R E2 , R E3 , R E4 , R E6 , R E7 , R E8 , R E9 and R E10 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 X ;

[0025] 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 11 -(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 11 -(CR c R d ) t -, -(CR c R d ) u -OC(=O)-(CR c R d ) t -, -(CR c R d ) u -NR 11 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 Rd ) t -, -(CR c R d ) u - C(=S)NR 11 -, -(CR c R d ) t -, -(CR c R d ) u - OC(=S)-(CR c R d ) t -, -(CR c R d ) u - NR 11 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 11 -, -(CR c R d ) t -, -(CR c R d ) u - OS(=O) r -, -(CR c R d ) t -, -(CR c R d ) u - NR 11 S(=O) r -, -(CR c R d ) t -, C 1-4 alkylene, C 2-4 alkenylene and C 2-4alkynylene is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ;

[0026] R 11 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 X11 ;

[0027] 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 ;

[0028] each M is independently selected from a NO donor;

[0029] each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 and R X11 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, 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 ) uOR 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 , -(CRc1 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 ) uNR 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 ;

[0030] 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 ;

[0031] 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 selected from the group consisting of R Y ;

[0032] 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 ;

[0033] or each Rc1 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 ;

[0034] 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 R Y ;

[0035] 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);

[0036] each r is independently selected from the group consisting of 1 and 2;

[0037] each t is independently selected from an integer between 0 and 10;

[0038] each u is independently selected from an integer between 0 and 10;

[0039] each k is independently selected from 1, 2, 3, and 4;

[0040] each q is independently selected from 0, 1, 2, and 3;

[0041] the total number of M in the molecule is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0042] In another aspect, there is provided a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0043] In another aspect, there is provided the use of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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

[0044] Figures 1 to 5 show the protective effects of compounds 001, 004, 005, 006, 007, respectively, on NMDA-induced retinal neuronal cell damage.

[0045] Figure 6 shows the IOP responses of normotensive beagle dogs to vehicle, timolol maleate, and compounds 004, 005, 006, 007. The ordinate is the change in intraocular pressure from baseline (ΔIOP %). The curve closest to the baseline in each group is that of the vehicle group.

[0046] Figure 7 shows the IOP responses of a rat model of ocular hypertension to vehicle, timolol maleate, and compounds 001, 005, 007.

[0047] Figure 8 shows the IOP responses of a rat model of ocular hypertension to vehicle, timolol maleate, and compounds 001, 005, 007. The ordinate is the change in intraocular pressure from baseline (ΔIOP %). DETAILED DESCRIPTION

[0048] 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.

[0049] DEFINITIONS

[0050] 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 terms as commonly understood by those skilled in the art, including variations and equivalents thereof that are apparent to those skilled in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate better understanding of the present application. When a name of an article is used herein, it refers to the corresponding article or its active ingredient. All patents, published patent applications and publications recited herein are incorporated herein by reference.

[0051] When a range, preferably a range or a preferred upper or lower limit, is recited as an amount, concentration, or other numerical value or parameter, it is contemplated as being a shorthand way of referring to any and every included value falling within the indicated range, regardless of whether additional, non- recited minimum or maximum limits are stated or otherwise apparent. Unless otherwise stated, numerical ranges recited herein are intended to include all end points within the range and all integers and fractions within the range. For example, recitation of a range, e.g., "C1-C10" or "C1-C10", encompasses a range of 1-10 carbon atoms and is to be understood as also encompassing any sub-range within the range, e.g., C1-C9, C2-C8, C3-C7, C4-C6, C5-C6, and so on, as well as each individual number, e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, and so on. Similarly, recitation of a range, e.g., "C3-C10" or "C3-C10", is also to be understood as encompassing a range of 3-10 carbon atoms and is to be understood as also encompassing any sub-range within the range, e.g., C3-C9, C4-C8, C5-C7, C6-C6, and so on, as well as each individual number, e.g., C3, C4, C5, C6, C7, C8, C9, C10, and so on. 10 1-10 2-3 2-4 2-5 3-4 3-5 3-6 3-7 1-2 1-3 1-4 1-5 1-6 1-7 1-8 10 10 3-10 3-4 3-5 3-6 3-7 3-8 4-5 4-6 10 ​​​​​​​​​​​​​​​​​​​​​​​​​​For example, the expression "3-14 membered" is to be understood as encompassing any sub-range therein and each individual point value, 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 similar manner.

[0052] When any variable (e.g., R X ) occurs more than one time in a compound or structure, its definition in each occurrence is independent of its definition at every other occurrence. For example, the expression "each R X is independently selected from" means that if there are multiple R X , each R X is selected independently on each occurrence. Other variables or expressions should be interpreted similarly.

[0053] 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 one embodiment, "at least one" means 1, 2, 3, or 4.

[0054] The terms "optionally" or "optional" mean that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0055] The terms "substituted" and "substitution" mean that one or more (e.g., one, two, three, or four) hydrogens on the designated atom is 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 a substitution is described, it is understood that the substitution can be one or more hydrogen atoms, provided that the structure enables the compound to be in a stable state.

[0056] Unless specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent. When a bond to a substituent is shown as being through an atom of a ring, then such substituent can be bonded to any atom in the ring which can be substituted.

[0057] The expressions "comprising", "including", "containing", and "having" are inclusive 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 claim to the specified materials or steps plus an optional amount of insubstantial materials or steps. It is to be understood that the expression "comprising" encompasses the expressions "consisting of' and "consisting essentially of'.

[0058] 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.

[0059] The term "hydrocarbyl" refers to a monovalent group derived from a hydrocarbon. Examples of hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups.

[0060] The term "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached 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 from 1 to 10 carbon atoms, referred to as C 1-10 alkyl groups, such as C 1-6 alkyl groups, C 1-4 alkyl groups, C 1-3 alkyl groups, C 1-2 alkyl groups, C3alkyl groups, C4alkyl groups, 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, and the like. Non-limiting examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-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, and the like.

[0061] A divalent group refers to a group obtained by removing one hydrogen atom from an atom of the corresponding monovalent group having a free valence electron. A divalent group has two attachment sites to the rest of the molecule, where the two attachment sites can be on the same atom or on two different atoms of the divalent group.

[0062] "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.

[0063] 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", for example 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.

[0064] 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", for example 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.

[0065] "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-.

[0066] 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 monocyclic, fused polycyclic, bridged or spirocyclic structure. Cycloalkyl groups can have 3-10 carbon atoms, i.e., "C 3-10 cycloalkyl", for example 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.

[0067] The terms "cycloalkyl" and "cycloalkyl group" have the same meaning herein and are used interchangeably. Cycloalkyl refers to saturated cyclic hydrocarbyl groups. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (C 3-10 ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l. l. l]pentyl, and bicyclo[2. l. l]hexyl. In some embodiments, the cycloalkyl group is a C 3-7 monocyclic or bicyclic cycloalkyl group, preferably a C 3-6 monocyclic cycloalkyl group, in particular cyclopropyl.

[0068] The term "heterocyclyl" or "heterocyclohydrocarbyl" refers to a monocyclic or bicyclic ring system (3-14 membered, 7-14 membered, 3-8 membered, 3-7 membered, 4-6 membered, 5-6 membered) having, for example, 3-14 ring atoms (e.g., having 7-14, 3-8, 3-7, 4-6, or 5-6 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 C. The ring system can be saturated (which can also be understood as a corresponding "heterocycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring). Optionally, the heterocyclyl group can be benzo-fused. The "heterocyclyl" or "heterocyclohydrocarbyl" is not aromatic. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino. In some embodiments, the imino is unsubstituted (=NH), or substituted with a group recited in context. In some embodiments, the imino is substituted with -OR, wherein R is H or C 1-10 alkyl.

[0069] The heterocyclyl group can be, for example, a four-membered ring, such as an azetidinyl, an oxetanyl; or a five-membered ring, such as a tetrahydrofuranyl, a dioxolinyl, a pyrrolidinyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, an oxopyrrolidinyl, a 2-oxoimidazolidin-l-yl; or a six-membered ring, such as a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl, a 1,1-dioxo-l,2-thiazin-2-yl, or a trithianyl; or a seven-membered ring, such as a diazepinyl. The heterocyclyl group can be a bicyclic ring, without limitation, such as a five-membered and five-membered ring, such as an octahydrocyclopenta[c]pyrrolyl; or a five-membered and six-membered bicyclic ring, such as an octahydropyrrolo[l,2-b]pyrazinyl.

[0070] The heterocyclyl group can be a bicyclic ring, without limitation, such as a five-membered and five-membered ring, such as an octahydrocyclopenta[c]pyrrolyl; or a five-membered and six-membered bicyclic ring, such as an octahydropyrrolo[l,2-b]pyrazinyl.

[0071] 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.

[0072] Exemplary bicyclic heterocycles also include:

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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 cytotoxicity. Expression of iNOS is often associated with inflammatory responses.

[0078] 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.

[0079] Flavonoids are a class of compounds with a 2-phenyl chromone skeleton. For some natural products among flavonoids, the literature has reported 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.

[0080] 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.

[0081] "Normal intraocular pressure" refers to the intraocular pressure under normal physiological conditions. Correspondingly, "high intraocular pressure" refers to the intraocular pressure higher than normal, for example, "high intraocular pressure" refers to the 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 the intraocular pressure of, for example, about 20 mmHg or more. The intraocular pressure can be measured using a tonometer. High intraocular pressure can cause compression, ischemia of the retina, optic nerve, leading to retinal optic nerve damage.

[0082] As an example, the high intraocular pressure related disease includes, but is not limited to, glaucoma, optic nerve damage.

[0083] The term "optic nerve damage related disease" refers to a disease symptomatic of or caused by optic nerve damage.

[0084] As an example, the optic nerve damage related disease includes, but is not limited to, neurodegenerative eye disease, damage caused by trauma or surgery, and ocular lesions caused by diabetes, inflammation, or tumors.

[0085] The term "organic small molecule" or "low molecular weight compound" refers to a molecule of a size comparable to organic molecules commonly used in pharmaceuticals. In a particular embodiment, the organic small molecule has a size of about 100 to about 2000 Da, preferably about 200 to about 1000 Da, for example, about 200 to about 900 Da, about 200 to about 800 Da, about 200 to about 700 Da, about 200 to about 600 Da, about 200 to about 500 Da.

[0086] The pharmaceutically acceptable salts of the compounds of the present application include both acid and base addition salts. Methods for preparing the pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.

[0087] The compounds of the present application encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopically enriched compounds, metabolites, or prodrugs thereof.

[0088] The compounds of the present application can exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds. For example, the compounds of the present application can exist as E or Z isomers of carbon-carbon double bonds or carbon-nitrogen double bonds, where "E" represents the more substituted double bond in the anti- position relative to the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog convention, and "Z" represents the more substituted double bond in the syn- position relative to the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present application can also exist as mixtures of "E" and "Z" isomers. Isomeric forms also include cis- and trans- isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, such as an enantiomeric or disastereomeric mixtures. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0089] Optically pure enantiomers can be obtained from racemic mixtures by conventional methods, for example, by forming diastereomeric salts using an optically active acid or base, or by covalent diastereomeric derivatives. Mixtures of diastereomers can be separated by methods known in the art, for example, by chromatography or fractional crystallization based on the physical and / or chemical differences between the diastereomers. The optically active base or acid addition salt of the separated diastereomer is then liberated from the salt.

[0090] The compounds of the present application can exist as solvates (preferably hydrates), wherein the compound of the present application contains solvent, particularly, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0091] The present application also encompasses all possible crystalline forms or polymorphs of the compounds of the present application, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

[0092] The compounds of the present application can exist in isotopically-labeled or enriched forms, containing one or more atoms that differ from the most common or naturally occurring isotopic forms of the atoms. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, 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.

[0093] Also included within the scope of the present application are metabolites of the compounds of the present application, that is, substances formed in vivo following administration of a compound of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like.

[0094] The present application further includes within its scope prodrugs of the compounds of the present application, which are certain derivatives of the compounds of the present application that have less or no pharmacological activity as such but, when administered into or onto the body, are converted into the compounds of the present application by, for example, hydrolytic cleavage.

[0095] The term "polymorph" or "polymorphs" refers to a single polymorph or a mixture of more than one polymorph in any ratio.

[0096] The term "crystal form" or "crystal" refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0097] The term "amorphous" refers to any solid material that is not crystalline, i.e., that does not exhibit a three-dimensional order.

[0098] The term "pharmaceutically acceptable" means within the scope of sound medical judgment that contact with the tissues of a patient does not cause undue toxicity, irritation, allergic response, and the like.

[0099] 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 other components of the composition in which it is contained. The carrier would not interfere with the biological activity of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, a sweetener, a diluent, a preservative, a dye / colorant, a flavoring agent, a surfactant, a wetting agent, a dispersing agent, a disintegrant, a stabilizer, a solvent, or an emulsifying agent.

[0100] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest.

[0101] The terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" in reference to a drug, pharmaceutical agent, or active ingredient refer to a sufficient amount of the drug or agent to produce a desired effect, which is acceptable in terms of 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 testing.

[0102] The term "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) suffering from 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.).

[0103] Compounds of formula (I)

[0104] In one aspect, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I): a — F1 (I)

[0105] wherein,

[0106] "-" represents a covalent attachment;

[0107] each D1 is independently a moiety comprising a nitric oxide donor;

[0108] F1 is a moiety having a flavone structure;

[0109] a is any integer from 0 to 10.

[0110] In one embodiment, the compounds of formula (I) do not include the following structure:

[0111] wherein R is a substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted benzyl; the substituents are C1-4alkyl, C 1-4 alkoxy; n is an integer from 2 to 8.

[0112] In one embodiment, a is 1, 2, or 3, preferably 1 or 2, in particular 1. In one embodiment, F1 is 5,6,7-trihydroxy-4-oxo-2-phenyl-4H-chromen.

[0113] In one embodiment, Formula (I) has the structure of Formula (I-1) below:

[0114] wherein,

[0115] R 1 is 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 A1 R B1 , -OR A1 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -OC(=O)R A1 , -C(=O)NR A1 R B1 , -NR A1 C(=O)R B1 , -NR A1 C(=NR E1 )R B1 , -OC(=O)NR A1 R B1 , -NR A1 C(=O)OR B1 , -NR A1 C(=O)NR A1 R B1 , -NR A1 C(=S)NR A1 R B1 , -NR A1 C(=NR E1 )NR A1 R B1 , -S(=O) r R A1 , -S(=O)(=NR E1 )R B1 , -N=S(=O)R A1 R B1 , -S(=O)2OR A1 , -OS(=O)2R A1 , -NR A1 S(=O)r R B1 , A1 S(=O)(=NR E1 )R B1 , r NR A1 R B1 , E1 S(=O)(=NR A1 )NR B1 R A1 , A1 S(=O)2NR B1 R A1 , 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 X1 ;

[0116] 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 , -NR A2 C(=O)NR A2 RB2 -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 independently selected from the group consisting of R X2 ;

[0117] R 3 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 A3 R B3 , -OR A3 , -SRA3 -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 R X3substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C

[0118] R 4 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 )RB4 -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 independently selected from the group consisting of R X4 ;

[0119] R 5 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 X5 ;

[0120] 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 , -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 A6C(=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 ;

[0121] R 7 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 1-4alkylene-heteroaryl, CN, NO2, -NR A7 R B7 , -OR A7 , -SR A7 , -C(=O)R A7 , -C(=O)OR A7 , -OC(=O)R A7 , -C(=O)NR A7 R B7 , -NR A7 C(=O)R B7 , -NR A7 C(=NR E7 )R B7 , -OC(=O)NR A7 R B7 , -NR A7 C(=O)OR B7 , -NR A7 C(=O)NR A7 R B7 , -NR A7 C(=S)NR A7 R B7 , -NR A7 C(=NR E7 )NR A7 R B7 , -S(=O) r R A7 , -S(=O)(=NR E7 )R B7 , -N=S(=O)R A7 R B7 , -S(=O)2OR A7 , -OS(=O)2R A7 , -NR A7 S(=O) r R B7 , -NR A7 S(=O)(=NR E7 )R B7 , -S(=O) r NR A7 R B7 , -S(=O)(=NR E7 )NR A7 R B7 , -NR A7 S(=O)2NR A7 R B7 , -NR A7 S(=O)(=NR E7 )NR A7 R B7 and Each 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. X7 Substituents of the substituents;

[0122] R 8 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 A8 R B8 -OR A8 -SR A8 -C(=O)R A8 -C(=O)OR A8 -OC(=O)R A8 -C(=O)NR A8 R B8 -NR A8 C(=O)R B8 -NR A8 C(=NR E8 )R B8 -OC(=O)NR A8 R B8 -NR A8 C(=O)OR B8 -NR A8 C(=O)NR A8 R B8 -NR A8 C(=S)NR A8 R B8 -NR A8 C(=NR E8 )NR A8 R B8 -S (=O) r R A8 -S(=O)(=NR) E8 )R B8 -N = S(=O)R A8 R B8 -S(=O)2OR A8 -OS(=O)2R A8 -NR A8S(=O) r R B8 , -NR A8 S(=O)(=NR E8 )R B8 , -S(=O) r NR A8 R B8 , -S(=O)(=NR E8 )NR A8 R B8 , -NR A8 S(=O)2NR A8 R B8 , -NR A8 S(=O)(=NR E8 )NR A8 R B8 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 X8 ;

[0123] R 9 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 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)NRA9 R B9 -NR A9 C(=S)NR A9 R B9 -NR A9 C(=NR E9 )NR A9 R B9 -S (=O) r R A9 -S(=O)(=NR) E9 )R B9 -N = S(=O)R A9 R B9 -S(=O)2OR A9 -OS(=O)2R A9 -NR A9 S(=O) r R B9 -NR A9 S(=O)(=NR E9 )R B9 -S (=O) r NR A9 R B9 -S(=O)(=NR) E9 )NR A9 R B9 -NR A9 S(=O)2NR A9 R B9 -NR A9 S(=O)(=NR E9 )NR A9 R B9 and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is unsubstituted or is selected independently from at least one of the following groups: R0. X9 Substituents of the substituents;

[0124] R 10 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 A10 R B10 -ORA10 -SR A10 -C(=O)R A10 -C(=O)OR A10 -OC(=O)R A10 -C(=O)NR A10 R B10 -NR A10 C(=O)R B10 -NR A10 C(=NR E10 )R B10 -OC(=O)NR A10 R B10 -NR A10 C(=O)OR B10 -NR A10 C(=O)NR A10 R B10 -NR A10 C(=S)NR A10 R B10 -NR A10 C(=NR E10 )NR A10 R B10 -S(=O) r R A10 -S(=O)(=NR E10 )R B10 -N=S(=O)R A10 R B10 -S(=O)2OR A10 -OS(=O)2R A10 -NR A10 S(=O) r R B10 -NR A10 S(=O)(=NR E10 )R B10 -S(=O) r NR A10 R B10 -S(=O)(=NR E10 )NR A10 R B10 -NR A10 S(=O)2NR A10 R B10 -NR A10 S(=O)(=NR E10 )NR A10 R B10 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 X10 ;

[0125] or "R 1 and R 2 " or "R 1 and R 4 " or "R 2 and R 3 " or "R 6 and R 7 " or "R 7 and R 8 " or "R 8 and R 9 " or "R 9 and R 10 ", 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 ;

[0126] each R A1 , R A2 , R A3 , R A4 , R A6 , R A7 , R A8 , R A9 , R A10 , R B1 , R B2 , R B3 , R B4 , R B6 , R B7 , R B8 , R B9 and R B10 are 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- 4alkylene-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 X ;

[0127] or "R A1 and R B1 " or "R A2 and R B2 " or "R A3 and R B3 " or "R A4 and R B4 " or "R A6 and R B6 " or "R A7 and R B7 " or "R A8 and R B8 or "R A9 and R B9 " or "R A10 and R B10 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 selected from the group consisting of R X ;

[0128] each R E1 , R E2 , R E3 , R E4 , R E6 , R E7 , R E8 , R E9 and R E10 is independently selected from the group consisting of hydrogen, C 1-10 1-6 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 X ;

[0129] 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-(CRc R d ) t -, -(CR c R d ) u -NR 11 -(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 11 -(CR c R d ) t -, -(CR c R d ) u -OC(=O)-(CR c R d ) t -, -(CR c R d ) u -NR 11 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 11 -(CR c R d ) t -, -(CR c Rd ) u -OC(=S)-(CR c R d ) t -、-(CR c R d ) u -NR 11 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 11 -(CR c R d ) t -、-(CR c R d ) u -OS(=O) r -(CR c R d ) t -、-(CR c R d ) u -NR 11 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;

[0130] R 11 Selected from hydrogen and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X11 Substituents of the substituents;

[0131] 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 ;

[0132] each M is independently selected from the group consisting of NO donors; NO represents nitric oxide;

[0133] each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 and R X11 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, 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 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;

[0134] 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 R Y ;

[0135] 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 ;

[0136] each R c1 and R d1 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R Y ;

[0137] 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 ;

[0138] each Re1 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 ;

[0139] 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);

[0140] each r is independently selected from the group consisting of 1 and 2;

[0141] each t is independently selected from an integer between 0 and 10;

[0142] each u is independently selected from an integer between 0 and 10;

[0143] each k is independently selected from the group consisting of 1, 2, 3, and 4;

[0144] each q is independently selected from the group consisting of 0, 1, 2, and 3;

[0145] the total number of M in the molecule is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0146] In one embodiment, each R A1 , R A2 , R A3 , R A4 , R A6 , R A7 , R A8 , R A9 , R A10 , R B1 , R B2 , R B3 , R B4 , R B6 , R B7 , R B8 , R B9 and R B10 is independently selected from 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 A1 , R A2 , R A3 , R A4 , R A6 , R A7 , R A8 , R A9 , R A10 , R B1 , R B2 , R B3 , R B4 , R B6 , R B7 , R B8 , R B9 and R B10 is independently selected from hydrogen, methyl and

[0147] In one embodiment, each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 and R X11 is independently selected from halogen, C 1-10 alkyl, CN, NO2, -(CR c1 R d1 ) u NR a1 R b1 , -(CRc1 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)OR b1 、-(CR c1 R d1 ) u NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) u S(=O) r R b1 、-(CR c1 R d1 ) u S(=O)2OR b1 、-(CR c1 R d1 ) u OS(=O)2R b1 、-(CR c1 R d1 ) u NR a1 S(=O) r R b1 、-(CR c1 Rd1 ) u S(=O) r NR a1 R b1 and preferably selected from the group consisting of 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 by at least one substituent independently selected from the group consisting of R Y .

[0148] In one embodiment, each R Y is independently selected from the group consisting of 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.

[0149] In one embodiment, u is 0. In one embodiment, t is 0.

[0150] In one embodiment, R 1 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -NR A1 R B1 , -OR A1 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -OC(=O)R A1 , -C(=O)NR A1 R B1 , -NR A1 C(=O)R B1 , -OC(=O)NR A1 R B1 , -NR A1 C(=O)OR B1 , -NR A1 C(=O)NR A1 R B1 , -S(=O) r R A1 , -S(=O)2OR A1 , -OS(=O)2R A1 , -NR A1 S(=O) r R B1 , -S(=O) r NR A1 R B1 and preferably selected from the group consisting of hydrogen, -OR A1 , -OC(=O)R A1 , -OS(=O)2R A1 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 X1 In one embodiment, R 1 is selected from the group consisting of hydrogen, -OR A1 and In particular In one embodiment, each R A1 is hydrogen.

[0151] In one embodiment, each R A1 is methyl.

[0152] In one embodiment, R 2 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C3-10 cycloalkyl, heterocyclyl, -C(=O)R 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 R B2 , -S(=O) r NR A2 R B2 and preferably selected from the group consisting of hydrogen, -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 selected from the group consisting of hydrogen, -OR A2 and preferably selected from the group consisting of -OR A2 and especially -OR A2 In one embodiment, each R A2 is hydrogen. In one embodiment, each R A2 is methyl.

[0153] In one embodiment, R 3 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C(=O)R 1-4 alkylene-C 3-10cycloalkyl, 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, -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 selected from the group consisting of hydrogen, -OR A3 and preferably selected from the group consisting of -OR A3 and especially -OR A3 In one embodiment, each R A3 is hydrogen. In one embodiment, each R A3 is methyl.

[0154] In one embodiment, (1) R 1 is R 2 and R 3 is -OH, or (2) R 2 is R 1 and R 3 is -OH, or (3) R 1 and R 2 are each independently R 3 is -OH, or (4) R 1 , R 2 and R 3 are each independently

[0155] In one embodiment, R 4 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 A4 R B4 , -OR A4 , -SR A4 , -C(=O)R A4 , -C(=O)OR A4 , -OC(=O)R A4 , -C(=O)NR A4 R B4 , -NR A4 C(=O)R B4 , -OC(=O)NR A4 R B4 , -NR A4 C(=O)OR B4 , -NR A4 C(=O)NR A4 R B4 , -S(=O) r R A4 , -S(=O)2OR A4 , -OS(=O)2R A4 , -NR A4 S(=O) r R B4 , -S(=O) r NR A4 R B4 and preferably selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A4 R B4 , -OR A4 , -OC(=O)R A4 , -OS(=O)2R A4 and more preferably selected from hydrogen, -OR A4 , -OC(=O)R A4 , -OS(=O)2R A4 , and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X4 In one embodiment, R 4 is hydrogen.

[0156] In one embodiment, R 5 is hydrogen.

[0157] 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)2R A6 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 X6 In one embodiment, R 6 is hydrogen.

[0158] In one embodiment, R 7 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 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, halogen, C 1-10 alkyl, CN, NO2, -NR A7 R B7 , -OR A7 , -OC(=O)R A7 , -OS(=O)2R A7 and more preferably selected from the group consisting of hydrogen, -OR A7 , -OC(=O)R A7 , -OS(=O)2RA7 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X7 In one embodiment, R 7 is hydrogen.

[0159] In one embodiment, R 8 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 A8 R B8 , -OR A8 , -SR A8 , -C(=O)R A8 , -C(=O)OR A8 , -OC(=O)R A8 , -C(=O)NR A8 R B8 , -NR A8 C(=O)R B8 , -OC(=O)NR A8 R B8 , -NR A8 C(=O)OR B8 , -NR A8 C(=O)NR A8 R B8 , -S(=O) r R A8 , -S(=O)2OR A8 , -OS(=O)2R A8 , -NR A8 S(=O) r R B8 , -S(=O) r NR A8 R B8 and preferably selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A8 R B8 , -OR A8 , -OC(=O)R A8 , -OS(=O)2R A8 and more preferably selected from hydrogen, -OR A8 , -OC(=O)R A8 , -OS(=O)2R A8 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 X8 In one embodiment, R 8 is hydrogen.

[0160] In one embodiment, R 9 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 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)OR B9 , -NR A9 C(=O)NR A9 R B9 , -S(=O) r R A9 , -S(=O)2OR A9 , -OS(=O)2R A9 , -NR A9 S(=O) r R B9 , -S(=O) r NR A9 R B9 and preferably selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A9 R B9 , -OR A9 , -OC(=O)R A9 , -OS(=O)2R A9 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 X9 In one embodiment, R 9is hydrogen.

[0161] In one embodiment, R 10 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 A10 R B10 , -OR A10 , -SR A10 , -C(=O)R A10 , -C(=O)OR A10 , -OC(=O)R A10 , -C(=O)NR A10 R B10 , -NR A10 C(=O)R B10 , -OC(=O)NR A10 R B10 , -NR A10 C(=O)OR B10 , -NR A10 C(=O)NR A10 R B10 , -S(=O) r R A10 , -S(=O)2OR A10 , -OS(=O)2R A10 , -NR A10 S(=O) r R B10 , -S(=O) r NR A10 R B10 and preferably selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A10 R B10 , -OR A10 , -OC(=O)R A10 , -OS(=O)2R A10 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 X10 In one embodiment, R 10 is hydrogen.

[0162] In one embodiment, R 6 , R 7 , R 8 , R 9and at least two of R 10 are hydrogen.

[0163] In one embodiment, R 6 , R 7 , R 8 , R 9 , R 10 are hydrogen.

[0164] In one embodiment, each L is independently selected from 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 11 -(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 11 -(CR c R d ) t -,(CR c R d ) u -OC(=O)-(CR c R d ) t -,(CR c R d ) u -NR 11 C(=O)-(CR c R d ) t - and C1-4 alkylene, wherein alkylene is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y 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 .

[0165] 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 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y .

[0166] In one embodiment, represents the attachment of the NO donor to the rest of the molecule via a linker; wherein, -(L) k - is a linker that is attached to one M, and to q M; the brackets indicate that M can be attached at any position of the linker, as long as a stable chemical structure is formed. may be attached to the rest of the molecule via, for example, a C-C bond, an amide bond, an ester bond, or an ether bond, in particular via an ester bond.

[0167] When calculating the value of q, the number of M is included when R c or R d is M or -C 1-4 alkylene-M. In one embodiment, q is 0, may be represented as -(L) k -M.

[0168] In one embodiment, the structure of -(L) k is selected from the group consisting of -(CH2) j -, -(CH2) j1 -O-(CH2) j2 -, -(CH2) j1 -​​​​​-OC(=O)-(CH2) j2 -, -(CH2) j1 -C(=O)-(CH2) j2 -, -(CH2) j1 -OC(=O)-(CH2) i -O-(CH2) j2 -, -(CH2) j1 -C(=O)-(CH2) i -O-(CH2) j2 -, -(CH2) j1 -OC(=O)-(CH2) i1 -O-(CH2) i2 -O-(CH2) j2 - and -(CH2) j1 -C(=O)-(CH2) i1 -O-(CH2) i2 -O-(CH2) j2 -; wherein i, i1and i2are integers from 1 to 10, in particular 1; j, j1and j2are each independently integers from 0 to 10.

[0169] In one embodiment, the structure of -(L) k - is selected from -(CH2) j -, -O-, -O-CH2-, wherein j is an integer from 0 to 10.

[0170] In one embodiment, the structure of -(L) k - is selected from -(CH2) j -, wherein j is an integer from 0 to 10.

[0171] In one embodiment, each NO donor is independently selected from the group consisting of nitrate esters, furazan nitroxides, azo oxides, sulfonitrites and sydnone imines. In one embodiment, the azo oxide is an azoium diol salt.

[0172] In one embodiment, M is wherein

[0173] R 12 is -NR A12 R B12 ; R B12 and R B12 are independently selected from the group consisting of hydrogen, C 1-10 alkyl and C2-10 alkenyl, wherein each alkyl and alkenyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X

[0174] or "R A12 and R B12 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

[0175] In one embodiment, each R X is independently selected from the group consisting of halogen, C 1-10 alkyl, -C(=O)-C 1-10 alkyl and -C(=O)O(C 1- 10 alkyl).

[0176] In one embodiment, M is wherein R 13 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, -OH and -O(C 1-10 alkyl).

[0177] In one embodiment, M is wherein R 14 and R 15 are independently selected from C 1-10 alkyl, R 16 is selected from C 1-10 alkyl, -C(=O)-C 1-10 alkyl, -C(=O)O(C 1-10 alkyl), -C(=O)NH(C 1-10 alkyl) and -C(=O)S(C 1- 10 alkyl).

[0178] In one embodiment, each M is independently selected from the group consisting of -ONO2, preferably from the group consisting of -ONO2, wherein R is CN or phenylsulfonyl, wherein the phenyl ring of the phenylsulfonyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R Y

[0179] In one embodiment, each M is the same when multiple M are present. In another embodiment, each M can be the same or different when multiple M are present.

[0180] In one embodiment, the structure of -CH2)​​​j -ONO2, preferably selected from -(CH2) j -ONO2,

[0181] In one embodiment, by an amide or ester or ether bond to other parts of the molecule, in particular by an ester bond.

[0182] In one embodiment, formula (I-1) has the structure of formula (I-2-1), (I-2-2) or (I-2-3) as follows:

[0183] wherein,

[0184] L 1 , L 2 and L 3 are independently selected from L;

[0185] M 1 , M 2 and M 3 are independently selected from M;

[0186] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , L, M are as defined in formula (I-1).

[0187] In another embodiment, formula (I-1) has the structure of formula (I-3) as follows:

[0188] wherein,

[0189] L 1 and L 2 are independently selected from L;

[0190] M 1 and M 2 are independently selected from M;

[0191] R 3 , R 4 , R 5 , R 6 , R 7 , R 8R 9 R 10 L, M are as defined in formula (I-1).

[0192] In another embodiment, formula (I-1) has the structure of formula (I-4):

[0193] wherein,

[0194] L 1 L 2 and L 3 are independently selected from L;

[0195] M 1 M 2 and M 3 are independently selected from M;

[0196] R 4 R 5 R 6 R 7 R 8 R 9 R 10 L, M are as defined in formula (I-1).

[0197] In one embodiment, in formula (I-2-1), (I-2-2), (I-2-3), (I-3) and (I-4), -L 1 -M 1 has the structure selected from

[0198] In one embodiment, in formula (I-2-1), (I-2-2), (I-2-3), (I-3) and (I-4), -L 2 -M 2 has the structure

[0199] In one embodiment, in formula (I-2-1), (I-2-2), (I-2-3), (I-3) and (I-4), -L 3 -M 3 has the structure

[0200] In one embodiment, formula (I-2-1) has the structure of formula (I-5-1):

[0201] wherein,

[0202] L 1 and M 1 are as defined in formula (I-2-1).

[0203] In an embodiment, Formula (I-2-2) has the structure of Formula (I-5-2) as follows:

[0204] wherein,

[0205] L 2 and M 2 are as defined in Formula (I-2-2).

[0206] In an embodiment, Formula (I-2-3) has the structure of Formula (I-5-3) as follows:

[0207] wherein,

[0208] L 3 and M 3 are as defined in Formula (I-2-3).

[0209] In an embodiment, Formula (I-3) has the structure of Formula (I-6) as follows:

[0210] wherein,

[0211] L 1 , L 2 , M 1 and M 2 are as defined in Formula (I-3).

[0212] In an embodiment, Formula (I-4) has the structure of Formula (I-7) as follows:

[0213] wherein,

[0214] L 1 , L 2 , L 3 , M 1 , M 2 and M 3 are as defined in Formula (I-4).

[0215] In an embodiment, the present application provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0216] Pharmaceutical compositions and pharmaceutical formulations

[0217] 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, isotopologue, metabolite, or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0218] 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.

[0219] 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.

[0220] Therapeutic methods and uses

[0221] 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.

[0222] 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 for 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, optionally in combination with a second therapeutic agent.

[0223] 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 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.

[0224] 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, optionally in combination with a second therapeutic agent.

[0225] In an embodiment, the disease, disorder, or condition is selected from the group consisting of glaucoma, neurodegenerative ocular diseases, and optic nerve damage.

[0226] In one embodiment, the disease, disorder or condition is selected from the group consisting of glaucoma, age-related macular degeneration, diabetic retinopathy, cataract, uveitis, keratitis, high intraocular pressure induced by retinal vascular occlusion, and optic nerve damage.

[0227] Combination therapy

[0228] The compound of the present application or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present application can be used alone or in combination with other therapeutic agents.

[0229] For example, the use of an adjuvant can enhance the therapeutic effect of the compound of the present application (e.g., the therapeutic benefit of the adjuvant alone is minimal, but when used in combination with another drug, the therapeutic benefit to the individual is enhanced), or, for example, the use of the compound of the present application in combination with another therapeutic agent that is also therapeutically beneficial can enhance the therapeutic benefit to the individual. For example, when treating glaucoma, the use of the compound of the present application in combination with another drug that treats glaucoma can enhance the clinical benefit. Therapies that can be combined include, but are not limited to, physical therapy, psychological therapy, small molecule targeted therapeutic agents (e.g., kinase inhibitors), etc. Regardless of the disease, disorder or condition, the therapeutic benefit to the individual from the two therapies should have an additive or synergistic effect. Beneficial effects

[0230] The present application provides novel small molecule compounds containing a nitric oxide (NO) donor that exhibit outstanding intraocular pressure-lowering activity and protection of optic nerve cells.

[0231] Therefore, the compound of the present application is capable of treating or preventing high intraocular pressure-related diseases and optic nerve damage-related diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy, cataract, uveitis, keratitis, high intraocular pressure induced by retinal vascular occlusion, and optic nerve damage, and has good prospects for development as a drug.

[0232] The compound of the present application achieves at least one of the following technical effects:

[0233] (1) high activity or strong protective effect on target cells or tissues.

[0234] (2) excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0235] (3) excellent pharmacokinetic properties (e.g., good corneal absorption and / or other route of absorption, good stability in plasma, cornea and / or aqueous humor, appropriate half-life and duration of action).

[0236] (4) excellent safety (fewer side effects, wider therapeutic window), etc.

[0237] (5) lower risk of resistance (less likely to develop resistance), etc.

[0238] Examples

[0239] 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 used 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.

[0240] Instruments, materials and reagents

[0241] Unless otherwise specified, the instruments and reagents used in the examples are commercially available. The reagents can be used directly without further purification.

[0242] Compound B: CAS No. 491-67-8, available from companies such as Merck, etc. The structure is

[0243] LCMS: Shimadzu LC20

[0244] Semi-preparative HPLC: Column: F-Prepulite XP tC 18 40*200mm*7mm; Mobile phase: [water(0.225%FA)-ACN]

[0245] NMR: BRUKER 400 MHZ

[0246] Intraocular pressure measurement was performed using tonometer Icare TONOVET Plus.

[0247] Synthetic scheme

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] Synthetic scheme 1

[0254] The following examples are provided so 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.

[0255] Example 1 5,7-Dihydroxy-4-oxo-2-phenyl-4H-chromen-6-yl 6-(nitrooxy)hexanoate (Compound 001)

[0256] 1.1 Synthesis of intermediate L1-2

[0257] To a solution of methyl 6-hydroxyhexanoate (100 g, 684.1 mmol) in dichloromethane was added concentrated nitric acid (2.02 eq), concentrated sulfuric acid (2.0 eq), and the reaction was continued for 2 hours in an ice water bath. The reaction mixture was purified to give intermediate L1-2 (15.3 g, 77.3 mmol) as a colorless or yellow oil.

[0258] 1.2 Synthesis of intermediate L1-3

[0259] Intermediate L1-2 (123 g, 643.4 mmol) was dissolved in a mixture of tetrahydrofuran and water, and LiOH (5.0 eq) was added and reacted for 12 h to obtain intermediate L1-3 (1.3 g, 7.34 mmol).

[0260] 1.3 Synthesis of compound 001

[0261] Intermediate L1-3 (1.3 g, 7.34 mmol) was reacted with compound B (1.0 eq), EDCI, DMAP in a mixed solvent of DCM and DMF (1:1) to obtain compound 001 (1.7667 g, 4.12 mmol). The yield was 56.13%, and the purity was 99.66%. The results of HSQC, HMBC, and NOE spectrum analysis proved the connection position of intermediate L1-3.

[0262] LCMS: ESI-MS m / z 430.1 [M+H] + .

[0263] 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.98 (s, 1H), 11.28 (s, 1H), 8.18-8.00 (m, 2H), 7.67-7.56 (m, 3H), 7.02 (s, 1H), 6.69 (s, 1H), 4.54 (t, J = 6.4 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.77-1.65 (m, 4H), 1.54-1.43 (m, 2H).

[0264] Example 2 5-Hydroxy-4-oxo-2-phenyl-4H-chromen-6,7-diyl bis(6-(nitrooxy)hexanoate) (compound 002)

[0265] 2.1 Synthesis of intermediate L2-2

[0266] To a solution of methyl 6-hydroxyhexanoate (100 g, 684.1 mmol) in dichloromethane, concentrated nitric acid (2.02 eq) and concentrated sulfuric acid (2.0 eq) were added, and the reaction was continued for 2 h in an ice water bath. The reaction system was purified to obtain intermediate L2-2 (15.3 g, 77.3 mmol) as a colorless or yellow oil.

[0267] 2.2 Synthesis of intermediate L2-3

[0268] Intermediate L2-2 (123 g, 643.4 mmol) was dissolved in a mixture of tetrahydrofuran and water, and LiOH (5.0 eq) was added and reacted for 12 h to obtain intermediate L2-3 (200 mg, 1.13 mmol).

[0269] 2.3 Synthesis of compound 002

[0270] Intermediate L2-3 (200 mg, 1.13 mmol) was reacted with compound B (1.0 eq), EDCI (3.5 eq), DMAP (1.0 eq) in a mixed solvent of DMF and DCM (1:1) at room temperature for 12 h. Purification by column chromatography gave compound 002 (60.2 mg, 0.11 mmol). Yield 9.05%, purity 95%.

[0271] LCMS: ESI-MS m / z 589.2 [M+H] + .

[0272] 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.05 (s, 1H), 8.25-7.99 (m, 2H), 7.73-7.52 (m, 3H), 7.36-6.70 (m, 2H), 4.60-4.49 (m, 4H), 2.72-2.59 (m, 4H), 1.77-1.58 (m, 8H), 1.56-1.38 (m, 4H).

[0273] Example 3 4-Oxo-2-phenyl-4H-chromen-5,6,7-triyl tris(6-(nitrooxy)hexanoate) (compound 003)

[0274] 3.1 Synthesis of compound 003

[0275] Compound 002 (470 mg, 0.80 mmol) was reacted with EDCI, DMAP (0.2 eq) in a mixed solvent (DCM:DMF = 1:1) for 12 h. Purification by semi-preparative HPLC gave compound 003 (348 mg, 0.46 mmol) with a yield of 99.02% and a purity of 93%.

[0276] LCMS: ESI-MS m / z 748.2 [M+H] + .

[0277] 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.09 (d, J = 6.8 Hz, 2H), 7.85 (s, 1H), 7.60 (d, J = 8.0 Hz, 3H), 6.96 (s, 1H), 4.57-4.52 (m, 6H), 2.71-2.65 (m, 6H), 1.76-1.66 (m, 12H), 1.50-1.41 (m, 6H).

[0278] Example 4 5,7-Dihydroxy-4-oxo-2-phenyl-4H-chromen-6-yl 2-(4- (nitrooxy)butoxy)acetate (Compound 004)

[0279] 4.1 Synthesis of intermediate L4-2

[0280] 1,4-Butanediol (10 g, 111 mmol) was reacted with ethyl bromoacetate (1.0 eq), NaH (1.0 eq) in tetrahydrofuran (ice water bath), and intermediate L4-2 (3.1 g, 17.6 mmol) was obtained by purification.

[0281] 4.2 Synthesis of intermediate L4-3

[0282] To a solution of intermediate L4-2 (3.1 g, 17.6 mmol) in dichloromethane was added concentrated nitric acid (4.0 eq), concentrated sulfuric acid (3.0 eq), and intermediate L4-3 (3.4 g, 15.37 mmol) was obtained by purification under low temperature (-5-5 °C) conditions.

[0283] 4.3 Synthesis of intermediate L4-4

[0284] Intermediate L4-3 (3.4 g, 15.37 mmol) was dissolved in a THF / H2O mixed solvent, and hydrolysis was performed by adding LiOH (1.0 eq), and intermediate L4-4 (2.1 g, 10.88 mmol) was obtained by purification.

[0285] 4.4 Synthesis of compound 004

[0286] Intermediate L4-4 (2.1 g, 10.88 mmol) was reacted with compound B (1.0 eq), EDCI in a DMF and DCM (1:1) mixed solvent, and compound 004 (1.07 g, 2.41 mmol) was obtained by purification with a yield of 22.1% and a purity of 97.1%. The results of HSQC, HMBC, and NOE spectrum analysis confirmed the connection position of intermediate L4-4.

[0287] LCMS: ESI-MS m / z 446.1 [M+H] + .

[0288] 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.04 (s, 1H), 11.35 (br s, 1H), 8.17-8.02 (m, 2H), 7.66-7.56 (m, 3H), 7.03 (s, 1H), 6.71 (s, 1H), 4.60-4.52 (m, 2H), 4.44 (s, 2H), 3.61 (t, J = 6.0 Hz, 2H), 1.82-1.72 (m, 2H), 1.69-1.61 (m, 2H).

[0289] Example 5 4-(2-(2-((5,7-dihydroxy-4-oxo-2-phenyl-4H-chromen-6-yl)oxy)-2- oxooxyethoxy)ethoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide (Compound 005)

[0290] 5.1 Synthesis of intermediate L5-2

[0291] 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (3.0 g, 8.19 mmol) was dissolved in THF / H2O and reacted with tert-butyl acetate glycol (3.0 eq), NaOH (10.0 eq) at room temperature for 3 h. The crude intermediate L5-2 was obtained.

[0292] 5.2 Synthesis of intermediate L5

[0293] To the crude intermediate L5-2, TFA was added and reacted for 1 h. Purification gave intermediate L5 (1.0 g, 2.91 mmol).

[0294] 5.3 Synthesis of Compound 005

[0295] Intermediate L5 (1.0 g, 2.91 mmol) was dissolved in DCM / DMF and reacted with compound B (1.1 eq), HOBT (0.5 eq) and EDCI (1.5 eq) at room temperature. Compound 005 (938.02 mg, 1.57 mmol) was obtained with a yield of 53.95% and a purity of 99.2%. HSQC, HMBC, NOE spectral analysis results proved the connection position of intermediate L5.

[0296] LCMS: ESI-MS m / z 597.1 [M+H]+ .

[0297] 1 H NMR (DMSO-d6, 400 MHz): d (ppm) 13.07 (s, 1H), 11.27-11.61 (m, 1H), 8.07-8.15 (m, 2H), 8.04 (dd, J = 8.40, 1.13 Hz, 2H), 7.87 (s, 1H), 7.67-7.76 (m, 2H), 7.55-7.66 (m, 3H), 7.04 (s, 1H), 6.73 (s, 1H), 4.57-4.66 (m, 4H), 3.97-4.04 (m, 2H).

[0298] Example 6 (Z)-2-(2-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-2- oxooxy)-1-(pyrrolidin-1-yl)azo 1-oxide (Compound 006)

[0299] 6.1 Synthesis of intermediate L6-2

[0300] 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 autoclave, 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 L6-2.

[0301] 6.2 Synthesis of intermediate L6-3

[0302] Stir the intermediate L6-2 obtained from 6.1 with methyl bromoacetate (1.2 eq) at room temperature to obtain intermediate L6-3.

[0303] 6.3 Synthesis of intermediate L6-4

[0304] Hydrolyze the intermediate L6-3 obtained from 6.2 using LiOH. Finally obtain the purified intermediate L6-4 (13.7 g, 72.5 mmol).

[0305] 6.4 Synthesis of Compound 006

[0306] Intermediate L6-4 (1 g, 5.3 mmol) was reacted with compound B (1.0 eq), EDCI, DMAP in mixed solvent of DCM and DMF (1:1). Purification gave compound 006 (1.24 g, 2.8 mmol). Yield 52.83%, purity 97.78%.

[0307] LCMS: ESI-MS m / z 442.1 [M+H] + .

[0308] 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.30 (s, 1H), 8.09-7.98 (m, 2H), 7.58-7.46 (m, 3H), 6.90 (s, 1H), 6.71 (s, 1H), 4.95 (s, 2H), 3.68-3.53 (m, 4H), 2.01-1.83 (m, 4H).

[0309] Example 7 3-cyano-4-((2-((5,6-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-2- oxooxyethyl)methyl)-1,2,5-oxadiazole 2-oxide (compound 007)

[0310] 7.1 Synthesis of intermediate L7-2

[0311] To a solution of 3-carbamoyl-4-hydroxymethyl-1,2,5-oxadiazole-2-oxide (500 mg, 3.14 mmol) in dichloromethane was added di-tert-butyl dicarbonate (1.2 eq) and DMAP (0.5 eq) and reacted at room temperature for 1 h to give intermediate L7-2 (450 mg, 1.737 mmol).

[0312] 7.2 Synthesis of intermediate L7-3

[0313] Intermediate L7-2 (450 mg, 1.737 mmol) was mixed with tert-butyl 2-bromoacetate (1.5 eq), potassium carbonate (3 eq) in sufficient amount of tetrahydrofuran and reacted at room temperature for 12 h. Purification gave intermediate L7-3 (171 mg, 0.46 mmol

[0314] 7.3 Synthesis of intermediate L7-4

[0315] Intermediate L7-3 was added to a mixed solvent (TFA: DCM = 1:1) and stirred at room temperature for 2 h to remove the tert-butoxycarbonyl group. Purification gave intermediate L7-4.

[0316] 7.4 Synthesis of intermediate L7-5

[0317] Intermediate L7-4 was dissolved in dichloromethane and reacted with DIEA (2.5 eq), TFAA (2.0 eq) in an ice water bath for 1 hour. Purification gave intermediate L7-5.

[0318] 7.5 Synthesis of compound 007

[0319] Intermediate L7-5 (10 mg, 0.05 mmol) was reacted with compound B (1.0 eq), EDCI, DMAP in a mixed solvent of DCM and DMF (1:1). Purification gave compound 007 (11.85 mg, 0.026 mmol). Yield 52.1%, purity 97.56%.

[0320] LCMS: ESI-MS m / z 452.0 [M+H] + .

[0321] 1 H NMR (DMSO-d6, 400 M Hz): δ (ppm) 9.30 (s, 1H), 7.98-8.09 (m, 2H), 7.46-7.58 (m, 3H), 6.95 (s, 1H), 6.71 (s, 1H), 4.60 (s, 2H), 4.27 (s, 2H).

[0322] Protective effect of compound of effect example 1 on retinal nerve cell injury caused by NMDA

[0323] To verify the protective effect of the compound on the optic nerve cells, the following test was performed using retinal ganglion cells (RGC).

[0324] N-methyl-D-aspartate (NMDA) can activate NMDA receptors on the cell membrane of RGC, trigger intracellular calcium aggregation, further activate intracellular calcium cascade, and induce glutamate excitotoxicity. Glutamate excitotoxicity is the last pathway of the nerve death process of various neuronal degenerative diseases. At present, NMDA is often used to induce glutamate excitotoxicity and oxidative stress, causing apoptosis of in vitro cultured retinal nerve cells. This apoptosis model is used to study the neuroprotective effect of drugs.

[0325] 1.1 Cell culture: RGC-5 cells (Guangzhou Jinnyou Biological Technology Co., Ltd.) were placed in DMEM medium containing 10% fetal bovine serum, cultured in a 5% CO2, 37°C incubator, and passaged once every 2-3 days by 0.25% trypsin digestion.

[0326] 1.2 MTT colorimetric method for determining cell survival rate:

[0327] (1) RGC-5 cells (1 x 10 5 cells / mL) were inoculated into a 96-well culture plate, and after adhering, the cells were divided into 8 groups: NMDA injury group (negative control group), blank control group, positive control group, and compound 001, 004, 005, 006, 007 treatment groups. Each group had 6 replicate wells.

[0328] (2) For compound 001, 004, 005, 006, 007 treatment groups, each group was divided into 3 subgroups and treated with the following concentrations of compounds: 0.1 μM, 1 μM, 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.

[0329] (3) The culture plate was placed in a 5% CO2, 37°C cell incubator for 12 h.

[0330] (4) Discard the culture medium and rinse with phosphate buffered saline (PBS) (Adamas life) for 3 times. Except for the blank control group, 10 μM glycine and 10 μM NMDA (Adamas life) were added to the rest of the groups for 30 min, and then rinsed with PBS for 3 times before returning to the original culture medium environment.

[0331] (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 marker to calculate the cell survival rate.

[0332] 1.3 Hoechst staining:

[0333] (1) The cells were grouped and treated according to the methods similar to steps (1) to (4) of 1.2 above, but the RGC-5 cells were cultured on cover slips, and the compound 001, 004, 005, 006, 007 treatment groups were treated with 1 μM of the compounds, instead of the three concentrations described in 1.2 above.

[0334] (2) with polyphosphorous acid (4%) fixation, PBS washing 3 times, then adding hoechst 33258 (Sigma-Aldrich) working solution staining 5 min, rinsing 3 times, then mounting, and observing the results under a fluorescence microscope. Under the fluorescence microscope, the living cells are dyed into homogeneous blue fluorescence, and the apoptotic cells are bright blue granular blocks, and the nucleus is pyknosis. Randomly select 6 fields to calculate the percentage of apoptosis (percentage of apoptosis = number of apoptotic nuclei / total number of nuclei x 100%).

[0335] 1.4 Data analysis:

[0336] The results of MTT colorimetric method showed that, compared with the negative control group, the cell survival rate of each subgroup in the positive control group and the compound 001, 004, 005, 006, 007 treatment groups was significantly improved (* represents P<0.05, ** represents P<0.01), as shown in Figures 1 to 5.

[0337] The results of Hoechst staining showed that the percentage of apoptotic cells in the negative control group was (39.88±0.76)%, while that in the blank control group was (2.32±0.62)%, and the difference was statistically significant (P<0.05); the percentage of cell apoptosis in the compound 001, 004, 005, 006, 007 treatment groups and the positive control group was (10.84±1.33)%, (11.46±1.35)%, (10.87±0.93)%, (11.24±1.51)%, (11.69±1.05)%, and (10.92±1.13)%, respectively, which were significantly lower than that in the negative control group (P<0.05). See Table 1.

[0338] Table 1 Effect of compounds on the percentage of retinal nerve cell apoptosis caused by NMDA

[0339] Example 2 Effect of compounds on the intraocular pressure of beagle dogs

[0340] 1. Compound 004, 005, 006, 007 was dissolved in solvent (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.

[0341] 2. Beagle dogs with a body weight of about 10-14 kg and an age of about 9-21 months (Jiangsu Yadong Experimental Animal Research Institute Co., Ltd.) were selected (3 dogs in each group).

[0342] 3. Before the start of the test, all animals were subjected to physical examination, and the anterior segment and fundus were normal, so as to confirm the health of the animals and their suitability for the study. Animals that failed the physical examination were excluded or replaced before the start of the test.

[0343] 4. At least 4 weeks of behavioral and conscious ocular pressure training is required before the test until stable IOP values are obtained.

[0344] 5. In the experimental administration phase, the following scheme is used for grouping: 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 004, 005, 006, 007 treatment groups (administered 0.25% compound solution). The administration route is conjunctival sac eye drop administration, and the administration volume is 50 μL / eye / time, twice a day at about 10:00 and 17:00, for 15 consecutive days. The first day of administration is recorded as Day 1. When administering, gently pull open the eyelid to avoid touching the eyeball surface, use a pipette to suck 50 μL of solvent or test product and gently drop it into the conjunctival sac, and gently close the eyelid several times.

[0345] 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; see Table 2 and Figure 6 for detailed test data.

[0346] The change (%) in IOP is calculated using the following formula:

[0347] The percentage of IOP reduction (△IOP%) = [IOP (treatment group) - IOP (baseline)] / IOP (baseline)*100

[0348] Table 2 Effect of compounds on the intraocular pressure of beagle dogs T. Test: compared with the vehicle group, *** indicates p≤0.001.

[0349] 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 004, 005, 006, 007 treatment groups were significantly different from that of the control group.

[0350] Effect Example 3 Effect of compounds on the intraocular pressure of rats

[0351] 1. Compound 001, 005, 007 was dissolved in solvent (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.

[0352] 2. Select 90 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 58, and solvent group 16.

[0353] 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.

[0354] 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.

[0355] 5. In the experimental administration stage, select the successfully modeled rats (50) 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, 005, 007 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 efficacy test stage. The administration route is conjunctival sac instillation of eye drops in the right eye of the rats, and the administration volume is 20 μL / eye / time. The eye drops are administered twice a day at 10:00 am and 17:00 pm, for 15 consecutive days. The first day of administration is recorded as Day 1. When administering, the eyelids are gently pried open to avoid touching the eyeball surface, 20 μL of solvent or test product is gently dropped into the conjunctival sac using 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, 005, 007 treatment groups (administered 0.25% compound solution).

[0356] 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.

[0357] Table 3 Influence of the compound on the intraocular pressure of rats T. Test: compared with the solvent group, *** indicates p≤0.001.

Claims

1. A compound of formula (I-1): wherein R 1 selected from hydrogen, halogen, 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 3-6cycloalkenyl, heterocyclyl, -C 1-4 1-6alkylene-heterocyclyl, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl, -C 1-4 1-6alkylene-heteroaryl, CN, NO2, -NR A1 R B1 , -OR A1 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -OC(=O)R A1 , -C(=O)NR A1 R B1 , -NR A1 C(=O)R B1 , -NR A1 C(=NR E1 )R B1 , -OC(=O)NR A1 R B1 , -NR A1 C(=O)OR B1 , -NR A1 C(=O)NR A1 R B1 , -NR A1 C(=S)NR A1 R B1 , -NR A1 C(=NR E1 )NR A1 R B1 , -S(=O) r R A1 , -S(=O)(=NR E1 )R B1 , -N=S(=O)R A1 R B1 , -S(=O)2OR A1 , -OS(=O)2R A1 , -NR A1 S(=O) r R B1 , -NR A1 S(=O)(=NR E1 )R B1 , -S(=O) r NR A1 R B1 , -S(=O)(=NR E1 )NR A1 R B1 , -NR A1 S(=O)2NR A1 R B1 , -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 X1 ; 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 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, -OH, -O-C 1-10 alkyl and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X5 ; and each R is independently selected from the group consisting of H, halogen, -OR, -N(R)2, -CN, -C(O)R, -C(O)OR, 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 R 7 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 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, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R X7 ; 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 8 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 A8 R B8 , -OR A8 , -SR A8 , -C(=O)R A8 , -C(=O)OR A8 , -OC(=O)R A8 , -C(=O)NR A8 R B8 , -NR A8 C(=O)R B8 , -NR A8 C(=NR E8 )R B8 , -OC(=O)NR A8 R B8 , -NR A8 C(=O)OR B8 , -NR A8 C(=O)NR A8 R B8 , -NR A8 C(=S)NR A8 R B8 , -NR A8 C(=NR E8 )NR A8 R B8 , -S(=O) r R A8 , -S(=O)(=NR E8 )R B8 , -N=S(=O)R A8 R B8 , -S(=O)2OR A8 , -OS(=O)2R A8 , -NR A8 S(=O) r R B8 , -NR A8 S(=O)(=NR E8 )R B8 , -S(=O) r NR A8 R B8 , -S(=O)(=NR E8 )NR A8 R B8 , -NR A8 S(=O)2NR A8 R B8 , -NR A8 S(=O)(=NR E8 )NR A8 R B8 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 X8 ; 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 9 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 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 , -S(=O) r R A9 , -S(=O)(=NR E9 )R B9 , -N=S(=O)R A9 R B9 , -S(=O)2OR A9 , -OS(=O)2R A9 , -NR A9 S(=O) r R B9 , -NR A9 S(=O)(=NR E9 )R B9 , -S(=O) r NR A9 R B9 , -S(=O)(=NR E9 )NR A9 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 R 10 selected from hydrogen, halogen, C 1-10 1-6alkyl, C 2-10 2-6alkenyl, C 2-10 2-6alkynyl, C 3-10 ycloalkyl, -C 1-4 alkylene-C 3- 10 ycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, CN, NO2, -NR A10 R B10 , -OR A10 , -SR A10 , -C(=O)R A10 , -C(=O)OR A10 , -OC(=O)R A10 , -C(=O)NR A10 R B10 , -NR A10 C(=O)R B10 , -NR A10 C(=NR E10 )R B10 , -OC(=O)NR A10 R B10 , -NR A10 C(=O)OR B10 , -NR A10 C(=O)NR A10 R B10 , -NR A10 C(=S)NR A10 R B10 , -NR A10 C(=NR E10 )NR A10 R B10 , -S(=O) r R A10 , -S(=O)(=NR E10 )R B10 , -N=S(=O)R A10 R B10 , -S(=O)2OR A10 , -OS(=O)2R A10 , -NR A10 S(=O) r R B10 , -NR A10 S(=O)(=NR E10 )R B10 , -S(=O) r NR A10 R B10 , -S(=O)(=NR E10 )NR A10 R B10 , -NR A10 S(=O)2NR A10 R B10 , -NR A10 S(=O)(=NR E10 )NR A10 R B10 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 X10 ; or "R 1 and R 2 " or "R 1 and R 4 " or "R 2 and R 3 " or "R 6 and R 7 " or "R 7 and R 8 " or "R 8 and R 9 " or "R 9 and R 10 " together with the carbon atom to which they are attached form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, which ring is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X ; each R A1 , R A2 , R A3 , R A4 , R A6 , R A7 , R A8 , R A9 , R A10 , R B1 , R B2 , R B3 , R B4 , R B6 , R B7 , R B8 , R B9 and R B10 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- 1-4alkylene-C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 1-4alkylene-heterocyclyl, aryl, -C 1-4 1-4alkylene-aryl, heteroaryl, -C 1-4 1-4alkylene-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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -CN, -N(R)2, -C(O)R, -C(O)OR, -C or "R A1 and R B1 " or "R A2 and R B2 " or "R A3 and R B3 " or "R A4 and R B4 " or "R A6 and R B6 " or "R A7 and R B7 " or "R A8 and R B8 " or "R A9 and R B9 " or "R A10 and R B10 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 E1 , R E2 , R E3 , R E4 , R E6 , R E7 , R E8 , R E9 and R E10 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 11 -(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 11 -(CR c R d ) t -, -(CR c R d ) u -OC(=O)-(CR c R d ) t -, -(CR c R d ) u -NR 11 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 11 -, -(CR c R d ) t -, -(CR c R d ) u - OC(=S)-(CR c R d ) t -, -(CR c R d ) u - NR 11 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 11 -, -(CR c R d ) t -, -(CR c R d ) u - OS(=O) r -, -(CR c R d ) t -, -(CR c R d ) u - NR 11 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 R 11 selected from hydrogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X11 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R 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 , R X9 , R X10 and R X11 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 hydrogen, C a1 and R b1 is independently selected from 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); each r is independently selected from 1 and 2; each t is independently selected from an integer from 0 to 10; each u is independently selected from an integer from 0 to 10; each k is independently selected from 1, 2, 3, and 4; each q is independently selected from 0, 1, 2, and 3; the total number of M in the molecule is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound of claim 1, wherein -(L) k the structure of - is selected from -(CH2) j - -(CH2) j1 - -(CH2) j2 - -(CH2) j1 - OC(=0)-(CH2) j2 - -(CH2) j1 - C(=0)-(CH2) j2 - -(CH2) j1 - OC(=0)-(CH2) i - -(CH2) j2 - -(CH2) j1 - C(=0)-(CH2) i - -(CH2) j2 - -(CH2) j1 - OC(=0)-(CH2) i1 - -(CH2) i2 - -(CH2) j2 - and -(CH2) j1 - C(=0)-(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 -, 3. 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 .

4. The compound of any one of claims 1-3, wherein the total number of M in the molecule is 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or 2; and / or when multiple M are present, each M is the same.

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

6. The compound of any one of claims 1-5, wherein R 1 selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1- 4alkylene-heterocyclyl, CN, NO2, -NR A1 R B1 , -OR A1 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -OC(=O)R A1 , -C(=O)NR A1 R B1 , -NR A1 C(=O)R B1 , -OC(=O)NR A1 R B1 , -NR A1 C(=O)OR B1 , -NR A1 C(=O)NR A1 R B1 , -S(=O) r R A1 , -S(=O)2OR A1 , -OS(=O)2R A1 , -NR A1 S(=O) r R B1 , -S(=O) r NR A1 R B1 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent selected independently from R X1 ; Preferably, R 1 selected from hydrogen, -OR A1 and In particular 7. The compound of any one of claims 1-6, wherein R 2 selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1- 4alkylene-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 R B2 , -S(=O) r NR A2 R B2 and wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent selected independently from R X2 ; Preferably, R 2 selected from hydrogen, -OR A2 and In particular -OR A2 .

8. The compound of any one of claims 1-7, wherein R 3 selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1- 4alkylene-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 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent selected independently from R X3 ; Preferably, R 3 selected from hydrogen, -OR A3 and In particular -OR A3 .

9. The compound of any one of claims 1-8, wherein 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 alkyl is unsubstituted or substituted with at least one substituent independently selected from R X4 ; and the like. Preferably, R 4 is hydrogen.

10. The compound of any one of claims 1-9, wherein R 5 is hydrogen.

11. The compound of any one of claims 1-10, wherein 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 and / or R 7 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A7 R B7 , -OR A7 , -OC(=O)R A7 , -OS(=O)2R A7 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X7 and / or R 8 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A8 R B8 , -OR A8 , -OC(=O)R A8 , -OS(=O)2R A8 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X8 and / or R 9 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A9 R B9 , -OR A9 , -OC(=O)R A9 , -OS(=O)2R A9 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X9 and / or R 10 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A10 R B10 , -OR A10 , -OC(=O)R A10 , -OS(=O)2R A10 and wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X10 .

12. The compound of claim 11, wherein R 6 is hydrogen; and / or R 7 is hydrogen; and / or R 8 is hydrogen; and / or R 9 is hydrogen; and / or R 10 is hydrogen.

13. 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), or Formula (I-2-3) as follows: wherein, L 1 , L 2 and L 3 are independently selected from L; M 1 , M 2 and M 3 are independently selected from M; or Formula (I-1) has the structure of Formula (I-3) as follows: wherein, L 1 and L 2 is independently selected from L; M 1 and M 2 is independently selected from M; or Formula (I-1) has the structure of Formula (I-4) as follows: wherein, L 1 , L 2 and L 3 are independently selected from L; M 1 , M 2 and M 3 are independently selected from M.

14. The compound of claim 13, wherein - L 1 - M 1 the structure is selected from and / or; - L 2 - M 2 the structure of and / or; - L 3 - M 3 the structure of 15. The compound of claim 13 or 14 having the structure of Formula (I-5-1), Formula (I-5-2), Formula (I-5-3), Formula (I-6), or Formula (I-7): ###00015### ###00016### ###00017### ###00018### ###00019### 16. A compound, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

17. 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.

18. Use of a compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a 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.

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

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