Heterocyclic compounds, pharmaceutical compositions and uses thereof

Abstract

The present application relates to a heterocyclic compound, a pharmaceutical composition, and uses thereof. The heterocyclic compound has the structural formula of Formula I. The heterocyclic compound provided by the present invention has significant Rho kinase inhibitory activity, and its enzymatic activity and cellular activity are superior to those of existing ROCK inhibitors such as ripasudil, netarsudil, and vermosudil, and has great applicability. JPEG2026504900000037.jpg65140

Description

[Technical Field]

[0001] The present application provides heterocyclic compounds, stereoisomers containing the compounds, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions. The heterocyclic compounds are inhibitors that target ROCK and can be used to regulate diseases mediated by Rho kinase. [Background technology]

[0002] The Rho / ROCK (Rho-associated kinase) signaling pathway induces cytoskeletal reorganization, cell migration, adhesion, and stress fiber formation, and is involved in various physiological functions. The ROCK family consists of ROCK1 and ROCK2. ROCK1 is highly expressed in the lung, liver, spleen, kidney, and testis, while ROCK2 is highly expressed in the brain and heart. ROCK1 indirectly interacts with the cadherin-catenin complex by binding to p120-catenin, a scaffolding protein of E-cadherin. ROCK1 can concentrate at the center of microtubule organization and at the edges of pseudopodia in motile cells, and is involved in cell migration. ROCK2 is primarily localized in the cytoplasm and is localized to the plasma membrane by its C-terminal domain, where it associates with vimentin and actin stress fibers.

[0003] ROCK mediates numerous pathophysiological signals and is involved in various physiological functions, including endothelial permeability, tissue contraction, and growth. ROCK inhibitors have potential applications in diseases such as asthma, cancer, glaucoma, insulin resistance, renal failure, neurodegeneration, and osteoporosis. Two ROCK1 / ROCK2 inhibitors, ripasudil and netarsudil, are approved for the treatment of glaucoma, and one ROCK2 inhibitor, belmosudil, is approved for the treatment of chronic graft-versus-host disease (cGVHD). Summary of the Invention [Problem to be solved by the invention]

[0004] However, currently available ROCK inhibitors have weak activity, and the functional and clinical value of ROCK has not been fully realized. Therefore, the development of drugs targeting ROCK is urgently needed to address unmet clinical needs. In this application, highly active heterocyclic compounds targeting ROCK with novel scaffolds and their pharmaceutical compositions have been invented for use in modulating Rho kinase-mediated diseases. [Means for solving the problem]

[0005] One aspect of the present application provides a compound of Formula I, its isotopic isomer, or a pharmaceutically acceptable salt solvate, active metabolite, crystalline polymorph, isotopically labeled form, isomer, or prodrug thereof: JPEG2026504900000002.jpg65140

[0006] Another aspect of the present invention provides methods for preparing compounds of Formula I, isotopic isomers or pharmaceutically acceptable salts thereof, active metabolites, crystalline polymorphs, isotopically labeled compounds, isomers or prodrugs thereof, and uses thereof for treating diseases mediated by Rho kinase. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows the 24-hour intraocular pressure change curves of the test group animals at different times after administration. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present application will be described in more detail through the following embodiments, through which the features and advantages of the present application will be more clearly defined.

[0009] The term "exemplary" is used herein to mean "an example," "an embodiment," or "serving as an illustration." An embodiment described herein as "exemplary" should not be construed as superior or advantageous over other embodiments.

[0010] Furthermore, the technical features in different embodiments of the present application described below can be combined with each other if they are not contradictory.

[0011] definition Unless otherwise defined, all technical terms in this specification have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise specified, all patents, patent applications, and disclosure materials cited throughout this specification are incorporated herein by reference in their entirety. When a trade name is mentioned in this specification, it is intended to refer to that product or active ingredient.

[0012] It is to be understood that the foregoing brief description and the following detailed description are exemplary and explanatory only and are not intended to limit the subject matter of the present invention in any way. It is important to note that, as used in the specification and claims, the singular forms "a," "an," and "the" include the plural of the referenced item unless the context clearly dictates otherwise. It is also to be noted that, unless otherwise indicated, the terms "or" and "alternative" are used to indicate "and / or." Furthermore, the use of the term "including," such as "comprising," "containing," and "containing," is not limiting.

[0013] Definitions of standard chemical terms are found in Carey and Sundberg's "Advanced Organic Chemistry 4 thReference can be made to literature such as "The Journal of Chemistry, Vol. A (2000) and B (2001), Plenum Press, New York." Unless otherwise specified, conventional methods within the skill of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacological methods, are used. Unless specific definitions are provided, the nomenclature, laboratory procedures, and techniques associated with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry used herein are known to those skilled in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, drug delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). For example, reactions and purification techniques can be performed using kits accompanied by manufacturer-provided instructions, according to methods known in the art, or according to the methods described herein. In general, the techniques and steps can be performed by conventional methods well known in the art and described in various general or more specific publications. Such documents are cited and discussed in this application.

[0014] When a substituent is represented by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that results when the structural formula is written from right to left. For example, CHO is equivalent to OCH.

[0015] The term "substituted or unsubstituted" encompasses both "substituted" and "unsubstituted," where "substituted" means that any one or more hydrogen atoms on a given atom are replaced with a substituent, provided that the valence of the given atom is normal and the substituted compound is stable, and "unsubstituted" means that no hydrogen atoms on a given atom are replaced with a substituent. For example, "substituted or unsubstituted ethyl" (e.g., where the substituent is a halogen) includes unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). As will be understood by those skilled in the art, any group containing one or more substituents will not introduce a substituent or substitution pattern that is spatially impossible and / or cannot be synthesized. When a substituent is an oxo group (i.e., =0), this means that two hydrogen atoms on the same atom are replaced.

[0016] When any variable (e.g., R) occurs more than once in any composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0 to 2 R, then that group may optionally be substituted with up to 2 R, and each occurrence of R is an independent option. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds. The term "optionally" or "may" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance.

[0017] As used herein, C m~n means that the moiety has m to n carbon atoms. For example, 1~8 " group has 1 to 8 carbon atoms in the moiety, i.e., the group is said to contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, ... 8 carbon atoms. Thus, for example, "C 1~8"Alkyl" refers to an alkyl group containing 1 to 8 carbon atoms. That is, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, octyl, etc. Numeric ranges herein, such as "1 to 8," refer to each integer within the range; for example, "1 to 8 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, or 8 carbon atoms.

[0018] The term "alkyl" refers to an optionally substituted straight-chain or an optionally substituted branched-chain saturated aliphatic hydrocarbon group connected to the rest of the molecule by a single bond. As used herein, "alkyl" can have from 1 to about 8 carbon atoms, such as from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, hexyl, and longer alkyl groups such as heptyl and octyl. When a numerical range exists for a group defined herein, e.g., "alkyl," it is preferred to use a range such as "C 1~8 "Alkyl" refers to alkyls consisting of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, and also includes, for example, "C 1~4"Alkyl" refers to alkyls composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. In this specification, alkyls also include those without a specified numerical range.

[0019] The term "alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain monovalent hydrocarbon group having at least one C=C double bond. The alkenyl may have from 2 to about 8 carbon atoms, such as, but not limited to, from 2 to about 6 carbon atoms, or from 2 to about 4 carbon atoms. The double bond in these groups may be in either the cis or trans configuration, and both isomers should be understood to be included. Examples of alkenyl include, but are not limited to, ethylenyl (CH=CH), 1-propenyl (CHCH=CH), isopropenyl (C(CH)=CH), butenyl, and 1,3-butadienyl. When a numerical range exists for alkenyl as defined herein, for example, "C 2-8 "Alkenyl" refers to alkenyl consisting of 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In this specification, alkenyl also includes those without a specified numerical range.

[0020] The term "alkynyl" refers to an optionally substituted, straight- or branched-chain monovalent hydrocarbon group having at least one C≡C triple bond. The alkynyl may have, for example, but not limited to, 2 to about 8 carbon atoms, such as 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadinyl. When a numerical range exists for alkynyl as defined herein, for example, "C 2-8 "Alkynyl" refers to alkynyl consisting of 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In this specification, alkynyl also includes those without a specified numerical range.

[0021] The term "cycloalkyl" refers to a non-aromatic carbocyclic ring, including a saturated carbocyclic ring (e.g., cycloalkyl) or an unsaturated carbocyclic ring (e.g., cycloalkenyl). Carbocyclic rings may be monocyclic carbocyclic rings (having one ring), e.g., monocyclic cycloalkyl, bicyclic carbocyclic rings (having two rings), e.g., bicyclic cycloalkyl, or polycyclic carbocyclic rings (having two or more rings). Rings may be bridged or spiro-connected. Carbocyclic rings (e.g., cycloalkyl or cycloalkenyl) may have 3 to 8 carbon atoms, e.g., 3 to about 6 ring carbon atoms or 3 to about 5 ring carbon atoms.

[0022] The term "aryl" refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, e.g., 6 to 12 or 6 to 10, ring carbon atoms, and may be a monocyclic aryl, a bicyclic aryl, or a polycyclic aryl. A bicyclic aryl or a polycyclic aryl may be a monocyclic aryl fused to another independent ring, such as an aliphatic ring, a heterocyclic ring, an aryl ring, or an aryl heterocyclic ring. Non-limiting examples of monocyclic aryls include monocyclic aryls having 6 to about 12, 6 to about 10, or 6 to about 8 ring carbon atoms, such as phenyl; an example of a bicyclic aryl is naphthyl; and examples of polycyclic aryls include phenanthryl, anthracenyl, and azulenyl.

[0023] The term "heteroaryl" refers to an optionally substituted heteroaryl containing about 5 to about 20, e.g., 5 to 12 or 5 to 10, skeletal ring atoms, wherein at least one (e.g., 1 to 4, 1 to 3, 1 to 2) ring atom is a heteroatom. The heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin heteroatoms. Heteroaryl includes monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings), or polycyclic heteroaryl (having two or more rings). In embodiments where two or more heteroatoms are present in a ring, the two or more heteroatoms may be the same, or some or all of the two or more heteroatoms may be different from one another. A bicyclic heteroaryl or higher polycyclic heteroaryl may be a monocyclic heteroaryl fused to another independent ring, such as an aliphatic ring, a heterocyclic ring, an aryl ring, or an aryl heterocyclic ring (collectively referred to as a fused cycloheteroaryl). Non-limiting examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, and the like.

[0024] The terms "heterocyclyl" and "heterocyclic group" refer to non-aromatic heterocycles, including saturated or unsaturated heterocycles (containing unsaturated bonds) that do not have a completely conjugated π-electron system, and are classified as non-aromatic monocyclic, fused polycyclic, bridged, or spirocyclic. Among these, one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) of the ring atoms are heteroatoms, such as oxygen, nitrogen, or sulfur atoms. Heterocycles include monocyclic heterocycles (having one ring), bicyclic heterocycles (having two bridged rings), and polycyclic heterocycles (having two or more bridged rings), including spirocycles. Heterocyclyls may have 3 to about 20, e.g., 3 to about 10, 3 to about 8, 4-8, 4-7, 5 to about 8, or 5 to about 6 ring atoms. Non-limiting examples of heterocyclyl include oxiranyl, thioethanethiol, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxetanyl, thiepanyl, oxazabicyclo[2.2.1]heptyl, and azapyro[3.3]heptyl, and the like.

[0025] The term "halo" or "halogen" refers to an optionally substituted group (e.g., alkyl, alkenyl, alkynyl, alkoxy, etc.) in which at least one hydrogen atom is replaced with a halogen (e.g., fluorine, chlorine, bromine, iodine, or a combination thereof). In some embodiments, two or more hydrogens are replaced with halogens that are identical to each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogens are replaced with halogens that are not identical to each other (e.g., 1-chloro-1-fluoro-1-iodoethyl).

[0026] The term "alkoxy" refers to an alkyl ether (O-alkyl), and non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0027] The term "alkyl acyl" refers to a group having an alkyl group attached to -CO-, and non-limiting examples of the term include formyl, acetyl, propanoyl, butyryl, and the like. For example, the term "C 1-6 "Alkyl acyl" means C 1-6 It refers to a group formed by bonding an alkyl group to a -CO- group. 1-4 "Alkyl acyl" means C 1-4 It refers to a group formed by bonding an alkyl group with -CO-.

[0028] The term "alkylsulfonyl" refers to an alkyl group attached to -SO2-, and non-limiting examples of the term include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like. For example, the term "C 1-6 "Alkylsulfonyl" means -SO2- with C 1-6 It refers to a group to which an alkyl group is attached. 1-4 "Alkylsulfonyl" means -SO2- with C 1-4 It refers to a group to which an alkyl group is bonded.

[0029] The term "heteroarylacyl" refers to a group in which a heteroaryl group is attached to -CO-. For example, the term "C 5~20 "Heteroarylsulfonyl" means -CO- to C 5~20 Refers to a group to which a heteroaryl group is attached. 5~20 "Heteroaryl" is defined above.

[0030] The terms "monocyclic ring," "monocyclic group," and "monocyclic ring system" refer to a single ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl) structure. The terms "polycyclic ring," "polycyclic group," and "polycyclic ring system" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl) in which one, two, or more ring atoms share two adjacent rings; for example, the polycyclic rings may be "fused rings," "spirocyclic rings," or "bridged rings."

[0031] The term "bicyclic carbocycle" refers to an aromatic or non-aromatic ring containing two rings, where each atom in the ring is carbon and the two rings share one, two, or more ring atoms. For example, the rings are "fused rings" or "spirocycles." Rings joined through non-adjacent atoms are referred to as "bridged" rings, e.g., C5-C 12 and includes, but is not limited to, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[2.1.1]pentyl. Each ring of the bicyclic carbocycle can be substituted with a substituent as described above, such as a halogen atom, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF, -CN, and the like. The term "C5-C 12 "Bicyclic carbocycle" means a bicyclic carbocycle having 5 to 12 carbon atoms in the ring, excluding the carbon atoms on the substituents, and C5-C 12 Spirocyclic carbocycles, C5-C 12 Fused carbocyclic ring or C5-C 12 It may contain bridged carbocycles.

[0032] Other radical terms used herein include "hydroxyl" which refers to an --OH group, "sulfhydryl" which refers to an --SH group, "cyano" which refers to a --CN group, and "carboxy" which refers to a --COOH group.

[0033] The term "membered" refers to the number of atoms that make up the backbone of the ring. For example, pyridine is a six-membered ring and pyrrole is a five-membered ring.

[0034] The term "pharmaceutically acceptable" means that the compound, material, composition and / or dosage form is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals and does not cause excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0035] The term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component or agent, i.e., a "carrier," that facilitates the introduction of the compound into cells or tissues, including, but not limited to, stabilizers, diluents, suspending agents, thickeners, and / or excipients.

[0036] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and free base of a particular compound without any undesirable biological or other effects. Unless otherwise specified, salts in this invention can refer to metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexyleneamine, and the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfinic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts formed with alkaline amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.

[0037] Pharmaceutically acceptable salts can be synthesized from parent compounds containing acid or base groups using conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of the compound with the stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropyl alcohol, or acetonitrile are generally preferred. The term "solvate," as used herein, refers to a physical association of a compound with one or more solvent molecules, which may contain varying degrees of ionic and covalent bonding (e.g., hydrogen bonding). It has been found that such solvates can be isolated. For example, one or more solvent molecules may be present in the crystalline lattice of a crystal. The term "solvate" includes both solvent phases and separable solvates. Numerous examples of corresponding solvates exist, including ethanol solvates and methanol solvates. A "hydrate" is a solvate containing water (HO) molecules as the solvent. One or more compounds of the present invention can optionally be prepared as a solvate. The preparation of solvates is well known. For example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004), describes the preparation of a solvate of the antifungal drug fluconazole, i.e., using ethyl acetate and water. EC van Tonder et al., AAPS Pharm Sci Tech., 5(1), article 12 (2004); and A.L. Bingham et al., Chem. Commun., 603-604 (2001) also describe similar methods for preparing solvates and hydrates. A typical, non-limiting example of a preparation process involves dissolving a compound of the present invention in a desired amount of a desired solvent (organic solvent, water, or a mixture thereof) at room temperature or higher, cooling, and allowing the solution to stand to precipitate crystals, which are then isolated and separated by standard methods. The presence of the solvate- (hydrate-) forming solvent (water) in the crystals can be verified by IR spectroscopy.

[0038] The term "active metabolite" refers to an active derivative of a compound that is produced when the compound is metabolized. The term "polymorphs" refers to compounds of the present invention that exist in different crystalline structures.

[0039] The term "isotopically labeled compound" refers to a compound of the present invention that is labeled with an isotope. For example, the isotopes in the compound of the present invention include various isotopes of elements such as H, C, N, O, P, F, and S. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 S is included.

[0040] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention, which, after administration to a subject, is capable of directly or indirectly providing a compound of the present invention or its pharmaceutically active metabolite or residue. Particularly preferred derivatives or prodrugs are compounds that, when administered to a patient, can enhance the bioavailability of the compounds of the present application (e.g., allow an oral compound to be more easily absorbed into the bloodstream) or contribute to the delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system). Prodrugs can be prepared by modifying functional groups present in the compound in such a way that they are capable of breaking down to the parent compound by routine manipulation or in vivo. Various prodrug forms are well known in the art. See Prodrugs as Novel Delivery Systems (1987) Vol. 14 of the ACS Symposium Series by T. Higuchi and V. Stella, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, for a discussion of prodrugs.Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, are incorporated herein by reference.

[0041] The term "stereoisomer" refers to an isomer resulting from differences in the spatial arrangement of atoms in a molecule. The compounds of the present invention contain structures such as asymmetric or chiral centers, double bonds, and the like. Therefore, the compounds of the present invention may include various isomers, such as optical isomers, geometric isomers, tautomers, and blocking isomers. These isomers, as well as their single isomers and racemates, are also within the scope of the present invention. For example, optical isomers can be prepared as optically active (R)- and (S)-isomers, as well as D- and L-isomers, by chiral resolution, chiral synthesis, chiral reagents, or other conventional techniques. For example, diastereoisomers can be separated by reaction with an appropriate optically active substance (e.g., chiral alcohol or Mosher's acid chloride) and converted into diastereoisomers, which can then be separated and converted (e.g., hydrolyzed) into the corresponding single isomers. Separation can also be achieved, for example, by chromatographic columns.

[0042] The "pharmaceutical compositions" herein can be prepared by methods well known in the pharmaceutical art and can be administered or administered by various routes. This depends on whether local or systemic treatment is required and the area to be treated. The "pharmaceutical compositions" herein can be administered topically (e.g., transdermally, via the skin, eye, and mucous membranes, including intranasal, vaginal, and rectal), pulmonary (e.g., inhalation or insufflation of powders or aerosols, including administration via a nebulizer; intratracheal, intranasal), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Administration can be parenterally in the form of a single bolus dose or, for example, by continuous infusion pump. Pharmaceutical compositions herein may be in the form of, but are not limited to, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle); ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders, and the like.

[0043] The pharmaceutical compositions herein can be formulated in unit dosage form, with a single dosage containing about 0.1 to 1000 mg, usually about 5 to 1000 mg, and more usually about 100 to 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete, single dosage units suitable for use in human patients and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in admixture with a suitable pharmaceutical carrier.

[0044] The term "individual" refers to an individual, including mammals and non-mammals, suffering from a disease, condition, or pathology, etc. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm animals, such as cows, horses, sheep, goats, and pigs; domesticated animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs.

[0045] The term "treatment" and other similar synonyms include ameliorating, alleviating, or improving symptoms of a disease or condition, preventing other symptoms, improving or preventing the underlying metabolic causes of a symptom, inhibiting a disease or condition, e.g., halting the progression of a disease or condition, ameliorating a disease or condition, improving a disease or condition, ameliorating symptoms caused by a disease or condition, or halting the symptoms of a disease or condition. Furthermore, the term may also encompass prophylactic purposes. The term also encompasses achieving a therapeutic and / or prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. Furthermore, curing or ameliorating one or more physiological symptoms associated with an underlying disease is also a therapeutic effect, e.g., when an improvement in the patient's condition is observed even though the patient is still affected by the underlying disease. For prophylactic effects, the composition or compound can be administered to a patient at risk of developing a particular disease, or to a patient who is experiencing one or more physiological symptoms of the disease, even if the disease has not yet been diagnosed.

[0046] The term "amount required to achieve the desired therapeutic effect" or "therapeutically effective amount" refers to an amount of at least one drug or compound sufficient, upon administration, to ameliorate to some extent one or more symptoms of the disease or condition being treated. The result may be reduction and / or amelioration of the signs, symptoms, or etiology of the disease, or any other desired change in a biological system. Techniques such as dose escalation studies can be used to determine the appropriate effective amount for any individual case. The actual dosage of a compound, pharmaceutical composition, or drug will typically be determined by a physician based on relevant circumstances, such as the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0047] The proportion or concentration of a compound of the present invention in a pharmaceutical composition does not need to be fixed and will depend on various factors, such as dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the compound of the present invention may be provided in an aqueous physiological buffer solution containing about 0.1 to 10% w / v of the compound. A typical dosage range is about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. Dosage will likely depend on variables such as the type and progression of the disease or condition, the general health of the particular patient, the relative biological potency of the selected compound, the excipient formulation, and its route of administration.

[0048] The term "administration" refers to a method that allows a compound or composition to be delivered to a desired site of biological action. These methods include, but are not limited to, oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, and intraarterial injection or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein. For example, see Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0049] The term “IC 50 " means a 50% inhibition of the maximal effect obtained in the assay measuring such effect.

[0050] compound The present application provides heterocyclic compounds of Formula I, or pharmaceutically acceptable salts, solvates, active metabolites, crystalline polymorphs, isotopically labeled forms, isomers, or prodrugs thereof: JPEG2026504900000003.jpg54117

[0051] where: X, Y and Z are each independently selected from C atoms or N atoms, provided that X, Y and Z are not simultaneously C atoms;

[0052] R1 is -NHR 11 , -OR 11 , -SR 11 or -C(=O)NHR 11 where R 11 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl, substituted or unsubstituted C 5~20 Heteroaryl, substituted or unsubstituted C 1~6 Alkyl acyl, substituted or unsubstituted C 1~6 Alkyl sulfonyl, substituted or unsubstituted C 5~20 Heteroarylacyl, and substituted or unsubstituted C 1~6 alkoxy; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , -C(=O)R 33 , hydroxyl, carboxy, sulfhydryl, substituted C 3~8 Cycloalkyl, substituted C 3~8 Heterocyclyl, substituted C 6~20 Aryl and substituted C 5~20 selected from the group consisting of heteroaryl;

[0053] R2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Haloalkyl, substituted or unsubstituted C 1~6 The substituents are selected from the group consisting of alkoxy, cyano, amino, hydroxyl, carboxy, and sulfhydryl; 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR31 R 32 , selected from the group consisting of hydroxyl, carboxy, and sulfhydryl;

[0054] R3 is selected from the group consisting of cyano, -CONH2 and carboxy; R4 and R5 are each independently hydrogen, halogen, or -NR 31 R 32 , substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl or substituted and unsubstituted C 5~20 heteroaryl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , selected from the group consisting of hydroxyl, carboxy, and sulfhydryl;

[0055] wherein (i) R and R are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, or substituted and unsubstituted bicyclic carbocycles; the substituents are halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , hydroxyl, oxo, carboxy, and sulfhydryl; and further, R6 and R8 are not all hydrogen;

[0056] or (ii) R6 and R8 and the C atom to which R6 and R8 are attached together form a 4- to 8-membered monocyclic or polycyclic ring system; said 4- to 8-membered monocyclic or polycyclic ring system is 41 optionally replaced by;

[0057] R7 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 1~6 Haloalkyl, substituted or unsubstituted C 1~6 Selected from the group consisting of alkoxy, amino, hydroxyl, carboxy, and sulfhydryl;

[0058] Alternatively, R6 is hydrogen, and R8, the C atom to which R8 is attached, and R7 and the C atom to which R7 is attached together form a 5- to 8-membered carbocyclic ring; the 5- to 8-membered carbocyclic ring may be joined by one or more R 41 optionally replaced by;

[0059] R 31 and R 32 are each independently hydrogen, sulfonamido, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl and substituted or unsubstituted C 5~20 heteroaryl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, hydroxyl, -C(=O)OR 34 and sulfhydryl;

[0060] R 33 is hydrogen, substituted or unsubstituted C 1~8 Alkyl, substituted or unsubstituted C 1~8 Alkoxy, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 6~20 Aryl and substituted and unsubstituted C 5~20 heteroaryl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , selected from the group consisting of hydroxyl, carboxy, and sulfhydryl; R 34 is hydrogen, substituted or unsubstituted C 1~8 Alkyl, substituted or unsubstituted C 1~8 Haloalkyl, substituted or unsubstituted C 1~8 Alkoxy and substituted or unsubstituted C 3~8 cycloalkyl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 selected from the group consisting of heteroaryl, cyano, hydroxyl, carboxy, and sulfhydryl;

[0061] R 41 is hydrogen, halogen, oxo, cyano, hydroxyl, substituted or unsubstituted C 1~8 Alkyl, substituted or unsubstituted C 1~8 Haloalkyl, substituted or unsubstituted C 1~8 Alkoxy, and substituted or unsubstituted C 3~8 cycloalkyl; the substituents are selected from the group consisting of halogen, C 1~8Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , hydroxyl, carboxy and sulfhydryl.

[0062] In the present application, when X, Y, and Z are C atoms or N atoms, the C atoms or N atoms may be connected to hydrogen atoms necessary to satisfy the valence of the C atoms or N atoms. For example, when Z is an N atom, the N atom is further connected to hydrogen atoms that satisfy the valence of the N atom, and when X and Y are N atoms, the N atoms do not need to be further connected to hydrogen atoms. In one embodiment, X and Y are N atoms, and Z is a C atom or an N atom. In another embodiment, X, Y, and Z are all N atoms.

[0063] In one embodiment, R1 is -NHR 11 where R 11 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl, substituted or unsubstituted C 5~20 Heteroaryl, substituted or unsubstituted C 1~6 Alkyl acyl, substituted or unsubstituted C 1~6 Alkyl sulfonyl, substituted or unsubstituted C 5~20 Heteroarylacyl, and substituted or unsubstituted C 1~6 alkoxy; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , -C(=O)R 33 , hydroxyl, sulfhydryl, substituted C 3~8 Cycloalkyl, substituted C 3~8 Heterocyclyl, substituted C 6~20 Aryl and substituted C 5~20 The inventors have discovered that R1 is selected from the group consisting of -NHR 11 We have discovered that when R1 is present, the presence of one active hydrogen in R1 can enhance the ROCK bioactivity of the compound.

[0064] In one embodiment, R1 is -NHR 11 where R 11 is hydrogen and substituted or unsubstituted C 1~6 alkyl, and the substituents are selected from the group consisting of -NR 31 R 32 , -C(=O)R 33 , and substituted or unsubstituted C 3~8 In one embodiment, R1 is selected from the group consisting of -NHR 11 and R 11 is selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted isopropyl, optionally substituted butyl, optionally substituted tert-butyl, optionally substituted pentyl, and optionally substituted hexyl, and the substituents are -NR 31 R 32 , -C(=O)R 33 , and substituted or unsubstituted C 3~8 Heterocyclyl (wherein the substituents are C substituted, e.g., methyl, ethyl, propyl, isopropyl, etc.) 1~6 Preferably, R 11 is a substituted or unsubstituted C 1~6 alkyl, and the substituents are selected from the group consisting of -NR 31 R 32where R 31 and R 32 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~8 Heterocyclyl (wherein the substituents are C substituted, e.g., methyl, ethyl, propyl, isopropyl, etc.) 1~6 Preferably, R 11 is a substituted or unsubstituted C 1~6 alkyl, and the substituent is selected from the group consisting of -C(=O)R 33 where R 33 are independently substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~8 Heterocyclyl (substituents are C 1~6 alkyl, such as methyl, ethyl, propyl, isopropyl, etc.

[0065] In one aspect, JPEG2026504900000004.jpg73168.

[0066] In one embodiment, R1 is -OR 11 and R 11 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl, substituted or unsubstituted C 5~20 Heteroaryl, substituted or unsubstituted C 1~6 Alkyl acyl, substituted or unsubstituted C 1~6 Alkyl sulfonyl, substituted or unsubstituted C 5~20 Heteroarylacyl, and substituted or unsubstituted C 1~6 alkoxy; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , -C(=O)R 33 , hydroxyl, and sulfhydryl; preferably, R 11 is hydrogen, and substituted or unsubstituted C 1~6 alkyl, and the substituents are selected from the group consisting of -NR 31 R 32 , -C(=O)R 33 , and substituted or unsubstituted C 3~8 heterocyclyl.

[0067] In one embodiment, R1 is -C(=O)NHR 11 where R 11 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl, substituted or unsubstituted C 5~20 Heteroaryl, substituted or unsubstituted C 1~6 Alkyl acyl, substituted or unsubstituted C 1~6 Alkyl sulfonyl, substituted or unsubstituted C 5~20 Heteroarylacyl, and substituted or unsubstituted C 1~6 alkoxy; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , -C(=O)R33 , selected from the group consisting of hydroxyl and sulfhydryl; Preferably, R 11 is hydrogen, and substituted or unsubstituted C 1~6 alkyl, and the substituents are selected from the group consisting of -NR 31 R 32 , -C(=O)R 33 , and substituted or unsubstituted C 3~8 heterocyclyl.

[0068] In each embodiment described above for R, R 31 and R 32 are each independently hydrogen, sulfonamido, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl, and substituted or unsubstituted C 5~20 heteroaryl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, hydroxyl, -C(=O)OR 34 and sulfhydryl;

[0069] R 33 is hydrogen, substituted or unsubstituted C 1~8 Alkyl, substituted or unsubstituted C 1~8 Alkoxy, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 6~20 Aryl, and substituted or unsubstituted C 5~20 heteroaryl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , selected from the group consisting of hydroxyl, carboxy, and sulfhydryl; R 34 is hydrogen, substituted or unsubstituted C 1~8 Alkyl, substituted or unsubstituted C 1~8 Haloalkyl, substituted or unsubstituted C 1~8 Alkoxy, and substituted or unsubstituted C 3~8 cycloalkyl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 It is selected from the group consisting of heteroaryl, cyano, hydroxyl, carboxy and sulfhydryl.

[0070] In each embodiment described above for R, R 31 and R 32 are each independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, or substituted or unsubstituted C 3~8 Heterocyclyl (wherein the substituents are C substituted, e.g., methyl, ethyl, propyl, isopropyl, etc.) 1~6 R may be alkyl. 33 are independently substituted or unsubstituted C 1~6 Alkyl, or substituted or unsubstituted C 3~8 Heterocyclyl (wherein the substituents are C substituted, e.g., methyl, ethyl, propyl, isopropyl, etc.) 1~6 It can be alkyl.

[0071] In one embodiment, R1 is -NH2 and R2 is hydrogen.

[0072] In one embodiment, R4 and R5 are each independently hydrogen, halogen, or -NR 31 R 32 , substituted or unsubstituted C 3~8 Heterocyclyl, substituted or unsubstituted C 6~20 Aryl, and substituted or unsubstituted C 5~20 heteroaryl; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , hydroxyl, carboxy, and sulfhydryl. In one embodiment, R4 and R5 are all hydrogen.

[0073] In one embodiment, R6 and R7 are hydrogen; R8 is selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, and substituted or unsubstituted bicyclic carbocycle; the substituents are halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , hydroxyl, oxo, carboxy and sulfhydryl.

[0074] In one embodiment, R6 and R7 are hydrogen; R8 is a substituted or unsubstituted C5-C 12 bicyclic carbocycles, wherein the bicyclic carbocycles are selected from the group consisting of C5-C 12 Spirocyclic carbocycles, C5-C 12 Fused carbocycles and C5-C 12bridged carbocycles; the substituents are selected from the group consisting of halogen, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, C 6~20 Aryl, C 5~20 Heteroaryl, cyano, -NR 31 R 32 , hydroxyl, oxo, carboxy and sulfhydryl.

[0075] In one embodiment, the bicyclic carbocycle has the following structural formula: JPEG2026504900000005.jpg40148.

[0076] In one embodiment, R6 and R7 are hydrogen; R8 is selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, and substituted or unsubstituted cyclohexyl, and the substituents are C 1~6 Preferably, R is cyclopropyl; alternatively, R is cyclohexyl; alternatively, R is selected from the group consisting of cyclobutyl, 3-methyl-cyclylbut-1-yl, and 3,3-dimethyl-cyclylbut-1-yl.

[0077] In one embodiment, R6 is hydrogen, and R8, the C atom to which R8 is bonded, and R7 and the C atom to which R7 are bonded together form a 5- to 8-membered carbocyclic ring. In one embodiment, the 5- to 8-membered carbocyclic ring is selected from the group consisting of a cyclylpentane ring and a cyclohexane ring.

[0078] In one embodiment, R6 and R8 and the C atom to which R6 and R8 are attached together form a 4- to 8-membered monocyclic or polycyclic ring system; R7 is hydrogen. In one embodiment, R6 and R8 and the C atom to which R6 and R8 are attached together form a 4- to 8-membered monocyclic ring system, such as C4~8 Cycloalkane ring, or C 3~8 In one embodiment, the 4- to 8-membered monocyclic or polycyclic ring system may be a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an azetidine ring, an azocyclopentane ring, an azacyclohexane ring, an oxetane ring, an oxolane ring, an oxacyclohexane ring, a thietane ring, a thiolane ring, a thiacyclohexane ring, or the like. These 4- to 8-membered monocyclic or polycyclic ring systems may be formed by one or more R 41 , such as hydrogen, halogen, oxo, cyano, hydroxyl, substituted or unsubstituted C 1~8 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, tert-butyl, etc.), substituted or unsubstituted C 1~8 Haloalkyl, substituted or unsubstituted C 1~8 Alkoxy or substituted or unsubstituted C 3~8 The cycloalkyl may be optionally substituted.

[0079] Preferably, the 4-8 membered monocyclic or polycyclic ring system has the following structural formula: JPEG2026504900000006.jpg27160.

[0080] Here, C* indicates the connection position in the structural formula, and two groups are bonded thereto, one of which is a pyrazole ring structure and the other of which is a -CR3R7 structure.

[0081] In one embodiment, R3 is cyano.

[0082] In one embodiment, the compound is selected from the group consisting of the following compounds: JPEG2026504900000007.jpg225163JPEG2026504900000008.jpg167170

[0083] In the present invention, the compounds described in the present invention can be prepared by the following methods. The following methods and examples are intended to illustrate these methods. These processes and examples should not be construed as limitations of the present invention in any way. The compounds described herein can be synthesized by standard synthetic techniques known to those skilled in the art, or can be synthesized by combining methods known in the art with the methods described herein.

[0084] The chemical reactions of the examples of the present invention are carried out in suitable solvents, which must be appropriate for the chemical transformations of the present invention and the reagents and materials required therefor. To obtain the compounds of the present invention, it may be necessary for those skilled in the art to modify or select synthetic steps or reaction processes based on existing embodiments.

[0085] An important consideration in planning any synthetic route in this field is the selection of an appropriate protecting group for the reactive functional group (e.g., amino in the present invention). For the trained practitioner, Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991) is an authority in this area. All references cited herein are incorporated herein in their entirety.

[0086] The reactions described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by, for example, nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), optical methods such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0087] The compounds of general formula I of the present invention can be prepared by one skilled in the art of organic synthesis using standard methods in the art by the following process: Aldehyde or ketone compound 1 undergoes a Witting reaction with a phosphate ester substituted with R3 and R7 to produce compound 2, which then undergoes a Michael addition reaction with compound 3 to remove the protecting group, yielding the compound of Formula I of the present invention. Some chiral compounds were then separated using a chiral column (chiral column CHIRAL ART Amylose-C, NEO 3>25 cm, mobile phase A: CO2, mobile phase B: IPA, flow rate 90 mL / min, gradient: 50% B). Pharmaceutical Compositions and Uses The present invention also provides a pharmaceutical composition comprising the compound according to any one of the above technical configurations, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

[0088] The pharmaceutical composition may be in the form of, but not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, rectal dosage forms, etc. For example, the pharmaceutical composition may be oral tablets, capsules, pills, powders, sustained-release formulations, solutions and suspensions, sterile solutions, suspensions or emulsions for parenteral gastrointestinal injection, ointments, creams, gels, etc. for external use, eye drops for external use, inhalants for external use, or suppositories for rectal administration.

[0089] The pharmaceutical composition may also contain other active ingredients or drugs, which are used in combination (drug combination) with the compound or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled form, isomer, or prodrug thereof.

[0090] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled product, isomer, or prodrug thereof, as well as the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating a disease mediated by Rho kinase, wherein Rho kinase includes types such as ROCK1 and ROCK2.

[0091] The present application also relates to a method for treating a disease mediated by Rho kinase, comprising administering to a patient in need thereof a therapeutically effective amount of the above-described azacycloalkane compound or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled form, isomer, or prodrug thereof, or the above-described pharmaceutical composition, wherein Rho kinase includes types such as ROCK1 and ROCK2.

[0092] In one embodiment, the disease mediated by Rho kinase is asthma, cancer, glaucoma, insulin resistance, renal failure, neurodegeneration, or osteoporosis.

[0093] The heterocyclic compounds provided by the present invention have significant Rho kinase inhibitory activity, and their enzymatic and cellular activities are superior to those of existing ROCK inhibitors such as ripasudil, netarsudil, and vermosudil, and have great applicability. To clarify the purpose, technical configuration, and advantages of the present invention, the technical configuration of exemplary embodiments of the present invention will be further described below.

[0094] Example 1: 2-(4-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)acetonitrile JPEG2026504900000010.jpg73123

[0095] Synthetic Route: JPEG2026504900000011.jpg71159

[0096] Step A: 2-(tetrahydro-4H-thiopyran-4-ylidene)acetonitrile JPEG2026504900000012.jpg31106

[0097] Sodium hydride (826 mg, 34.4 mmol, 2.0 eq) was added to a solution of diethyl (cyanomethyl)phosphonate (3.04 g, 17.2 mmol, 1.0 eq) in tetrahydrofuranyl (50 mL) at 0 °C, and the reaction mixture was incubated for 0.5 h at 0 °C. Tetrahydro-4H-thiopyran-4-one (2 g, 17.2 mmol, 1.0 eq) was added to the reaction mixture, and the temperature was raised to 25 °C and the reaction mixture was continued for 2 h. After completion of the reaction, the reaction mixture was poured into aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to give a colorless liquid product (2 g, yield = 83%).

[0098] LC-MS(ESI), m / z: [M+H] + =140.2.

[0099] Step B: 2-(1,1-dihydrodioxy-4H-thiopyran-4-ylidene)acetonitrile Potassium peroxymonosulfonate (4.98 g, 14.38 mmol, 2.0 eq) was added to a solution of 2-(tetrahydro-4H-thiopyran-4-ylidene)acetonitrile (1 g, 7.19 mmol, 1.0 eq) in methanol (20 mL) and water (10 mL) at room temperature, and the reaction mixture was incubated at 25 °C for 7 h. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid product (900 mg, yield = 73%).

[0100] LC-MS (ESI), m / z: [M+H] + =172.1.

[0101] Step C: 2-(4-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran-4-ylacetonitrile A solution of 2-(1,1-dihydrodioxy-4H-thiopyran-4-ylidene)acetonitrile (342 mg, 2 mmol, 2.0 eq), 4-(7-(2-trimethylsilylethoxymethyl)-7H-pyrrolopyrrolidin-4-ylpyrazole (330 mg, 1 mmol, 1.0 eq), and 1,8-diazepinebicyclo[5.4.0]undec-7-ene (456 mg, 3 mmol, 1.5 eq) in acetonitrile (20 mL) was reacted at room temperature for 16 h at 25 °C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:3) to give the pale yellow solid product (360 mg, yield = 72%).

[0102] LC-MS (ESI), m / z: [M+H] + =502.2.

[0103] Step D: 2-(4-(3-amino-4-(7-(methylol)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)acetonitrile A solution of 2-(4-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran-4-ylacetonitrile (300 mg, 0.6 mmol, 1.0 eq) in trifluoroacetic acid (3 mL) and dichloromethane (9 mL) was stirred at room temperature for 2 h at 25 °C. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0104] LC-MS (ESI), m / z: [M+H] + = 402.1.

[0105] Step E: 2-(4-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)acetonitrile JPEG2026504900000016.jpg84145 Ethylenediamine (1 mL) was added to a solution of 2-(4-(3-amino-4-(7-(methylol)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)acetonitrile in methanol (10 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give a white solid product (97 mg, yield = 36%).

[0106] LC-MS (ESI), m / z: [M+H] + = 372.1.

[0107] 1 H-NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 7.55 (dd, J = 3.6, 2.4 Hz, 1H), 7.09 (dd, J = 3.6, 2.0 Hz, 1H), 6.36 (s, 2H), 3.31 - 3.21 (m, 4H), 3.13 - 3.02 (m, 4H), 2.48 - 2.42 (m, 2H).

[0108] The following examples were prepared starting from the respective aldehydes or ketones with reference to the experimental routes and methods in Example 1: JPEG2026504900000017.jpg255166JPEG2026504900000018.jpg251165JPEG202 6504900000019.jpg255165JPEG2026504900000020.jpg254165JPEG20265049000 00021.jpg251164JPEG2026504900000022.jpg250166JPEG2026504900000023.j pg227165JPEG2026504900000024.jpg252164JPEG2026504900000025.jpg234165

[0109] Bioactivity experiments 1. Compound enzyme activity (IC 50 )test (1) ROCK1 / 2 test experiment method a) On an Echo 655, 50 nL of diluted compound working solution was transferred per well to a reaction plate (784075, Greiner).

[0110] b) The reaction plate was sealed with sealing film and centrifuged at 1000 g for 1 minute. c) A kinase solution was prepared. d) 5 μL of kinase solution was added to each well of the reaction plate, which was then sealed with sealing film, centrifuged at 1000 g for 30 seconds, and left at room temperature for 10 minutes.

[0111] e) STK2-substrate-biotin A mixture of kinase substrate and ATP was prepared. f) 5 μL of a mixture of STK2-substrate-biotin and ATP was added to the reaction plate, and the plate was centrifuged at 1000 g for 30 seconds to initiate the reaction.

[0112] g) ROCK1 kinase was reacted at room temperature for 20 minutes, and ROCK2 kinase was reacted at room temperature for 30 minutes. h) A mixture of Sa-XL 665 (125 nM) and STK-antibody-Cryptate was prepared using HTRF test buffer.

[0113] i) 10 μL of Sa-XL 665 and STK-antibody-Cryptate mixture was added to each well, centrifuged at 1000 g for 30 seconds, and incubated at room temperature for 1 hour.

[0114] The signals at 615 nm (Cryptate) and 665 nm (XL665) were read on an Envision 2104, and the degree of kinase activity was characterized using the signal intensity.

[0115] Kinase activity data are expressed as the alignment of the kinase activity of the test compound with that of the blank group (containing only DMSO), and the IC 50 Values ​​were obtained by curve fitting with Prism software (GraphPad 7.0). The specific test results are shown in Table 1 below:

[0116] Table 1. Enzyme activity of compounds JPEG2026504900000026.jpg201162

[0117] wherein Ripasudil has the following structural formula: JPEG2026504900000027.jpg79147

[0118] Netarsudil has the following structural formula: JPEG2026504900000028.jpg55168

[0119] Vermosudil has the following structural formula: JPEG2026504900000029.jpg119166

[0120] As can be seen from the data in the table, the enzymatic activity of the compounds in the examples of the present invention was superior to that of commercially available ROCK inhibitors, Ripasudil, Netarsudil, and Belmosudil. Some compounds had very strong activity against ROCK1 / 2 kinase.

[0121] 2. Cellular activity of compounds (IC 50 ) Test (Myosin light chain phosphorylation test by cell in situ Western blotting (In-CellWestern) ROCK induces cytoskeletal changes by phosphorylating two amino acid sites, T18 / S19, of myosin light chain. The rat smooth muscle cell line A7r5 was used. A7r5 cells were incubated in DMEM containing 10% FBS. Phospho-MLC-T18 / S19-specific antibodies and secondary detection antibodies were used to detect myosin light chain phosphorylation levels by in situ Western blotting. Cells treated with positive compounds served as positive controls, while a group treated with the compound's solvent alone served as a negative control. Cell nuclei were stained with DRAQ5 and used as an internal standard. Absolute IC50 values ​​were determined by fitting a nonlinear regression curve with a variable slope using GraphPad Prism 7.0 software.

[0122] On day 1, A7r5 cells were resuspended in serum-free medium and seeded at a density of 5,000 cells per well into PDL-coated, 384-well, clear-bottom black plates. They were serum-starved for 4 hours and then incubated with the cells and compounds in serum-free medium for 1 hour. Each well was fixed with 50 μL of 8% PFA (paraformaldehyde) for 1 hour at room temperature. The liquid was discarded, and the cells were permeabilized with 90 μL of ice-cold methanol for 1 hour at 4°C. The plate was then washed three times with PBST (0.1% Tween 20-PBS) using an automated dispenser. After gently tapping the plate dry, 50 μL of blocking solution was added to each well and blocked for 1 hour at room temperature. Phospho-MLC-T18 / S19-specific antibodies were diluted 1:200 in blocking solution and added in 20 μL to each well. The wells were sealed with membranes and incubated overnight at 4°C.

[0123] The next day, the liquid in the wells was discarded, and the plate was washed five times with PBST using an automated dispenser. After gently tapping the plate dry, the secondary detection antibody was diluted 1:800 in blocking solution, and DRAQ5 was diluted 1:1000. 20 μL was added to each well and incubated at room temperature for 1 hour. The liquid in the wells was discarded, and the plate was washed three times with PBST using an automated dispenser, followed by three washes with ddH2O. After gently tapping the plate dry, it was scanned using a LICOR Odyssey near-infrared imaging scanner.

[0124] The specific test results are shown in Table 2 below:

[0125] Table 2 Cellular activity of compounds JPEG2026504900000030.jpg119166From the data in the table, the compounds in the examples of the present invention have better cellular activity than the commercially available ROCK inhibitors ripasudil, netarsudil and vermosudil, and also have a stronger ability to induce cytoskeletal changes by phosphorylating the two amino acid sites T18 / S19 of myosin light chain.Therefore, the compounds of the present invention have broader application value.

[0126] 3. Effect of the compound on hypertonic saline-induced glaucoma in Norway rats Test Method: After anesthetizing the animals, the lateral canthus of the right eye was incised, and a polypropylene ring was placed at the equatorial plane of the eyeball, with the gap in the ring positioned in the superior quadrant of the eyeball, leaving only one upper scleral surface vein. Under a microscope, the conjunctiva was incised to expose the scleral surface vein. A microneedle was inserted parallel to the vascular wall toward the limbus and into the vascular cavity. Immediately, a microsyringe was used to inject 50 μL of 1.85 M (10.8%) hypertonic saline (filtered through a 0.22 μm pore size filter and stored until use) at a speed of 2500 nL / sec. After injection, the polypropylene ring was removed, and antibiotic ointment was applied to the operated eye. In the right eye of the control rat, only the episcleral vein was punctured without injection of hypertonic saline solution.

[0127] After the model was created, intraocular pressure (IOP) was continuously measured in both eyes using a rebound tonometer, once every three days for six measurements, and the average value was recorded. After the IOP stabilized (approximately 20 days later), the animals were randomly assigned to three groups (five animals per group) based on the most recent IOP measurement and body weight: a sham-operated group, a model control group, and a test substance (0.02% Example 29) group. After group assignment, eye drops were administered once daily, one drop at a time. During the administration period, dynamic IOP (detecting the IOP change curve from 0 to 24 hours after administration) was measured once a week until the end of the study.

[0128] Test results: The intraocular pressure change curve within 24 hours after administration showed that compared with the model control group, intraocular pressure significantly decreased 6 hours after administration and gradually stabilized over 24 hours. The percentage decrease in intraocular pressure is shown in Figure 1.

[0129] The experimental results showed that in a hypertonic saline-induced Norway rat glaucoma model, the compounds of the present invention had a strong effect in reducing intraocular pressure in animals, and the compounds of the present invention have the potential to treat ocular diseases such as ocular hypertension.

[0130] Although the present invention has been described in connection with the above preferred embodiments, these embodiments are merely exemplary and for the purpose of illustration only, and on this basis various alternatives and improvements can be made to the present application, all of which fall within the scope of protection of the present application.

Claims

1. A heterocyclic compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof: wherein X, Y and Z are each independently selected from a C atom or a N atom, and X, Y and Z are not simultaneously C atoms; R １ Ha-NHR １１ , -OR １１ , -SR １１ or -C(=O)NHR １１ where R １１ are each independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Cycloalkyl, substituted or unsubstituted C ３～８ Heterocyclyl, substituted or unsubstituted C ６～２０ Aryl, substituted or unsubstituted C ５～２０ Heteroaryl, substituted or unsubstituted C １～６ Alkyl acyl, substituted or unsubstituted C １～６ Alkylsulfonyl, substituted or unsubstituted C ５～２０ Heteroarylacyl, and substituted or unsubstituted C １～６ alkoxy; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , -C(=O)R ３３ , hydroxyl, carboxy, sulfhydryl, substituted C ３～８ Cycloalkyl, substituted C ３～８ Heterocyclyl, substituted C ６～２０ Aryl and substituted C ５～２０ selected from the group consisting of heteroaryl; R ２ is hydrogen, halogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C １～６ Haloalkyl, substituted or unsubstituted C １～６ The substituents are selected from the group consisting of alkoxy, cyano, amino, hydroxyl, carboxy, and sulfhydryl; １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , hydroxyl, carboxy, and sulfhydryl; R ３ is cyano, -CONH ２ and carboxy; R ４ and R ５ are each independently hydrogen, halogen, or —NR ３１ R ３２ , substituted or unsubstituted C ３～８ Heterocyclyl, substituted or unsubstituted C ６～２０ Aryl, and substituted or unsubstituted C ５～２０ heteroaryl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , hydroxyl, carboxy, and sulfhydryl; where (i) R ６ and R ８ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, and substituted or unsubstituted bicyclic carbocycle; the substituents are halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ hydroxyl, oxo, carboxy, and sulfhydryl; and ６ and R ８ is not all hydrogen; Or, (ii) R ６ and R ８ , and R ６ and R ８ are attached to form together a 4- to 8-membered mono- or polycyclic ring system; said 4- to 8-membered mono- or polycyclic ring system is ４１ optionally substituted with; R ７ is hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C １～６ Haloalkyl, substituted or unsubstituted C １～６ selected from the group consisting of alkoxy, amino, hydroxyl, carboxy, and sulfhydryl; Or, R ６ is hydrogen, and R ８ , R ８ and the C atom to which R is bonded. ７ and R ７ are bonded together to form a 5- to 8-membered carbocyclic ring; said 5- to 8-membered carbocyclic ring is ４１ optionally substituted with; R ３１ and R ３２ are each independently hydrogen, sulfonamido, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～８ Cycloalkyl, substituted or unsubstituted C ３～８ Heterocyclyl, substituted or unsubstituted C ６～２０ Aryl, and substituted or unsubstituted C ５～２０ heteroaryl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, hydroxyl, —C(═O)OR ３４ and sulfhydryl; R ３３ is hydrogen, substituted or unsubstituted C １～８ Alkyl, substituted or unsubstituted C １～８ Alkoxy, substituted or unsubstituted C ３～８ Cycloalkyl, substituted or unsubstituted C ６～２０ Aryl, and substituted or unsubstituted C ５～２０ heteroaryl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , hydroxyl, carboxy, and sulfhydryl; R ３４ is hydrogen, substituted or unsubstituted C １～８ Alkyl, substituted or unsubstituted C １～８ Haloalkyl, substituted or unsubstituted C １～８ Alkoxy, and substituted or unsubstituted C ３～８ cycloalkyl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ selected from the group consisting of heteroaryl, cyano, hydroxyl, carboxy, and sulfhydryl; R ４１ is hydrogen, halogen, oxo, cyano, hydroxyl, substituted or unsubstituted C １～８ Alkyl, substituted or unsubstituted C １～８ Haloalkyl, substituted or unsubstituted C １～８ Alkoxy, or substituted and unsubstituted C ３～８ cycloalkyl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , hydroxyl, carboxy and sulfhydryl.

2. 2. The heterocyclic compound according to claim 1, wherein X, Y and Z are all N atoms, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof.

3. R １ is -NHR １１ where R １１ are each independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Cycloalkyl, substituted or unsubstituted C ３～８ Heterocyclyl, substituted or unsubstituted C ６～２０ Aryl, substituted or unsubstituted C ５～２０ Heteroaryl, substituted or unsubstituted C １～６ Alkyl acyl, substituted or unsubstituted C １～６ Alkylsulfonyl, substituted or unsubstituted C ５～２０ Heteroarylacyl, and substituted or unsubstituted C １～６ alkoxy; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , -C(=O)R ３３ , hydroxyl, sulfhydryl, substituted C ３～８ Cycloalkyl, substituted C ３～８ Heterocyclyl, substituted C ６～２０ Aryl and substituted C ５～２０ selected from the group consisting of heteroaryl; Preferably, R １１ represents hydrogen, substituted and unsubstituted C １～６ alkyl, and the substituents are selected from the group consisting of -NR ３１ R ３２ , -C(=O)R ３３ and substituted or unsubstituted C ３～８ heterocyclyl; R ３１ and R ３２ are each independently hydrogen, sulfonamido, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～８ Cycloalkyl, substituted or unsubstituted C ３～８ Heterocyclyl, substituted or unsubstituted C ６～２０ Aryl, and substituted or unsubstituted C ５～２０ heteroaryl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, hydroxyl, —C(═O)OR ３４ and sulfhydryl; R ３３ is hydrogen, substituted or unsubstituted C １～８ Alkyl, substituted or unsubstituted C １～８ Alkoxy, substituted or unsubstituted C ３～８ Cycloalkyl, substituted or unsubstituted C ６～２０ Aryl, and substituted or unsubstituted C ５～２０ heteroaryl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ , hydroxyl, carboxy, and sulfhydryl; R ３４ is hydrogen, substituted or unsubstituted C １～８ Alkyl, substituted or unsubstituted C １～８ Haloalkyl, substituted or unsubstituted C １～８ Alkoxy, and substituted or unsubstituted C ３～８ cycloalkyl; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ 2. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, selected from the group consisting of heteroaryl, cyano, hydroxyl, carboxy, and sulfhydryl.

4. R １１ is a substituted or unsubstituted C １～６ alkyl, and the substituents are selected from the group consisting of -NR ３１ R ３２ where R ３１ and R ３２ are each independently hydrogen, substituted or unsubstituted C １～６ Alkyl, and substituted or unsubstituted C ３～８ 4. The heterocyclic compound according to claim 3, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, selected from the group consisting of heterocyclyls.

5. R １１ is a substituted or unsubstituted C １～６ alkyl, and the substituent is -C(=O)R ３３ where R ３３ are independently substituted or unsubstituted C １～６ Alkyl, and substituted or unsubstituted C ３～８ 4. The heterocyclic compound according to claim 3, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, selected from the group consisting of heterocyclyls.

6. The heterocyclic compound of claim 3 or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof selected from the group consisting of:

7. R １ Ha-NH ２ and R ２ The heterocyclic compound of claim 1 , or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, wherein

8. R ４ and R ５ and R are each independently 0 or 1. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, wherein all of R, R, and R are hydrogen.

9. R ６ and R ７ is hydrogen; R ８ is selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, and substituted or unsubstituted bicyclic carbocycle; the substituents are halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ 2. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, wherein the heterocyclic compound is selected from the group consisting of hydroxyl, oxo, carboxy, and sulfhydryl.

10. R ８ is a substituted or unsubstituted C ５ -C １２ bicyclic carbocycles, wherein the bicyclic carbocycle is selected from the group consisting of C ５ -C １２ Spirocyclic carbocycle, C ５ -C １２ Fused carbocyclic rings and C ５ -C １２ bridged carbocycles; the substituents are selected from the group consisting of halogen, C １～８ Alkyl, C １～８ Haloalkyl, C １～８ Alkoxy, C ３～８ Cycloalkyl, C ３～８ Heterocyclyl, C ６～２０ Aryl, C ５～２０ Heteroaryl, cyano, -NR ３１ R ３２ 10. The heterocyclic compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, wherein the heterocyclic compound is selected from the group consisting of hydroxyl, oxo, carboxy, and sulfhydryl.

11. The bicyclic carbocycle is selected from the group consisting of the following structural formulas:

11. The heterocyclic compound according to claim 10, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

12. R ８ is selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, and substituted or unsubstituted cyclohexyl, and the substituents are １～６ 11. The heterocyclic compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof, wherein the heterocyclic compound is selected from the group consisting of alkyl.

13. R ８ is cyclopropyl; Or, R ８ is cyclohexyl; Or, R ８ is selected from the group consisting of cyclobutyl, 3-methyl-cyclylbut-1-yl, and 3,3-dimethyl-cyclylbut-1-yl, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

14. R ６ is hydrogen, and R ８ , R ８ and the C atom to which R is bonded. ７ and R ７ and the C atoms to which are bonded together form a 5- to 8-membered carbocyclic ring, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof according to claim 1.

15. The heterocyclic compound according to claim 14, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof, wherein the 5- to 8-membered carbocyclic ring is selected from the group consisting of cyclylpentanecyclyl and cyclohexanecyclyl.

16. R ６ and R ８ , and R ６ and R ８ are attached to the C atoms together form a 4- to 8-membered mono- or polycyclic ring system; R ７ The heterocyclic compound of claim 1 , or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, wherein

17. The 4- to 8-membered monocyclic or polycyclic ring system is selected from the group consisting of the following structural formulas: wherein C* indicates the attachment position of the structural formula.

17. The heterocyclic compound of claim 16, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

18. R ３ 2. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, wherein R is cyano.

19. The compound is selected from the group consisting of the following compounds:

2. The heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

20. A pharmaceutical composition comprising the heterocyclic compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

21. Use of the heterocyclic compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof, and the pharmaceutical composition according to claim 20, in the preparation of a medicament for treating a disease mediated by Rho kinase.

22. 22. The use according to claim 21, wherein the disease mediated by Rho kinase is asthma, cancer, glaucoma, insulin resistance, renal failure, neurodegeneration or osteoporosis.

23. A method for treating a disease mediated by Rho kinase, comprising administering to a patient in need thereof a therapeutically effective amount of the heterocyclic compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof, or the pharmaceutical composition according to claim 20.

24. 24. The method of claim 23, wherein the disease mediated by Rho kinase is asthma, cancer, glaucoma, insulin resistance, renal failure, neurodegeneration, or osteoporosis.

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