Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein the compound has the structure of formula (XVII):

wherein:

R is selected from the group consisting of H and C 1-6 alkyl;

R 2 is selected from the group consisting of H and C 1-6 alkyl;

R 3 , R 4 , R 7 , and R 7′ , at each occurrence, are each independently selected from the group consisting of H, halogen, —NH 2 , —OH, C 1-6 alkyl and —OR 5 ;

R 9 , at each occurrence, is each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 and —C 1-6 alkylene-O(P═O) (OH) 2 ;

R 10 is selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 and —C 1-6 alkylene-O(P═O) (OH) 2 ;

the above alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, heteroaromatic ring and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl and —OR 5 ;

R 5 , at each occurrence, is each independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;

m, at each occurrence, is each independently an integer of 0, 1, 2 or 3; and

n is an integer of 0, 1 or 2.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein the compound is selected from the group consisting of:

No.

Structural Formula

TDI01470

TDI01903

TDI01904

TDI01905

TDI01907

TDI01910

TDI01915

TDI01917

TDI01920

TDI01921

TDI01923

TDI01924

TDI01925

TDI01926

TDI01927

TDI01928

TDI01929

TDI01930

TDI01931

TDI01932

3. A method of inhibiting a Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof.

4. A method for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, to a subject in need thereof, wherein the disease is selected from the group consisting of an autoimmune disorder; a cardiovascular disorder; inflammation; a central nervous system disorder; an arterial thrombotic disorder; a fibrotic disorder; a metabolic syndrome; insulin resistance; hyperinsulinemia; type 2 diabetes; glucose intolerance; osteoporosis; and an ocular disorder.

5. A method for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof, wherein the disease is selected from the group consisting of lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), lung fibrosis, psoriasis, corneal graft rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chron's disease, primary biliary cirrhosis, acute pancreatitis, contact dermatitis, delayed hypersensitivity, septic shock, osteoporosis, osteoarthritis, neuronal inflammation, Osier-Weber syndrome, restenosis, fungal infection, parasitic infection, and viral infection.

6. The compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, of claim 1 wherein the compound has the structure below:

7. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of claim 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is in the form of a solid, semi-solid, liquid, or gas preparation.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein R is H.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein R 2 is H.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein R 3 is H.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein R 4 , R 7 , and R 7′ , at each occurrence, are each independently selected from the group consisting of H, F and methoxy.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein R 9 is H.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein Rim is methyl, ethyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, oxetanyl, monofluoromethyl, difluoromethyl, acetyl, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 ,

15. The compound according to claim 14 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein R 10 is methyl.

16. A method of inhibiting ROCK2, comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof.

17. The method according to claim 4 , wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis, Crohn's disease, atopic dermatitis, eczema, and graft-versus-host disease (GVHD).

18. The method according to claim 4 , wherein the cardiovascular disorder is selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, and erectile dysfunction.

19. The method according to claim 4 , wherein the inflammation is selected from the group consisting of asthma, cardiovascular inflammation, ulcerative colitis, and renal inflammation.

20. The method according to claim 4 , wherein the central nervous system disorder is selected from the group consisting of neuronal degeneration, spinal cord injury, Huntington's disease, Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

21. The method according to claim 4 , wherein the arterial thrombotic disorder is selected from the group consisting of platelet aggregation, and leukocyte aggregation.

22. The method according to claim 4 , wherein the fibrotic disorder is selected from the group consisting of liver fibrosis, lung fibrosis, and kidney fibrosis.

23. The method according to claim 4 , wherein the ocular disorder is selected from the group consisting of ocular hypertension, age related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma and retinitis of prematurity (ROP).

24. The method according to claim 23 , wherein the glaucoma is selected from the group consisting of primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal tension glaucoma, secondary glaucoma and neo vascular glaucoma.

25. A method for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof, wherein the disease is selected from the group consisting of lupus, autoimmune nephritis, allograph rejection, allergic inflammation, and inflammatory bowel disease.

26. A method for slowing the progression of or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof, wherein the disease is a neoplastic disease selected from the group consisting of a lymphoma, leukemia, astrocytoma, sarcoma, and blastoma.

27. A method for slowing the progression of or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof, wherein the disease is carcinoma selected from the group consisting of squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, uterine carcinoma, salivary gland carcinoma, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, and head and neck cancer.

28. A method for slowing the progression of or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof to a subject in need thereof, wherein the disease is selected from the group consisting of soft tissue sarcoma, hemangioma, and angiofibroma.