ROCK2 inhibitors in the treatment of obesity

Abstract

In particular, therapies using Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitors and, optionally, glucagon-like peptide 1 receptor (GLP-1) agonists are provided herein. Therapies may be used to treat type 2 diabetes and / or obesity and to promote weight loss.

Description

[Technical Field]

[0001] Reference to electronic sequence listings This application includes a sequence listing submitted electronically in XML format, the entire contents of which are incorporated herein by reference. The XML file, created on September 26, 2024, is named "SeqList-332930-48376.xml" and has a size of 31,680 bytes. [Background technology]

[0002] This disclosure provides methods for the treatment of obesity and / or type 2 diabetes. This disclosure provides therapeutic methods using a Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitor and, optionally, a glucagon-like peptide 1 receptor (GLP-1) agonist to treat obesity, treat type 2 diabetes, and / or promote weight loss in a subject. This disclosure also provides methods for treating obesity in a subject and / or promoting weight loss while maintaining muscle mass in a subject by administering a therapeutically effective dose of the ROCK2 inhibitor to the subject. Furthermore, methods using combinations of ROCK2 and GLP-1 agonists, as well as kits for using them, are also provided. [Overview of the project]

[0003] A method for treating and / or promoting weight loss in a subject by administering a therapeutically effective dose of a ROCK2 inhibitor to the subject is described herein.

[0004] Furthermore, methods for reducing HbA1c; and / or preventing or treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin-dependent diabetes; and / or preventing or treating obesity or reducing body weight are described herein, wherein the methods include administering a therapeutically effective dose of a ROCK2 inhibitor and optionally a therapeutically effective dose of a GLP-1 agonist to a patient in need thereof.

[0005] Furthermore, this specification describes methods for maintaining muscle mass in subjects undergoing treatment for obesity and / or experiencing weight loss by administering a therapeutically effective dose of a ROCK2 inhibitor to the subject during treatment / weight loss. Subjects undergoing treatment for obesity and / or weight loss may receive dietary calorie restriction, obesity or other surgical interventions, and one or more of the following weight-loss medications: GLP-1 agonists; sodium-glucose transporter 2 (SGLT2) inhibitors such as bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, sotagliflozin and tofogliflozin; lipase inhibitors such as orlistat (Alli,Xenical); melanocortin 4 receptor agonists such as cetomelanotide (Imcivree); naltrexone-bupropion; phentermine; phentermine-topiramate; metformin; diethylpropion (amphepramon); and combinations thereof. Advantageously, in the method of this disclosure, the ROCK2 inhibitor is administered to the subject to reduce muscle loss in the subject during weight loss.

[0006] In other embodiments, the Disclosure provides a method for treating and / or promoting weight loss in a subject by administering a therapeutically effective dose of a ROCK2 inhibitor and, optionally, a therapeutically effective dose of a GLP-1 agonist to the subject. In one embodiment, the Disclosure also provides a method for treating obesity in a subject, the method comprising administering a combination of a therapeutically effective dose of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist to the subject. In another embodiment, the Disclosure provides a method for promoting weight loss in a subject, the method comprising administering a combination of a therapeutically effective dose of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist to the subject. Advantageously, in the methods of the Invention, the ROCK2 inhibitor is administered to the subject to reduce the subject's muscle loss during weight loss.

[0007] Furthermore, methods for treating type 2 diabetes and / or reducing HbA1c in subjects by administering a therapeutically effective dose of a ROCK2 inhibitor are also described herein. Methods for maintaining muscle mass in subjects receiving treatment for type 2 diabetes are also described herein by administering a therapeutically effective dose of a ROCK2 inhibitor. Those receiving treatment for type 2 diabetes may receive dietary calorie restriction and one or more medications for type 2 diabetes, such as GLP-1 agonists; sodium-glucose transporter 2 (SGLT2) inhibitors such as bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, sotagliflozin, and tofogliflozin; lipase inhibitors such as orlistat (Alli, Xenical); melanocortin 4 receptor agonists such as cetomelanotide (Imcivree); naltrexone-bupropion; phentermine; phentermine-topiramate; metformin; diethylpropion (amphepramon); and combinations thereof.

[0008] In one embodiment, the present disclosure provides a method for treating type 2 diabetes in a subject in need thereof. The method comprises administering a therapeutically effective dose of a combination of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist to the subject.

[0009] In some embodiments, the ROCK2 inhibitor is ribonucleic acid (RNA). In some embodiments, the ROCK2 inhibitor is antisense RNA against ROCK2 transcription. In some embodiments, the ROCK2 inhibitor is small interfering RNA (siRNA) or microRNA (miRNA). In some embodiments, the combinations include ROCK2 inhibitors which are compounds following formulas (AI), (BI), (CI), (DI), (EI), (FI), (GI), (HI), (JI), (KI), (LI) and one or more of their subgroups, and exemplary compounds thereof. In some embodiments, the ROCK2 inhibitor is belmosdil (2-(3-(4-((1H-indazole-5-yl)amino)quinazoline-2-yl)phenoxy)-N-isopropylacetamide) or a pharmaceutically acceptable salt thereof. In other embodiments, the ROCK2 inhibitor is zelasdil or a pharmaceutically acceptable salt thereof. In other embodiments, the ROCK2 inhibitor is selected from compound A, compound B, compound C, and compound D, or pharmaceutically acceptable salts thereof. In one embodiment, the ROCK2 inhibitor is (6-(4-((4-(1H-pyrazole-4-yl)phenyl)amino)pyrimidine-2-yl)-1-methyl-1H-indole-2-yl)(3,3-difluoroazetidine-1-yl)methanone (compound A), or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the GLP-1 agonist is a compound having the structure of formula (MI), (NI), (OI), (O-II), (PI), (QI), (RI) and their subgroups, or an exemplary compound thereof. In some embodiments, the GLP-1 agonist is a peptide having, but not limited to, the amino acid sequences of SEQ ID NOs: 4-8, 9, 18 and 19-30. In some embodiments, the GLP-1 agonist may be a peptide containing, but not limited to, the amino acid sequences of SEQ ID NOs: 1-30. In some embodiments, the GLP-1 agonist is semaglutide, exenatide, lilaglutide, albiglutide, dulaglutide, lixisenatide, tilzepatide, rotiglyprone, letatoltide, taspoglutide, orformiglyprone, or danuglyprone. In a particular embodiment, the GLP-1 agonist is semaglutide. In other embodiments, the GLP-1 agonist is tilzepatide.

[0011] Furthermore, kits comprising a combination of (i) a therapeutically effective dose of a ROCK2 inhibitor and (ii) a therapeutically effective dose of a GLP-1 agonist are also provided. In some embodiments, the kit may be used to treat a target type 2 diabetes. In some embodiments, the kit may be used to treat a target obesity. In some embodiments, the kit may be used for a weight loss program.

[0012] Other aspects of the present invention are disclosed below. [Brief explanation of the drawing]

[0013] [Figure 1] This shows the absolute body weight change of obese mice treated with a ROCK2 inhibitor (compound A) and / or semaglutide, compared to untreated mice and mice fed a lean solid diet. [Figure 2] The dose-dependent weight loss in mice treated with compound A over the study period (2A) and at the end of the study (2B) is shown. [Figure 3]This shows a decrease in blood glucose levels during feeding in mice treated with compound A. [Figure 4] The following shows the measured blood glucose levels under feeding in mice treated with compound A at baseline (-1 week, 4A), week 3 (4B), and week 6 (4C). [Figure 5] This shows a decrease in blood HbA1c levels in mice treated with compound A. [Figure 6] This shows the body weight over the test days in a diet-induced obesity (DIO) model of mice treated with a ROCK2 inhibitor (compound A), a GLP-1 agonist (tilzepatide, TZP), or a combination of compound A and TZP. [Figure 7] This shows the oral glucose load in mice after oral administration of glucose. [Figure 8] This demonstrates the effect of compound A and / or tilzepatide on fasting blood glucose levels in mice during the DIO test. [Figure 9] This demonstrates the effect of compound A and / or tilzepatide on HbA1c levels in mice during the DIO test. [Figure 10] The relative lean body mass (%) of the mouse cohort during the DIO study is shown at baseline, week 4, week 7, and week 12. [Figure 11-1] This shows the weight of adipose tissue (eWAT, iWAT, and scWAT) in a cohort of mice from the DIO study. It demonstrates that treatment of DIO mice with a ROCK2 inhibitor (compound A) results in a reduction in adipose tissue. [Figure 11-2] This shows the weight of adipose tissue (eWAT, iWAT, and scWAT) in a cohort of mice from the DIO study. It demonstrates that treatment of DIO mice with a ROCK2 inhibitor (compound A) results in a reduction in adipose tissue. [Figure 12] The DIO trial showed that energy expenditure increased in a cohort of mice administered compound A. [Figure 13] The DIO study showed that in a cohort of mice administered compound A, the amount of uncoupling protein 1 (UCP1) in adipose tissue increased. [Figure 14]This study demonstrates a decrease in hepatic glycogen in a diet-induced obesity (DIO) model of mice treated with compound A, or a combination of compound A and TZP. [Figure 15] This study demonstrates that GLUT4 levels in the muscles of a diet-induced obesity (DIO) model in mice treated with compound A improve and recover. [Figure 16-1] These images show (A) baseline, (B) week 7, and (C) week 12 fasting plasma insulin levels in a cohort of mice from the DIO study. Treatment of DIO mice with a ROCK2 inhibitor (compound A) demonstrates a significant reduction in plasma insulin levels and improved insulin sensitivity. [Figure 16-2] These images show (A) baseline, (B) week 7, and (C) week 12 fasting plasma insulin levels in a cohort of mice from the DIO study. Treatment of DIO mice with a ROCK2 inhibitor (compound A) demonstrates a significant reduction in plasma insulin levels and improved insulin sensitivity. [Figure 17-1] These images show (A) baseline, (B) week 7, and (C) week 12 fasting plasma leptin levels in a cohort of mice from the DIO study. Treatment of DIO mice with a ROCK2 inhibitor (compound A) resulted in a significant decrease in plasma leptin levels. [Figure 17-2] These images show (A) baseline, (B) week 7, and (C) week 12 fasting plasma leptin levels in a cohort of mice from the DIO study. Treatment of DIO mice with a ROCK2 inhibitor (compound A) resulted in a significant decrease in plasma leptin levels. [Modes for carrying out the invention]

[0014] The present invention will now be described further. Different embodiments of the present invention are provided in the following sections. Each of the embodiments presented may be combined with any other embodiments, unless otherwise explicitly indicated. In particular, any feature indicated as preferred or beneficial may be combined with any other feature indicated as preferred or beneficial.

[0015] In particular, therapies comprising Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitors, and methods of using ROCK2 inhibitors in the treatment of conditions or diseases including but not limited to type 2 diabetes and / or obesity, are provided herein. The methods provided herein may be used to lower HbA1c levels and / or blood glucose levels in patients.

[0016] The methods provided herein may be used for the treatment of hyperglycemia and / or impaired glucose tolerance.

[0017] In other embodiments, the method may be used, in particular, in conjunction with maintaining or reducing muscle mass in patients, in the prevention or treatment of obesity and / or weight loss.

[0018] Furthermore, combination therapies comprising ROCK2 inhibitors and glucagon-like peptide-1 receptor (GLP-1) agonists, methods of using combination therapies in the treatment of conditions or diseases including but not limited to type 2 diabetes and / or obesity, and kits comprising dosage forms of ROCK2 inhibitors and GLP-1 agonists are also provided herein.

[0019] Combination therapies may be used in the treatment of the target type 2 diabetes. The combination therapies disclosed herein include therapeutically effective doses of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist, which may synergistically enhance the treatment of type 2 diabetes.

[0020] The combination therapy may also be used in weight loss programs and kits, which may include dosage forms of ROCK2 inhibitors and GLP-1 agonists. The combination therapy may be used in weight loss programs or routines for subjects with or without type 2 diabetes or its risk. Advantageously, administration of ROCK2 inhibitors may reduce muscle loss experienced by patients, which is often associated with GLP-1 agonist use.

[0021] ROCK2 inhibitors In this disclosure, therapeutic methods include the use of ROCK2 inhibitors, particularly selective ROCK2 inhibitors.

[0022] Rho-related coiled-coil protein kinase 2 (ROCK) is a serine / threonine kinase belonging to the AGC (PKA, PKG, and PKC) kinase family, comprising two isoforms, ROCK1 and ROCK2. These two isoforms are differentially expressed and regulated in specific tissues. For example, ROCK1 is expressed at relatively high levels and ubiquitously, while ROCK2 is preferentially expressed in certain tissues, including the heart, brain, and skeletal muscle. ROCK2 inhibitors have been shown to be effective in inflammatory disease models.

[0023] The compounds used in the methods and compositions disclosed herein are ROCK inhibitors, particularly selective inhibitors of ROCK2. The compounds provide excellent inhibitory activity against ROCK2 and preferably have good selectivity (higher selectivity for ROCK2 compared to ROCK1). The compounds may further provide one or more of the following: good physicochemical properties (e.g., solubility, physical stability and / or chemical stability), good pharmacokinetic properties (e.g., improved bioavailability, appropriate half-life and duration of action), and acceptable safety (low toxicity and / or low side effects, therapeutic window).

[0024] Regarding ROCK2 inhibitors, for example, they are disclosed in WO2019 / 000682, WO 2019 / 000683, WO2019 / 001572, WO2020 / 094111, WO2020 / 177587, WO2020 / 259528, WO2022 / 042711, WO2022 / 042712, WO2006 / 105081, WO2019 / 145729, WO2007 / 007737, WO90 / 05723, WO2011 / 130740, WO2005 / 037197, WO2008 / 110846, WO2005 / 082890, WO2005 / 037197; U.S. Patent No. 10,323,023, No. 10,329,282, No. 11,390,609, No. 8,357,693, No. 9,815,820, No. 10,183,931, No. 10,696,660, No. 11,311,541, No. 11,497,751, No. 8,193,193, No. 4,997,834, No. 9,221,808, No. 7,547,779, No. 8,497,294, No. 7,592,357, No. 7,547,779, WO2023 / 209692 (Title: Inhibitors of ROCK2) and WO2024 / 110851, the disclosures of each of which are incorporated herein by reference in their entirety.

[0025] In one aspect, the ROCK2 inhibitor is of formula (A-I):

Chemical Formula

[0026] In this embodiment, the ROCK2 inhibitor is defined by formula (A-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R A1 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1~C6 alkyl)-ORA11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, R A2 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12, -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, Alternatively, R A1 and R A2 These elements combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which may be unsubstituted or C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 , C1~C3 perfluoroalkyl, -NR A11 -(C1~C6 alkyl)NR A11 R A12 and -NR A11 -(C1~C6 alkyl)-OR A11 Substituted with 1 to 3 substituents selected from the group consisting of, R A3 and R A4 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-OR A11 -(C1~C6 alkyl)-NR A11 R A12 , -(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 and -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 Selected from the group consisting of, Alternatively, R A3 and R A4 This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 , oxo, -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11-C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R A5 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, n1 is between 0 and 3. R A7 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-OR A11 -(C1~C6 alkyl)-NR A11 R A12 , -(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 and -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 Selected from the group consisting of, Each x1 is independently selected from 0 and 1. Each R A11 and R A12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R A11 and R A12 When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0027] In some embodiments, the ROCK2 inhibitor is expressed by formula (A-III): [ka] It has the structure or a pharmaceutically acceptable salt thereof. A1 , R A2 , RA3 , R A4 , R A5 , R A7 , X 4 And n1 are as described above.

[0028] In some embodiments, the ROCK2 inhibitor is expressed by formula (A-IIIa): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R A1 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1-C(=O)OR A11 Selected from the group consisting of, R A2 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, Alternatively, R A1 and R A2These elements combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which may be unsubstituted or C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 , C1~C3 perfluoroalkyl, -NR A11 -(C1~C6 alkyl)NR A11 R A12 and -NR A11 -(C1~C6 alkyl)-OR A11 Substituted with 1 to 3 substituents selected from the group consisting of, R A3 and R A4 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C 10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-OR A11 -(C1~C6 alkyl)-NR A11 R A12 , -(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 and -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 Selected from the group consisting of, Alternatively, R A3 and R A4This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 , oxo, -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R A5These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, n1 is between 0 and 3. R A7 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-OR A11 -(C1~C6 alkyl)-NR A11 R A12 , -(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl)x1 -C(=O)OR A11 and -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 Selected from the group consisting of, Each x1 is independently selected from 0 and 1. Each R A11 and R A12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R A11 and R A12 When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0029] In some embodiments, the ROCK2 inhibitor is expressed by formula (A-IIIb): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R A1 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 RA12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, R A2 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11, -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, Alternatively, R A1 and R A2 These elements combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which may be unsubstituted or C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 , C1~C3 perfluoroalkyl, -NR A11 -(C1~C6 alkyl)NR A11 R A12 and -NR A11 -(C1~C6 alkyl)-OR A11 Substituted with 1 to 3 substituents selected from the group consisting of, R A3 and R A4 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C 10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-OR A11 -(C1~C6 alkyl)-NR A11 R A12 , -(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11and -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 Selected from the group consisting of, Alternatively, R A3 and R A4 This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR A11 , oxo, -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1-C(=O)OR A11 Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R A5 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR A11 -O-(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl)-OR A11 , -NR A11 R A12 -O-(C1~C6 alkyl)-NR A11 R A12 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-NR A11 R A12 , -NR A11 -(C1~C6 alkyl)-OR A11 , -(C1~C6 alkyl) x1 -C(=O)R A11 -O-(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 , -C(=O)OR A11 , -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 , -NR A11 -(C1~C6 alkyl) x1 -C(=O)R A11 and -NR A11 -(C1~C6 alkyl) x1 -C(=O)OR A11 Selected from the group consisting of, n1 is between 0 and 3. R A7 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-OR A11-(C1~C6 alkyl)-NR A11 R A12 , -(C1~C6 alkyl) x1 -C(=O)R A11 , -(C1~C6 alkyl) x1 -C(=O)OR A11 and -(C1~C6 alkyl) x1 -C(=O)NR A11 R A12 Selected from the group consisting of, Each x1 is independently selected from 0 and 1. Each R A11 and R A12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R A11 and R A12 When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0030] In some embodiments, R A5 n1 is either hydrogen or n1 is 0.

[0031] In some embodiments, the ROCK2 inhibitor has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0032] Compounds of formula (AI) and its subgroups, as well as other ROCK2 inhibitors disclosed, may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2019 / 000682, WO2019 / 000683, WO2019 / 001572, WO2020 / 094111, WO2020 / 177587, WO2020 / 259528, WO2022 / 042711, WO2022 / 042712, and U.S. Patents 10,323,023, 10,329,282, and 11,390,609, and WO2023 / 209692 (the full contents of which are incorporated herein by reference, respectively).

[0033] In another embodiment, the ROCK2 inhibitor is given by formula (BI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, X B1 is N or CH, X B2 is N or CH, X B3 is N or CR B3 And, X B4 is N or CR B4 And, X B5 It is selected from the group consisting of C, CH, and N. a1 is selected from 1 or 2. The dotted line represents an optional double bond. Each R B1 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR B11 , and -NR B11 R B12 Selected from the group consisting of, Alternatively, two R atoms bonded to the same carbon or adjacent carbon atoms. B1However, together they form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S, and N, and may be unsubstituted or optionally substituted with 1-3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl. b1 is selected from 0, 1, and 2. R B2 The group is selected from H, halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl. R B3 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)ORB11 Selected from the group consisting of, R B4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, Alternatively, R B3 and R B4These combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 , C1~C3 perfluoroalkyl, -NR B11 -(C1~C6 alkyl)NR B11 R B12 and -NR B11 -(C1~C6 alkyl)-OR B11 It is substituted with 1 to 3 substituents selected from the group consisting of, or it is unsubstituted. Each R B5 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11, -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, n2 is between 0 and 3. R B6 and R B7 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -O-(C1~C6 alkyl)-C(=O)NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11-(C1-C6 alkyl) x2 -C(=O)R B11 , and -NR B11 -(C1-C6 alkyl) x2 -C(=O)OR B11 are selected from the group consisting of alternatively, R B6 and R B7 together form a 5-membered or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O and S, which is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C 10 aryl, C5-C 10 heteroaryl, 3-10 membered heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 aryl), -C1-C6 alkyl-(C5-C 10 heteroaryl), -C1-C6 alkyl-(3-10 membered heterocyclyl), halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR B11 R B12 , -O-(C1-C6 alkyl)-NR B11 R B12 , C1-C3 perfluoroalkyl, -NR B11 -(C1-C6 alkyl)NR B11 R B12 , -NR B11 -(C1-C6 alkyl)-OR B11 , and -C(=O)-N(R B8 )(R B9 ) which is substituted with 1 to 3 substituents selected from the group consisting of, or unsubstituted, and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH, and NH2 R B8 and R B9are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, 5-14 membered heteroaryl, C 6~12 aralkyl, -(C1-C6 alkyl)-OR B11 , -(C1-C6 alkyl)-NR B11 R B12 , -(C1-C6 alkyl) x2 -C(=O)R B11 , -(C1-C6 alkyl) x2 -C(=O)OR B11 and -(C1-C6 alkyl) x2 -C(=O)NR B11 R B12 (each of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl in the group is optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2), or, R B8 and R B9 together with the nitrogen to which they are attached, form (i) a 4-6 membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from N, O and S, or (ii) a 5-10 membered heterobicyclic ring system having 0 to 3 additional ring heteroatoms selected from N, O and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or substituted with halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR B11 , oxo, -O-(C1-C6 alkyl)-OR B11 , -(C1-C6 alkyl)-OR B11 , -NR B11 R B12 , -O-(C1-C6 alkyl)-NR B11 R B12 , -(C1-C6 alkyl)-NR B11 R B12 , -NR B11 -(C1-C6 alkyl)-NRB11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Substituted with 1 to 4 substituents selected from the group consisting of, Each x2 is independently selected from 0 and 1, and Each R B11 and R B12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R B11 and R B12 When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0034] In some embodiments, the ROCK2 inhibitor is expressed by formula (B-II): [ka] has the structure or a pharmaceutically acceptable salt thereof, wherein X B1 is N or CH, X B2 is N or CH, X B3 is N or CR B3 , X B4 is N or CR B4 , X B5 is selected from the group consisting of C, CH, and N, the dotted line represents an optional double bond, each R B1 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR B11 , and -NR B11 R B12 , selected from the group consisting of alternatively, two R groups bound to the same carbon or adjacent carbons B1 together form a 3- to 6-membered ring, which optionally may contain 0 to 2 ring heteroatoms selected from O, S and N, and is unsubstituted or optionally substituted with 1 to 3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl b1 is selected from 0, 1, and 2, R B3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 , -O-(C1-C6 alkyl)-OR B11 , -(C1-C6 alkyl)-OR B11 , -NR B11 R B12 , -O-(C1-C6 alkyl)-NR B11 R B12 , -(C1-C6 alkyl)-NR B11 R B12 , -NR B11-(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, R B4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x22 -C(=O)ORB11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x22 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x22 -C(=O)OR B11 Selected from the group consisting of, Alternatively, R B3 and R B4 These combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 , C1~C3 perfluoroalkyl, -NR B11 -(C1~C6 alkyl)NR B11 R B12 and -NR B11 -(C1~C6 alkyl)-OR B11 It is substituted with 1 to 3 substituents selected from the group consisting of, or it is unsubstituted. Each R B5 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 RB12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, n2 is between 0 and 3. X 6 , NR B10 Selected from the group consisting of O and S, X 7 It is selected from the group consisting of CH and N, R B8 and R B9 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C 10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-OR B11 -(C1~C6 alkyl)-NR B11 R B12 , -(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 and -(C1~C6 alkyl) x2 -C(=O)NRB11 R B12 A group consisting of the following is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Alternatively, R B8 and R B9 Together with the nitrogen to which they are bonded, they provide (i) 4-6 membered heterocyclic rings having 0-2 further ring heteroatoms selected from N, O, and S, or (ii) 5-10 membered heterobicyclic ring systems having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic rings or heterobicyclic ring systems are unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR B11 , oxo, -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NRB11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Substituted with 1 to 4 substituents selected from the group consisting of, R B10 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C5-C 10 Aryl, C5~C 10 Heteroaryl, 3-10 member heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 Aryl), -C1~C6 alkyl-(C5~C 10 Heteroaryl), -C1~C6 alkyl-(3~10 member heterocyclyl), -(C1~C6 alkyl)-NR B11 R B12 ,-(C1~C6 alkyl)NR B11 R B12 , -(C1~C6 alkyl)-OR B11 and -C(=O)-N(R B11 )(R B12 A group consisting of ) is selected, and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Each x2 is independently selected from 0 and 1, and Each R B11 and R B12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R B11 and R B12When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0035] In some embodiments, the ROCK2 inhibitor is expressed by formula (B-III): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, X B2 is N or CH, X B3 is N or CR B3 And, X B5 It is selected from the group consisting of C, CH, and N. The dotted line represents an optional double bond. Each R B1 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, oxo, -CN, C1-C3 perfluoroalkyl, -OR B11 , and -NR B11 R B12 Selected from the group consisting of, Alternatively, two R atoms bonded to the same carbon or adjacent carbon atoms. B1 However, together they form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S, and N, and may be unsubstituted or optionally substituted with 1-3 substituents selected from halo, C1-C3 alkyl, NH2, OH, and O-C1-C3 alkyl. b1 is selected from 0, 1, and 2. R B3These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, R B4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 RB12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, Alternatively, R B3 and R B4 These combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 , C1~C3 perfluoroalkyl, -NR B11 -(C1~C6 alkyl)NR B11 R B12 and -NR B11 -(C1~C6 alkyl)-OR B11 It is substituted with 1 to 3 substituents selected from the group consisting of, or it is unsubstituted. Each R B5 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, oxo, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, n2 is between 0 and 3. X B6 , NR B10 Selected from the group consisting of O and S, X B7 It is selected from the group consisting of CH and N, R B8 and R B9These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C 10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-OR B11 -(C1~C6 alkyl)-NR B11 R B12 , -(C1~C6 alkyl) x -C(=O)R B11 , -(C1~C6 alkyl) x -C(=O)OR B11 and -(C1~C6 alkyl) x -C(=O)NR B11 R B12 A group consisting of the following is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Alternatively, R B8 and R B9 Together with the nitrogen to which they are bonded, they provide (i) 4-6 membered heterocyclic rings having 0-2 further ring heteroatoms selected from N, O, and S, or (ii) 5-10 membered heterobicyclic ring systems having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic rings or heterobicyclic ring systems are unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR B11 , oxo, -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NRB11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Substituted with 1 to 4 substituents selected from the group consisting of, R B10 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C5-C 10 Aryl, C5~C 10 Heteroaryl, 3-10 member heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 Aryl), -C1~C6 alkyl-(C5~C 10 Heteroaryl), -C1~C6 alkyl-(3~10 member heterocyclyl), -(C1~C6 alkyl)-NR B11 R B12 ,-(C1~C6 alkyl)NR B11 R B12 , -(C1~C6 alkyl)-OR B11 and -C(=O)-N(R B11 )(R B12A group consisting of ) is selected, and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Each x2 is independently selected from 0 and 1, and Each R B11 and R B12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R B11 and R B12 When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0036] In some embodiments, the ROCK2 inhibitor is expressed by formula (B-IV): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R B3 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11-(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, R B4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)ORB11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, Alternatively, R B3 and R B4 These combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 , C1~C3 perfluoroalkyl, -NR B11 -(C1~C6 alkyl)NR B11 R B12 and -NR B11 -(C1~C6 alkyl)-OR B11 It is substituted with 1 to 3 substituents selected from the group consisting of, or it is unsubstituted. X B6 , NR B10 Selected from the group consisting of O and S, X B7 It is selected from the group consisting of CH and N, R B8 and R B9 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C 10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-ORB11 -(C1~C6 alkyl)-NR B11 R B12 , -(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 and -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 A group consisting of the following is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Alternatively, R B8 and R B9 Together with the nitrogen to which they are bonded, they provide (i) 4-6 membered heterocyclic rings having 0-2 further ring heteroatoms selected from N, O, and S, or (ii) 5-10 membered heterobicyclic ring systems having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic rings or heterobicyclic ring systems are unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR B11 , oxo, -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2-C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Substituted with 1 to 4 substituents selected from the group consisting of, R B10 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C5-C 10 Aryl, C5~C 10 Heteroaryl, 3-10 member heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 Aryl), -C1~C6 alkyl-(C5~C 10 Heteroaryl), -C1~C6 alkyl-(3~10 member heterocyclyl), -(C1~C6 alkyl)-NR B11 R B12 ,-(C1~C6 alkyl)NR B11 R B12 , -(C1~C6 alkyl)-OR B11 and -C(=O)-N(R B11 )(R B12 A group consisting of ) is selected, and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Each x2 is independently selected from 0 and 1, and Each R B11 and R B12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, RB11 and R B12 When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0037] In some embodiments, the ROCK2 inhibitor is expressed by formula (BV): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R B3 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11, -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, R B4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halo, -CN, C1-C3 perfluoroalkyl, -OR B11 -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Selected from the group consisting of, Alternatively, RB3 and R B4 These combine to form a 5- or 6-membered saturated or unsaturated condensed ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are C1-C6 alkyl, halo, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 , C1~C3 perfluoroalkyl, -NR B11 -(C1~C6 alkyl)NR B11 R B12 and -NR B11 -(C1~C6 alkyl)-OR B11 It is substituted with 1 to 3 substituents selected from the group consisting of, or it is unsubstituted. R B8 and R B9 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-10 member heterocyclyl, and C6-C 10 Aryl, 5-14 member heteroaryl, C 6~12 Aralkyl, -(C1~C6 alkyl)-OR B11 -(C1~C6 alkyl)-NR B11 R B12 , -(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 and -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 Selected from the group consisting of, each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Alternatively, R B8 and RB9 Together with the nitrogen to which they are bonded, they provide (i) 4-6 membered heterocyclic rings having 0-2 further ring heteroatoms selected from N, O, and S, or (ii) 5-10 membered heterobicyclic ring systems having 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic rings or bicyclic ring systems are unsubstituted or halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, C1-C6 fluoroalkyl, C1-C3 perfluoroalkyl, -OR B11 , oxo, -O-(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl)-OR B11 , -NR B11 R B12 -O-(C1~C6 alkyl)-NR B11 R B12 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-NR B11 R B12 , -NR B11 -(C1~C6 alkyl)-OR B11 , -(C1~C6 alkyl) x2 -C(=O)R B11 -O-(C1~C6 alkyl) x2 -C(=O)R B11 , -(C1~C6 alkyl) x2 -C(=O)OR B11 -C(=O)-R B11 , -C(=O)OR B11 , -(C1~C6 alkyl) x2 -C(=O)NR B11 R B12 , -NR B11 -(C1~C6 alkyl) x2 -C(=O)R B11 and -NR B11 -(C1~C6 alkyl) x2 -C(=O)OR B11 Substituted with 1 to 4 substituents selected from the group consisting of, R B10These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C5-C 10 Aryl, C5~C 10 Heteroaryl, 3-10 member heterocyclyl, -C1-C6 alkyl-(C3-C7 cycloalkyl), -C1-C6 alkyl-(C5-C 10 Aryl), -C1~C6 alkyl-(C5~C 10 Heteroaryl), -C1~C6 alkyl-(3~10 member heterocyclyl), -(C1~C6 alkyl)-NR B11 R B12 ,-(C1~C6 alkyl)NR B11 R B12 , -(C1~C6 alkyl)-OR B11 and -C(=O)-N(R B11 )(R B12 A group consisting of ) is selected, and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may optionally be substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 perfluoroalkyl, oxo, halo, -CN, -OH and NH2. Each x2 is independently selected from 0 and 1, and Each R B11 and R B12 These are independently selected from the group consisting of H and C1-C6 alkyl groups. Alternatively, R B11 and R B12 The method according to claim 1, wherein when both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, the heterocyclic ring being unsubstituted or substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl) and -(C1-C6 alkyl)-OH.

[0038] In some embodiments, the ROCK2 inhibitor is [ka] It has the structure or a pharmaceutically acceptable salt thereof.

[0039] The synthesis and biological assays of formula (BI) and its subgroups are described in WO2024 / 110851 (title: Inhibitors of ROCK2), the entire disclosure of which is incorporated herein by reference.

[0040] In one embodiment, the ROCK2 inhibitor is given by formula (CI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R C1 is -O-(CH2) y3 -CO2R C12 -O-(CH2) y3 -C(=O)NR C13 R C14 -O-(CH2) y3 -heteroaryl, -O-(CH2) y3 -Cycloalkyl, -OC(=O)-(CH2) y3 -NR C13 R C14 -O-(CH2) z3 -NR C13 R C14 -NH-C(=O)-(CH2-NR C13 R C14 -NH-C(=O)-X 3 -R C15 -NH-(CH2) y3 -NR C13 R C14 Selected from the group consisting of, R C12 These are C1~C6 alkyl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C16 R C17 -(C1~C6 alkyl)-C(=O)NR C16 R C17Selected from the group consisting of -(C1~C6 alkyl)-O-(C1~C6 alkyl)-O-(C1~C6 alkyl), aryl, aralkyl, heteroaryl, C3~C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted at one or more carbon atoms with 1-3 substituents independently selected from halo, C1~C6 alkoxy, hydroxy, amino, cyano, and C1~C3 perfluoroalkyl groups. R C13 and R C14 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), and -(C1-C6 alkyl)-NR C16 R C17 -(C1~C6 alkyl)-C(=O)NR C16 R C17 , selected from the group consisting of aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C13 and R C14 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. X 3 These are selected from covalent bonds, O, NH, and C1-C6 alkyl groups. R C15These are selected from the group consisting of heteroaryls, C3-C7 cycloalkyls, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. or R C15 These are -(C1~C6 alkyl)-O-(C1~C6 alkyl) and -(C1~C6 alkyl)-NR C16 R C17 , -CO2R C18 -O-(CH2) x3 -CO2R C18 , and -C(=O)NR C16 R C17 Selected from, R C16 and R C17 Each of these is independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C16 and R C17 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. R C18 These are H, aryl, aralkyl, heteroaryl, C1~C6 alkyl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C16 R C17A group consisting of -(C1~C6 alkyl)-O-(C1~C6 alkyl)-O-(C1~C6 alkyl) is selected, and each of these may optionally be substituted with 1 to 3 substituents independently selected from halo, C1~C6 alkoxy, hydroxy, amino, cyano, and C1~C3 perfluoroalkyl groups. x3 is selected from 0 to 6. y3 is selected from 0 to 6. Each R C2 These are independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluorolower alkyl. Each R C3 These are independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluorolower alkyl. R C4 H, -(CH2) a3 -NR C43 R C44 ,-YR C42 -O-(CH2) a3 -CO2R C42 -O-(CH2) a3 -C(=O)NR C43 R C44 -O-(CH2) a3 -heteroaryl, -O-(CH2) a3 -Cycloalkyl, -OC(=O)-(CH2) a3 -NR C43 R C44 -O-(CH2) c3 -NR C43 R C44 -NH-C(=O)-(CH2) a -NR C43 R C44 -NH-C(=O)-YR C45 -NH-C(=O)-(CH2) a3 -NR C43 R C44 Selected from, R C42 These are C1~C6 alkyl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C46 RC47 -(C1~C6 alkyl)-C(=O)NR C46 R C47 A group consisting of -(C1~C6 alkyl)-O-(C1~C6 alkyl)-O-(C1~C6 alkyl) is selected, and each of these may optionally be substituted at one or more carbon atoms with 1 to 3 substituents independently selected from halo, C1~C6 alkoxy, hydroxy, amino, cyano, and C1~C3 perfluoroalkyl groups. R C43 and R C44 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), and -(C1-C6 alkyl)-NR C46 R C47 -(C1~C6 alkyl)-C(=O)NR C46 R C47 , selected from the group consisting of aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C43 and R C44 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. Y is selected from covalent bonds, O, NH, and C1-C6 alkyl groups. R C45 H, aryl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), -(C1~C6 alkyl)-NR C46 R C47 , -CO2R C48 -O-(CH2)b3 -CO2R C48 , and -C(=O)NR C46 R C47 Selected from the group consisting of, R C46 and R C47 Each of these is independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C46 and R C47 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. R C48 These are H, aryl, aralkyl, heteroaryl, C1~C6 alkyl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C46 R C47 A group consisting of -(C1~C6 alkyl)-O-(C1~C6 alkyl)-O-(C1~C6 alkyl) is selected, and each of these may optionally be substituted with 1 to 3 substituents independently selected from halo, C1~C6 alkoxy, hydroxy, amino, cyano, and C1~C3 perfluoroalkyl groups. a3 is selected from 0 to 6. b3 is selected from 0 to 6. c3 is selected from 2 to 6. R C5 H, C1-C6 alkyl, -(CH2) d3 -C(=O)-NR C53R C54 -C(=O)-(CH2) d3 -NR C53 R C54 -C(=O)-XR C55 , and -C(=O)-(CH2) d3 -NR C53 R C54 Selected from the group consisting of, R C53 and R C54 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), and -(C1-C6 alkyl)-NR C56 R C57 -(C1~C6 alkyl)-C(=O)NR C56 R C57 , selected from the group consisting of aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C53 and R C54 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. R C55 These are H, aryl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C56 R C57 , -CO2R C58 -O-(CH2) e3 -CO2R C58 , and -C(=O)NR C56 R C57 Selected from the group consisting of, RC56 and R C57 Each of these is independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C56 and R C57 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. R C58 These are H, aryl, aralkyl, heteroaryl, C1~C6 alkyl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C56 R C57 A group consisting of -(C1~C6 alkyl)-O-(C1~C6 alkyl)-O-(C1~C6 alkyl) is selected, and each of these may optionally be substituted with 1 to 3 substituents independently selected from halo, C1~C6 alkoxy, hydroxy, amino, cyano, and C1~C3 perfluoroalkyl groups. d3 is selected from 0 to 6. e3 is selected from 0 to 6. R C6 H, C1-C6 alkyl, -(CH2) r3 -C(=O)-NR C63 R C64 -C(=O)-(CH2) r3 -NR C63 R C64 -C(=O)-XR C65 , and -C(=O)-(CH2) r3-NR C63 R C64 Selected from the group consisting of, R C63 and R C64 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), and -(C1-C6 alkyl)-NR C66 R C67 -(C1~C6 alkyl)-C(=O)NR C66 R C67 , selected from the group consisting of aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C63 and R C64 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. R C65 These are H, aryl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C66 R C67 , -CO2R C68 -O-(CH2) s3 -CO2R C68 , and -C(=O)NR C66 R C67 Selected from the group consisting of, R C66 and R C67Each of these is independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C66 and R C67 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. R C68 These are H, aryl, aralkyl, heteroaryl, C1~C6 alkyl, -(C1~C6 alkyl)-O-(C1~C6 alkyl), and -(C1~C6 alkyl)-NR C66 R C67 A group consisting of -(C1~C6 alkyl)-O-(C1~C6 alkyl)-O-(C1~C6 alkyl) is selected, and each of these may optionally be substituted with 1 to 3 substituents independently selected from halo, C1~C6 alkoxy, hydroxy, amino, cyano, and C1~C3 perfluoroalkyl groups. r3 is selected from 0 to 6. s3 is selected from 0 to 6, n3 is selected from 0 to 4. m3 is selected from 0 to 3, and p3 is selected from 0 and 1.

[0041] In some implementation forms, in equation (CI), each R C4 and R C5 R is independently H or an unsubstituted C1-C6 alkyl group. In some embodiments, R C4and R C5 H is H.

[0042] In some embodiments, the ROCK2 inhibitor is expressed by formula (C-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof. C1 , R C2 , R C3 n3 and m3 are the same as those in the compound of formula I.

[0043] In some embodiments, the ROCK2 inhibitor is expressed by formula (C-III): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R C13 and R C14 These are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), and -(C1-C6 alkyl)-NR C16 R C17 -(C1~C6 alkyl)-C(=O)NR C16 R C17 , selected from the group consisting of aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C13 and R C14These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. R C16 and R C17 Each of these is independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, and 3-12 membered heterocyclic rings containing up to 3 heteroatoms, each of which may optionally be substituted with 1-3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl. or R C16 and R C17 These may together form a 3- to 12-membered heterocyclic ring having up to 3 heteroatoms, which may optionally be substituted with 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano, and C1-C3 perfluoroalkyl groups. Each R C2 These are independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluorolower alkyl. Each R C3 These are independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluorolower alkyl. n is selected from 0 to 4. m is selected from 0 to 3.

[0044] In some embodiments, in formula (C-III), each R C13 and R C14R is independently H or an unsubstituted C1-C6 alkyl group. In some embodiments, each R C13 and R C14 These are independently unsubstituted C1-C6 alkyl groups. In some embodiments, each R C13 and R C14 R is independently methyl or ethyl. In some embodiments, R C13 and R C14 It is methyl.

[0045] In some embodiments, the ROCK2 inhibitor is [ka] It has the structure of or a pharmaceutically acceptable salt thereof. Compound E is also known as vermosdil or KD025.

[0046] Compounds of formula (CI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in U.S. Patents 8,357,693, 9,815,820, 10,183,931, 10,696,660, and 11,311,541 (the full contents of which are incorporated herein by reference).

[0047] In one embodiment, the ROCK2 inhibitor is given by formula (DI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R D1 , LR D2 And here, L is a combination or -L D1 -L D2 -and, In the formula, L D1 is a combination, -(CR A R B ) 1~3 -, -O(CR A R B ) 1~3 -,-(CRA R B ) 0~3 O- and -NR C (CR A R B ) 1~3 - Selected from the group consisting of and L D2 is a combination, -(CR A R B ) 1~3 -, -O-, -NR D -, -C(O)NR D -, -NR D C(O)-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)2NR D -, -NR D S(O)2-, -S(O)2-, -S(O)(NR D )-, -NR D C(O)NR E -, -OC(O)NR D -and-C(O)NR D Selected from the group consisting of S(O)2-, R D2 H, CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR F C1-C6 alkyl groups substituted with -NR F R G C1-C6 alkyl groups substituted with -OR F C replaced by 1~4 Haloalkyl, OH-substituted C 3~8 C substituted with cycloalkyl or 3- to 8-membered heterocycloalkyl groups 1~4 C substituted with alkyl or 6-membered heteroaryl groups 1~4 Alkyl, -(CR H R I ) 1~3 Ure F ,-(CR H R I ) 1~3 NR F R G ,-(CR N R O ) 1~3 C(O)OR F ,-(CR N R O ) 1-3 C(O)NRF R G , C 3~10 Selected from the group consisting of carbocyclic ring systems and 3- to 10-membered heterocyclic ring systems, the carbocyclic ring system or heterocyclic ring system is defined as =O, -NR F R G , -C(O)R F Hello, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl or -OR F C replaced by 1~4 It is either substituted with alkyl or unsubstituted. R D3 Each time it appears, Halo, C 1~4 Alkyl, C1-C6 haloalkyl, -CN, -OR J ,=O,-OR J C replaced by 1~4 Alkyl, -NR J R K , -NR J R K C replaced by 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-substituted C 1~4 C substituted with alkyl, 3-8 member heterocycloalkyl, and 3-8 member heterocycloalkyl groups. 1~4 Independently selected from the group consisting of alkyls, or two R D3 The heteroaryl group can optionally bond to form a phenyl group, or the heteroaryl group can be a halo or C 1~4 It may be substituted with alkyl, R D4 H, C 1~4 Alkyl, -OR L C replaced by 1~4 Alkyl, -NR L R L C replaced by 1~4 Alkyl, C 3~8 Cycloalkyl, substituted or unsubstituted phenyl, 3-8 member heterocycloalkyl, C 3~8 Cycloalkyl-substituted C 1~4 C substituted with alkyl or 3- to 8-membered heterocycloalkyl groups 1~4Selected from the group consisting of alkyl groups and substituted or unsubstituted 5 or 6-membered heteroaryl groups, where the phenyl or heteroaryl group may be substituted with a halo or a C1-4 alkyl group. R D5 H, halo, -OR J , C 1~4 Alkyl, C 1~6 Haloalkyl, C 1~4 Alkenyl, -CN and C 3~8 Selected from the group consisting of cycloalkyl groups, R D6 H, Halo, C 1~4 Alkyl, C 1~6 Haloalkyl, -CN and C 3~8 Selected from the group consisting of cycloalkyl groups, n4 is 0, 1, or 2. R A and R B H, C 1~4 Alkyl or C 1~4 Selected from the group consisting of haloalkyls, or R A and R B Together with the atoms to which they are bonded, they form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R C , R D , R E , R F and R G These are H and C, respectively, independently. 1~4 Alkyl and C 1~4 Selected from the group consisting of haloalkyls, R H and R I R is located on the same carbon atom. H and R I Except for one pair, each is H, and together with its carbon atom, forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. R J , R K , R L , R M , R N and R OEach instance is independently selected from the group consisting of H or C1-4 alkyl groups.

[0048] In some embodiments, the ROCK2 inhibitor is expressed by formula (D-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, in formula (D-II), R D1 is, -L D1 -L D2 -R D2 In some embodiments, L D1 L is a bond, D2 -NR D -, -C(O)NR D -, -NR D In some embodiments, R D1 teeth, [ka] In some embodiments, R D2 These are C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl) or C1-C6 haloalkyl groups (e.g., mono, di, or perfluoroC1-C6 alkyl groups).

[0050] In some embodiments, in formula (D-II), R D4 is hydrogen or C 1~4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl). In some embodiments, R D4 It is methyl.

[0051] In some embodiments, in formula (D-II), R D5 is hydrogen, halo, C 1~4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or t-butyl), C1~6 Haloalkyl (e.g., mono, di, or perfluoroC1-C6 alkyl), or C 3~8 These are cycloalkyl compounds (e.g., cyclopropyl, cyclobutyl, or cyclopentyl, cyclohexyl). In some embodiments, R D5 It is cyclopropyl.

[0052] In some embodiments, exemplary ROCK2 inhibitors are [ka] It has the structure or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the ROCK2 inhibitor is of formula (D-IIIa) or (D-IIIb): [ka] It has the structure or a pharmaceutically acceptable salt thereof.

[0054] Compounds of formula (DI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in U.S. Patent No. 11,497,751 (the entire contents of which are incorporated herein by reference).

[0055] In one embodiment, the ROCK2 inhibitor is defined by formula (E-Ia) or (E-Ib): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, Each R E1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogen, -CN, -OR E11 , or -NR E11 R E12 And, n5 is an integer between 0 and 3. Each R E2These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogen, -CN, -OR E21 , or -NR E21 R E22 And, m5 is an integer between 0 and 10, and Each R E11 , R E12 , R E21 , and R E22 These are independently H and C1-C6 alkyl groups.

[0056] In some embodiments, the ROCK2 inhibitor is of formula (E-IIa) or (E-IIb): [ka] It has the structure or a pharmaceutically acceptable salt thereof. E1 and R E2 As stated above.

[0057] In some embodiments, R E1 R is hydrogen or an unsubstituted C1-C3 alkyl group (e.g., methyl, ethyl, or propyl). In some embodiments, R E2 R is hydrogen, a halogen (e.g., F, Cl, or Br), or an unsubstituted C1-C3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, R E1 and R E2 is hydrogen. In some embodiments, R E1 F is R E2 is methyl. In some embodiments, R E1 It is methyl, and R E2 It is methyl.

[0058] In some embodiments, the ROCK2 inhibitor is [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0059] Compounds of formula (EI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2007 / 007737 and U.S. Patent No. 8,193,193 (the entire contents of which are incorporated herein by reference).

[0060] In one embodiment, the ROCK2 inhibitor is given by formula (FI): [ka] Having the structure of or its isomers, or pharmaceutically acceptable salts thereof, in the formula, R F1 and R F2 R' and R'' are identical or different, each being hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl, aralkyl, piperidyl, or pyrrolidinyl (any of which may have substituents on the ring), or -CR'=NR'', where R' is hydrogen, alkyl, amine, heterocycloalkyl, heteroaryl, or cycloalkyl, and R' and R'' are optionally bonded to form a heterocycloalkyl or heteroaryl. R F1 and R F2 It forms a heterocyclic ring that, together with a nitrogen atom, may have an oxygen atom, a sulfur atom, or optionally, a substituted nitrogen atom within the ring. Each R F3 and R F4 These are independently hydrogen or alkyl, R F5 These are hydrogen, halogen, alkyl, alkoxy, aralkyl, or haloalkyl, A is an alkylene optionally substituted with a single bond or a C1-C3 alkyl group. X is either =CH- or =N-, and n6 is an integer between 0 and 8.

[0061] In some embodiments, the ROCK2 inhibitor is expressed by formula (F-II): [ka] It has the structure or isomers thereof, or pharmaceutically acceptable salts thereof. F1 , R F2 , R F3 , R F5 And n6 are as described above.

[0062] In some embodiments, X = N-.

[0063] Several embodiments, each R F1 , R F2 , R F3 , and R F5 n6 is independently hydrogen, or in some embodiments, n6 is 0 or 1.

[0064] In some embodiments, the ROCK2 inhibitor is [ka] It has the structure or isomers thereof, or pharmaceutically acceptable salts thereof.

[0065] These compounds of formula (FI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO90 / 05723 and U.S. Patent No. 4,997,834 (the full contents of which are incorporated herein by reference).

[0066] In one embodiment, the ROCK2 inhibitor is given by formula (GI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, n7 is 1, 2, or 3. Each R G1 and R G2 These are independently hydrogen, alkyl, or acetyl. R G3is a cycloalkyl or aryl, where cycloalkyl or aryl is -OH, -CO2CH3, -C(O)NH2, -C(O)CH3, -NO2, -NH2, -NR 6 R 7 Carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, cycloalkyl, aryl, -OCX G 3, -OCHX G 2, -OCH2X G , optionally substituted with one or more of -OSO2CH3, -tosyl, or halogens, R 6 and R 7 These are independently H, alkyl, -SO2CH3, -C(O)CH3, or -C(O)NH2, and X G It is a halogen.

[0067] In some embodiments, the ROCK2 inhibitor is expressed by formula (G-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R G4 -OH, -CO2CH3, -C(O)NH2, -NO2, -NH2, -NR G5 R G6 , alkoxy, alkylalkoxy, alkyl, -OSO2CH3, tosyl, or halogen, Each R G5 and R G6 These are independently hydrogen or alkyl, m7 is an integer from 0 to 6, and R G1 , R G2 , and n7 are as described above.

[0068] In some embodiments, R G4 It is bonded to the meta position on the phenyl ring. In some embodiments, m7 is 0 or 1. In some embodiments, R G4 It is -OH.

[0069] In some embodiments, the ROCK2 inhibitor is structure [ka] or a pharmaceutically acceptable salt thereof.

[0070] Compounds of formula (GI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2011 / 130740 and U.S. Patent No. 9,221,808 (the entire contents of which are incorporated herein by reference).

[0071] In one embodiment, the ROCK2 inhibitor is given by formula (HI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R H1 These are halogen, cyano, methyl, ethyl, hydroxyethyl, methoxyethyl, or cyclopropyl. R H2 is hydrogen or halogen, R H3 is hydrogen, halogen, trifluoromethyl, or pentafluoroethyl, and R H4 It is either hydrogen or a halogen.

[0072] In some embodiments, R H1 R is hydrogen or a C1-C3 alkyl group (e.g., methyl, ethyl, or propyl). In some embodiments, R H2 is a halogen (e.g., F, Cl, or Br). In some embodiments, R H3 is a halogen (e.g., F, Cl, or Br). In some embodiments, R H4 This is a halogen (for example, F, Cl, or Br).

[0073] In some embodiments, the ROCK2 inhibitor is structure [ka] or a pharmaceutically acceptable salt thereof.

[0074] These compounds of formula (HI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2005 / 037197 and U.S. Patent No. 7,547,779 (the full contents of which are incorporated herein by reference).

[0075] In one embodiment, the ROCK2 inhibitor is given by formula (JI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R J1 is an aryl or heteroaryl group, Each R J2 and R J3 These are independently selected from hydrogen or C1-C4 alkyl groups. Each R J4 , R J5 and R J6 These are independently selected from hydrogen, halogen, or C1-C4 alkyl groups. R J7 These are hydrogen, halogen, OH, -CO2CH3, -C(O)NH2, -NO2, or C1-C4 alkyl. n8 is an integer from 0 to 3, and m8 is an integer between 0 and 8.

[0076] In some embodiments, the ROCK2 inhibitor is expressed by formula (J-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R J8is hydrogen, halogen, OH, -CO2CH3, -C(O)NH2, -NO2, or C1-C4 alkyl, and R J2 , R J3 , and R J7 As stated above.

[0077] In some embodiments, the ROCK2 inhibitor is structure [ka] or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the ROCK2 inhibitor is structure [ka] or a pharmaceutically acceptable salt thereof.

[0079] These compounds of formula (JI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2008 / 110846 and U.S. Patent No. 8,497,294 (the full contents of which are incorporated herein by reference).

[0080] In one embodiment, the ROCK2 inhibitor is given by formula (KI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, Each R K1 and R K2 These are independently selected from the group consisting of hydrogen and C1-C6 alkyl groups. R K3 These are phenyl; naphthyl; and quinolinyl compounds optionally substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, and phenyl. R K4 It is selected from the group consisting of hydrogen and methyl, RK5 These are C1-C3 alkyl groups, R K6 is hydrogen or hydrogen, and Each R K7 and R K8 These are independently selected from the group consisting of hydrogen halogens and C1-C3 alkyl groups.

[0081] In some embodiments, the ROCK2 inhibitor is expressed by formula (K-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R K3 is an optionally substituted aryl or heteroaryl, R K4 is a hydrogen- or optionally substituted C1-C2 alkyl group, R K5 These are optionally substituted C1-C2 alkyl groups. R K6 is hydrogen or halogen, and Each R K7 and R K8 These are hydrogen, halogens, and optionally substituted C1-C3 alkyl groups.

[0082] In some embodiments, R K3 is a substituted phenyl. In some embodiments, R K4 , R K7 and R K8 is hydrogen. In some embodiments, R K4 is a substituted C1-C2 alkyl (e.g., methyl or ethyl). In some embodiments, R K6 This is a halogen (for example, F, Cl, or Br).

[0083] In some embodiments, the ROCK2 inhibitor is structure [ka] or a pharmaceutically acceptable salt thereof.

[0084] These compounds of formula (KI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2005 / 082890 and U.S. Patent No. 7,592,357 (the full contents of which are incorporated herein by reference).

[0085] In one embodiment, the ROCK2 inhibitor is given by formula (LI): [ka] It has the structure or a pharmaceutically acceptable salt thereof, in the formula, X L The bond is C1-C6 alkylene, NH, O, S, SO or S(O)2, R L1 is hydrogen, or a C1-C6 alkyl group. R L2 is a C1-C6 alkyl or optionally substituted phenyl, R L3 These are hydrogen, C1-C6 alkyl, and C 3~7 It is either cycloalkyl or R L3 and R L4 However, together they form a ring, and Each R L4 and R 5 These are independently hydrogen or C1-C6 alkyl groups.

[0086] In some embodiments, the ROCK2 inhibitor is expressed by formula (L-II): [ka] It has the structure or a pharmaceutically acceptable salt thereof. L1 As stated above.

[0087] In some embodiments, the ROCK2 inhibitor has the following structure: [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the ROCK2 inhibitor of formula (L-II) comprises a hydrochloride salt.

[0088] These compounds of formula (LI) and its subgroups may be synthesized and assayed in vitro for ROCK2 inhibitory activity, for example, as described in WO2005 / 037197 and U.S. Patent No. 7,547,779 (the full contents of which are incorporated herein by reference).

[0089] In some embodiments, the ROCK2 antagonist is ribonucleic acid (RNA), such as antisense RNA. Antisense RNA (asRNA), also called antisense transcript or antisense oligonucleotide, is a single-stranded RNA that is complementary to and hybridizes with protein-translation messenger RNA (mRNA), thereby inhibiting the translation of the mRNA into protein. Antisense RNA may be classified into short (less than 200 nucleotides) and long (more than 200 nucleotides) non-coding RNAs (ncRNAs). The primary function of asRNA is to regulate gene expression. asRNA molecules can be synthetically designed and created and are widely used as research tools for gene knockdown. They are also applied in therapeutics. In some embodiments, the ROCK2-targeting antisense RNA contains one or more non-natural nucleic acids. In some embodiments, the antisense RNA is administered by injection or inhalation. In some embodiments, the ROCK2-targeting antisense RNA is selective for ROCK2 mRNA. In some embodiments, the ROCK2-targeting antisense RNA does not bind to ROCK1 mRNA. The design and use of selective antisense RNA molecules are commonplace in the art.

[0090] In some embodiments, the ROCK2 antagonist is RNA interference (RNAi), small inhibitory RNA (siRNA), or microRNA (miRNA). As used herein, “RNAi” generally refers to any RNA molecule that induces RNA interference within a cell. Examples of RNAi include, but are not limited to, small inhibitory RNA (siRNA), microRNA (miRNA), and small hairpin RNA (shRNA). RNA interference (RNAi) has been shown to be a useful tool for gene silencing in determining gene function and can be used as a therapeutic agent to suppress genes associated with the development of several diseases. Gene regulation by RNAi can occur via small RNAs known as microRNAs (miRNAs). MicroRNAs can be regulators of various cellular processes. siRNA or miRNA, through the use of artificial siRNA or miRNA, can enable the degradation of target gene products (e.g., genes encoding ROCK2, and genes associated with the production or regulation of ROCK2) using endogenous cellular RNAi mechanisms. In some embodiments, siRNA or miRNA selectively degrades ROCK2 mRNA. In some embodiments, siRNA or miRNA does not degrade ROCK1 mRNA. The design and use of selective siRNA molecules are commonplace in the art.

[0091] Small inhibitory or interfering RNAs (siRNAs) can be double-stranded RNA molecules, such as RNA with a length of 19-25 (e.g., 19-23) base pairs, that induce RNA interference within cells. Small hairpin RNAs (shRNAs) can be RNA molecules, such as double-stranded RNA with approximately 19-25 (e.g., 19-23) base pairs linked by short loops (e.g., about 4-11 nucleotides), that induce RNA interference within cells.

[0092] MicroRNAs (miRNAs) can be RNA molecules having a short (e.g., 19-25 base pairs) sequence of double-stranded RNA that induces RNA interference within cells, is linked by loops, and contains one or more additional sequences of double-stranded RNA that include one or more bulges (e.g., mispairs or unpaired base pairs). As used herein, the term “miRNA” encompasses endogenous miRNAs as well as exogenous or heterologous miRNAs. In some embodiments, “miRNA” may refer to pri-miRNA or pre-miRNA. During miRNA processing, a pri-miRNA transcript is produced. The pri-miRNA is processed by Drosha-DGCR8, and pre-miRNA is produced by cleaving one or more sequences, leaving a 5' flanking region, a guide strand, a loop region, a non-guide strand, and a 3' flanking region; or pre-miRNA having a 5' flanking region, a non-guide strand, a loop region, a guide strand, and a 3' flanking region. Next, the pre-miRNA is transported to the cytoplasm and processed by Dicer to obtain siRNA having a guide strand and a non-guide (or passenger) strand. The guide strand is then used by the RISC complex to catalyze gene silencing, for example, by recognizing a target RNA sequence complementary to the guide strand.

[0093] While the above describes exemplary ROCK2 inhibitors known to date, other compounds that have been shown to possess ROCK2 inhibitory activity may also be used.

[0094] This specification discloses a method for determining kinase inhibition. For example, the kinase activity of an enzyme and the inhibitory ability of a test compound can be determined by measuring the enzyme-specific phosphorylation of a substrate. Commercially available assays and kits can be used. For example, kinase inhibition can be determined using the IMAP® assay (Molecula Devices). This assay method uses a fluorescently tagged peptide substrate. Phosphorylation of the tagged peptide by the kinase of interest promotes the binding of the peptide to trivalent metal-based nanoparticles via a specific high-affinity interaction between the phosphate group and the trivalent metal. Fluorescence polarization increases as the nanoparticle approaches. Inhibition of the kinase by a kinase inhibitor prevents the phosphorylation of the substrate, thereby limiting the binding of the fluorescently tagged substrate to the nanoparticles. Such assays are compatible with microwell assay formats and allow for ICing of multiple compounds. 50 This makes it possible to measure both simultaneously.

[0095] As mentioned above, Rho proteins are members of the small GTP-binding protein family and function via two downstream isoforms: Rho-related coiled-coil protein kinase 1 (ROCK1) and Rho-related coiled-coil protein kinase 2 (ROCK2). These kinases may exhibit various cellular functions, including cell motility, proliferation, adhesion, migration, and apoptosis. Various nonspecific ROCK inhibitors have been developed to date, such as fasudil (approved in 1995 for the treatment of cerebral vasospasm) and ripasudil (approved in 2014 for the treatment of glaucoma). Due to the lack of isoform selectivity, hypotension may be induced as a dose-limiting side effect due to ROCK1 inhibition. However, ROCK2 selective inhibitors may show little to no hypotensive effect. In addition, inhibiting ROCK1 may not result in immune enhancement due to the distribution of ROCK1 in organs and tissues.

[0096] Therefore, the ROCK2 selective inhibitors disclosed herein may be used in the therapies provided herein with little or no adverse health risks. Inhibitors that specifically target ROCK2 rather than ROCK1 are preferred for the therapies disclosed herein.

[0097] GLP-1 Agonist Glucagon-like peptide 1 (GLP-1) is a fragment of the mammalian (e.g., human) proglucagon molecule and is a glucose-dependent insulinotropic agent that stimulates or influences insulin production in diabetic patients and has been shown to regulate further insulin activity for the treatment of diabetes. Another active fragment, glucagon-like insulinotropic peptide (GLIP), is a cleaved form but corresponds to the active fragment of GLP-1, GLP-1(7-36), and is a natural form found (secreted) in the body after food intake.

[0098] In this disclosure, combination therapy also includes the use of a GLP-1 agonist. A GLP-1 agonist as described herein may be a peptide or polypeptide substantially similar in biological or physiological function to glucagon-like peptide 1 (GLP-1), e.g., GLP-1(7-36: SEQ ID NO: 1) or GLP-1(7-37: SEQ ID NO: 2). In some embodiments, a GLP-1 agonist as described herein may be a peptide or polypeptide substantially similar in biological or physiological function to an exendin (e.g., exendin 4, SEQ ID NO: 3). [Table 1]

[0099] In some embodiments, a GLP-1 agonist as described herein may contain a chemical functional group or modification that can be introduced on at least one amino acid residue (e.g., a side chain). In some embodiments, a GLP-1 agonist as described herein may contain a chemical functional group or modification that can be introduced on at least one amino acid residue (e.g., the backbone). In some embodiments, a GLP-1 agonist as described herein may contain a chemical functional group or modification that can substitute for at least one amino acid residue. In some embodiments, a GLP-1 agonist as described herein may contain a chemical functional group or modification that can be introduced on the C-terminal amino acid residue of the GLP-1 sequence. In some embodiments, a GLP-1 agonist as described herein may contain a chemical functional group or modification that can be introduced on the N-terminal amino acid residue of the GLP-1 sequence. In some embodiments, a GLP-1 agonist as described herein may contain a fusion amino acid sequence or peptide sequence at at least the C-terminus or N-terminus of the GLP-1 sequence.

[0100] In some embodiments, GLP-1 agonists as described herein may have at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% homology to amino acid sequences 1-39 of GLP-1. In some embodiments, GLP-1 agonists as described herein may have at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% homology to amino acid sequences 7-36 of GLP-1.

[0101] In some embodiments, GLP-1 agonists as described herein may have biological or physiological effects similar to or enhanced by GLP-1 (e.g., increased glucose-dependent stimulation of insulin secretion, reduced gastric emptying, suppression of food intake, increased natriuretic and diuretic effects, prolongation of in vivo half-life, and / or regulation of β-cell proliferation). For example, GLP-1 agonists are disclosed in WO 96 / 29342, WO 98 / 08871, WO 99 / 43708, WO 00 / 3433, WO 00 / 69911, WO 02 / 4622, U.S. Patent Nos. 8,129,343, 5,424,286, 6,268,343, 7,452,966, 6,528,486, and 9,981,013, the full contents of each of these are incorporated herein by reference.

[0102] In one embodiment, the GLP-1 agonist is given by formula (MI): [ka] (MI) structure included, During the ceremony, Xaa7 contains L-histidine, imidoazopropionyl, α-hydroxyhistidine, D-histidine, desaminohistidine, 2-aminohistidine, β-hydroxyhistidine, homohistidine, N α -acetyl-histidine, N α -Formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine, Xaa8 is Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib (α-aminoisobutyric acid), (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid. Xaa 16is Val or Leu, Xaa 18 It is Ser, Lys, or Arg, Xaa 19 is Tyr or Gln, Xaa 20 is Leu or Met, Xaa 22 It is Gly, Glu, or Aib (α-aminoisobutyric acid), Xaa 23 These are Gln, Glu, Lys, or Arg. Xaa 25 It is Ala or Val, Xaa 27 It is Glu or Leu, Xaa 30 It is Ala, Glu, or Arg. Xaa 33 is Val or Lys, Xaa 34 These are Lys, Glu, Asn, or Arg. Xaa 35 It is Gly or Aib (α-aminoisobutyric acid), Xaa 36 It is either Arg, Gly, or Lys, or it does not exist. Xaa 37 is Gly, Ala, Glu, Pro, Lys, or does not exist, and B and U together form the acylation part, where U is [ka] [ka] Selected from, m is 0, 1, 2, 3, 4, 5, or 6. n is 1, 2, or 3. s is 0, 1, 2, or 3. t is 0, 1, 2, 3, or 4. p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. Furthermore, B is, [ka] It is an acidic group selected from, In the formula, l is 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0103] In some embodiments, in formula (MI), BU- is [ka] [ka] Selected from, In the formula, l is 14, 15, 16, 17, 18, 19, or 20. p is 1, 2, 3, 4, 7, 8, 9, 10, 11 or 12. s is 0, 1, or 2. t is either 0 or 1.

[0104] In some embodiments, in formula (MI) or (M-II), B is [ka] And, Furthermore, l is 14, 16, 18, or 20.

[0105] In a particular embodiment, in formula (MI), BU is [ka] That is the case.

[0106] In one embodiment, the GLP-1 agonist is given by formula (M-II): [ka] It includes the structure, During the ceremony, U is [ka] A spacer selected from, In the formula, n is 12, 13, 14, 15, 16, 17, or 18. l is 12, 13, 14, 15, 16, 17 or 18. m is 0, 1, 2, 3, 4, 5, or 6. s is 0, 1, 2, or 3. p is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. Furthermore, B is, [ka] Xaa7, Xaa8, Xaa 16 Xaa 16 Xaa 17 Xaa 18 Xaa 19 Xaa 20 Xaa 22 Xaa 23 Xaa 25 Xaa 27 Xaa 30 Xaa 33 Xaa 34 Xaa 35 Xaa 36 , and Xaa 37 Selected from.

[0107] In a particular embodiment, in formula (M-II), BU is [ka] [ka] Selected from, In the formula, l is 14, 15, or 16. n is 15, 16, 17, or 18. p is 3, 7, 11, or 24.

[0108] In certain embodiments, Xaa7 is His or desaminohistidine.

[0109] In certain embodiments, Xaa8 is Ala, Gly, Val, Leu, Ile, Lys, or Aib.

[0110] In a particular embodiment, Xaa 16 is Val, and Xaa18 is Ser.

[0111] In a particular embodiment, Xaa 19 It is Tyr.

[0112] In a particular embodiment, Xaa 20 It is Luu.

[0113] In a particular embodiment, Xaa 22 This is Gly, Glu, or Aib.

[0114] In a particular embodiment, Xaa 23 This is either Gln or Glu.

[0115] In a particular embodiment, Xaa 25 It is Ala.

[0116] In a particular embodiment, Xaa 27 It is Glu.

[0117] In a particular embodiment, Xaa 30 It is either Ala or Glu.

[0118] In a particular embodiment, Xaa 33 It is Val.

[0119] In a particular embodiment, Xaa 34 It is either Lys or Arg.

[0120] In a particular embodiment, Xaa 35 It is either Gly or Aib.

[0121] In a particular embodiment, Xaa 36 It is either Arg or Lys.

[0122] In a particular embodiment, Xaa 37 It is either Gly, an amide, or absent.

[0123] In certain embodiments, Xaa7 is His or desaminohistidine, Xaa8 is Ala, Gly, Val, Leu, Ile, Lys or Aib, and Xaa 16 is Val, Xaa 18 is Ser and Xaa 19 is Tyr and Xaa 20 is Leu and Xaa 22 is Gly, Glu or Aib, and Xaa 23 is Gln or Glu, Xaa 25 is Ala and Xaa 27 is Glu, Xaa 30 is Ala or Glu, Xaa 33 is Val, Xaa 34 is Lys or Arg, Xaa 35 is Gly or Aib, Xaa 36 is Arg or Lys and Xaa 37 It is either Gly, an amide, or absent.

[0124] In some embodiments, the GLP-1 agonist contains 5, 6, 7, 8, 9, 10, or 15 or fewer amino acid residues that have been replaced, added, or deleted. For example, one amino acid near the C-terminal or N-terminal amino acid sequence (e.g., Xaa7 or Xaa 37 ) may be missing or truncated.

[0125] In some embodiments, in (MI), U is [ka] In some embodiments, in (MI), B is [ka] And in the formula, l is 14, 16, or 18.

[0126] In a particular embodiment, the GLP-1 agonist is expressed by the formula: [ka] It has, l is as described above.

[0127] In a particular embodiment, the GLP-1 agonist is expressed by the formula: [ka] It has the following characteristics. In certain embodiments, the GLP-1 agonist is semaglutide.

[0128] In some embodiments, compounds of formula (MI) or (M-II), and exemplary compounds, can be formulated for subcutaneous injection. In some embodiments, compounds of formula (MI) or (M-II), and exemplary compounds, can be formulated for oral administration.

[0129] These compounds of formula (MI) or (M-II) and their subgroups may be synthesized and assayed in vitro, for example, as described in WO2006 / 097537, or U.S. Patents 8,536,122 and 8,129,343 (the full contents of which are incorporated herein by reference).

[0130] In one embodiment, the GLP-1 agonist comprises a peptide having the amino acid sequence of SEQ ID NOs: 4-8. [Table 2]

[0131] In certain embodiments, an exemplary GLP-1 agonist is exenatide.

[0132] In some embodiments, the peptides of SEQ ID NOs: 4-8 may function as insulin or an insulin-like hormone. In some embodiments, the peptides of SEQ ID NOs: 4-8 may stimulate the production of insulin or an insulin-like hormone. In some embodiments, the peptides of SEQ ID NOs: 4-8 may be formulated for subcutaneous injection. In some embodiments, the peptides of SEQ ID NOs: 4-8 may be formulated for sustained-release subcutaneous injection.

[0133] These peptides of Sequence ID Nos. 4-8, their variants, and formulations containing them may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in U.S. Patent Nos. 5,424,286, 6,515,117, and 7,456,254 (the full contents of which are incorporated herein by reference).

[0134] In one embodiment, the GLP-1 agonist is given by formula (NI): [ka] It includes the structure, Xaa7 is either a modified amino acid, His, or is deleted. Xaa8 is either Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is missing. Xaa9 is either Glu, Asp, or Lys, or it is deleted. Xaa 10 It is either Gly or missing. Xaa 11 It is either Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys, or it is missing. Xaa 12 It is either Phe or missing, Xaa 13 It is either a thrush or missing, Xaa 14 It is either Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or it is missing. Xaa 15 It is either an Asp or missing. Xaa 16 It is either Val, Ala, Gly, Ser, Thr, Leu, Ile, Glu, Asp, or Lys, or is missing. Xaa 17 It is either Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or it is missing. Xaa 18 Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, mata is Lys, Xaa 19 These are Tyr, Phe, Trp, Glu, Asp, or Lys. Xaa 20 These are Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys. Xaa 21 is Glu, Asp, or Lys, Xaa 22 These are Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys. Xaa 23 These are Gln, Asn, Arg, Glu, Asp, or Lys. Xaa 24 These are Ala, Gly, Ser, Tr, Leu, Ile, Val, Arg, Glu, Asp, or Lys. Xaa 25 These are Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys. Xaa26 These are Lys, Arg, Gln, Glu, Asp, or His. Xaa 27 This is Glue, Asp, or Lys, Xaa 30 These are Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys. Xaa 31 These are Trp, Phe, Tyr, Glu, Asp, or Lys. Xaa 32 These are Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys. Xaa 33 These are Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys. Xaa 34 These are Lys, Arg, Glu, Asp, or His. Xaa 35 These are Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys. Xaa 36 These are Arg, Lys, Glu, Asp, or His. Xaa 37 It is either Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or it is missing. Xaa 38 It is either Arg, Lys, Glu, Asp, or His, or it is missing. Xaa 39 It is either Arg, Lys, Glu, Asp, or His, or it is missing. Xaa 40 It is either Asp, Glu, or Lys, or it is missing. Xaa 41 It is either Phe, Trp, Tyr, Glu, Asp, or Lys, or it is missing. Xaa 42It is either Pro, Lys, Glu, or Asp, or it is missing. Xaa 43 It is either Glu, Asp, or Lys, or it is missing. Xaa 44 It is either Glu, Asp, or Lys, or it is missing. Xaa 45 It is either Val, Glu, Asp, or Lys, or it is missing. Alternatively, it may be an ester, amide, or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, Xaa 37 Xaa 38 Xaa 39 Xaa 41 Xaa 42 Xaa 43 or Xaa 44 If Xaa is missing, then each amino acid downstream of that amino acid is also missing. In some embodiments, Xaa8, Xaa9, Xaa 10 Xaa 11 Xaa 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 or Xaa 17 If an amino acid is deleted at a specific position, then all amino acids upstream of that amino acid are also deleted.

[0136] In certain embodiments, the GLP-1 agonist is expressed by formula (N-II): [ka] It includes the structure.

[0137] In certain embodiments, in formula (N-II), Xaa8 is Ala. In certain embodiments, Xaa9 is Glu. In certain embodiments, Xaa 11 is Thr. In a particular embodiment, Xaa 14 is Ser. In certain embodiments, Xaa16 is Val. In a particular embodiment, Xaa 17 is Ser. In certain embodiments, Xaa 18 is Ser. In certain embodiments, Xaa 19 is Tyr. In certain embodiments, Xaa 20 is Leu. In certain embodiments, Xaa 21 is Glu. In a particular embodiment, Xaa 22 is Gly. In certain embodiments, Xaa 23 is Gln. In a particular embodiment, Xaa 24 This is Ala. In certain embodiments, Xaa 25 This is Ala. In certain embodiments, Xaa 26 This is Lys. In certain embodiments, Xaa 27 is Glu. In a particular embodiment, Xaa 30 This is Ala. In certain embodiments, Xaa 31 is Trp. In a particular embodiment, Xaa 32 is Leu. In certain embodiments, Xaa 33 is Val. In a particular embodiment, Xaa 34 is Arg. In certain embodiments, Xaa 35 is Gly. In certain embodiments, Xaa 36 is Arg. In certain embodiments, Xaa 37 It is Gly.

[0138] In a particular embodiment, in formula (N-II), Xaa8 is Ala, Xaa9 is Glu, and Xaa 11 is Thr, Xaa 14 is Ser and Xaa 16 is Val, Xaa 17 is Ser and Xaa 18 is Ser and Xaa 19 is Tyr and Xaa 20 is Leu and Xaa 21 is Glu, Xaa 22 Gly and Xaa23 is Gln and Xaa 24 is Ala and Xaa 25 is Ala and Xaa 26 Lys and Xaa 27 is Glu, Xaa 30 is Ala and Xaa 31 is Trp, Xaa 32 is Leu and Xaa 33 is Val, Xaa 34 is Arg, Xaa 35 Gly and Xaa 36 is Arg and Xaa 37 It is Gly.

[0139] In some embodiments, in formula (NI) or (N-II), Xaa 26 The ε-amino group of Lys in is optionally substituted with a lipophilic substituent via a spacer. In some embodiments, the lipophilic substituent is (i)CH3(CH2) n CO-(wherein n is 6, 8, 10, 12, 14, 16, 18, 20 or 22), (ii) HOOC(CH2) m CO- (wherein m is 10, 12, 14, 16, 18, 20, or 22), or (iii) litocyl. In some embodiments, the spacer is (i) an unbranched alkane α,ω-dicarboxylic acid group having 1 to 7 methylene groups, (ii) an amino acid residue other than Cys, or (iii) γ-aminobutanoyl. In certain embodiments, the lipophilic substituent is Xaa via the spacer. 26 It is linked to the ε-amino group of Lys.

[0140] In a particular embodiment, Xaa 26 Lys 26 (N ε -Tetradecanoyl). In certain embodiments, Xaa 26 Lys 26 (N ε -(ω-carboxynonadecanoyl)). In certain embodiments, Xaa 26 Lys26 (N ε -(ω-carboxyheptadecanoyl)). In certain embodiments, Xaa 26 Lys 26 (N ε -(ω-carboxyundecanoyl)). In certain embodiments, Xaa 26 Lys 26 (N ε -(ω-carboxypentadecanoyl)). In certain embodiments, Xaa 26 Lys 26 (N ε -Litcoil)) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α -Hexadecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α -Tetradecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α -Litcoil))) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α -Octadecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -decanoyl). In certain embodiments, Xaa 26 Lys 26 (N ε -Hexadecanoyl). In certain embodiments, Xaa 26 Lys 26 (N ε -Octanoyl). In certain embodiments, Xaa 26 Lys 26 (N ε -dodecanoyl). In certain embodiments, Xaa 26 Lys 26(N ε (N 68 (γ-aminobutyroyl-(N γ -Hexadecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-D-glutamyl(N α -Hexadecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α - Dodecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(β-alanil(N α -Hexadecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(α-glutamyl(N α -Hexadecanoyl))) In certain embodiments, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α -decanoyl))) In certain embodiments, Xaa 34 Arg 34 -GLP-1(7-37). In a specific embodiment, Xaa 26 Lys 26 (N ε -(γ-glutamyl(N α - Dodecanoyl))) and Xaa 34 Arg 34 -GLP-1(7-37).

[0141] In certain embodiments, exemplary GLP-I agonists are [ka] It has the structure of [the object]. In the embodiment, the GLP-1 agonist may be liraglutide.

[0142] GLP-1 agonists having formula (NI) or (N-II), and variants thereof, may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in U.S. Patent No. 6,268,343 (the entire contents of which are incorporated herein by reference).

[0143] In one embodiment, the GLP-1 agonist comprises at least one GLP-1 domain fused with recombinant human albumin. In some embodiments, the GLP-1 domain has approximately 80%, 85%, 90%, 95%, or 99% amino acid sequence homology with endogenous human GLP-1 (SEQ ID NO: 1 or 2).

[0144] In certain embodiments, the GLP-1 agonist has the amino acid sequence of SEQ ID NO: 9. [ka]

[0145] In one embodiment, a GLP-1 agonist may comprise at least one GLP-1 domain and an Fc moiety of an immunoglobulin fused to one or more GLP-1 domains. In some embodiments, the linker in (OI) is a polymer linker (e.g., PEG). In some embodiments, the linker in (OI) is a peptide linker. For example, the N-terminal glycine of the peptide linker is directly fused to the C-terminal glycine residue of the GLP-1 domain, and the C-terminal serine of the linker (e.g., peptide or polymer) is directly fused to the N-terminal alanine of the Fc moiety.

[0146] In some embodiments, the GLP-1 agonist is expressed by formula (OI) [ka] It has the structure of [the object].

[0147] In some embodiments, the GLP-1 domain has homology or sequence similarity of approximately 80%, 85%, 90%, or 95% or more to human GLP-1 (SEQ ID NO: 1 or 2).

[0148] In certain embodiments, the GLP-1 agonist may comprise at least one GLP-1 domain selected from SEQ ID NOs: 10-15, the peptide linker of SEQ ID NO: 16, and a fusion Fc moiety of an immunoglobulin having the amino acid sequence of SEQ ID NO: 17. [Table 3-1] [Table 3-2]

[0149] In certain embodiments, Xaa8 is Gly. In certain embodiments, Xaa 16 This is Pro or Glu. In certain embodiments, Xaa 17 is Phe, Val, or Ala. In certain embodiments, Xaa 18 is Leu, Glu, or Ala. In certain embodiments, Xaa 80 This is Asn or Ala. In certain embodiments, Xaa 230 It is either Lys or does not exist.

[0150] In certain embodiments, the GLP-1 agonist has the amino acid sequence of SEQ ID NO: 18. [ka]

[0151] GLP-1 agonists having formula (OI), and their variants, may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in WO2005 / 000892 and / or U.S. Patent No. 7,452,966 (the full contents of which are incorporated herein by reference).

[0152] In certain embodiments, the GLP-1 agonist may contain 6-lysine conjugated to exendin 4 at its C-terminus or N-terminus (SEQ ID NOs: 19, 20, 22, 24, 25, or 26). The peptide may be further modified such that the C-terminal glycine residue is removed and replaced with an amide group. [Table 4-1] [Table 4-2]

[0153] In the embodiment, the GLP-1 agonist may be lixisenatide.

[0154] GLP-1 agonists and their variants (e.g., conjugates) may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in U.S. Patent No. 6,528,486 (the entire contents of which are incorporated herein by reference).

[0155] In one embodiment, a GLP-1 agonist may comprise at least one GLP-1 domain (e.g., exendin 4) and one or more IgG4 molecules (e.g., the Fc portion of an immunoglobulin) fused to the GLP-1 domain. For example, a polymer linker (e.g., PEG) is covalently bonded to one of the amino acids of the GLP-1 domain, and the IgG4 peptide is fused to the GLP-1 domain.

[0156] In certain embodiments, the GLP-1 agonist is given by formula (O-II) [ka] It has the structure of [the object].

[0157] In some embodiments, the GLP-1 domain in formula (O-II) has a sequence homologous to exendin 4 (sequence number 3), e.g., about 80%, 85%, 90%, or 95% or more homology or similarity. In certain embodiments, the GLP-1 domain has a sequence of exendin (e.g., exendin 4, sequence number 3).

[0158] In some embodiments, the linker in (O-II) is a polymer linker (e.g., PEG). In some embodiments, the linker in (O-II) is a peptide linker. In some embodiments, the linker in (O-II) is a polymer-peptide hybrid.

[0159] In certain embodiments, the GLP-1 domain has the sequence of SEQ ID NO: 27. In certain embodiments, the Fc portion of the immunoglobulin has the sequence of SEQ ID NO: 28. In certain embodiments, the GLP-1 agonist includes the amino acid sequence of SEQ ID NO: 27 and the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the N-terminus of SEQ ID NO: 28 is linked to Lys at the 26th amino acid (the underlined portion in SEQ ID NO: 27) via a polymer linker. [Table 5]

[0160] In one embodiment, the GLP-1 agonist is given by formula (PI): [ka] Having a structure, During the ceremony, Xaa1 is Aib, Xaa2 is Aib, Xaa3 is Phe or 1-Nal(1-naphthylalanine), p1 is 1 to 2, and p2 is between 10 and 20.

[0161] In a particular embodiment, the GLP-1 agonist is given by formula (P-II): [ka] Having a structure, p1 is as described above.

[0162] In some embodiments, p1 is 1. In some embodiments, p1 is 2.

[0163] In certain embodiments, the GLP-1 agonist is [ka] It has the structure of [the object]. In this embodiment, the GLP-1 agonist is tilzepatide.

[0164] GLP-1 agonists having formulas (PI), (P-II), and their subgroups may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in Sun B, et al. Proc Natl Acad Sci US A. 2022 Mar 29;119(13), Bokvist KB, Coskun T., Cummins RC, Alsina-Fernandez J., US No. 9,474,780 (the full contents of which are incorporated herein by reference).

[0165] In one embodiment, the GLP-1 agonist is given by equation (QI): [ka] Having the structure or a pharmaceutically acceptable salt thereof, During the ceremony, Each R Q1 These are independently F, Cl, -CN, -CH3, or -CF3, q1 is 0, 1, 2, or 3. Each R Q2 These are independently F, Cl, or -CN, q2 is 0, 1, or 2. Each R Q3 These are independently F, -OH, -CN, and -C 1~3 Alkyl, -OC 1~3 Alkyl, or -C 3~4 It is either cycloalkyl or R Q3 These two combine into a ring, C 3~4 A spirocycloalkyl group may be formed, where C 1~3 Alkyl and -OC 1~3 Alkyl, cycloalkyl, or spirocycloalkyl groups may be substituted with 0 to 3 F atoms and 0 to 1 -OH group, to the extent permitted by their valence. q3 is 0, 1, or 2. Y is either CH or N. R Q4 is -CH2CH2OCH3, C 1~3 Alkilen-R Q5 , or C 1~3 Alkilen-R Q6 And here, R Q5 is a substituted (e.g., substituted with halogen, alkyl, amine, or alkoxy) or unsubstituted 4-6 member heterocycloalkyl, and R Q6 These are substituted (e.g., substituted with halogens, alkyls, amines, or alkoxys) or unsubstituted 5-6 member heteroaryl compounds. Z Q1 is either CH or N; Z Q2 and Z Q3 These are, independently, -CR QZ Or N, however Z 1 or Z 3 If Z is N, Q2 -CR QZ and Each R QZ These are independently H, F, Cl, or -CH3.

[0166] In some embodiments, Z Q1 , Z Q2 , and Z Q3is -CH=. In a particular embodiment, GLP-1 is (Q-II): [ka] Having a structure, R Q1 , R Q2 , R Q3 , R Q4 q1, q2, and q3 are as described above.

[0167] In some embodiments, Y is -CH-. In a particular embodiment, GLP-1 is (Q-III): [ka] Having a structure, R Q1 , R Q2 , R Q3 , R Q4 q1, q2, and q3 are as described above.

[0168] In some embodiments, R Q4 is, -CH 2 -R Q5 And R Q5 teeth, [ka] That is the case.

[0169] In some embodiments, q1 is 1 or 2. In some embodiments, each R Q1 These are, independently, halogen, C 1~3 It is alkyl or -CN. In some embodiments, q2 is 0. In some embodiments, q3 is 0.

[0170] In certain embodiments, the GLP-1 agonist has the following structure: [ka] It holds. In this embodiment, the GLP-1 agonist may be danuglypron.

[0171] GLP-1 agonists having formulas (QI), (Q-II), (Q-III) and their subgroups may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in WO2018 / 109607 and / or U.S. Patent No. 11,512,070 (the full contents of which are incorporated herein by reference).

[0172] In one embodiment, the GLP-1 agonist is given by equation (Q-IV): [ka] Having a structure, In the formula, Y, Z Q1 , Z Q2 , Z Q3 , R Q1 , R Q2 , R Q3 , R Q4 q1, q2, and q3 are as described above.

[0173] In some embodiments, Z Q1 , Z Q2 , and Z Q3 is -CH=. In some embodiments, the GLP-1 agonist is (QV): [ka] Having a structure, In the formula, Y, Z Q1 , Z Q2 , Z Q3 , R Q1 , R Q2 , R Q3 , R Q4 q1, q2, and q3 are as described above.

[0174] In some embodiments, Y is -CH-. In certain embodiments, GLP-1 is (Q-VI): [ka] Having a structure, In the formula, R Q1 , R Q2 , R Q3 , R Q4 q1, q2, and q3 are as described above.

[0175] In some embodiments, R Q4 is, -CH 2 -R Q5 And R Q5 teeth, [ka] That is the case.

[0176] In some embodiments, q2 is 1 and R Q2 is -CH3-. In a particular embodiment, GLP-1 is (Q-VII): [ka] Having a structure, In the formula, R Q1 , R Q3 , R Q4 Q1 and Q3 are as described above.

[0177] In some embodiments, q1 is 1 or 2. In some embodiments, each R Q1 These are, independently, halogen, C 1~3 It is alkyl or -CN. In some embodiments, q3 is 0.

[0178] In certain embodiments, the GLP-1 agonist has the following structure: [ka] It has the following characteristics. In the embodiment, the GLP-1 agonist may be rotiglypron.

[0179] GLP-1 agonists having formulas (Q-IV), (QV), (Q-VI), and (Q-VII), and their subgroups, may be synthesized or expressed and assayed in vitro or in vivo, for example, as described in U.S. Patent Publications US2022 / 0348564 and US2022 / 0193063 (the entire contents of which are incorporated herein by reference).

[0180] In one embodiment, the GLP-1 agonist is given by formula (RI): [ka] Having a structure, In the formula, X R1 This is -N= or -CH=, Y R1 It is selected from -C(=O)-, -CH-, and -S(=O)2-, Q R1 C 6~10 It is an aryl or 5-10 member heteroaryl, where C 6~10 Aryl and 5-10 membered heteroaryls are optionally composed of a halogen atom, C 1~6 Alkyl (where C 1~6 Alkyl is optionally substituted with one or more halogen atoms) and C 1~6 With 1 to 5 substituents independently selected from the alkoxy, Q R2 This is a 3-12 member heterocyclyl or a 5-10 member heteroaryl, where the 3-12 member heterocyclyl and 5-10 member heteroaryl are optionally a halogen atom, C 1~6 Alkyl (where C 1~6 Alkyl is optionally substituted with one or more halogen atoms), C 1~6 Alkoxy and -NR Ra R Rb Substituted with 1 to 3 substituents independently selected from and 2 C 1~6 Alkyl alkyl groups, along with the carbon atoms to which they are bonded, are C 3~8 It can form a carbocyclic ring, and R Ra and R RbC is a hydrogen atom. 1~6 Alkyl, and (C 1~6 Independently selected from alkyl)carbonyl, R R1 , R R2 , and R R3 These are a hydrogen atom and C, respectively. 1~6 Alkyl (where C 1~6 Alkyl elements can optionally include halogen atoms and C 1~6 (Substituted with one or more substituents independently selected from alkoxy and hydroxyl) R R4 , R R5 and R R6 This includes hydrogen atoms, halogen atoms, and C 1~6 Selected independently of alkyl, R R7 and R R8 These are, independently, hydrogen atoms or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms can optionally include halogen atoms and C 3~15 Substituting with one or more substituents independently selected from the cycloalkyl group, or R R7 and R R8 Together with the carbon atoms to which they are bonded, C 3~15 A cycloalkane ring may be formed, where R R7 and R R8 C formed by these together 3~15 The cycloalkane ring can optionally contain 1 to 3 carbon atoms. 1~6 Substituted with alkyl, where C 1~6 Alkyl atoms can optionally be halogen atoms, hydroxyl atoms, or -NR 7a R 7b , C 1~6 Substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines, and R 7a and R 7b C is a hydrogen atom. 1~6 Alkyl, and (C 1~6 Independently selected from alkyl)carbonyl, r1 is an integer between 0 and 3, and r2 is an integer between 0 and 5. RR9 teeth, [ka] -CO2R R9F , and -C(=O)-NR R9G R R9H Selected from the group consisting of, R R9A , R R9B , R R9C , R R9D , and R R9G These are, independently, hydrogen atoms and C 1~6 Alkyl (where C 1~6 Alkyl atoms can optionally include halogen atoms and C 1~6 (substituted with one or more substituents independently selected from the alkoxykill), and (C 1~6 Independently selected from alkyl)carbonyl, R R9E C is optionally substituted with a hydrogen atom or one or more halogen atoms. 1~6 It is alkyl, R R9G is a hydrogen atom or C 1~6 It is alkyl, R R9H C is a hydrogen atom. 1~6 Alkyl, (C 1~6 Alkyl)carbonyl, cyano, or -S(=O) r3 -R R9I And R3 is an integer from 0 to 2, and R R9I C 1~6 It is alkyl, Z R1 teeth, [ka] Selected from the group consisting of, In the formula, R RZA C is a hydrogen atom. 1~6 Alkyl, and (C 1~6 Selected from alkyl)carbonyl, R RZB and R RZC These are, independently, hydrogen atoms, or C 1~6It is an alkyl group, where r4 is an integer from 1 to 3, and r5 and r6 are independently integers from 0 to 10 (* represents the bond position with the pyrazolopyridine structure, and ** represents Z R2 (This indicates the connection position with) Z R2 C 1~6 Alkyl, C 3~15 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Selected from the group consisting of aryls and 5-10 membered heteroaryls, where C 3~15 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5-10 member heteroaryls are optional. Oxo, halogen, -CN, -NR RZD R RZE (Here, R RZD and R RZE C is a hydrogen atom. 1~6 Alkyl, and (C 1~6 Independently selected from alkyl)carbonyl, where C 1~6 Alkyl atoms can optionally include hydroxyl, halogen, and C atoms. 1~6 (Substituted with one or more substituents independently selected from the alkoxy), -C(=O)-NR RZF R RZG (Here, R RZF and R RZG C is a hydrogen atom. 1~6 Alkyl, and (C 1~6 Independently selected from alkyl)carbonyl, where C 1~6 Alkyl atoms can optionally include hydroxyl, halogen, and C atoms. 1~6 (Substituted with one or more substituents independently selected from the alkoxy), -S(=O) r7 -R RZH (Here, r7 is an integer from 0 to 2, and R RZH is a hydrogen atom or C 1~6 Alkyl, g)C 1~6 It is alkyl, and here, C 1~6Alkyl atoms can optionally be halogen atoms, hydroxyl atoms, or -NR RZI R RZJ , C 1~6 Substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines, where R TZI and R RZJ These are, independently, hydrogen atoms, or C 1~6 It is alkyl, and here, the 3-12 member heterocyclyl is optionally hydroxy, C 1~6 (Substituted with one or more substituents independently selected from alkyl and 3- to 12-membered heterocyclines), C 1~6 Alkoxy(where C 1~6 The alkoxy can optionally contain a hydroxyl atom, a halogen atom, and C. 1~6 (Substituted with one or more substituents independently selected from the alkoxy), 3-12 member heterocyclines (where 3-12 member heterocyclines are selected at will, C 1~6 Alkyl and (C 1~6 (substituted with one or more substituents independently selected from the alkyl (carbonyl) group), C 6~10 Ariel (here, C 6~10 Aaryl is optional, with one or more (C 1~6 )alkyl)carbonyl, optionally substituted with a 5-10 member heteroaryl, where the 5-10 member heteroaryl is optionally C 1~6 Alkyl, C 1~6 (Substituted with one or more substituents independently selected from the alkoxy), -NR RZK R RZL , and 3-12 member heterocyclines (where R RZK and R RZL C is a hydrogen atom. 1~6 Alkyl and (C 1~6 Independently selected from alkyl)carbonyl, where 3-12 member heterocyclyls are optionally selected, C 1~6 Alkyl and (C 1~6 (substituted with one or more substituents independently selected from the alkyl (carbonyl) group), Alternatively, these salts may be substituted with 1 to 5 substituents independently selected from them.

[0181] In some embodiments, Y R1 is -C(=O)-. In some embodiments, X R1 is -CH=. In certain embodiments, the GLP-1 agonist has the following structure: [ka] It holds.

[0182] In some embodiments, Q R1 is phenyl or pyridyl, and phenyl or pyridyl is a halogen (e.g., F, Cl, or Br) and C 1~6 It is substituted with 1 to 4 substituents independently selected from the alkyl group. In some embodiments, Q R1 Q is a phenyl compound substituted with one or more elements independently selected from halogens (e.g., F, Cl, or Br) and methyl. In some embodiments, Q R1 teeth, [ka] That is the case.

[0183] In some embodiments, Q R2 is a 6-membered heterocyclyl or a 5-6 membered heteroaryl, and the 6-membered ring heterocyclyl and the 5-6 membered heteroaryl are independently and optionally comprised of one or more C 1~6 Alkyl-substituted and two C 1~6 Alkyl alkyl groups, together with the carbon atoms to which they are bonded, form C 3~8 A carbon-cyclic ring can be formed. In some embodiments, Q R2 is one or more C 1~6 Optionally substituted with alkyl groups [ka] In some embodiments, Q R2 teeth, [ka] That is the case.

[0184] In some embodiments, Z R2 C 1~6 Alkyl, C 3~15 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, where C 3~15 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5-10 member heteroaryls are optionally selected as oxo, halogen, and C. 1~6 It is substituted with 1 to 4 substituents independently selected from the alkyl group. In some embodiments, Z R2 These are oxo, halogen, and C 1~6 Optionally substituted with alkyl groups [ka] In a particular embodiment, Z R2 These are oxo, halogen, and C 1~6 Optionally substituted with alkyl groups [ka] In some embodiments, Z R2 teeth, [ka] That is the case.

[0185] Several embodiments, each R R1 and R R3 These are, independently, hydrogen or C 1~3 It is alkyl. In some embodiments, R R1 is hydrogen. In some embodiments, R R1 C 1~3 It is alkyl. In some embodiments, R R3 is hydrogen. In some embodiments, R R3 C 1~3It is alkyl. In certain embodiments, R R1 is hydrogen, and R R3 It is methyl.

[0186] Several embodiments, each R R7 and R R8 These are, independently, hydrogen or C 1~6 It is alkyl. In some embodiments, R R7 and R R8 Both are hydrogen. In some embodiments, R R7 and R R8 Both are C 1~6 It is alkyl. In some embodiments, R R7 is a hydrogen atom, and R R8 C 1~6 It is alkyl.

[0187] In some embodiments, R R7 and R R8 Together with the carbon atoms to which they are bonded, C 3~8 C that forms and is formed on a cycloalkane ring 3~8 Cycloalkyl groups are optionally composed of 1-2 C 1~6 substituted with alkyl, and C 1~6 Alkyl is optional, hydroxy, C 1~6 It is substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines.

[0188] In some embodiments, both r1 and r2 are 0. In some embodiments, R 9 teeth, [ka] That is. R R9B As stated above.

[0189] In a particular embodiment, [ka] teeth, [ka] It has the structure of [the object].

[0190] In some embodiments, Z R1 teeth, [ka] In the formula, * represents the binding position with the pyrazolopyridine structure, and ** represents Z 2 This indicates the connection point with [the other element].

[0191] In some embodiments, Z R2 C 1~6 Alkyl, C 3~15 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, where C 3~15 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5-10 member heteroaryls are optionally selected as oxo, halogen, and C. 1~6 It is substituted with 1 to 4 substituents independently selected from the alkyl group. In some embodiments, Z R2 These are oxo, halogen, and C 1~6 Optionally substituted with alkyl groups [ka] In a particular embodiment, Z R2 These are oxo, halogen, and C 1~6 Optionally substituted with alkyl groups [ka] In some embodiments, Z R2 teeth, [ka] That is the case. In some embodiments, -Z R1 -Z R2 -teeth, [ka] That is the case.

[0192] In certain embodiments, exemplary GLP-1 agonists of formula (RI) or (R-II) are: [ka] That is the case. In this embodiment, the GLP-1 agonist may be olformlipron.

[0193] GLP-1 agonists having formulas (RI), (R-II), and their subgroups may be synthesized or expressed and assayed in vitro, for example, as described in WO2018 / 056453 and U.S. Patent No. 10,858,356 (the full contents of which are incorporated herein by reference).

[0194] In one embodiment, the GLP-1 agonist may have the sequence of sequence numbers 29-30. [Table 6] In embodiments, the GLP-1 agonist may be letatoltide. In embodiments, the GLP-1 agonist may be taspoglutide.

[0195] Semaglutide (e.g., Ozempic (subcutaneous) and Rybelsus (oral) for diabetes, manufactured by Novo Nordisk and approved in 2017; Wegovy (subcutaneous) for obesity), exenatide (e.g., Byetta (subcutaneous) and Bydureon (subcutaneous, ER) manufactured by AstraZeneca and approved in 2005 / 2012), liraglutide (e.g., Victoza for diabetes, Saxenda for obesity, manufactured by Novo Nordisk and approved in 2010), albiglutide (e.g., Tanzeum, manufactured by GSK and approved in 2014), dulaglutide (e.g., Eli Various GLP-1 agonists have been developed to date, including Trulicity (manufactured by Lilly and approved in 2014), lixisenatide (e.g., Adlyxin, manufactured by Sanofi and approved in 2016), and tilzepatide (e.g., Mounjaro, manufactured by Eli Lilly in combination with a GIP analog and approved in 2022). The GLP-1 agonists disclosed herein may be used in the treatment of metabolic diseases, such as type 2 diabetes, by playing a crucial physiological role in glucose homeostasis, for example, by stimulating insulin production and secretion and promoting the proliferation of healthy pancreatic β-cells. Furthermore, the GLP-1 agonists disclosed herein may contribute to weight loss by suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism, and reducing fat deposition.

[0196] definition As used herein, the term “heteroatom” means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen (N), oxygen (O), and sulfur (S).

[0197] The term "halogen" or "halo" represents -F, -Cl, -Br, or -I. Preferred halogens are -F, -Cl, and -Br.

[0198] The term "hydroxyl" means -OH.

[0199] As used herein, the term "oxo" refers to an oxygen atom (i.e., substituent = O) that has a double bond to another atom, particularly to carbon.

[0200] The term "alkyl" refers to the radical of a saturated aliphatic group, including linear and branched alkyl groups. Therefore, C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and others.

[0201] The term "cycloalkyl" refers to a saturated carbocyclic group having 3 to 7 carbon atoms in its ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0202] The term "alkenyl" refers to a linear or branched hydrocarbyl ("C2-C6 alkenyl") having a double bond and 2 to 6 carbon atoms. Examples of alkenyls include vinyl, 1-propenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. If the compounds of this disclosure contain an alkenyl group, the compounds may exist as E-type, Z-type, or any mixture thereof.

[0203] The term "alkynyl" refers to a linear or branched hydrocarbyl ("C2-C6 alkynyl") having a triple bond and 2 to 6 carbon atoms. Examples of alkynyls include ethynyl and propynyl.

[0204] As used herein, the term “aryl” includes five- and six-membered monocyclic aromatic groups that may contain 0 to 4 heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups having heteroatoms in their ring structure may also be referred to as “aryl heterocyclic,” “heteroaromatic,” or “heteroaryl.” The term “aryl” also includes seven- to fourteen-membered polycyclic ring systems having two or more cyclic rings (rings that are “fused rings”) in which two or more carbons are shared by two adjacent rings, wherein at least one of the rings is aromatic (including heteroaryl), and the other cyclic rings may be, for example, fused cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclic groups. A monocyclic heteroaryl group may have 1 to 3 ring heteroatoms, and a condensed polycyclic heteroaryl group may have 1 to 5 ring heteroatoms, with the ring heteroatoms being selected from N, O, and S.

[0205] The terms "heterocyclyl," "heterocyclic," or "heterocycloalkyl" group refer to a 3- to 10-membered ring structure, more preferably a 5- or 6-membered ring, in which the ring structure contains 1 to 4 heteroatoms. The heterocycle may also be polycyclic. Examples of heterocyclic groups include thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactam, for example, azetidinone and pyrrolidinone, sultam, sultone, etc.

[0206] As used herein, the terms "alkylaryl" and "aralkyl" refer to C1-C6 alkyl groups substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0207] As used herein, the definitions of each notation, such as alkyl, m, n, and R, are intended to be independent of their definitions elsewhere in any given structure when they appear more than once in that structure.

[0208] It should be understood that the terms "substituted," "substituted," or "substituted with" imply that such substitution conforms to the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.

[0209] Each of the ROCK2 inhibitors and GLP-1 agonists provided herein may exist and be administered as their pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid addition salts of the compounds disclosed herein, as well as inorganic and organic base addition salts of the compounds disclosed herein. References to ROCK2 inhibitors or GLP-1 agonists are understood to include neutral compounds and any pharmaceutically acceptable salts of the ROCK2 inhibitor or GLP-1 agonist. A pharmaceutically acceptable salt form may be selected according to standard pharmacopoeias based on the chosen route of administration.

[0210] As described above, certain embodiments of ROCK2 and / or GLP-1 agonists may contain basic functional groups such as amino acids and can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. These salts can be prepared in situ in the administration vehicle or dosage form manufacturing process, or separately by reacting the compounds of the present invention in purified free base form with a suitable organic or inorganic acid and isolating the salts thus formed during subsequent purification. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J.Pharm.Sci.66:1-19).

[0211] Examples of pharmaceutically acceptable salts of the subject compound include conventional non-toxic salts or quaternary ammonium salts of the compound derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid (salicyclic), sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isothionic acid.

[0212] In other cases, the compounds provided in this disclosure may contain one or more acidic functional groups and thus be able to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts may similarly be prepared in situ in the administration vehicle or dosage form manufacturing process, or they may be prepared by separately reacting the purified compound in its free acid form with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Typical alkali salts or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine (see, for example, Berge et al. above).

[0213] Certain compounds provided in this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure intends to include all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof, within the scope of the invention. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included in the invention.

[0214] Where defined herein, with respect to protein-inhibitor interactions, terms such as “inhibition,” “to inhibit,” and “to inhibit” mean a negative effect (e.g., reduction) on the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means a negative effect (e.g., reduction) on the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition means the alleviation of a disease or the symptoms of a disease. In embodiments, inhibition means the reduction of the activity of a particular protein target. Thus, inhibition includes, at least partially, partially or completely, blocking a stimulus, reducing, preventing or delaying activation, or inactivating, desensitizing or downmodulating signaling or enzyme activity or the amount of a protein. In embodiments, inhibition means a reduction in the activity of a target protein resulting from a direct interaction (e.g., the inhibitor binds to the target protein). In embodiments, inhibition means a reduction in the activity of a target protein due to an indirect interaction (e.g., the inhibitor binds to a protein that activates the target protein, thereby preventing the activation of the target protein). The term "inhibitor" may include synthetic or biological molecules (e.g., small molecules, nucleic acids, peptides, or antibodies) that inhibit or negatively affect (e.g., reduce) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. Preferred inhibitors are small molecules. Inhibitors can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more compared to a control in the absence of the inhibitor or antagonist. In certain cases, the activity may be 1.5, 2, 3, 4, 5, or 10 times or more lower than the expression or activity in the absence of the inhibitor.

[0215] Obesity / Weight Loss In one embodiment, the method is for the prevention or treatment of obesity or weight loss in a subject, and the method comprises administering a therapeutically effective dose of a ROCK2 inhibitor (e.g., a ROCK2 inhibitor disclosed herein) to the subject.

[0216] Determining who is a candidate for weight loss intervention may begin with an assessment of body type index or BMI. Typically, medication may be prescribed to individuals with a BMI of approximately 30 or higher, or a BMI of approximately 27 or higher, if the person has one or more weight-related health conditions. On an individual case basis, the clinician may consider the patient's current health status, other medications, and family medical history.

[0217] A method for treating and / or promoting weight loss in a subject includes administering a therapeutically effective dose of a ROCK2 inhibitor to the subject in combination, optionally, with one or more additional therapeutic agents and / or pharmaceuticals that may promote weight loss in the subject. Subjects receiving treatment for obesity and / or weight loss may receive dietary calorie restriction, as well as one or more weight-loss medications, such as GLP-1 agonists; sodium-glucose transporter 2 (SGLT2) inhibitors such as bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, sotagliflozin and tofogliflozin; lipase inhibitors such as orlistat (Alli,Xenical); melanocortin 4 receptor agonists such as cetomelanotide (Imcivree); naltrexone-bupropion; phentermine; phentermine-topiramate; metformin; diethylpropion (amphepramon); and combinations thereof. In one embodiment, the treatment method comprises a therapeutically effective dose of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist.

[0218] Weight loss is a key goal in the management of several chronic conditions, including type 2 diabetes. GLP-1 agonists, SGLT2 inhibitors, and other therapeutic agents can promote or induce clinically significant weight loss. However, this weight loss may not be solely due to a decrease in body fat mass or the subject's overall weight. When a subject loses weight, not all of the resulting weight loss can be attributed to a decrease in the patient's body fat mass. Rather, a significant portion of the weight loss (e.g., approximately 25%–33%) may be a result of a decrease in lean body mass and, primarily, a loss of skeletal muscle. This is important because skeletal muscle has several crucial functions in terms of physical function and quality of life, and in terms of the subject's metabolic health. Skeletal muscle acts as the primary site for glucose processing (lower skeletal muscle mass contributes to poorer glycemic control) and is a strong determinant of resting metabolic rate. Therefore, the loss of skeletal muscle that occurs with weight loss can increase the subject's chances of weight regrowth. Given the importance of skeletal muscle and lean body mass to metabolic health and physical function, maintaining muscle mass during weight loss is a crucial consideration. Consequently, attention should be paid to muscle loss in subjects undergoing weight loss induced by GLP-1 agonists, SGLT2 inhibitors, dietary restrictions, bariatric surgery, or other treatments to facilitate weight loss.

[0219] Advantageously, the inventors have found that when a ROCK2 inhibitor is administered to a subject undergoing weight loss, the amount of lean body mass and / or skeletal muscle lost by the subject during weight loss is significantly reduced. In aspect, the present disclosure provides a method for maintaining muscle mass in a subject undergoing treatment for obesity and / or experiencing weight loss by administering a therapeutically effective dose of a ROCK2 inhibitor to the subject during treatment / weight loss. Patients receiving treatment for obesity and / or weight loss may receive one or more of the following: dietary calorie restriction, as well as weight-loss medications, such as GLP-1 agonists; sodium-glucose transporter 2 (SGLT2) inhibitors such as bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, erzgliflozin, ipragliflozin, luseogliflozin, sotagliflozin, and tofogliflozin; lipase inhibitors such as orlistat (Alli, Xenical); melanocortin 4 receptor agonists such as cetomelanotide (Imcivree); naltrexone-bupropion; phentermine; phentermine-topiramate; metformin; diethylpropion (amphepramon); and combinations thereof. In embodiments, the treatment comprises a therapeutically effective dose of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist.

[0220] In one embodiment, the present disclosure provides a method for treating or preventing obesity in a subject, the method comprising (i) administering a therapeutically effective amount of (6-(4-((4-(1H-pyrazole-4-yl)phenyl)amino)pyrimidine-2-yl)-1-methyl-1H-indole-2-yl)(3,3-difluoroazetidine-1-yl)methanone (compound A) or a pharmaceutically acceptable salt thereof to the subject, and optionally (ii) a therapeutically effective amount of a glucagon-like peptide (GLP-1) agonist to the subject.

[0221] In one embodiment, the present disclosure provides a method for promoting weight loss in a subject, the method comprising (i) administering a therapeutically effective amount of (6-(4-((4-(1H-pyrazole-4-yl)phenyl)amino)pyrimidine-2-yl)-1-methyl-1H-indole-2-yl)(3,3-difluoroazetidine-1-yl)methanone (compound A) or a pharmaceutically acceptable salt thereof to the subject, and optionally (ii) a therapeutically effective amount of a glucagon-like peptide (GLP-1) agonist to the subject.

[0222] In one embodiment, the present disclosure provides a method for reducing or preventing muscle loss in patients being treated for obesity, weight loss, and / or type 2 diabetes, the method comprising administering a therapeutically effective amount of (6-(4-((4-(1H-pyrazole-4-yl)phenyl)amino)pyrimidine-2-yl)-1-methyl-1H-indole-2-yl)(3,3-difluoroazetidine-1-yl)methanone (compound A) or a pharmaceutically acceptable salt thereof to the target. Treatments for obesity, weight loss, and / or type 2 diabetes may include dietary calorie restriction, obesity or other surgical interventions, as well as the administration of one or more weight-loss medications, e.g., GLP-1 agonists, sodium-glucose transporter 2 (SGLT2) inhibitors, lipase inhibitors, melanocortin 4 receptor agonists, naltrexone-bupropion, phentermine, phentermine-topiramate, metformin, diethylpropion (amphepramon), and combinations thereof.

[0223] type 2 diabetes In another embodiment, the method is used in reducing HbA1c; and / or in the prevention or treatment of type 2 diabetes, hyperglycemia, or impaired glucose tolerance, and the method comprises administering a therapeutically effective dose of a ROCK2 inhibitor to a subject in need thereof.

[0224] In one embodiment, the disclosure provides a method for reducing glycated hemoglobin (HbA1c) in a subject by administering a therapeutically effective dose of a ROCK2 inhibitor to the subject. HbA1c is an important indicator of long-term glycemic control, having the ability to reflect the cumulative glycemic history over the past two to three months. HbA1c levels not only provide a reliable criterion for chronic hyperglycemia but also correlate well with the risk of long-term diabetic complications. Elevated HbA1c is also an independent risk factor for coronary heart disease and stroke in a subject, with or without diabetes. In another embodiment, the disclosure provides a method for improving or even restoring insulin sensitivity in a patient suffering from decreased insulin sensitivity (insulin resistance) by administering a therapeutically effective dose of a ROCK2 inhibitor to the patient. In embodiments, the patient may be diagnosed with type 2 diabetes, or the patient may be recognized or diagnosed as being at high risk of developing type 2 diabetes and / or recognized or diagnosed as experiencing symptoms of developing type 2 diabetes or progression to type 2 diabetes (i.e., prediabetes). Insulin resistance reduces glucose transport to cells, leading to compensatory increases in β-cellular insulin production and hyperinsulinemia. Metabolic consequences of insulin resistance can include hyperglycemia, hypertension, dyslipidemia, hyperuricemia, elevated inflammatory markers, endothelial dysfunction, and prothrombotic conditions. Insulin resistance is a major factor in the development of type 2 diabetes, cardiovascular disease, fatty liver disease, neurodegenerative diseases, and obesity-related cancers. Treatment with ROCK2 inhibitors may reduce or reverse insulin resistance and improve or restore blood glucose levels.

[0225] In another embodiment, the disclosure provides a method for reducing muscle atrophy in various atrophic conditions. Muscle atrophy is caused by an imbalance in the synthesis and breakdown of contractile proteins, which can be induced by various pathological conditions, including type 2 diabetes. In one embodiment, the method is to reduce or prevent muscle loss associated with type 2 diabetes, and the method comprises administering a therapeutically effective dose of a ROCK2 inhibitor to a patient in need. In patients with inadequate insulin management, it is thought that insufficient insulin action inhibits muscle cell growth and proliferation, thereby leading to a decrease in skeletal muscle mass in diabetic individuals. Patients with type 2 diabetes may initially exhibit mild muscle atrophy in middle age, which can become more substantial with age and diabetic neuropathy. Poor muscle quality in patients with type 2 diabetes can negatively impact muscle function, ability to perform daily activities, and quality of life, ultimately increasing the risk of premature death. Systemic inflammation caused by obesity and chronic overnutrition not only contributes to insulin resistance but also promotes muscle atrophy through decreased muscle protein synthesis and increased ubiquitin-proteasome, lysosomal-proteasome, and caspase-3-mediated proteolysis. New findings suggest that the inflammation-sensitive nuclear factor κB (NF-κB) and signaling transcription factor 3 (STAT3) pathways contribute to muscle atrophy in patients with type 2 diabetes. Furthermore, in the muscles of obese patients with type 2 diabetes, various pro-inflammatory pathways, including chemokine (cc motif) ligand (CCL2), STAT3, cytokine signaling 3 suppressor (SOCS3), and NF-κB, undergo upregulation.

[0226] In one embodiment, the present disclosure provides a method for treating a target type 2 diabetes, the method comprising (i) administering a therapeutically effective amount of (6-(4-((4-(1H-pyrazole-4-yl)phenyl)amino)pyrimidine-2-yl)-1-methyl-1H-indole-2-yl)(3,3-difluoroazetidine-1-yl)methanone (compound A) or a pharmaceutically acceptable salt thereof to the target, and optionally (ii) a therapeutically effective amount of a glucagon-like peptide (GLP-1) agonist to the target.

[0227] Combination therapy Combination therapy including a ROCK2 inhibitor and a GLP-1 agonist may be used for (i) reducing HbA1c, (ii) preventing or treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin-dependent diabetes, and / or (iii) preventing or treating obesity and reducing body weight. The method involves administering a therapeutically effective dose of a GLP-1 agonist and a therapeutically effective dose of a ROCK2 inhibitor to a subject in need.

[0228] The methods disclosed herein involve administering a combination therapy agent to a target that provides a therapeutically effective dose of a ROCK2 inhibitor and a therapeutically effective dose of a GLP-1 agonist. ROCK2 inhibitors may include one or more compounds having formulas (AI), (BI), (CI), (DI), (EI), (FI), (GI), (HI), (JI), (KI), (LI) and their subgroups, exemplary compounds thereof, or derivatives thereof that can be obtained or known by those skilled in the art. GLP-1 agonists may include those or compounds having the structure of formulas (MI), (NI), (OI), (O-II), (PI), (QI), (RI) and their subgroups, or exemplary compounds thereof. Alternatively, GLP-1 agonists may include amino acid sequences including, but not limited to, SEQ ID NOs: 4-8, 9, 18 and 19-30. In some embodiments, GLP-1 agonists may include amino acid sequences including, but not limited to, SEQ ID NOs: 1-30. The exemplary compounds or peptides described herein, or their derivatives, may be obtained or known by those skilled in the art or by reference.

[0229] ROCK2 inhibitors and GLP-1 agonists may be co-administered to the patient. “Co-administration” means simultaneous or sequential administration of ROCK2 inhibitors and GLP-1 agonists. ROCK2 inhibitors and GLP-1 agonists may be administered to the patient in separate dosage forms; that is, combination therapy includes administration of a dosage form containing a ROCK2 inhibitor and a dosage form containing a GLP-1 agonist. Alternatively, ROCK2 inhibitors and GLP-1 agonists may be administered to the patient in a combination formulation, for example, a dosage form containing both a ROCK2 inhibitor and a GLP-1 agonist. In some embodiments, the combination formulation is a subcutaneous formulation. In some embodiments, the combination formulation is an oral formulation. In some embodiments, the ROCK2 inhibitor and the GLP-1 agonist may be administered to the patient in separate formulations, for example, ROCK2 as an oral formulation and the GLP-1 agonist as a subcutaneous formulation, or ROCK2 as a subcutaneous formulation and the GLP-1 agonist as an oral formulation. Furthermore, the ROCK2 inhibitor and the GLP-1 agonist may be administered simultaneously or at different times.

[0230] In some embodiments, ROCK2 inhibitors and GLP-1 agonists are co-administered. As used herein, the term “co-administration” refers to any form of administration of ROCK2 inhibitor and GLP-1 agonist therapeutic formulations such that one formulation is administered while the other therapeutic formulation remains effective in the body. Thus, ROCK2 inhibitors and GLP-1 agonists are simultaneously effective in the patient, which may include a synergistic effect of the two drugs. Therefore, patients receiving such treatment may benefit from the additive or synergistic effects of the combined ROCK2 inhibitor and GLP-1 agonist. In particular, combination therapy may result in improved outcomes such as reduced severity, delayed or complete cessation of relapse, or reduced side effects of the primary drug due to prior treatment with the secondary drug.

[0231] In some embodiments, the efficacy or therapeutic effect of a GLP-1 agonist may be improved by at least approximately 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in combination with a ROCK2 inhibitor compared to the same treatment with a GLP-1 agonist alone, as measured, for example, by glucose loading or by measuring blood glucose. In some embodiments, pancreatic insulin production may be increased by at least approximately 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in combination with a ROCK2 inhibitor compared to the same treatment with a GLP-1 agonist alone, as measured, for example, by measuring the patient's blood glucose. In some embodiments, patient obesity, as measured, for example by measuring weight loss, can be reduced or decreased by at least about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more with combination therapy with a ROCK2 inhibitor compared to the same treatment with a GLP-1 agonist as a monotherapy.

[0232] In some embodiments, combination therapy using a ROCK2 inhibitor and a GLP-1 agonist, as well as co-administration methods, may also reduce the dose and / or frequency of GLP-1 agonist administration compared to using a GLP-1 agonist alone or other existing single therapeutic agents, while achieving the same therapeutic effect and / or improvement.

[0233] The routes of administration and regimens of the combinations disclosed herein may vary considerably depending on the pre- and post-treatment conditions, the degree of progress in insulin production, the age and physical condition of the subject, the exact combination selected, and other factors. The administration regimen may include multiple doses at intervals, and the therapeutic agents may be administered simultaneously or sequentially. When the two therapeutic agents are administered sequentially, the first therapeutic agent may be administered 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, or 96 hours before the administration of the second therapeutic agent.

[0234] In some embodiments, the combination therapy includes administering a ROCK2 inhibitor before administering a GLP-1 agonist. For example, the ROCK2 inhibitor-containing therapy may be administered 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, or 96 hours before the GLP-1 agonist is administered. The ROCK2 inhibitor-containing therapy may be administered at the same time (simultaneously) as the GLP-1 agonist-containing therapy. In some embodiments, the ROCK2 inhibitor-containing therapy may be administered additionally 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, or 96 hours after the GLP-1 agonist-containing therapy has been administered.

[0235] ROCK2 inhibitors described herein may preferably include compounds having the structures of formulas (AI), (BI), (CI), (DI), (EI), (FI), (GI), (HI), (JI), (KI), (LI), or their subgroups, or exemplary compounds thereof. ROCK2 inhibitors may be selected from, but are not limited to, Compound A, Compound B, Compound C, Compound D, Belmosdil (KD025), Zelasdil, Y-27632, Fasudil, GSK429286A, RKI-1447, TC-S 7001, TC-S 7004, Hydroxyfasudil, GSK269962A, Lipasudil, AT13148, RX007, and their derivatives, isomers, hydrates, or pharmaceutically acceptable salts.

[0236] In one embodiment, the ROCK2 inhibitor is (6-(4-((4-(1H-pyrazole-4-yl)phenyl)amino)pyrimidine-2-yl)-1-methyl-1H-indole-2-yl)(3,3-difluoroazetidine-1-yl)methanone (compound A), or a pharmaceutically acceptable salt thereof.

[0237] The GLP-1 agonists described herein may include compounds having the structures of formulas (MI), (NI), (OI), (O-II), (PI), (QI), (RI), and their subgroups, or exemplary compounds thereof. GLP-1 agonists may include amino acid sequences including, but not limited to, SEQ ID NOs: 4-8, 9, 18, and 19-30. In some embodiments, GLP-1 agonists may include amino acid sequences including, but not limited to, SEQ ID NOs: 1-30. In some embodiments, GLP-1 agonists are semaglutide, exenatide, lilaglutide, albiglutide, dulaglutide, lixisenatide, tylzepatide, rotiglyprone, letatoltide, taspoglutide, orformlipron, or danuglyprone. In certain embodiments, the GLP-1 agonist is semaglutide. In other embodiments, the GLP-1 agonist is tylzepatide.

[0238] In some embodiments, the ROCK2 inhibitor and the GLP-1 agonist are formulated in a single composition. Alternatively, the ROCK2 inhibitor and the GLP-1 agonist are prepared separately and / or formulated in separate compositions.

[0239] Patients may be those who are recognized or diagnosed as being at high risk of developing type 2 diabetes, and / or who are recognized or diagnosed as having symptoms of developing type 2 diabetes or progressing to type 2 diabetes (i.e., prediabetes). Patients may have a relative with type 2 diabetes, blood tests suggesting that the patient may have developed type 2 diabetes, and / or one or more symptoms associated with developing type 2 diabetes.

[0240] Blood tests may include assays of the patient's blood glucose levels, such as glycated hemoglobin (A1C) testing, random blood glucose testing, or fasting blood glucose testing. An A1C of approximately 5.7–6.4% may indicate prediabetes. In random blood glucose testing, blood samples are taken randomly, and random blood glucose levels of approximately 200 mg / dL (11.1 mmol / L) or higher suggest the development of diabetes. In fasting blood glucose testing, fasting blood glucose levels of approximately 100–125 mg / dL (5.6–6.9 mmol / L) may indicate prediabetes, while fasting blood glucose levels of approximately 126 mg / dL (7 mmol / L) or higher in two separate tests may indicate advanced disease progression or diabetes.

[0241] Pharmaceutical composition In one embodiment, the present disclosure provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of a ROCK2 inhibitor and a therapeutically effective amount of a GLP-1 agonist, each of which is formulated using one or more pharmaceutically acceptable carriers. As described later, the pharmaceutical compositions of this disclosure may be formulated for administration in solid or liquid form, including (1) oral administration, e.g., oral tablets (aqueous or non-aqueous solutions or suspensions), tablets, e.g., for buccal, sublingual, and systemic absorption, boluses for application to the tongue, powders, granules, pastes; (2) parenteral administration, e.g., subcutaneous, intramuscular, intravenous, or epidural injection, e.g., administration by sterile solution or suspension, or sustained-release formulation; (3) topical application, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin; (4) vaginal or rectal administration, e.g., suppositories, vaginal suppositories, creams, or foams; (5) sublingual administration; (6) intraocular administration; (7) transdermal administration; or (8) transnasal administration.

[0242] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues, with toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit-risk ratio.

[0243] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle involved in transporting or carrying the compound of interest from one organ or body part to another, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium or zinc, or stearic acid (steric acid)), solvent, or solvent encapsulation material. Each carrier must be compatible with the other components of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository waxes; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, e.g., pr (11) Polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) Esters, e.g., ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Phenothermally hydrated substances; (17) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) pH buffers; (21) Polyesters, polycarbonates, and / or polyanhydrides; and (22) Other non-toxic and compatible substances used in pharmaceutical formulations.

[0244] The compounds of this disclosure can be formulated using conventional carriers and excipients, which may be selected to conform to common practice. Tablets may contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and may generally be isotonic if intended for delivery by means other than oral administration. All formulations may optionally contain excipients, e.g., those shown in the “Handbook of Pharmaceutical Excipients” (1986). Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid.

[0245] While ROCK2 inhibitors and / or GLP-1 agonists disclosed herein (hereinafter referred to as “active ingredients”) may be administered alone, it may be preferable to provide them as pharmaceutical formulations. Formulations of the present disclosure, both for animal and human use, include, in addition to at least one active ingredient as provided above, one or more acceptable carriers for it, and optionally other therapeutic ingredients, in particular further therapeutic ingredients as described herein.

[0246] A pharmaceutical composition may include a composition containing an active ingredient (e.g., a compound or combination described herein, including embodiments or examples) in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular use may depend, among other things, on the condition being treated. When administered in a manner to treat a disease (e.g., type 2 diabetes), such a composition may contain an amount of the active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule and / or reducing, eliminating, or delaying the progression of disease symptoms (e.g., increasing insulin secretion or regrowth of insulin-producing cells in the pancreas).

[0247] Examples of formulations include those suitable for the route of administration provided herein. The formulations may be conveniently provided in unit dosage forms and may be prepared by any method well known in the field of pharmacy. The techniques and overall formulations can be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods involve the step of combining the active ingredient with a carrier corresponding to one or more adjuncts. Generally, formulations are prepared by uniformly and densely combining the active ingredient with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, shaping the product.

[0248] Formulations of the present disclosure suitable for oral administration may be provided as separate single entities, each containing a predetermined amount of the active ingredient, for example, as capsules, cachets, or tablets; as powders or granules; as liquids or suspensions made of aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be administered as a bolus, lick, or paste.

[0249] Tablets can be produced by compression or wet tableting, optionally with one or more adjuncts. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Wet tablets can be produced by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or imprinted, and optionally formulated to result in a slow or controlled release of the active ingredient therefrom.

[0250] When formulated as an ointment, the active ingredient may be used with an ointment base that is either paraffinic or water-miscible. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base.

[0251] If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400), as well as mixtures thereof. The topical formulation may preferably include compounds that enhance the absorption or penetration of the active ingredient from the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0252] The oil phase of the emulsions of this disclosure may consist of known components in known forms. The phase may simply contain an emulsifier (also known as an emulsion), but preferably a mixture of at least one emulsifier and a fat or oil, or both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. It is also preferable to include both oil and fat. In summary, emulsifiers (or others) with or without stabilizers constitute a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of a cream formulation.

[0253] Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. A further suitable emulsifier and emulsion stabilizer for use in the formulations of the present disclosure is Tween® 80.

[0254] The selection of oils or fats suitable for formulation is based on the ability to produce the desired properties. The cream formulation should preferably be a non-oily, non-staining, washable product with a viscosity suitable for avoiding leakage from tubes or other containers. Linear or branched mononucleotide or dinucleotide alkyl esters, such as di-isoadipates, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or admixtures of branched esters known as crodamolCAP, the latter three being recommended esters. These may be used alone or in combination, depending on the required properties. Alternatively, high-melting-point lipids, such as white soft paraffin and / or liquid paraffin, or other mineral oils may be used.

[0255] The pharmaceutical formulations described herein include, in addition to the combination described herein, one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, oral tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavorings, colorings, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in miscible with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia gum; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to slow disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0256] Formulations for oral use may also be provided as hard gelatin capsules containing the active ingredient mixed with an inert solid diluent, such as starch, mannitol, calcium phosphate, or kaolin, or as soft gelatin capsules containing the active ingredient mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0257] The aqueous suspensions of this disclosure comprise an active material mixed with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, as well as dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxides and partial esters derived from fatty acids and anhydrous hexitol (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins and Captisol (= sulfobutyl ether beta-cyclodextrin; SEB-beta-CD).

[0258] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Oral suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those listed above, and flavorings may be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0259] The dispersible powders and granules of this disclosure, suitable for the preparation of aqueous suspensions by the addition of water, provide the active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Further excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0260] The pharmaceutical compositions of this disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring rubbers, such as acacia rubber and / or tragacanth rubber, naturally occurring phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and anhydrous hexitol, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavorings. The syrups and elixirs may be formulated using sweeteners, such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, or colorings.

[0261] The pharmaceutical compositions of this disclosure may also be in the form of sterile injection preparations, for example, aqueous or oily sterile injection suspensions. These suspensions may be formulated according to known techniques using the preferred dispersants or wetting agents and suspending agents mentioned above. The sterile injection preparations may also be sterile injection solutions prepared with non-toxic, parenterally acceptable diluents or solvents, for example, solutions prepared with 1,3-butanediol, or may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include, in particular, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils may be conventionally used as solvents or suspensions. For this purpose, any odorless and tasteless fixative oil, including synthetic mono or diglycerides, may be used. In addition, fatty acids such as oleic acid may also be used in the preparation of injections. Acceptable vehicles and solvents that may be used include, in particular, water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0262] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form may vary depending on the host being treated and the specific mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient combined with a suitable and convenient amount of carrier material, which may vary from about 5% to about 95% (by weight) of the total composition. Pharmaceutical compositions may be prepared to provide an amount that is easily measurable for administration. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of active ingredient per milliliter of solution in order that a suitable volume can be infused at a rate of about 30 mL / hour.

[0263] Suitable formulations for topical administration in the mouth include oral tablets containing the active ingredient in a flavored base, usually sucrose and acacia gum or tragacanth gum; flavored tablets containing the active ingredient in an inert base, for example, gelatin and glycerin, or sucrose and acacia gum; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0264] Formulations for rectal administration may be provided as suppositories using a suitable base, such as cocoa butter or salicylate.

[0265] Formulations suitable for intrapulmonary or nasal administration have particle sizes ranging from 0.1 to 500 microns, for example, 0.5, 1, 30, and 35 microns, and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily liquid formulations of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and delivered together with other therapeutic agents, such as compounds.

[0266] Suitable formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that are isotonic with the blood of the recipient to whom the formulation is intended; as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0267] The formulations are provided in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-drying conditions requiring only the addition of a sterile liquid carrier, such as water for injection. Immediate injectable solutions and suspensions are prepared from the sterile powders, granules, and tablets of the types described above. Preferred unit dose formulations are those containing a daily dose or a unit daily secondary dose, or an appropriate portion thereof, of the active ingredient, as listed herein above.

[0268] This disclosure further provides an animal composition comprising at least one active ingredient as defined above, together with an animal carrier for the same.

[0269] An animal carrier is a material useful for administering a composition, and it may also be a solid, liquid, or gaseous material that is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These animal compositions may be administered orally, parenterally, or by any other desired route.

[0270] The compounds of the present disclosure are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more of the compounds of the present disclosure as active ingredients, wherein the release of the active ingredients is controlled and regulated to enable administration at a lower frequency or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0271] Patients receiving this treatment include primates, particularly humans, and any other mammals that require it, such as horses, cattle, pigs, and sheep, as well as poultry and pets such as cats and dogs.

[0272] In one embodiment, the Disclosure also provides a kit comprising a pharmaceutical composition of a formulation containing the combination described herein. The kit may include product instructions for the combined administration in which, for example, a first pharmaceutical composition comprising a ROCK2 inhibitor and a second pharmaceutical composition comprising a GLP-1 agonist are administered simultaneously or sequentially (co-administered). For example, the kit may instruct the administration of a ROCK2 inhibitor to a subject before administration of a GLP-1 agonist formulation. [Examples]

[0273] Example 1 ADP-Glo ​​Kinase Assay (Promega). The ADP-Glo® kinase assay is a luminescent ADP detection assay that allows for the measurement of kinase activity based on the amount of ADP produced during the kinase reaction. The kinase reaction is carried out in a suitable kinase reaction buffer (1x) in the presence of ATP, S6K substrate (KRRRLASLR), and ROCK kinase. Immediately after the reaction is complete, any unused ATP is depleted by the addition of the ADP-Glo® reagent. Then, the kinase detection reagent is added to convert ADP to ATP, and the newly synthesized ATP is measured using a luciferase / luciferin reaction. The luminescence is proportional to the amount of ADP produced and therefore proportional to the kinase activity. The ADP-Glo® kinase assay was performed in a 384-well plate format as follows.

[0274] Preparation of kinase detection reagent: The kinase detection buffer was thawed at room temperature (RT). If precipitate was present, it was dissolved by incubating the buffer at 37°C for 15 minutes while continuously swirling, or by carefully aspirating the supernatant from the bottle with a pipette. After equilibrating both the kinase detection buffer and the kinase detection substrate to room temperature, the entire volume of the kinase detection buffer was transferred to the bottle containing the kinase detection substrate to reconstitute the lyophilized substrate, and then gently mixed to obtain a homogeneous solution.

[0275] Preparation of kinase reaction buffer: The kinase reaction buffer was freshly prepared before each experiment. The composition of this buffer is shown in Table 1 below. [Table 7]

[0276] Preparation of ADP-Glo ​​reagent. Before performing the assay, three types of mixtures were prepared on ice: Mixture 1-kinase reaction buffer (1x) contains ROCK1 or ROCK2 The mixed 2-kinase reaction buffer (1x) contains S6K peptide. The mixed 3-kinase reaction buffer (1x) contains ATP.

[0277] The final conditions for performing the ADP-Glo ​​kinase assay are shown in Table 2 below: [Table 8]

[0278] The reagent volume ratio in the assay was 1:1:2 for kinase reactant to ADP-Glo® reagent to kinase detection reagent. In a 384-well plate, the volumes per well were 5 μl for kinase reactant, 5 μl for ADP-Glo® reagent, and 10 μl for kinase detection reagent.

[0279] Standard curves were generated for the conversion of ATP to ADP. To estimate the amount of ADP produced in the kinase reaction, standard curves representing the luminescence corresponding to the conversion of ATP to ADP were created, based on the ATP concentration used in the kinase reaction. These conversion curves represent the amount of ATP and ADP that can be obtained during the reaction at specific conversion percentages within the range of 100% conversion to approximately 0% conversion. Standard samples used to create the ATP to ADP conversion curves were prepared by mixing appropriate volumes of stock solutions of ATP and ADP.

[0280] IC15 of kinase inhibitors 50 Determining the value Each plate contained a positive control (1 μM compound A for ROCK2, 1 μM RKI-1447 for ROCK1); a vehicle control (1% DMSO); a blank control (kinase reaction buffer (1x)); a low control (substrate and ATP, no kinase); and an autophosphorylation control (kinase and ATP, no substrate). The test compound and reference compound were diluted with 100% DMSO to obtain a 10 mM stock solution. Each compound was tested in 8 serial dilutions in 2 replicates. The final concentration of DMSO in the reaction product was 1% (maximum 50 nL).

[0281] 5 μl / well of kinase reaction buffer (1x) was dispensed into a blank control well. 2 μl / well of kinase reaction buffer (1x) was dispensed into a protein-free control (low control) well and a substrate-free (autophosphorylated) well. The plate was sealed with adhesive film and then rotated briefly (1 minute, 1000 rpm).

[0282] 2 μl / well of kinase (2.5x) solution was dispensed into the corresponding wells of the assay plate. The plate was sealed with adhesive film and then rotated briefly (1 minute, 1000 rpm).

[0283] 2 μl / well of S6K substrate (2.5x) solution was dispensed into the corresponding wells of the assay plate. The plate was sealed with adhesive film and then rotated briefly (1 minute, 1000 rpm).

[0284] 1 μl / well of ATP (5x) solution was dispensed into the corresponding wells of the assay plate. The final volume of the reaction was 15 μl. The plate was sealed with adhesive film and then rotated briefly (1 minute, 1000 rpm).

[0285] The plates were incubated at 25°C for 120 minutes at a shaking rate of 450 rpm.

[0286] After incubation was complete, the kinase reaction was terminated, the remaining ATP was depleted from the kinase reaction product, and ADP was converted to ATP, which is measured by the luciferase / luciferin reaction. 5 μl of ADP-Glo® reagent was dispensed to stop the kinase reaction and deplete any unused ATP. The plate was sealed with adhesive film, followed by a short rotation (1 minute, 1000 rpm), and incubated at 25°C for 40 minutes with a shaking rate of 450 rpm.

[0287] Ten μl of kinase detection reagent was dispensed to convert ADP to ATP and to introduce luciferase and luciferin to detect ATP. The plate was sealed with adhesive film, then briefly rotated (1 minute, 1000 rpm), and incubated at 25°C for 60 minutes with a shaking rate of 450 rpm.

[0288] After acclimatizing to darkness for 5 minutes, luminescence was measured using a PHERAstar FSX multimode plate reader (BMG Labtech). [Table 9]

[0289] Example 2 Mice were continuously fed a high-fat / calorie diet and then treated with semaglutide, compound A, or a combination of semaglutide and compound A. Figure 1 shows the absolute body weight change of obese mice treated with the ROCK2 inhibitor (compound A) and / or semaglutide, compared to untreated mice and mice on a lean solid diet. The figure shows that mice treated with a combination of compound A and semaglutide showed improved weight loss.

[0290] Example 3 ReninAAV UNx db / db mouse model of diabetic nephropathy and hypertension: Effect of selective ROCK2 inhibitor compound A treatment on hypertensive female unilateral nephrectomized db / db C57BLKS mice. This mouse model is established in the BKS background db / db mouse model (BKS.Cg-Dock7m+ / Leprdb / J), is homozygous for a missense mutation in the leptin receptor (Lepr db), and exhibits chronic hyperglycemia, pancreatic β-cell atrophy, and hypoinsulinemia.

[0291] Adeno-associated virus (reninAAV) hypertension encoding renin was induced using AAV8-TBG-m-Ren1d(F61R / P65S), an adeno-associated virus (AAV) construct expressing the mouse Ren1d gene with the F61R / P65S mutation under the control of a liver-specific thyroxine-binding globulin (TBG) promoter. To induce hypertension, a single bolus of the reninAAV construct was administered via tail vein injection to conscious animals one week prior to unilateral nephrectomy.

[0292] Details about the animal models used in the study are summarized below. [Table 10]

[0293] Body weight was measured once daily starting three days before the first dose and continued throughout the study. Body weight measured during the study is reported in Figure 2A, and final body weight is reported in Figure 2B. The data demonstrate that the ROCK2 inhibitor (compound A) promoted weight loss in the test mice.

[0294] Unilateral nephrectomy (UNx): Under isoflurane anesthesia, the upper part of the left kidney was incised and exposed externally. The renal hilum was identified and ligated with sutures. The kidney was then removed. The wound was closed with two layers of muscle and skin. Prophylactic analgesia was administered, and antibiotics were given and continued for three consecutive days postoperatively.

[0295] Speckle Tracking Echocardiography Co., Ltd.: All echocardiographic measurements were obtained by cardiac ultrasound. Echocardiography was performed under isoflurane anesthesia using a Vevo 3100 system (Visual Sonics, Fujifilm) equipped with an MX400 20-46 MHz linear array transducer. This was a non-invasive procedure, and the animals fully regained consciousness afterward. The animals were placed supine on a heated pad (40°C), and the fur on the chest was removed with depilatory cream. Ultrasound gel was preheated in a warm water bath and applied to the animals' chests. Body temperature was measured with a rectal probe, and the electrocardiogram (ECG) was continuously monitored during the examination. The preheated ultrasound gel was applied to the animals' chests. Two-dimensional (2D) visualization of the left ventricle (LV) in B-mode was recorded from parasternal long-axis (PLAX) and parasternal uniaxial (PSAX) views. Optimized recordings from the PLAX view were used for stock analysis to calculate total longitudinal strain (GLS) and reverse peak longitudinal strain ratio (RPLSR) to assess systolic and diastolic cardiac function, respectively. 2D-guided M-mode images from the PSAX were acquired to calculate estimates of ejection fraction (EF), shortening ratio (FS), LV wall thickness (LVAW / LVPW), and LV mass. From the apical four-chamber view, pulsed Doppler and tissue Doppler were used to measure diastolic parameters, such as early (E) and late (A) diastolic transmitral Doppler flow rates, isovolumetric diastolic time (IVRT), isovolumetric systolic time (IVCT), aortic ejection time (AET), and peak early diastolic velocity (e'). Measurements were calculated using Vevo LAB and VevoStrain software (VisualSonics, Fujifilm).

[0296] Blood glucose: A blood sample (10 μl) was collected in a heparinized glass capillary tube and immediately suspended in glucose / lactic acid solution buffer (EKF-diagnostics, Germany). Blood glucose (BG) was measured using a BIOSEN c-Line glucose meter (EKF-diagnostics, Germany) according to the manufacturer's instructions. The blood glucose (under food intake) profiles shown in Figures 3 and 4 demonstrate that compound A lowered blood glucose levels to lean body control levels.

[0297] Blood collection and plasma preparation In vivo blood sample: Tail vein blood was collected in a Microvette tube of appropriate size containing an anticoagulant, and mixed five times by inversion. The blood was allowed to stand at 4°C and centrifuged at 3000g for 10 minutes. The plasma supernatant was transferred to a new tube and immediately frozen on dry ice. The sample was stored at -70°C.

[0298] End-stage blood sample: Under isoflurane anesthesia, the peritoneal cavity was opened, and cardiac blood was collected using a syringe into an appropriately sized Microvette / Vacuette containing an anticoagulant. The sample was then inverted and mixed five times. The blood was allowed to stand at 4°C and centrifuged at 3000g for 10 minutes. The plasma supernatant was transferred to a new tube and immediately frozen on dry ice. The sample was stored at -70°C.

[0299] Blood and plasma assays Glycated hemoglobin A1c (HbA1c): Blood samples were collected in heparinized glass capillary tubes, immediately suspended in hemolysis reagent (Roche Diagnostics), and stored at -70°C until analysis. HbA1c was measured using a commercially available kit (Roche Diagnostics) with a cobas c 501 automated analyzer. The final HbA1c levels are shown in Figure 5. This demonstrates that compound A reduced HbA1c levels to the level of the lean body control.

[0300] NT-proANP: Blood samples were collected in EDTA tubes, plasma was separated, and stored at -70°C until analysis. Plasma NT-proANP was measured using a commercially available kit (Abcam) according to the manufacturer's instructions.

[0301] Example 4 This report describes the effects of ROCK2 inhibitor (compound A) and a combination of compound A and a GLP-1 agonist (tilzepatide) on metabolic parameters and energy expenditure in a diet-induced obesity (DIO) mouse model at neutral temperatures. Details of the animal model used in this study are summarized below. [Table 11]

[0302] Diet-induced obesity model In this mouse model of diet-induced obesity (DIO), test mice were fed a high-fat diet, which resulted in rapid weight gain. The DIO mice were male C57BI / 6J mice, and they were ready for the experiment after 20 weeks on a 60% high-fat diet. The high-fat diet was maintained throughout the experiment. The lean control group included male C57BI / 6J mice fed Altromin lean solid feed (1324, Brogaarden).

[0303] Approximately one week before the start of the study, DIO mice were randomized based on body weight and body fat mass (Echo MRI) to obtain baseline measurements (Echo MRI, 4-hour fasting blood glucose (FBG), 4-hour plasma insulin (PI), 4-hour leptin, HbA1c).

[0304] Test solutions and controls were prepared according to Table 4 below. [Table 12]

[0305] The study began on day 1 and continued daily, administering the compounds to lean and DIO mice according to Table 5. Compound A was administered orally (PO), and tilzepatide (TZP) was administered by subcutaneous injection (SC). [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4]

[0306] Each cohort was divided into five groups, with staggered timings between them. On the day of energy expenditure measurement, mice received an additional PM dose of compound A or compound A vehicle (vehicle A). The final dose was administered the day before the end of the study.

[0307] body weight Body weight was measured once daily starting three days before the first dose and continued throughout the 12-week trial. Body weight measured during the trial is reported in Figure 6. The data demonstrate that the ROCK2 inhibitor (compound A), and the combination of the ROCK2 inhibitor (compound A) and a GLP-1 agonist (TZP), promoted weight loss in obese mice induced by a high-fat diet in a model of diet-induced obesity.

[0308] Energy consumption (EE) Before performing EE measurements, mice were housed alone in an acclimatization cage for 48 hours, and then the same cage was connected to the airtight lid of the EE system (PhenoMaster, TSE Systems, Germany). Continuous airflow was used within the cage, which was optimized for indirect calorimetry of O2 consumption and CO2 production. O2 consumption and CO2 production were measured every 20 minutes for a total of 36 hours, including two dark periods and one light period. During this period, water and food were freely available in the cage, and the medication schedule was continued. Calibration procedures were performed before each test, as necessary.

[0309] O2 consumption was reported both as measured values ​​and as body weight-adjusted O2 and heat production. The purpose of body weight adjustment was to obtain mass-independent measurements of differences between treatment groups. Body weight-adjusted values ​​were obtained using a regression approach, similar to the approach reported by Muller et al. (Muller et al., Nature Metabolism, VOL 3, Sep 2021, 1134-1136), where linear regressions were fitted individually to data points for each treatment group to adjust for the values. Subsequently, the difference in mean adjusted values ​​between groups was evaluated using ANOVA and Dunnett's post-hoc test. The consumed O2 (VO2; ml / h) and generated CO2 (VCO2; ml / h) are calculated as the volumes of O2 and CO2 in inspiration and exhalation, the respiratory exchange ratio (RER; VCO2 / VO2) is calculated as the ratio, and the heat generation (heat; (RER*1.232+3.815)*VO2) / 1000) is calculated as the energy per unit time (kcal / h). Figure 12 shows that energy consumption (O2 consumption) increases in the mouse cohort administered compound A.

[0310] EchoMRI body composition The body composition of mice was evaluated using an EchoMRI 3-in-1 body composition analyzer (EchoMRI,US). Unanesthetized animals were placed in a plastic tube inside the MRI scanner for approximately 80 seconds. Body composition was reported as body fat mass and lean body mass. Figure 10 shows the relative lean body mass (%) at baseline, week 4, week 7, and week 12. The data demonstrate that compound A maintained lean body mass during the study.

[0311] Oral glucose tolerance test (OGTT) The animals were housed in clean cages and fasted for 4 hours prior to oral glucose administration. At time point 0, mice were orally administered 10 ml / kg of 200 mg / ml standard glucose solution (Fresenius Kabi, DK). Blood samples (10 μl) were collected in heparinized glass capillary tubes at various time points defined in the test protocol and immediately suspended in glucose / lactic acid solution buffer (EKF-diagnostics, Germany). Blood glucose (BG) was measured using a BIOSEN c-Line glucose meter (EKF-diagnostics, Germany) according to the manufacturer's instructions. After the last blood sample and / or drug administration, the animals were returned to their normal feeding schedule. The results of the oral glucose tolerance test are shown in Figure 7. This figure shows that blood glucose levels decreased after oral administration of glucose following administration of compound A.

[0312] Blood sample plasma preparation In vivo blood sample: Tail vein blood was collected in a Microvette tube of appropriate size containing an anticoagulant, and mixed five times by inversion. The blood was allowed to stand at 4°C and centrifuged at 3000g for 10 minutes. The plasma supernatant was transferred to a new tube and immediately frozen on dry ice. The sample was stored at -70°C.

[0313] End-stage blood sample: Under isoflurane anesthesia, the peritoneal cavity was opened, and cardiac blood was collected using a syringe into an appropriately sized Microvette / Vacuette containing an anticoagulant. The sample was then inverted and mixed five times. The blood was allowed to stand at 4°C and centrifuged at 3000g for 10 minutes. The plasma supernatant was transferred to a new tube and immediately frozen on dry ice. The sample was stored at -70°C.

[0314] Tissue collection Pancreas: At the end of the procedure, the splenic lobe of the pancreas was collected, divided into two, frozen at -70°C, or fixed by immersion in 10% neutral buffered formalin for 24 hours, then transferred to 70% EtOH, and subsequently embedded in paraffin.

[0315] Liver: After the animals were euthanized, the livers were collected and weighed. As specified in the table "End-of-Life Samples," and as described later, specific liver samples and biopsies were dissected and processed.

[0316] The liver was divided into the left lobe, middle lobe, right lobe, and caudate lobe. A liver FFPE piece (approximately 200 mg, less than 0.7 × 0.5 cm) was cut from the left lobe, fixed by immersion in 10% neutral buffered formalin for 24 hours, then transferred to 70% etOH, and subsequently embedded in paraffin. A liver frozen piece (approximately 150 mg) was dissected from the left middle lobe, placed in a tube, and directly placed in liquid nitrogen. The samples were stored at -70°C.

[0317] Liver samples were assayed for glycogen content by periodic acid Schiff's reagent (PAS) staining. Sections of FFPE tissue were oxidized with 0.5% periodic acid and rinsed with running distilled water. Subsequently, the sections were incubated with Schiff's reagent and washed with water. Counterstaining was performed in Meyer's hematoxylin, followed by washing with water. The sections were dehydrated stepwise with ethanol, washed with xylene, and covered with coverslips.

[0318] Quantitative evaluation of hepatic glycogen (PAS): PAS-positive staining was quantified by image analysis using VIS software (Visiopharm, Denmark). The VIS protocol is designed to analyze virtual slides in two steps: (1) rough detection of tissue at low magnification (1× objective) excluding the liver capsule, and (2) detection of PAS-positive staining by detecting PAS-positive cells at high magnification (10× objective). The quantitative estimation of PAS-positive staining is calculated as an area ratio (AF) as follows. AF PAS-陽性 +(area PAS-陽性 ) / (area 組織 +Area PAS-陽性 )

[0319] The results are shown in Figure 14. This figure demonstrates that liver glycogen levels decrease in DIO models of mice treated with compound A, or a combination of compound A and TZP.

[0320] fat Subcutaneous white adipose tissue (scWAT) was collected from the left anterior subcutaneous fat deposit, weighed, divided into two samples, collected in tubes, and frozen with liquid nitrogen or fixed by immersion in 10% neutral buffered formalin. Inguinal white adipose tissue (iWAT) was collected from the left posterior subcutaneous fat deposit, weighed, divided into two samples, collected in tubes, and frozen with liquid nitrogen or fixed by immersion in 10% neutral buffered formalin. Epididymal / gonadal white adipose tissue (eWAT / gWAT) was collected from the left fat body enclosing the testis, taking care not to collect the epididymis, weighed, divided into two samples, collected in tubes, and frozen with liquid nitrogen or fixed by immersion in 10% neutral buffered formalin.

[0321] muscle The gastrocnemius muscle (GAS) was dissected from the right hind limb, cut in half lengthwise, collected in a tube, and either frozen with liquid nitrogen and stored at 70°C, or fixed by immersion in 10% neutral buffered formalin.

[0322] The quadriceps muscle was dissected from the right hind limb. The knee ligament holding the quadriceps muscle in place was cut. Then the upper ligament was cut, and the quadriceps muscle was removed for further processing. The muscle was cut in half longitudinally, collected in a tube, and frozen in liquid nitrogen and stored at 70°C, or fixed by immersion in 10% neutral buffered formalin.

[0323] GLUT4 levels were assayed in the quadriceps muscle. The results are shown in Figure 15. This figure shows that GLUT4 levels in the muscle improved and even recovered in a diet-induced obesity (DIO) model of mice treated with compound A.

[0324] Immunohistochemical analysis using a single chromogen: Immunohistochemical analysis (IHC) of GLUT4 was performed using a standard procedure. Briefly, after antigen recovery and blockade of endogenous peroxidase activity, slides were incubated with the primary antibody (anti-GLUT4, Abcam, catalog ab33780). The primary antibody was detected using a high molecular weight-HRP-linker antibody conjugate. The primary antibody was visualized using DAB as the chromogen. Finally, sections were counterstained with hematoxylin, washed with tap water, dehydrated stepwise with ethanol, washed with xylene, and covered with coverslips.

[0325] Quantitative evaluation of immunoreactivity: IHC-positive staining was quantified by image analysis using VIS software (Visiopharm, Denmark). The VIS protocol is designed to analyze virtual slides in two steps: (1) rough tissue detection at low magnification (1× objective), and (2) detection of IHC-positive staining (immunohistochemical staining to detect GLUT4) at high magnification (10× objective).

[0326] The tibialis anterior muscle (TA) was dissected from the right hind limb. The tendon of the tibialis anterior muscle was exposed, and the fascia covering the muscle was gently removed. The distal tendon was severed, and the TA muscle was gently removed at its proximal attachment. The muscle was cut in half longitudinally, collected in a tube, and frozen with liquid nitrogen and stored at 70°C, or fixed by immersion in 10% neutral buffered formalin.

[0327] Microtome section preparation for formalin-fixed paraffin-embedded (FFPE) biopsies FFPE biopsies were placed in 10% neutral buffered formalin (10% NBF) for approximately 24 hours, then transferred to 70% EtOH and stored at 4°C. Next, the FFPE biopsies were infiltrated in Histokinette before embedding in the block. The biopsy tissue was cut to 3 μm on a microtome, and the sections were placed on Superfrost Plus slides and stored at 4°C.

[0328] Blood and plasma assays Leptin (Singleplex). Blood samples were collected in heparinized tubes, plasma was separated, and stored at -70°C until analysis. Samples were measured using a commercially available MSD platform (Meso Scale Diagnostics). Figure 17 shows fasting plasma leptin levels at (A) baseline, (B) week 7, and (C) week 12 for a cohort of mice in the DIO study. This figure demonstrates that treatment of DIO mice with a ROCK2 inhibitor (compound A) results in a significant decrease in plasma leptin levels.

[0329] Insulin. Blood samples were collected in heparinized tubes, plasma was separated, and stored at -70°C until analysis. Insulin levels were measured using a commercially available MSD platform (Meso Scale Diagnostics). Figure 16 shows fasting plasma insulin levels at (A) baseline, (B) week 7, and (C) week 12 for a cohort of mice in the DIO study. This figure demonstrates that treatment of DIO mice with a ROCK2 inhibitor (compound A) results in a significant decrease in plasma insulin levels / improvement of insulin sensitivity.

[0330] Exposure. Plasma samples were collected in K3 EDTA tubes and stored at -70°C until analysis. Plasma proteins were removed by adding an organic solvent and then centrifugation. The supernatant after protein precipitation was analyzed by LC-MS. Mean exposure values ​​were collected for each group, along with the standard deviation (SD) and coefficient of variation (CV%).

[0331] Glycated hemoglobin A1c (HbA1c): Blood samples were collected in heparinized glass capillary tubes, immediately suspended in hemolysis reagent (Roche Diagnostics), and stored at -70°C until analysis. HbA1c was measured using a commercially available kit (Roche Diagnostics) with a cobas c 501 automated analyzer. The results are shown in Figure 9. This figure demonstrates that compound A reduces HbA1c in a dose-dependent manner.

Claims

1. A method for treating a target type 2 diabetes, comprising administering to the target (i) a therapeutically effective amount of a Rho-related coiled-coil protein kinase 2 (ROCK2) inhibitor, and optionally (ii) a therapeutically effective amount of a glucagon-like peptide (GLP-1) agonist.

2. A method for treating or preventing obesity in a subject, comprising administering to the subject (i) a therapeutically effective amount of a Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, and optionally (ii) a therapeutically effective amount of a glucagon-like peptide (GLP-1) agonist.

3. A method for promoting weight loss in a subject, comprising administering to the subject (i) a therapeutically effective amount of a Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, and optionally (ii) a therapeutically effective amount of a glucagon-like peptide (GLP-1) agonist.

4. A method for reducing or preventing muscle loss in a patient being treated for obesity, weight loss, and / or type 2 diabetes, comprising administering a therapeutically effective dose of a ROCK2 inhibitor to the target.

5. The ROCK2 inhibitor is given by formula (A-I): 【Chemistry 1】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ａ１ is H, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C ３ to C ７ cycloalkyl, halo, -CN, C １ to C ３ perfluoroalkyl, -OR Ａ１１ , -O-(C １ to C ６ alkyl)-OR Ａ１１ , -(C １ to C ６ alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , -(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ -(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ -(C １ to C ６ alkyl)-OR Ａ１１ , -(C １ to C ６ alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ to C ６ alkyl) ｘ１ -C(=O)R Ａ１１ , -(C １ to C ６ alkyl) ｘ１ -C(=O)OR Ａ１１ , -C(=O)-R Ａ１１ , -C(=O)OR Ａ１１ , -(C １ to C ６ alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, R Ａ２ is H, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ７ cycloalkyl, halo, -CN, C １ -C ３ perfluoroalkyl, -OR Ａ１１ , -O-(C １ -C ６ alkyl)-OR Ａ１１ , -(C １ -C ６ alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ -C ６ alkyl)-NR Ａ１１ R Ａ１２ , -(C １ -C ６ alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ -(C １ -C ６ alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ -(C １ -C ６ alkyl)-OR Ａ１１ , -(C １ -C ６ alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ -C ６ alkyl) ｘ１ -C(=O)R Ａ１１ , -(C １ -C ６ alkyl) ｘ１ -C(=O)OR Ａ１１ , -C(=O)-R Ａ１１ , -C(=O)OR Ａ１１ , -(C １ -C ６ alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Alternatively, R Ａ１ and R Ａ２ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, ox1o, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ａ１１ - (C １ ~C ６ Alkyl) NR Ａ１１ R Ａ１２ and -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ａ３ and R Ａ４ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Alternatively, R Ａ３ and R Ａ４ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or the heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , ox1o, -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R Ａ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, ox1o, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, n1 is between 0 and 3. X Ａ１ CR Ａ６ or N, X Ａ２ CHR Ａ６ , NR Ａ７ , O or S, X Ａ３ is C, CH, or N, X Ａ４ is N or CH, X Ａ５ is N or CH, Each R Ａ６ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Each R Ａ７ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Each x1 is independently selected from 0 and 1, and Each R Ａ１１ and R Ａ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ａ１１ and R Ａ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The method according to any one of claims 1 to 4, wherein the molecule is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

6. The ROCK2 inhibitor is given by formula (A-II): 【Chemistry 2】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ａ１ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, R Ａ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Alternatively, R Ａ１ and R Ａ２ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ａ１１ - (C １ ~C ６ Alkyl) NR Ａ１１ R Ａ１２ and -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ａ３ and R Ａ４ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Alternatively, R Ａ３ and R Ａ４ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R Ａ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, oxo, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, n1 is between 0 and 3. R Ａ７ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Each x1 is independently selected from 0 and 1, and Each R Ａ１１ and R Ａ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ａ１１ and R Ａ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The method according to claim 5, wherein the molecule is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

7. The ROCK2 inhibitor is given by formula (A-III) 【Transformation 3】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ａ１ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, R Ａ２ is H, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C ３ to C ７ cycloalkyl, halo, -CN, C １ to C ３ perfluoroalkyl, -OR Ａ１１ , -O-(C １ to C ６ alkyl)-OR Ａ１１ , -(C １ to C ６ alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , -(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ -(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ -(C １ to C ６ alkyl)-OR Ａ１１ , -(C １ to C ６ alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ to C ６ alkyl) ｘ１ -C(=O)R Ａ１１ , -(C １ to C ６ alkyl) ｘ１ -C(=O)OR Ａ１１ , -C(=O)-R Ａ１１ , -C(=O)OR Ａ１１ , -(C １ to C ６ alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Alternatively, R Ａ１ and R Ａ２ together form a 5-membered or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with C １ to C ６ alkyl, halo, -CN, -OH, oxo, -O-(C １ to C ６ alkyl), -O-(C １ to C ６ alkyl)-OH, -O-(C １ to C ６ alkyl)-O-(C １ to C ６ alkyl), -NR Ａ１１ R Ａ１２ , -O-(C １ to C ６ alkyl)-NR Ａ１１ R Ａ１２ , C １ to C ３ perfluoroalkyl, -NR Ａ１１ -(C １ to C ６ alkyl)NR Ａ１１ R Ａ１２ and -NR Ａ１１ -(C １ to C ６ alkyl)-OR Ａ１１ with 1 to 3 substituents selected from the group consisting of R Ａ３ and R Ａ４ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Alternatively, R Ａ３ and R Ａ４ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R Ａ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, oxo, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, n1 is between 0 and 3. R Ａ７ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Each x1 is independently selected from 0 and 1, and Each R Ａ１１ and R Ａ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ａ１１ and R Ａ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The method according to claim 5, wherein the molecule is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

8. The ROCK2 inhibitor is given by formula (B-I): 【Chemistry 4】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, X Ｂ１ is N or CH, X Ｂ２ is N or CH, X Ｂ３ is N or CR Ｂ３ And, X Ｂ４ is N or CR Ｂ４ And, X Ｂ５ It is selected from the group consisting of C, CH, and N. a1 is selected from 1 or 2, The dotted line represents an optional double bond. Each R Ｂ１ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, oxo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , and -NR Ｂ１１ R Ｂ１２ Selected from the group consisting of, Alternatively, two R atoms bonded to the same carbon or adjacent carbon atoms. Ｂ１ However, together they form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S, and N, and may be unsubstituted, or optionally contain halo, C １ ~C ３ Alkyl, NH ２ OH, and O-C １ ~C ３ Substituted with 1 to 3 substituents selected from alkyl groups, b1 is selected from 0, 1, and 2. R Ｂ２ H, Halo, C １ ~C ３ Alkyl, NH ２ OH, and O-C １ ~C ３ Selected from alkyl groups, R Ｂ３ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, R Ｂ４ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, Alternatively, R Ｂ３ and R Ｂ４ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ｂ１１ - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ and -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ Substituted with 1 to 3 substituents selected from the group consisting of, Each R Ｂ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, oxo, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, n2 is between 0 and 3. R Ｂ６ and R Ｂ７ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-C(=O)NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, Alternatively, R Ｂ６ and R Ｂ７ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, C ５ ~C １０ Ariel, C ５ ~C １０ Heteroaryl, 3-10 membered heterocyclyl, -C １ ~C ６ Alkyl-(C) ３ ~C ７ Cycloalkyl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Aryl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Heteroaryl), -C １ ~C ６ Alkyl-(3-10 member heterocyclyl), halo, -CN, -OH, oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ｂ１１ - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , and -C(=O)-N(R Ｂ８ ) (Caution Ｂ９ ) are substituted with 1 to 3 substituents selected from the group consisting of ), and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally C １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH, and NH ２ It may be substituted with 1 to 3 substituents selected from the following: R Ｂ８ and R Ｂ９ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ and -(C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ A group consisting of C is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl is optionally selected. １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH and NH ２ It may be substituted with one to three substituents selected from the following: Alternatively, R Ｂ８ and R Ｂ９ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or the heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, C １ ~C ６ Fluoroalkyl, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Substituted with 1 to 4 substituents selected from the group consisting of, Each x2 is independently selected from 0 and 1, and Each R Ｂ１１ and R Ｂ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ｂ１１ and R Ｂ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The method according to any one of claims 1 to 4, wherein the molecule is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

9. The ROCK2 inhibitor is given by formula (B-V): 【Transformation 5】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ｂ３ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, R Ｂ４ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, Alternatively, R Ｂ３ and R Ｂ４ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ｂ１１ - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ and -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ｂ８ and R Ｂ９ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ and -(C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ A group consisting of C is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl is optionally selected. １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH and NH ２ It may be substituted with one to three substituents selected from the following: Alternatively, R Ｂ８ and R Ｂ９ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or the heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, C １ ~C ６ Fluoroalkyl, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Substituted with 1 to 4 substituents selected from the group consisting of, R Ｂ１０ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, C ５ ~C １０ Ariel, C ５ ~C １０ Heteroaryl, 3-10 membered heterocyclyl, -C １ ~C ６ Alkyl-(C) ３ ~C ７ Cycloalkyl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Aryl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Heteroaryl), -C １ ~C ６ Alkyl-(3-10 member heterocyclyl),-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ and -C(=O)-N(R Ｂ１１ ) (Caution Ｂ１２ A selection is made from the group consisting of ), and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally selected as C １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH and NH ２ It may be substituted with 1 to 3 substituents selected from the following: Each x2 is independently selected from 0 and 1, and Each R Ｂ１１ and R Ｂ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ｂ１１ and R Ｂ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The method according to claim 8, wherein the molecule is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

10. The ROCK2 inhibitor is 【Transformation 6】 The method according to any one of claims 1 to 4, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

11. The method according to any one of claims 1 to 4, wherein the ROCK2 inhibitor is selected from belmosdil (KD025), zelasdil, Y-27632, fasudil, GSK429286A, RKI-1447, azaindole 1 (TC-S 7001), hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and their derivatives, isomers, hydrates, or pharmaceutically acceptable salts.

12. The GLP-1 agonist is given by formula (M-I): 【Transformation 7】 It includes the structure, During the ceremony, Xaa ７ L-histidine, imidoazopropionyl, α-hydroxyhistidine, D-histidine, desaminohistidine, 2-aminohistidine, β-hydroxyhistidine, homohistidine, N α - Acetyl-histidine, N α -Formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine, Xaa ８ These are Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib (α-aminoisobutyric acid), (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid. Xaa １６ is Val or Leu, Xaa １８ is Ser, Lys, or Arg, Xaa １９ is Tyr or Glun, Xaa ２０ is Leu or Met, Xaa ２２ This is Gly, Glu, or Aib (α-aminoisobutyric acid), Xaa ２３ These are Glun, Glu, Lys, or Arg, Xaa ２５ It is either Ala or Val, Xaa ２７ is either Glu or Leu, Xaa ３０ is Ala, Glu, or Arg, Xaa ３３ is Val or Lys, Xaa ３４ These are Lys, Glu, Asn, or Arg. Xaa ３５ It is Gly or Aib (α-aminoisobutyric acid), Xaa ３６ is either Arg, Gly, or Lys, or does not exist. Xaa ３７ is Gly, Ala, Glu, Pro, Lys, or does not exist, and B and U together form the acylation part, where U is 【Chemistry 8-1】 【Chemistry 8-2】 Selected from, m is 0, 1, 2, 3, 4, 5, or 6. n is 1, 2, or 3. s is 0, 1, 2, or 3. t is 0, 1, 2, 3, or 4. p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. Furthermore, B is, 【Transformation 8】 It is an acidic group selected from, In the formula, l is 12, 13, 14, 15, 16, 17, 18, 19 or 20, The method according to any one of claims 1 to 11, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

13. Xaa ７ His or desaminohistidine, Xaa ８ These are Ala, Gly, Val, Leu, Ile, Lys, or Aib. Xaa １６ is Val, and Xaa １８ is Ser and Xaa １９ It is Tyr, Xaa ２０ It is Leu, Xaa ２２ is Gly, Glu, or Aib, Xaa ２３ is Glun or Glu, Xaa ２５ It is Ala and Xaa ２７ Glu is, Xaa ３０ is Ala or Glu, Xaa ３３ Val is, Xaa ３４ is Lys or Arg, Xaa ３５ It is Gly or Aib, Xaa ３６ is Arg or Lys, and / or Xaa ３７ The method according to claim 12, wherein is Gly, amide, or absent.

14. U is, 【Chemistry 9】 The method according to claim 12 or 13.

15. B is, 【Chemistry 10】 The method according to any one of claims 12 to 14, wherein l is 14, 16, or 14.

16. The GLP-1 agonist is given by formula (M-III): 【Chemistry 11】 Having a structure, The method according to any one of claims 12 to 15, wherein l is 12, 14, or 16.

17. The aforementioned GLP-1 agonist is 【Chemistry 12】 The method according to any one of claims 1 to 4.

18. The method according to any one of claims 1 to 4, wherein the GLP-1 agonist is selected from semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, tilzepatide, rotiglypron, letatoltide, taspoglutide, olformlipron, or danuglipron.

19. The method according to any one of claims 1 to 18, wherein the ROCK2 inhibitor and the GLP-1 agonist are administered simultaneously.

20. The method according to any one of claims 1 to 18, wherein the ROCK2 inhibitor and the GLP-1 agonist are administered sequentially.

21. The method according to any one of claims 1 to 20, wherein the ROCK2 inhibitor is administered orally and the GLP-1 agonist is administered subcutaneously.

22. A therapeutically effective dose of a Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, and A combination containing a therapeutically effective dose of a glucagon-like peptide (GLP-1) agonist.

23. The ROCK2 inhibitor is given by formula (A-I): 【Chemistry 13】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ａ１ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, R Ａ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Alternatively, R Ａ１ and R Ａ２ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, ox1o, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ａ１１ - (C １ ~C ６ Alkyl) NR Ａ１１ R Ａ１２ and -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ａ３ and R Ａ４ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Alternatively, R Ａ３ and R Ａ４ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or the heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , ox1o, -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R Ａ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, ox1o, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, n1 is between 0 and 3. X Ａ１ CR Ａ６ or N, X Ａ２ CHR Ａ６ , NR Ａ７ , O or S, X Ａ３ is C, CH, or N, X Ａ４ is N or CH, X Ａ５ is N or CH, Each R Ａ６ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Each R Ａ７ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Each x1 is independently selected from 0 and 1, and Each R Ａ１１ and R Ａ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ａ１１ and R Ａ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The combination according to claim 22, wherein it is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

24. The ROCK2 inhibitor is given by formula (A-II): 【Chemistry 14】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ａ１ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, R Ａ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Alternatively, R Ａ１ and R Ａ２ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ａ１１ - (C １ ~C ６ Alkyl) NR Ａ１１ R Ａ１２ and -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ａ３ and R Ａ４ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Alternatively, R Ａ３ and R Ａ４ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R Ａ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, oxo, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, n1 is between 0 and 3. R Ａ７ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Each x1 is independently selected from 0 and 1, and Each R Ａ１１ and R Ａ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ａ１１ and R Ａ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The combination according to claim 23, wherein it is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

25. The ROCK2 inhibitor is given by formula (A-III): 【Chemistry 15】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ａ１ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, R Ａ２ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, Alternatively, R Ａ１ and R Ａ２ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ａ１１ - (C １ ~C ６ Alkyl) NR Ａ１１ R Ａ１２ and -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ａ３ and R Ａ４ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Alternatively, R Ａ３ and R Ａ４ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ａ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Substituted with 1 to 4 substituents selected from the group consisting of, The dotted line represents an optional double bond. Each R Ａ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, oxo, -OR Ａ１１ , -O-(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-OR Ａ１１ , -NR Ａ１１ R Ａ１２ , -O-(C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , -O-(C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ , -C(=O)-R Ａ１１ , -C (=O) OR Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ , -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ and -NR Ａ１１ - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ Selected from the group consisting of, n1 is between 0 and 3. R Ａ７ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -(C １ ~C ６ Alkyl)-OR Ａ１１ , - (C １ ~C ６ Alkyl)-NR Ａ１１ R Ａ１２ , - (C １ ~C ６ Alkyl) ｘ１ -C(=O)R Ａ１１ , - (C １ ~C ６ Alkyl) ｘ１ -C (=O) OR Ａ１１ and -(C １ ~C ６ Alkyl) ｘ１ -C(=O)NR Ａ１１ R Ａ１２ Selected from the group consisting of, Each x1 is independently selected from 0 and 1, and Each R Ａ１１ and R Ａ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ａ１１ and R Ａ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The combination according to claim 23, wherein it is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

26. The ROCK2 inhibitor is given by formula (B-I), 【Chemistry 16】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, X Ｂ１ is N or CH, X Ｂ２ is N or CH, X Ｂ３ is N or CR Ｂ３ And, X Ｂ４ is N or CR Ｂ４ And, X Ｂ５ It is selected from the group consisting of C, CH, and N. a1 is selected from 1 or 2, The dotted line represents an optional double bond. Each R Ｂ１ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, oxo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , and -NR Ｂ１１ R Ｂ１２ Selected from the group consisting of, Alternatively, two R atoms bonded to the same carbon or adjacent carbon atoms. Ｂ１ However, together they form a 3-6 membered ring, which may optionally contain 0-2 ring heteroatoms selected from O, S, and N, and may be unsubstituted, or optionally contain halo, C １ ~C ３ Alkyl, NH ２ OH, and O-C １ ~C ３ Substituted with 1 to 3 substituents selected from alkyl groups, b1 is selected from 0, 1, and 2. R Ｂ２ H, Halo, C １ ~C ３ Alkyl, NH ２ OH, and O-C １ ~C ３ Selected from alkyl groups, R Ｂ３ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, R Ｂ４ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, Alternatively, R Ｂ３ and R Ｂ４ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ｂ１１ - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ and -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ Substituted with 1 to 3 substituents selected from the group consisting of, Each R Ｂ５ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, oxo, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, n2 is between 0 and 3. R Ｂ６ and R Ｂ７ H and C are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-C(=O)NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, Alternatively, R Ｂ６ and R Ｂ７ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, C ５ ~C １０ Ariel, C ５ ~C １０ Heteroaryl, 3-10 membered heterocyclyl, -C １ ~C ６ Alkyl-(C) ３ ~C ７ Cycloalkyl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Aryl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Heteroaryl), -C １ ~C ６ Alkyl-(3-10 member heterocyclyl), halo, -CN, -OH, oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ｂ１１ - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , and -C(=O)-N(R Ｂ８ ) (Caution Ｂ９ ) are substituted with 1 to 3 substituents selected from the group consisting of ), and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally C １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH, and NH ２ It may be substituted with 1 to 3 substituents selected from the following: R Ｂ８ and R Ｂ９ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ and -(C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ A group consisting of C is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl is optionally selected. １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH and NH ２ It may be substituted with one to three substituents selected from the following: Alternatively, R Ｂ８ and R Ｂ９ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or the heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, C １ ~C ６ Fluoroalkyl, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Substituted with 1 to 4 substituents selected from the group consisting of, Each x2 is independently selected from 0 and 1, and Each R Ｂ１１ and R Ｂ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ｂ１１ and R Ｂ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The combination according to claim 22, wherein it is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

27. The aforementioned ROCK2 inhibitor is given by formula (B-V) 【Chemistry 17】 It has the structure or a pharmaceutically acceptable salt thereof, in the formula, R Ｂ３ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, R Ｂ４ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, halo, -CN, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Selected from the group consisting of, Alternatively, R Ｂ３ and R Ｂ４ Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 ring heteroatoms selected from the group consisting of N, O, and S, which are unsubstituted or C １ ~C ６ Alkyl, Halo, -CN, -OH, Oxo, -O-(C １ ~C ６ Alkyl), -O-(C １ ~C ６ Alkyl)-OH,-O-(C １ ~C ６ Alkyl)-O-(C １ ~C ６ Alkyl), -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , C １ ~C ３ Perfluoroalkyl, -NR Ｂ１１ - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ and -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ Substituted with 1 to 3 substituents selected from the group consisting of, R Ｂ８ and R Ｂ９ These are H and C, which are independent of each other. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, 3-10 membered heterocyclyl, C ６ ~C １０ Aryl, 5-14 member heteroaryl, C ６～１２ Aralkil, - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ and -(C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ A group consisting of C is selected, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl is optionally selected. １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH and NH ２ It may be substituted with one to three substituents selected from the following: Alternatively, R Ｂ８ and R Ｂ９ This provides a 4-6 membered heterocyclic ring having (i) 0-2 further ring heteroatoms selected from N, O, and S, together with the nitrogen to which they are bonded, or a 5-10 membered heterobicyclic ring system having (ii) 0-3 further ring heteroatoms selected from N, O, and S, wherein the heterocyclic ring or the heterobicyclic ring system is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, C １ ~C ６ Fluoroalkyl, C １ ~C ３ Perfluoroalkyl, -OR Ｂ１１ , oxo, -O-(C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ , -NR Ｂ１１ R Ｂ１２ , -O-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl)-OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , -O-(C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ , -C(=O)-R Ｂ１１ , -C (=O) OR Ｂ１１ , - (C １ ~C ６ Alkyl) ｘ２ -C(=O)NR Ｂ１１ R Ｂ１２ , -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C(=O)R Ｂ１１ and -NR Ｂ１１ - (C １ ~C ６ Alkyl) ｘ２ -C (=O) OR Ｂ１１ Substituted with 1 to 4 substituents selected from the group consisting of, R Ｂ１０ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, C ５ ~C １０ Ariel, C ５ ~C １０ Heteroaryl, 3-10 membered heterocyclyl, -C １ ~C ６ Alkyl-(C) ３ ~C ７ Cycloalkyl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Aryl), -C １ ~C ６ Alkyl-(C) ５ ~C １０ Heteroaryl), -C １ ~C ６ Alkyl-(3-10 member heterocyclyl),-(C １ ~C ６ Alkyl)-NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl) NR Ｂ１１ R Ｂ１２ , - (C １ ~C ６ Alkyl)-OR Ｂ１１ and -C(=O)-N(R Ｂ１１ ) (Caution Ｂ１２ A selection is made from the group consisting of ), and each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally selected as C １ ~C ３ Alkyl, C １ ~C ３ Perfluoroalkyl, oxo, halo, -CN, -OH and NH ２ It may be substituted with 1 to 3 substituents selected from the following: Each x2 is independently selected from 0 and 1, and Each R Ｂ１１ and R Ｂ１２ H and C are independent of each other. １ ~C ６ Selected from the group consisting of alkyl groups, Alternatively, R Ｂ１１ and R Ｂ１２ When both are bonded to the same nitrogen, they together form a 4-7 membered heterocyclic ring having 0-2 further ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclic ring is unsubstituted or halo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ７ Cycloalkyl, -CN, -NH ２ , C １ ~C ３ Perfluoroalkyl, -OH, -O-(C １ ~C ６ Alkyl) and -(C １ ~C ６ The combination according to claim 26, wherein it is substituted with one to three substituents selected from the group consisting of alkyl)-OH.

28. The ROCK2 inhibitor is [Chemistry 18] The combination according to claim 22, or a pharmaceutically acceptable salt thereof.

29. The ROCK2 inhibitor is selected from belmosdil (KD025), zelasdil, Y-27632, fasudil, GSK429286A, RKI-1447, azaindole 1 (TC-S 7001), hydroxyfasudil, GSK269962A, ripasudil, AT13148, RX007, and their derivatives, isomers, hydrates, or pharmaceutically acceptable salts, as per claim 22.

30. The GLP-1 agonist is given by formula (M-I) 【Chemistry 19】 It includes the structure, During the ceremony, Xaa ７ L-histidine, imidoazopropionyl, α-hydroxyhistidine, D-histidine, desaminohistidine, 2-aminohistidine, β-hydroxyhistidine, homohistidine, N α - Acetyl-histidine, N α -Formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine, Xaa ８ These are Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib (α-aminoisobutyric acid), (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid. Xaa １６ is Val or Leu, Xaa １８ is Ser, Lys, or Arg, Xaa １９ is Tyr or Glun, Xaa ２０ is Leu or Met, Xaa ２２ This is Gly, Glu, or Aib (α-aminoisobutyric acid), Xaa ２３ These are Glun, Glu, Lys, or Arg, Xaa ２５ It is either Ala or Val, Xaa ２７ is either Glu or Leu, Xaa ３０ is Ala, Glu, or Arg, Xaa ３３ is Val or Lys, Xaa ３４ These are Lys, Glu, Asn, or Arg. Xaa ３５ It is Gly or Aib (α-aminoisobutyric acid), Xaa ３６ is either Arg, Gly, or Lys, or does not exist. Xaa ３７ is Gly, Ala, Glu, Pro, Lys, or does not exist, and B and U together form the acylation part, where U is 【Chemistry 21-1】 【Chemistry 21-2】 Selected from, m is 0, 1, 2, 3, 4, 5, or 6. n is 1, 2, or 3. s is 0, 1, 2, or 3. t is 0, 1, 2, 3, or 4. p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. Furthermore, B is, 【Chemistry 20】 It is an acidic group selected from, In the formula, l is 12, 13, 14, 15, 16, 17, 18, 19 or 20, The combination according to any one of claims 22 to 29, or a pharmaceutically acceptable salt thereof.

31. Xaa ７ His or desaminohistidine, Xaa ８ These are Ala, Gly, Val, Leu, Ile, Lys, or Aib. Xaa １６ is Val, and Xaa １８ is Ser and Xaa １９ It is Tyr, Xaa ２０ It is Leu, Xaa ２２ is Gly, Glu, or Aib, Xaa ２３ is Glun or Glu, Xaa ２５ It is Ala and Xaa ２７ Glu is, Xaa ３０ is Ala or Glu, Xaa ３３ Val is, Xaa ３４ is Lys or Arg, Xaa ３５ It is Gly or Aib, Xaa ３６ is Arg or Lys, and / or Xaa ３７ The combination according to claim 30, wherein is Gly, amide, or absent.

32. U is, 【Chemistry 21】 The method according to claim 30 or 31.

33. B is, 【Chemistry 22】 The combination according to any one of claims 30 to 32, wherein l is 14, 16, or .

34. The GLP-1 agonist is given by formula (M-III): 【Chemistry 23】 Having a structure, The combination according to any one of claims 30 to 33, wherein l is 12, 14, or 16.

35. The aforementioned GLP-1 agonist is 【Chemistry 24】 The combination described in claim 22.

36. The combination according to claim 22, wherein the GLP-1 agonist is selected from semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, tilzepatide, rotiglypron, letatoltide, taspoglutide, olformlipron, or danuglipron.

37. The combination according to any one of claims 22 to 36, wherein the ROCK2 inhibitor and the GLP-1 agonist are administered simultaneously.

38. The combination according to any one of claims 22 to 36, wherein the ROCK2 inhibitor and the GLP-1 agonist are administered sequentially.

39. The combination according to any one of claims 22 to 38, wherein the ROCK2 inhibitor is administered orally and the GLP-1 agonist is administered subcutaneously.

40. A weight loss kit comprising the combination described in any one of claims 22 to 39.

41. A kit for treating a target type 2 diabetes, comprising the combination described in any one of claims 22 to 39.

42. A kit for treating obesity, comprising the combination described in any one of claims 22 to 39.

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