Selective inhibitors of ROCK2 protein kinase and uses thereof

Abstract

The present invention relates to novel substituted bicyclic derivatives that can selectively inhibit the phosphorylation of ROCK2 and / or Rho kinase mediated myosin light chain phosphate, compositions comprising the derivatives, methods for making the derivatives and / or compositions, and methods of using the derivatives and / or compositions.

Description

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 496,815, filed April 18, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to novel substituted bicyclic derivatives that selectively inhibit phosphorylation of myosin light chain phosphate mediated by ROCK2 and / or Rho kinases, methods for their preparation, formulations thereof, and their use in the preparation of pharmaceuticals, as well as pharmaceutically acceptable salts, diastereomers, enantiomers, and racemates. Background Technology

[0003] Rho-associated coil-and-coil protein kinases (ROCK / Rho kinases / Rho-associated kinases) are downstream effectors of the small GTPases Rho (RhoA, RhoB, RhoC, and RhoE) and belong to the serine / threonine kinase family. The active GTP-bound form of Rho mediates several biological functions through the action of ROCK, including smooth muscle contraction, cell movement, and cytokinesis. ROCK proteins were identified in 1996 as proteins that bind to Rho GTPases. Two proteins were independently isolated as p160 and p164. These proteins were later identified as ROCK-1 and ROCK-2, respectively, and are isotypes of Rho-associated kinases. These two isotypes, ROCK-1 (ROCK-b / p160) and ROCK-2 (ROCK-a / p164), share 92% similarity in their amino acid sequences. Their structures include a catalytic kinase domain at the N-terminus, followed by a coiled-coil region (600 amino acids), and a Rho-binding domain and a pleckstrin homology (PH) domain at the C-terminus. They occupy distinct locations, and different physiological roles have been identified for each. ROCK-1 transcripts (a gene located on chromosome 18) are ubiquitous, with more prominent expression in the liver, kidneys, spleen, testes, thymus, and blood cells, while ROCK-2 mRNA (on chromosome 2) is more abundant in skeletal muscle and the brain, suggesting specific roles at these locations.

[0004] ROCK inhibitors have been considered for a variety of diseases, including cerebral ischemia, hypertension, erectile dysfunction, glaucoma, osteoporosis, cardiomegaly, diabetic cardiomyopathy, retinopathy, pulmonary hypertension, and atherosclerosis. However, their implementation is limited by a lack of knowledge about the involvement of specific ROCK isotypes. Whether isotype-specific targeting or combined ROCK inhibition will provide better treatment outcomes remains to be verified. Although their specificity for ROCK isotypes and other serine / threonine kinases (e.g., PRK2, PKC, cAMP-dependent protein kinases, and citron kinase) is not perfect, some non-specific ROCK2 inhibitors have shown promising results in certain pathological conditions, such as glaucoma and hypertension. However, further work is needed for isotype-selective ROCK2 inhibitors to be used clinically, but some research-based studies have largely helped to resolve the ambiguity surrounding the specific functions of ROCK-1 and ROCK-2. Given the crucial role of ROCK in the organization of the actin cytoskeleton, it is foreseeable that complete inhibition of both isotypes may lead to adverse events in patients. Therefore, selective ROCK2 inhibition may have a greater specific therapeutic index than dual inhibition of ROCK1 and ROCK2. Thus, understanding the individual function of each isoform in a specific disease could help improve safety and specificity and expand the therapeutic applications of ROCK inhibitors. Summary of the Invention

[0005] In one aspect, the present invention provides a novel compound represented by formula (1) that is capable of inhibiting Rho-associated coil-and-coil forming protein serine / threonine kinase (ROCK): Where X, Y, Z 1 Z 2 Z 3 R 1 R 2 R 3 and R 4 Defined in the specific implementation details below.

[0006] In another aspect, the present invention provides pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs of the novel compounds. Furthermore, the present invention provides pharmaceutically acceptable salts, hydrates, or solvates of the diastereomers, enantiomers, or racemates.

[0007] In another aspect, the present invention provides pharmaceutical compositions, each comprising the compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or combination thereof.

[0008] In yet another aspect, the present invention provides a method for treating or alleviating certain rock-mediated diseases or disorders by using said compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition. Non-limiting examples of said diseases or disorders include cardiovascular, pulmonary, inflammatory, neurological, or proliferative diseases or disorders.

[0009] In another aspect, the present invention provides methods for preparing said compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs. Detailed Implementation

[0010] 1. Compound In one aspect, the present invention provides a compound represented by formula (1), a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, a racemic mixture, a hydrate, a solvate, or a prodrug: in: X is CH2 or O; Y is either N or CH; Z 1 Z 2 and Z 3 Each can be either N or CH independently; n is 0, 1, 2, or 3; R 1 It is H, C2-C6 alkyl or CH2C3-C8 cycloalkyl, wherein the C2-C6 alkyl or CH2C3-C8 cycloalkyl may optionally be substituted by one or more suitable substituents, such as C1-C3 alkyl, hydroxy or C1-C3 alkoxy; R 2 It is a 5-6 membered heteroaryl or bicyclic heteroaryl, wherein the heteroaryl or bicyclic heteroaryl may optionally be substituted by one or more suitable substituents, such as halogens, CN, CHF2, CF3, C1-C3 alkyl or amino groups, wherein the 5-6 membered heteroaryl or bicyclic heteroaryl has 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and combinations thereof; and R 3 and R 4 Each is independently H, Cl, F, OH, OCD 3C1-C3 alkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy may optionally be substituted by one or more suitable substituents, such as OH or OMe, OEt or OPr. i .

[0011] In some implementations, R 1 It can be H, C2-C6 alkyl or C3-C8 cycloalkyl, wherein the C2-C6 alkyl and C3-C8 cycloalkyl can optionally be substituted by one or more suitable substituents, such as C1-C3 alkyl, hydroxy or C1-C3 alkoxy.

[0012] In some implementations, R 2 It can be one of the following groups: In some implementations, R 3 or R 4 It can independently be H, Cl, F, OH, methoxy, CD 3 , ethoxy or isopropoxy.

[0013] The articles “a” and “a kind” are used in this disclosure to refer to one or more of the grammatical objects of the article (i.e., at least one). For example, “an element” means one element or more elements.

[0014] Unless otherwise specified, the term "and / or" is used in this disclosure to mean "and" or "or". Unless it is explicitly stated that it refers only to substitutes or that the substitutes are mutually exclusive, the term "or" is used to refer to "and / or", but this disclosure supports the definition of "and / or" referring only to substitutes.

[0015] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the possibility that the event or condition occurs and the possibility that it does not occur. For example, "optionally substituted aryl" encompasses "aryl" and "substituted aryl" as defined herein. Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical, synthetically infeasible, and / or inherently unstable substitution or substitution pattern.

[0016] Unless otherwise specified, the term "optionally substituted" means that the group may be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range thereof) substituents listed for that group, wherein said substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents. For example, the optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical fragment may contain other functional groups, but does not necessarily have to have any additional functional groups.

[0017] The term "alkyl" as used alone or as part of a larger segment (e.g., "arylalkyl" or "cycloalkyl") refers to a straight-chain or branched hydrocarbon group having 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms (unless otherwise specified), and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents.

[0018] The term "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring group having 3 to 10 carbon atoms, or 3 to 7 carbon atoms, unless otherwise specified, and includes, for example, cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, cyclopentyl, etc. Cycloalkyl groups may be unsubstituted or substituted with one or more suitable substituents.

[0019] The term "heterogeneous" refers to the substitution of at least one carbon atom member in a ring system with at least one heteroatom (such as nitrogen, sulfur, sulfoxide, sulfone, and oxygen).

[0020] As used in this article, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0021] As used herein, the term "alkoxy" refers to the alkyl group bonded by oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, etc. Additionally, alkoxy can also refer to polyethers, such as -O-(CH2)2-O-CH3, etc. Alkoxy groups can be unsubstituted or substituted with one or more suitable substituents.

[0022] As used herein, the term "aryl" refers to an unsubstituted or substituted aromatic monocyclic or polycyclic group and includes, for example, carbocyclic aromatic groups (e.g., phenyl, naphthyl, etc.) and heteroaromatic groups (e.g., pyridyl, furanyl, phenylthio, etc.). The term "aryl" also includes an aromatic ring (e.g., a phenyl or pyridyl ring) fused to a non-aromatic carbocyclic or heterocyclic ring. The term "aryl" is used interchangeably with "aryl ring," "aromatic group," and "aromatic ring." A heteroaryl group has 4 to 14 atoms in a heteroaromatic ring, of which 1 to 9 atoms are independently selected from the group consisting of oxygen, sulfur, and nitrogen. A heteroaryl group has 1 to 3 heteroatoms in a 5- to 8-membered aromatic group. An aryl or heteroaryl group can be a monocyclic or bicyclic aromatic group. Typical aryl and heteroaryl groups include, for example, phenyl, quinolinyl, indazole, indolyl, dihydrobenzodioxynyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, pyrimidinyl, 3-methylpyridyl, benzothiophene, 2,4,6-tribromophenyl, 4-ethylbenzothiophene, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, pyrrole, pyrazole, imidazole, thiazole, etc. Aryl or heteroaryl groups can be unsubstituted or substituted with one or more suitable substituents.

[0023] As used in this article, the term "hydroxyl" refers to -OH.

[0024] As used in this article, the term "amino" refers to -NH2.

[0025] As used herein, the term "hydroxyalkyl" refers to any hydroxyl derivative of an alkyl radical. The term "hydroxyalkyl" includes any alkyl radical in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0026] As used herein, the term "arylalkyl" includes any alkyl group (e.g., benzyl, phenethyl, etc.) in which one or more hydrogen atoms are replaced by an aryl group.

[0027] As used herein, a "substituent" refers to a segment of a molecule covalently bonded to an atom within the molecule of interest. For example, a cyclic substituent can be a segment covalently bonded to an atom that is a ring member (preferably a carbon or nitrogen atom), such as a halogen, alkyl, haloalkyl, or other group. Substituents in aromatic groups are typically covalently bonded to the ring carbon atom. The term "substitution" refers to replacing a hydrogen atom in the molecular structure with a substituent such that the valence at the specified atom does not exceed, and such substitution results in a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity).

[0028] As described above, some groups may be unsubstituted or substituted at one or more available positions with one or more suitable substituents other than hydrogen, typically at positions 1, 2, 3, 4, or 5 with one or more suitable groups (which may be the same or different). Some groups are substituted with one, 2, 3, or 4 independently selected substituents. Suitable substituents include halogens, alkyl groups, haloalkyl groups, aryl groups, hydroxyl groups, alkoxy groups, hydroxyalkyl groups, amino groups, etc.

[0029] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of the compounds described herein. Such a material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of a composition comprising the material.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to a compound formulation that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound described herein.

[0031] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts (UK Journal of Pharmaceutical and Biosciences, Vol. 2(4), 01-04, 2014, which is incorporated herein by reference). Pharmaceutically acceptable acidic / anionic salts include acetates, benzenesulfonates, benzoates, bicarbonates, tartrates, bromides, and calcium edetate. (edetate), camphor sulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fumarate, glyceptate, gluconate, glutamate, glycolyllarsanilate, hexylresorcinol, hydrobromide, hydrochloride, hydroxynaphthylate, iodide, hydroxyethyl sulfonate, lactate, lacturonate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, dihydroxynaphthylate, pantothenate, phosphate / bisphosphate, polygalacturonate, salicylate, stearate, hypoacetate, succinate, sulfate, hydrogen sulfate, tannin, tartrate, teoclate, toluenesulfonate, and triethyliodide. Pharmaceutically acceptable basic / cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucosamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine.

[0032] Pharmaceutically acceptable acid salts are formed by reacting the free base form of a compound of Formula 1 with a suitable inorganic or organic acid, including but not limited to hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid (e.g., 2-naphthalenesulfonic acid), or hexanoic acid. Pharmaceutically acceptable acid addition salts of compounds of Formula 1 may include, for example, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid (e.g., 2-naphthalenesulfonic acid), or hexanoic acid.

[0033] The free acid or free base forms of the compounds of the present invention can be produced by methods known to those skilled in the art (e.g., see LD Bigley, SMBerg, DC Monkhouse, “…” for more details). Encyclopedia of Pharmaceutical Technology ".J. Swarbrick and JC Boylam (eds.), Vol. 13, MarcelDekker, Inc., 1995, pp. 453-499; the entire teachings of this document are incorporated herein by reference. The compounds of the invention in the form of acid addition salts can be prepared, for example, by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.) to convert them into the corresponding free base form. Similarly, the compounds of the invention in the form of base addition salts can be converted into the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).

[0034] The prodrug derivatives of the compounds of the present invention can be prepared by methods known to those skilled in the art (e.g., see Saulnier et al. for further details). Bioorg.Med.Chem.Letters , 1994, 4, 1985; Daniela Hartmann Jornada at.Al., Molecules 2016, 21, 42; the entire teachings of the cited literature are incorporated herein by reference. Protected derivatives of the compounds of the present invention can be prepared by methods known to those skilled in the art. A detailed description of techniques suitable for generating and removing protecting groups can be found in TW Greene, “ Green's Protective Groups in Organic Chemistry The full teachings of the document are incorporated herein by reference in its 4th edition, John Wiley and Sons, Inc., 2006.

[0035] The compounds of the present invention can be prepared as separate stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomers, separating the diastereomers and recovering the optically pure enantiomers. The separation of the enantiomers can be performed using covalent diastereomer derivatives of the compounds of the present invention, or by using a dissociable complex (e.g., a crystalline diastereomer salt). The diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and can be easily separated by utilizing these differences. The diastereomers can be separated by chromatography or by a separation / resolution technique based on solubility differences. The optically pure enantiomers and the resolving agent are then recovered by any practical method that does not cause racemization. A more detailed description of techniques suitable for separating the stereoisomers of compounds from racemic mixtures of compounds can be found in Jean Jacques, Andre Collet and Samuel H. Wilen, “ Enantiomers, Racemates and Resolutions “The teachings of John Wiley and Sons, Inc., 1981, are found herein and are incorporated herein by reference in their entirety.”

[0036] As used herein, the term "solvent" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula 1 or a pharmaceutically acceptable salt thereof) and a solvent. Such solvents used for the purposes of this invention do not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include water, acetone, methanol, ethanol, and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid.

[0037] 2. Composition In another aspect, the present invention provides a pharmaceutical composition comprising the compound, a salt, a diastereomer, an enantiomer, a racemic mixture, a hydrate, a solvate, a prodrug, or a pharmaceutical combination thereof. The composition may further comprise additional components. Non-limiting examples of such additional components include pharmaceutically acceptable carriers, diluents, excipients, and combinations thereof.

[0038] As used herein, the term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients.

[0039] As used herein, the term "drug combination" refers to a product resulting from the mixing or combination of more than one active ingredient.

[0040] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means, as used herein, that there is no lasting harmful effect on the overall health of the subject receiving the treatment.

[0041] As used herein, the term "carrier" refers to a compound or reagent that facilitates the incorporation of the compounds described herein into cells or tissues.

[0042] As used herein, the term "diluent" refers to a compound used to dilute the compounds described herein prior to delivery. Diluents may also be used to stabilize the compounds described herein.

[0043] Suitable pharmaceutically acceptable carriers, diluents, adjuvants, or excipients for use in the pharmaceutical compositions of the present invention include tablets (coated tablets), capsules (gelatin), solutions (aqueous solutions or water-ethanol solutions), syrups containing active substances, emulsions or inhalable powders (containing various sugars, such as lactose or glucose, salts, and mixtures of these excipients with each other), and aerosols (inhalation solutions containing or without propellants).

[0044] Excipients that may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicates and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite liquid, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium dodecyl sulfate).

[0045] 3. Methods using compounds or compositions In another aspect, the present invention provides a method for treating or alleviating certain protein kinase-mediated diseases or conditions by administering to a subject or patient a therapeutically effective amount of said compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition. In some embodiments, the present invention provides a method for treating or alleviating certain rock-mediated diseases or conditions by administering to a subject or patient a therapeutically effective amount of said compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition. In some embodiments, the present invention provides a method for treating or alleviating diseases or conditions known to involve rock.

[0046] In another aspect, the present invention provides a method for inhibiting enzyme activity, particularly the activity of ROCK1, ROCK2, PKCδ, PKCθ, PRK1, GSK3, PRK2, NEK1, and NEK4 kinases, by administering a therapeutically effective amount of the compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition to a subject or patient.

[0047] In another aspect, the present invention provides a method for inhibiting protein kinase activity (e.g., ROCK kinase activity) in a biological sample by contacting the biological sample with said compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition.

[0048] As used herein, the term "inhibitor" refers to a compound that inhibits one or more of the kinases described herein. For example, the term "ROCK inhibitor" refers to a compound that inhibits ROCK receptors or reduces signal transduction effects.

[0049] As used herein, the terms "protein kinase-mediated disease" or "disorder or disease or symptom mediated by inappropriate protein kinase activity" refer to any disease state mediated or regulated by the protein kinases described herein. Such disease states include, but are not limited to, fibrotic disorders; pulmonary fibrosis including cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endocardial myocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, joint fibrosis, Crohn's disease, myelofibrosis, Peroni disease, renal systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic fibrosis. Sexual sclerosis, mediastinal fibrosis, keloids and proliferative scars, glial scars, or renal fibrosis; cardiovascular diseases or disorders such as cerebral vasospasm, hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemia / reperfusion injury, stroke, bronchial asthma; glaucoma, premature birth, erectile dysfunction, or kidney diseases such as chronic renal failure, chronic nephritis, diabetic nephropathy, and IgA nephropathy; and proliferative disorders such as retinopathy, fibrosis, or invasive / metastatic cancer. These types of cancers include adenocarcinoma, adrenocortical carcinoma; bladder cancer; bone cancer; brain cancer; breast cancer; oral cancer; cervical cancer; colon cancer; colorectal cancer; endometrial cancer or uterine cancer; epidermoid carcinoma; esophageal cancer; eye cancer; follicular carcinoma; gallbladder cancer; gastrointestinal cancer; urogenital tract cancer; glioblastoma; pilocarcinoma; head and neck cancer; liver tumors; hepatocellular carcinoma; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; colorectal cancer; laryngeal cancer; liver cancer; lung cancer, such as lung adenocarcinoma, small cell lung cancer, squamous cell lung cancer, non-small cell lung cancer; melanoma; myeloproliferative disorders; neuroblastoma; ovarian cancer; papillary carcinoma; pancreatic cancer; peritoneal cancer; prostate cancer; rectal cancer; salivary gland cancer; sarcoma; squamous cell carcinoma; small cell carcinoma; small bowel cancer; stomach cancer; testicular cancer; thyroid cancer; and vulvar cancer. In a particular embodiment, the cancer being treated is melanoma, breast cancer, colon cancer, or pancreatic cancer.

[0050] As used herein, the term “treat / treating / treatment” means the means of preventing and / or treating the reduction, mitigation or improvement of symptoms of a disease or condition, prevention of additional symptoms, improvement or prevention of the underlying metabolic cause of symptoms, suppression of a disease or condition, prevention of the development of a disease or condition, relief of a disease or condition, remission of a disease or condition, relief of symptoms caused by a disease or condition, or cessation of symptoms of a disease or condition.

[0051] As used herein, the terms “subject” or “patient” include both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, cattle, horses, sheep, goats, pigs; rabbits, dogs, cats, rats, mice, guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc.

[0052] As used herein, the term "administration / administering" of the subject compound refers to providing a subject with the compound of the invention and / or its prodrug.

[0053] As used herein, the term "effective amount" or "therapeutic effective amount" means that an application of a sufficient amount of the compound described herein will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. The result may be a reduction and / or mitigation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount required for a composition comprising the compounds disclosed herein to provide a clinically significant reduction in the symptoms of a disease. An appropriate "effective" amount in any case may be determined using techniques such as dose escalation studies. By way of example only, the therapeutically effective amount of the compounds of the present invention may be in the range of, for example, about 0.01 mg / kg / day to about 1000 mg / kg / day, about 0.1 mg / kg / day to about 500 mg / kg / day, or about 0.1 mg (x2) / kg / day to about 500 mg (x2) / kg / day.

[0054] The compounds of the present invention are screened against a kinase group and the activity of at least one kinase on that group is inhibited. Examples of kinases include, but are not limited to, ROCK1 and rock2.

[0055] The compounds described herein are inhibitors of ROCK kinase activity and have therapeutic benefits in treating disorders associated with inappropriate kinase activity, particularly in treating and preventing disease states mediated by kinases, including ROCK kinases. Therefore, the present invention provides methods for modulating, and particularly inhibiting, the signal transduction cascades in which kinases function. These methods generally involve administering to a subject an effective amount of the compounds described herein, their salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, and / or compositions, or contacting cells expressing kinases with the compounds described herein, their salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, and / or compositions to modulate or inhibit the signal transduction cascade. The methods are also used to modulate, and particularly inhibit, downstream processes or cellular responses resulting from the activation of specific kinase signal transduction cascades. The methods are also practiced in vitro or in vivo as a treatment for diseases characterized by, caused by, or associated with the activation of kinase-dependent signal transduction cascades.

[0056] For the therapeutic use of the compounds provided herein, including compounds of Formula 1, their salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs, such compounds are administered alone or as part of a pharmaceutical composition in a therapeutically effective amount. Therefore, pharmaceutical compositions are provided herein comprising at least one compound provided herein, including at least one compound of Formula 1, its pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, or excipients.

[0057] Furthermore, such compounds and compositions may be administered alone or in combination with one or more adjunctive therapeutic agents. Non-limiting examples of such adjunctive therapeutic agents may include immune checkpoint inhibitors and chemotherapeutic agents that induce immunogenic cell death (ICD). Non-limiting examples of immune checkpoint inhibitors may include PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. Non-limiting examples of chemotherapeutic agents that induce immunogenic cell death (ICD) may include doxorubicin, idarubicin, mitoxantrone, tautomycin, calyculin A, salubrinal, oxaliplatin, bleomycin, and cyclophosphamide. Methods of administration of such compounds and compositions include, but are not limited to, intravenous administration, inhalation administration, oral administration, rectal administration, parenteral administration, intravitreal administration, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, topical administration, ophthalmic administration, buccal administration, tracheal administration, bronchial administration, sublingual administration, or ocular administration. The compounds provided herein are administered via known pharmaceutical formulations, including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, lotions, gels, ointments, or creams for topical administration, and so on. In some embodiments, such pharmaceutical compositions are formulated as tablets, pills, capsules, liquids, inhalers, nasal sprays, suppositories, solutions, gels, emulsions, ointments, eye drops, or ear drops.

[0058] The effective therapeutic dose will vary depending on the indicated disease, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration, and the desired treatment. The required dose will also vary depending on the mode of administration, the specific condition to be treated, and the desired effect.

[0059] Compounds of Formula 1 can be used to inhibit one or more protein kinases and to treat diseases and disorders mediated by protein kinases, such as cancer, autoimmune diseases, fibrotic disorders, cardiovascular diseases and neurodegenerative diseases.

[0060] As used herein, the term "biological sample" means an in vitro animal sample, and includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from animals or their extracts; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or their extracts. Inhibition of kinase activity, particularly ROCK kinase activity, in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological sample storage and bioassays. As used herein, the terms "ROCK-mediated disease" or "symptom" mean any disease or other harmful condition in which ROCK is known to play a role. ROCK is involved in a variety of important physiological functions in the vascular system, including smooth muscle contraction; cell proliferation, such as vascular smooth muscle cell proliferation; and cell adhesion and migration (see Hu and Lee, Expert Opin.Ther.Targets, 9(4):715-36,2005; Shimokawa and Takeshita, Arterioscler. Thromb. Vase. Biol. 25(9):1767-75,2005). ROCK is involved in inflammatory responses due to leukocyte migration, such as autoimmune diseases and allergic reactions (see Wettschureck et al., J. Mol. Med .80:629-38, 2002). Aberrant activation of the Rho / ROCK pathway has been observed in various disorders of the central nervous system (see Mueller et al., .80:629-38, 2002). Nature Rev ., 4:387-98, 2005). Furthermore, ROCK has been involved in tumor cell migration and invasion ((Riento and Ridley, 4:387-98, 2005). Nature Rev . 4:446-56, 2004) and osteoporosis (Ohnaka et al., Biochem. Biophys., Res. Commun . 287(2):337-4, 2001).

[0061] Specifically, the present invention relates to methods for treating or reducing the severity of the following diseases or disorders: cardiovascular diseases or disorders, such as cerebral vasospasm, hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemia / reperfusion injury, stroke, bronchial asthma; glaucoma, premature birth, erectile dysfunction or kidney diseases, such as chronic renal failure, chronic nephritis, diabetic nephropathy and IgA nephropathy; and proliferative disorders, such as retinopathy, fibrosis or invasive / metastatic cancer. These types of cancers include adenocarcinoma, adrenocortical carcinoma; bladder cancer; bone cancer; brain cancer; breast cancer; oral cancer; cervical cancer; colon cancer; colorectal cancer; endometrial cancer or uterine cancer; epidermoid carcinoma; esophageal cancer; eye cancer; follicular carcinoma; gallbladder cancer; gastrointestinal cancer; urogenital tract cancer; glioblastoma; pilocarcinoma; head and neck cancer; liver tumors; hepatocellular carcinoma; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; colorectal cancer; laryngeal cancer; liver cancer; lung cancer, such as lung adenocarcinoma, small cell lung cancer, squamous cell lung cancer, non-small cell lung cancer; melanoma; myeloproliferative disorders; neuroblastoma; ovarian cancer; papillary carcinoma; pancreatic cancer; peritoneal cancer; prostate cancer; rectal cancer; salivary gland cancer; sarcoma; squamous cell carcinoma; small cell carcinoma; small bowel cancer; stomach cancer; testicular cancer; thyroid cancer; and vulvar cancer. In a particular embodiment, the cancer being treated is melanoma, breast cancer, colon cancer, or pancreatic cancer.

[0062] In another aspect, the present invention provides a method for treating a subject with a fibrotic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I. Non-limiting examples of fibrotic disorders include pulmonary fibrosis including cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis and endocardial myocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, joint fibrosis, Crohn's disease, myelofibrosis, Peronis disease, renal systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scars, or renal fibrosis.

[0063] In one aspect, the present invention provides a method for treating a proliferative disease or condition, such as cancer, the method comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound of formula 1, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, a racemic mixture, a hydrate, a solvate, a prodrug, or a pharmaceutical composition or drug thereof, wherein the proliferative disease or condition includes, for example, lymphoma, osteosarcoma, melanoma, breast cancer, kidney cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, neuronal cancer, lung cancer, uterine cancer, or gastrointestinal cancer. In another aspect, the present invention provides a method for inhibiting cancer cell growth using the compounds described herein, their salts, diastereomers, enantiomers, racemic mixtures, hydrates, solvates, prodrugs, or any combination thereof, or compositions described herein.

[0064] In some implementations, the protein kinase-mediated disease or condition is an inflammatory disease or condition, a respiratory disease, or an autoimmune disease or condition, such as asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, breast cancer, HIV-related diseases, or lupus.

[0065] In another aspect, the present invention provides a method for treating cardiovascular diseases by administering to a subject a therapeutically effective amount of the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or any combination thereof, or the compositions described herein. Such cardiovascular diseases affect the heart or blood vessels and include, for example, atherosclerosis, arrhythmias, angina pectoris, myocardial ischemia, myocardial infarction, cardiac or vascular aneurysms, vasculitis, stroke, peripheral obstructive arterial disease of a limb, organ, or tissue, reperfusion injury following organ or tissue ischemia, endotoxin, surgical or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vasoconstriction, vascular abnormalities, or inflammation.

[0066] In another aspect, the present invention provides a method for treating cancer, the method comprising administering a composition to a subject in need, the composition comprising a therapeutically effective amount of at least one compound described herein, a salt thereof, a diastereomer, an enantiomer, a racemic mixture, a hydrate, a solvate, or a prodrug, and a therapeutically effective amount of at least one immune checkpoint inhibitor, wherein the cancer is adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, oral cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, epidermoid carcinoma, esophageal cancer, or eye cancer. Follicular carcinoma, gallbladder cancer, gastrointestinal cancer, genitourinary tract cancer, glioblastoma, pilocytic carcinoma, head and neck cancer, liver tumors, hepatocellular carcinoma, Hodgkin's disease, keratoacanthoma, renal cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, squamous cell lung cancer, non-small cell lung cancer, melanoma, myeloproliferative disorders, neuroblastoma, ovarian cancer, papillary carcinoma, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, small cell carcinoma, small bowel cancer, gastric cancer, testicular cancer, thyroid cancer, vulvar cancer, or any combination thereof. Examples of checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

[0067] In another aspect, the present invention provides a method for treating cancer, the method comprising administering a composition to a subject in need, the composition comprising a therapeutically effective amount of at least one compound described herein, its salt, diastereomer, enantiomer, racemic mixture, hydrate, solvate, or prodrug, and a therapeutically effective amount of at least one chemotherapeutic agent that induces immunogenic cell death (ICD), wherein the cancer is adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, oral cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, epidermoid carcinoma, etc. Esophageal cancer, eye cancer, follicular carcinoma, gallbladder cancer, gastrointestinal cancer, genitourinary tract cancer, glioblastoma, pilocarcinoma, head and neck cancer, liver tumors, hepatocellular carcinoma, Hodgkin's disease, keratoacanthoma, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, squamous cell lung cancer, non-small cell lung cancer, melanoma, myeloproliferative disorders, neuroblastoma, ovarian cancer, papillary carcinoma, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, small cell carcinoma, small bowel cancer, gastric cancer, testicular cancer, thyroid cancer, vulvar cancer, or any combination thereof. Examples of chemotherapeutic agents that induce immunogenic cell death (ICD) include, but are not limited to, doxorubicin, idarubicin, mitoxantrone, temnothiazines, sponge carcinogen A, salubrinal, oxaliplatin, bleomycin, and cyclophosphamide.

[0068] In the methods described above using the compounds of the present invention, the compounds described herein, their salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs are administered to a system comprising cells or tissues. In some embodiments, the compounds described herein, their salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or any combination thereof are administered to a human or animal subject. In still other embodiments, a pharmaceutical composition or drug comprising at least one of the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or any combination thereof is administered to a human or animal subject.

[0069] 4. Methods for preparing compounds In another aspect, the present invention provides methods for preparing said compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs. In some embodiments, said compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs can be prepared by methods including, but not limited to, one or more of the following: (a) Optionally, the compounds of the present invention are converted into pharmaceutically acceptable salts; (b) Optionally, the salt form of the compounds of the present invention is converted into a non-salt form; (c) Optionally converting the unoxidized form of the compounds of the present invention into a pharmaceutically acceptable form. N -Oxides; (d) Optionally, separate individual isomers of the compound of the present invention from the mixture of stereoisomers; (e) Optionally, converting the non-derivative compounds of the present invention into pharmaceutically acceptable prodrug derivatives; and (f) Optionally, the prodrug derivatives of the compounds of the present invention are converted into their non-derivative forms.

[0070] This document includes exemplary methods for preparing the compounds of the present invention, described in the embodiments, which will be described in detail below. Some embodiments of the present invention provide methods for preparing the compounds of the present invention, as shown in Method 1 or Method 2 below.

[0071] A bicyclic acid (2) is reacted with thionyl chloride or oxalyl chloride in dichloromethane in the presence of a catalytic amount of GMF to provide its acyl chloride (3). The resulting acyl chloride (3) is coupled with a bicyclic heteroaryl compound (4) in a Friedel-Craft acylation reaction in an organic solvent (dichloromethane or dichloroethane) in the presence of a Lewis acid (aluminum chloride, titanium chloride, or stannous chloride) to provide a ketone (5). The resulting ketone (5) is reacted with an alkyl bromide, alkyl chloride, or alkyl epoxide in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane, or dichloroethane) using an inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, K2HPO4, or K3PO4) at room temperature (RT) - 150°C for 5-24 hours to obtain... N - Alkylated compounds (6).

[0072] N -Alkylated compounds (6) also originate from bicyclic heteroaryl compounds (4) and are carried out under the reaction conditions mentioned above. N Alkylation to obtain (7), followed by Friedel-Craft acylation with acyl chloride (3) to prepare alternatively.

[0073] Using palladium catalysts (Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4 or Pd(dppf)Cl2) . DCM), utilizing Suzuki reaction conditions to... N - Alkylated compound (6) is reacted with boric acid or borate ester in the presence of an inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, CsF, K2HPO4 or K3PO4) at room temperature (RT) - 150 °C for 5-24 hours to provide compound (1).

[0074] N The alkylated compound (6) was also prepared alternatively from the bicyclic heteroaryl compound (4) (method 2).

[0075] The bicyclic heteroaryl compound (4) and N-Iodosuccinimide (NIS) is reacted in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane, or dichloroethane) at room temperature for 2–24 h to provide an iodobicyclic heteroaryl compound (8). The iodobicyclic heteroaryl compound (8) is reacted with an alkyl bromide, alkyl chloride, or alkyl epoxide in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane, or dichloroethane) using an inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, K2HPO4, or K3PO4) at room temperature (RT) - 150 °C for 5–24 h to obtain... N - Alkylated compound (10). Starting from bicyclic heteroaryl compound (4), it is obtained by N-alkylation (9), and then, as previously described, using N -Iodosuccinimide (NIS) is used to prepare (9) by iodination to alternatively prepare N - Alkylated compounds (10). Bicyclic acid (2) is coupled with a coupling agent (DCC, EDCI, HATU, HBTU, PyBop, or PyBrop) in an organic solvent (DMF, tetrahydrofuran, dichloromethane, or dichloroethane). N -Methoxymethylamine hydrochloride was coupled at room temperature for 2–24 h to provide Weinreb amide (11). Weinreb amide (11) was converted to ketone (6) by reacting it with an iodobicyclic heteroaryl compound (10) in THF at low temperature (-78–0 °C) in the presence of a Grignard reagent.

[0076] Non-limiting examples of the compounds described herein may include: (6-Chlorochrome-3-yl)-[1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chloro-2H-chromen-3-yl)-[6-(3-Chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(6-fluorochroman-3-yl) methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[2,3-b]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-b]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-[(2R)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-((S)-2-hydroxypropyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-chlorochroman-3-yl) methyl ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-((S)-2-hydroxypropyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((R)-6-chlorochroman-3-yl) methyl ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-((S)-2-hydroxypropyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-chloro-seromon-3-yl)methyl ketone methanesulfonate; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; (6-Fluorochrome-3-yl)-[1-(2-hydroxyethyl)-6-(3-methyl-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl]methyl ketone hydrochloride; [6-(3-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; [[6-(3-chloro-1H-pyrazol-4-yl)-1-[(2R)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[2,3-b]pyridin-3-yl]-(6-methoxy-chroman-3-yl) ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-chroman-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [(3S)-6-chloro-3-yl]-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [(3S)-6-chloro-3-yl]-[6-(5-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] ketone; [(3S)-6-chloro-3-yl]-[6-(5-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [(3S)-6-chloro-3-yl]-[1-[(2S)-2-hydroxypropyl]-6-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [(3R)-6-chloro-3-yl]-[1-[(2R)-2-hydroxypropyl]-6-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxybutyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxybutyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(3-hydroxycyclobutyl)methyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(3-hydroxycyclobutyl)methyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)indol-3-yl] methyl ketone; (6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)-1H-indol-3-yl)((S)-6-chlorochrome-3-yl) methyl ketone; (6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)-1H-indol-3-yl)((S)-6-chlorochrome-3-yl) methyl ketone; ((S)-6-chloro-3-yl)(1-(2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; (6-Chlorochrome-3-yl)-[1-[(2S)-2-hydroxypropyl]-6-(3-methoxy-1H-pyrazol-4-yl)indol-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[1-[(2R)-2-hydroxypropyl]-6-(3-methoxy-1H-pyrazol-4-yl)indol-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[2-(5-chloro-1H-pyrazol-4-yl)-7-[(2S)-2-hydroxypropyl]pyrrolo[2,3-d]pyrimidin-5-yl] methyl ketone; (2-(5-chloro-1H-pyrazol-4-yl)-7-((S)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-chlorochroman-3-yl) methyl ketone; (6-Chlorochrome-3-yl)-[2-(5-fluoro-1H-pyrazol-4-yl)-7-[(2S)-2-hydroxypropyl]pyrrolo[2,3-d]pyrimidin-5-yl] methyl ketone; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(6-fluorochroman-3-yl) methyl ketone; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-fluorochroman-3-yl) methyl ketone; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-fluorosom-3-yl) methyl ketone hydrochloride; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-fluorosomn-3-yl)methyl ketone methanesulfonate; (6-Fluorochroman-3-yl)(7-(2-hydroxy-2-methylpropyl)-2-(5-methoxy-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) methyl ketone; (6-Chlorochrome-3-yl)-[7-[(2S)-2-hydroxypropyl]-2-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-5-yl] methyl ketone; (6-Chlorochrome-3-yl)-[2-(5-fluoro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methyl-propyl)pyrrolo[2,3-d]pyrimidin-5-yl] ketone; (S)-(6-chloro-3-yl)(2-(5-fluoro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) methyl ketone; (S)-(6-chloro-3-yl)(2-(5-fluoro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) methyl ketone methanesulfonate; (6-Chlorochrome-3-yl)-[2-(5-chloro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methyl-propyl)pyrrolo[2,3-d]pyrimidin-5-yl] ketone; (6-Chlorochrome-3-yl)-[7-(2-hydroxy-2-methyl-propyl)-2-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-5-yl] ketone; (6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl) methyl ketone hydrochloride; (6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl) methyl ketone methanesulfonate; (2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-hydroxyethyl)-6-(1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; Chromium-3-yl-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; 2,3-Dihydro-1,4-benzodioxin-3-yl-[1-(2-hydroxyethyl)-6-(1 H -pyrrolo[2,3- b [Pyridin-3-yl]indol-3-yl]methyl ketone; [6-(3-chloro-1] H [-pyrazol-4-yl)-1-(2-hydroxyethyl)indol-3-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl) methyl ketone; Chromium-3-yl-[1-(2-hydroxyethyl)-6-(1 H -pyrrolo[2,3- b [Pyridin-3-yl]indol-3-yl]methyl ketone; [6-(3-chloro-1] H -pyrazol-4-yl)-1-(2-hydroxyethyl)indol-3-yl]-chroman-3-yl-methyl ketone; (6-Fluorochrome-3-yl)-[1-(2-hydroxyethyl)-6-(1-) H [-pyrazol-4-yl)indol-3-yl]methyl ketone; [1-(2-hydroxyethyl)-6-(1 H[-pyrazol-4-yl)indol-3-yl]-(7-methoxychroman-3-yl)methyl ketone; (6-Fluoro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6-Chloro-2,3-dihydro-1,4-benzodioxin-2-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6-Fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6,7-Dichloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6-Chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; [1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]-(6-methoxy-2,3-dihydro-1,4-benzodioxin-3-yl)methyl ketone; [6-(3-chloro-1] H [-pyrazol-4-yl)-1-(2-hydroxyethyl)indol-3-yl]-(6-methoxychroman-3-yl)methyl ketone; (6-chloro-3-yl)(6-(3-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)-1H-indol-3-yl) methyl ketone; (6-Chlorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; (S)-(6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; (R)-(6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; (6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; (S)-(6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; (R)-(6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; Chromium-3-yl(1-(2-hydroxyethyl)-6-(1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; Chromium-3-yl(1-(2-methoxyethyl)-6-(1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-methoxyethyl)-6-(1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-(trifluoromethyl)-1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-Fluoro-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-Fluoro-3-yl)(1-(2-hydroxyethyl)-6-(3-isopropyl-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; 2-(3-(6-chloro-3-carbonyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-1-yl)acetonitrile; (2,3-Dihydrobenzofuran-2-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (1-(2-hydroxyethyl)-6-(3-methoxy-1) H -pyrazole-4-yl)-1 H -Indazol-3-yl)(2-methyl-2,3-dihydrobenzo[ b [1,4]dioxin-2-yl)methyl ketone; Benzofurano-3-yl(1-(2-hydroxyethyl)-6-(3-methoxy-1) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(1-(2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(1-((R)-2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(1-((S)-2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(1-) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (chroman-3-yl(1-(2-hydroxyethyl)-6-(1) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (7-Fluoro-2,3-dihydrobenzo[ b [1,4]Dioxin-2-yl)(1-(2-hydroxyethyl)-6-(1 H -pyrazole-4-yl)-1 H -indazole-3-yl)methyl ketone; and (7-Chloro-2,3-dihydrobenzo[ b [1,4]Dioxin-2-yl)(1-(2-hydroxyethyl)-6-(1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone.

[0077] Example The present invention is further illustrated by the following examples, which illustrate the preparation of the compound of Figure 1 according to the present invention. These examples are for illustrative purposes only and are not intended, nor should they be construed as, limiting the invention in any way. Those skilled in the art will understand that variations and modifications can be made without changing the scope of the invention.

[0078] The nuclear magnetic resonance (NMR) and mass spectrometry (MS) spectra of the compounds described in the following examples and those described herein are consistent with the NMR and MS spectra of the compounds of the formula described herein.

[0079] Liquid chromatography-mass spectrometry (LC-MS) method: 1. The sample was run on an Agilent Technologies 6120 MSD system with a Zorbax Eclipse XDB-C18 (3.5 μ) reversed-phase column (4.6 × 50 mm) running at a flow rate of 1.5 mL / min at room temperature.

[0080] 2. The mobile phase uses solvent A (water / 0.1% formic acid) and solvent B (acetonitrile / 0.1% formic acid): 95% / 5% to 0% / 100% (A / B) for 5 minutes.

[0081] 3. Mass spectra (m / z) were recorded using electrospray ionization (ESI).

[0082] 4. Round the ionization data to the nearest integer.

[0083] Proton NMR spectrum: Unless otherwise specified, all 1 All H NMR spectra were run on Varian series Mercury 400 or 500 MHz. Conventional abbreviations for specifying the main peak were used: e.g., s (single), d (double), t (triple), q (quartet), m (multiple), and brs (broad singlet). All observed protons were reported as parts per million (ppm) from the low field of tetramethylsilane.

[0084] Example 1: Preparation of the compound Compound 1-1: Step 1: A mixture of 6-chlorochromium-3-carboxylic acid (6.0 g, 28.2 mmol), thionyl chloride (20.98 mL, 282.18 mmol), and DMF (0.1 mL, catalyst) in toluene (60 mL) was heated to reflux with stirring for 3 hours. The mixture was cooled to room temperature and concentrated to remove volatile organic solvents. The crude product was dissolved in acetonitrile (100 mL) and concentrated to provide 1a (crude product), a light brown oil, which was used directly in the next step without further purification.

[0085] Step 2: A mixture of 1a (5.4 g, 23 mmol) and 6-bromo-1H-pyrrolo[3,2-c]pyridine (3.7 g, 19 mmol) in dichloromethane (60 mL) was cooled in an ice bath, and aluminum chloride (9.4 g, 70 mmol) was added. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched at 0 °C with a saturated NH4Cl solution (100 mL) to form a solid precipitate. The mixture was then heated to room temperature and stirred for another 2 hours. The solid was collected by filtration and then washed with methanol. The resulting solid was dried under high vacuum to provide 1b (7.4 g) as a white solid in 80% yield. LC / MS values ​​were 391.0 and 393.0 [M+H]. + .

[0086] Step 3: A mixture of 1b (800 mg, 2.1 mmol), potassium carbonate (1.76 g, 1.3 mmol, 770 μL), and 2-chloro-N,N-dimethylethylamine hydrochloride (690 mg, 6.4 mmol) in DMF (20 mL) was heated to 70 °C and stirred overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography on a silica gel column using a 20–100% EtOAc / hexane gradient to give 1c (202 mg) as a white solid in 20% yield. LC / MS values ​​were 463.1 and 465.0 [M+H]. + .

[0087] Step 4: The mixture of intermediate 1c (202 mg, 430 μmol), [3-methoxy-1-(p-toluenesulfonyl)pyrazol-4-yl]boronic acid (190 mg, 650 μmol), potassium carbonate (2 M aqueous solution, 540 μL), and tetrakis(triphenylphosphine)palladium (25.0 mg, 22 μmol) in 1,4-dioxane (10 mL) was degassed by argon jet for 5 min, and the reaction mixture was heated to 70 °C and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (50 mL), and extracted twice with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 1d, which was used in the next step without further purification.

[0088] Step 5a, for pyrazole compounds protected by toluenesulfonyl (Ts): A solution of 1d (crude product, 230 mg) in THF (1 mL) was cooled on an ice bath and treated with 2N sodium hydroxide solution (2.0 mL). The solution was stirred at 0 °C for 30 min and neutralized with 1N HCl solution (4.0 mL), diluted with EtOAc (30 mL) and saturated Na2CO3 solution (30 mL). The aqueous phase was separated and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide compound 1-1-(6-chlorochrome-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] ketone as a white solid (101 mg, 210 μmol, 58% yield in steps 4 and 5a). LC / MS result: 480.2 [M+H] + .

[0089] Step 6a: ((6-chloro-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl) methyl ketone hydrochloride): 55 μL of 4M HCl in dioxane was slowly added to a solution of 1-1 (50 mg, 104 μmol) in acetone (1 mL) at room temperature to form a solid precipitate. After stirring for another 1 hour at room temperature, 2 mL of tert-butyl ether was added to completely precipitate the precipitate. The solid was collected by filtration under a nitrogen atmosphere, washed with tert-butyl ether, and dried under vacuum to give 1-59 (47.5 mg, 82%) as a white powder. LC / MS result: 480.2 [M+H] + .

[0090] Step 6a: ((6-chloro-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)methyl ketone methanesulfonate): A 1M solution (220 μL) of methanesulfonic acid in acetone was slowly added to a solution of 1-1 (50 mg, 104 μmol) in acetone (1 mL) at room temperature to form a solid precipitate. After stirring for another 1 hour at room temperature, tert-butyl ethyl ether (2 mL) was added to completely precipitate the solid. The solid was collected by filtration under a nitrogen atmosphere, washed with tert-butyl ethyl ether, and dried under vacuum to give 1-60 (60.3 mg, 90%) as a white powder. LC / MS result: 480.2 [M+H] + .

[0091] Step 5b, pyrazole compound for Boc protection: A solution of crude 3-chloro-4-(3-(6-chloro-2H-chromene-3-carbonyl)-1-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (40.7 mg) in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at ambient temperature. After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to provide the residue. The residue was dissolved in EtOAc (10 mL) and washed with 2 M Na2CO3 solution (10 mL). The aqueous layer was separated and extracted with EtOAc (5 mL). The combined organic matter was dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide compound 1-1-(6-chloro-2H-chromen-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone as a light brown solid (33.0 mg, 41.8 μmol; 55% yield in steps 4 and 5b). LC / MS result: 458.1 [M+H] + .

[0092] The following compounds 1-2 to 1-60 shown in Table 1 were prepared by a method similar to that described for the preparation of compound 1-1 (general scheme 1), using appropriate (4) with appropriate boric acid / ester (R2) and appropriate R 1 Preparation of substituents.

[0093] Table 1 Compound 2-1: 2,3-dihydro-1,4-benzodioxin-3-yl-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone Step 1: Add 6-bromo-1 HA solution of indole (2.00 g, 10.20 mmol) in DMSO (20 mL) was treated with ground potassium hydroxide (865 mg, 15.42 mmol) and stirred at room temperature for 50 min. A solution of 2-bromoethanol (1.53 g, 12.24 mmol) in DMSO (2.0 mL) was added dropwise (5 min), and stirring continued for two days. The solution was diluted with EtOAc (400 mL), washed successively with water (3 x 400 mL) and brine (400 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 2a, 2-(6-bromoindole-1-yl)ethanol (1.78 g, 7.41 mmol, 73% yield), as an oil. LC / MS results: 240.1, +242.1 [M+H] + .

[0094] Step 2: Cool the solution of 2-(6-bromoindol-1-yl)ethanol (2a, 1.78 g, 7.41 mmol) in DMF (70 mL) on an ice bath and use... N 1,78 mmol iodosuccinimide (NIS, 1.75 g, 7.78 mmol) was treated. The ice bath was removed, and the solution was stirred at room temperature for 90 min. The solution was diluted with EtOAc (500 mL), washed successively with water (3 x 500 mL) and brine (500 mL), dried (Na₂SO₄), filtered, treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide 2b, 2-(6-bromo-3-iodo-indol-1-yl)ethanol (2.17 g, 5.93 mmol, 80% yield), as a pale yellow solid. LC / MS values: 365.0, 367.0 [M+H] + .

[0095] Step 3: Place 2-(6-bromo-3-iodo-indol-1-yl)ethanol (2b, 249.9 mg, 682.8 μmol) in a 40 mL vial under nitrogen atmosphere, then add THF (9 mL). Cool the solution on dry ice / acetonitrile bath (approximately -42°C), then treat dropwise with isopropyl magnesium chloride (2M in THF, 0.72 mL) (for two minutes). After two minutes, replace the acetonitrile bath with an ice bath and stir the sample for 30 minutes. Cool the reaction mixture back to -42°C and add dropwise... N -Methoxy- NA solution of methyl-2,3-dihydro-1,4-benzodioxin-3-carboxamide (4-2, 183.6 mg, 822.5 μmol) in THF (2.5 mL) for 3 minutes. The reaction mixture was stirred for two hours, removed from the cold bath, and quenched by adding 12% NH4Cl (aqueous solution, 2 mL). THF was removed under reduced pressure. The aqueous residue was diluted to 20 mL with another aqueous solution of NH4Cl and extracted with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired [6-bromo-1-(2-hydroxyethyl)indol-3-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl) methyl ketone (2c, 56.6 mg, 140.7 μmol, 21% yield) in an oily form. LC / MS measured values: 402.1, 404.1 [M+H] + .

[0096] Step 4: A suspension of [6-bromo-1-(2-hydroxyethyl)indol-3-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl) methyl ketone (2c, 53.4 mg, 132.8 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (60.7 mg, 206.4 μmol), PdCl2(dppf)-CH2Cl2 (16.6 mg, 20.33 μmol), and tripotassium phosphate (88.6 mg, 417.4 μmol) in dioxane (2 mL) and water (0.24 mL) was bubbled under nitrogen for 6 minutes and shaken overnight at 65 °C. The solution was evaporated under reduced pressure, and the residue was mixed with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic matter was dried (Na₂SO₄), filtered, and evaporated under reduced pressure to provide tert-butyl 4-[3-(2,3-dihydro-1,4-benzodioxin-3-carbonyl)-1-(2-hydroxyethyl)indol-6-yl]pyrazole-1-carboxylate (2d, 95.8 mg). The residue was used without further purification. LC / MS result: 490.3 [M+H] + .

[0097] Step 5: The crude solution of tert-butyl 4-[3-(2,3-dihydro-1,4-benzodioxin-3-carbonyl)-1-(2-hydroxyethyl)indol-6-yl]pyrazole-1-carboxylic acid (2d, 95.8 mg) in DCM (1 mL) and MeOH (0.05 mL) was treated with TFA (0.5 mL) and shaken for 15 min. The solvent was evaporated under reduced pressure. The residue was dissolved in MeOH (10 mL) and evaporated under reduced pressure. The residue was dissolved in DCM (10 mL), washed successively with ammonium hydroxide (1 M) and brine (10 mL each), dried (Na2SO4), treated with silica gel, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 2,3-dihydro-1,4-benzodioxin-3-yl-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone 2-1 (16.2 mg, 41.6 μmol; yield of steps 4 and 5: 31%). LC / MS result: 390.2 [M+H] + .

[0098] Compound 2-2: (6-chloro-3-yl)-[1-(2-hydroxyethyl)-6-(1-yl)-[1-yl]-[2-hydroxyethyl]-[1-yl]-[2-hydroxyethyl]-[1-yl]-[2-hydroxyethyl]-[1-yl]-[2-hydroxyethyl]-[3-yl]-[2-hydroxyethyl]-[3-yl]-[2-yl ...3-yl]-[2-yl]-[3-yl]-[3-yl]-[2-yl]-[3-yl]-[3-yl]-[3-yl]-[3-yl]-[3-yl]-[3-yl]-[3-yl]-[3-yl]- H [-pyrazol-4-yl)indol-3-yl]methyl ketone Step 1: A solution of 2-(6-bromo-3-iodo-indol-1-yl)ethanol (2b, 598.1 mg, 1.63 mmol), imidazole (225.0 mg, 3.31 mmol), and DMAP (6.7 mg, 54.84 μmol) in DMF (4 mL) was treated with TBSCl (397.6 mg, 2.64 mmol) and stirred at room temperature for 16 hours. The solution was diluted with EtOAc (40 mL), washed successively with water and brine (40 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 2-(6-bromo-3-iodo-indol-1-yl)ethoxy-tert-butyl-dimethylsilane (2f, 0.63 g, 1.31 mmol, 80% yield) as a clear oil. LC / MS measured values: 479.9, 481.9 [M+H] + .

[0099] Step 2: A solution of 2-(6-bromo-3-iodo-indol-1-yl)ethoxy-tert-butyl-dimethylsilane (2f, 449.2 mg, 935.3 μmol) in anhydrous THF (13 mL) was cooled in a dry ice / acetonitrile bath (approximately -42°C) and then treated dropwise with isopropyl magnesium chloride (2 M in THF, 0.65 mL) (3 min). After three min, the acetonitrile bath was replaced with an ice bath, and the reaction mixture was stirred for 45 min. The reaction mixture was cooled back to -42°C, and 6-chloro- N -Methoxy- N 1-Methyl-chroman-3-carboxamide (4-1, 363.8 mg, 1.42 mmol) was dissolved in THF (3.6 mL) for 3 minutes. After 3 minutes, the dry ice bath was replaced with an ice-water bath, and the mixture was stirred for 2.5 hours. The reaction was quenched with water (2 mL), and the THF was evaporated under reduced pressure. The remaining aqueous solution was diluted with EtOAc (40 mL), washed successively with water and brine (40 mL each), dried (Na2SO4), filtered, treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide [6-bromo-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]indol-3-yl]-(6-chlorochroman-3-yl) methyl ketone as a clear yellow oil (2 g, 194.5 mg, 354.30 μmol, 38% yield). LC / MS values: 548.3, 550.3 [M+H] + .

[0100] Step 3: Bubble a suspension of [6-bromo-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]indol-3-yl]-(6-chlorochroman-3-yl) ketone (2 g, 63.9 mg, 116.4 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (52.4 mg, 178.1 μmol), PdCl2(dppf)-CH2Cl2 (15.1 mg, 18.5 μmol), and tripotassium phosphate (79.0 mg, 372.2 μmol) in dioxane (2.1 mL) and water (0.25 mL) under nitrogen for 5 minutes and shake overnight at 65°C. The solution was evaporated under reduced pressure, and the residue was dissolved in EtOAc (10 mL), washed successively with water and brine (10 mL each), dried (Na₂SO₄), filtered, and evaporated under reduced pressure to provide crude 4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(6-chlorochrome-3-carbonyl)indol-6-yl]pyrazole-1-carboxylic acid tert-butyl ester (2 h, 99.3 mg) as a red oil. The residue was used without further purification. LC / MS result: 636.2 [M+H] + .

[0101] Step 4: A solution of crude 4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(6-chlorochroman-3-carbonyl)indol-6-yl]pyrazole-1-carboxylic acid tert-butyl ester (2h, 99.3 mg) in DCM (1.0 mL) and MeOH (0.05 mL) was treated with TFA (1.0 mL) and stirred at room temperature. After about 2 hours, the solvent was evaporated under reduced pressure to provide a red residue. The material was dissolved in DCM (10 mL) and washed with 1M ammonium hydroxide. The aqueous layer was extracted with DCM (10 mL), and the combined organic layers were treated with methanol to provide a clear red solution. The solution was treated with silica gel and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide (6-chlorochroman-3-yl)-[1-(2-hydroxyethyl)-6-(1-hydroxyethyl)indol-6-yl]pyrazole-1-carboxylic acid tert-butyl ester as a brown solid. H [-pyrazol-4-yl)indol-3-yl]methyl ketone (2-2, 26.8 mg, 63.5 μmol; yield of steps 3 and 4: 55%). LC / MS result: 422.2 [M+H] + .

[0102] Compound 2-24: Chrom-3-yl-[1-(2-methoxyethyl)-6-(1 H [-pyrazole-4-yl)indazole-3-yl] methyl ketone Step 1: Add 6-bromo-3-iodine-1 H A suspension of 1-bromo-3-iodo-1-(2-methoxyethyl)indazole (2.00 g, 6.19 mmol) and potassium carbonate (2.57 g, 18.58 mmol) in DMF (30 mL) was stirred at room temperature for 75 min. 1-Chloro-2-methoxy-ethane (0.70 mL, 7.70 mmol) was added, and the suspension was stirred at 60 °C for 9 h. The mixture was diluted with EtOAc (225 mL), washed successively with water (3 x 225 mL) and brine (225 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 6-bromo-3-iodo-1-(2-methoxyethyl)indazole (3a, 1.70 g, 4.47 mmol, 72% yield) as a soft white solid. LC / MS values: 381.0, 383.0 [M+H] + .

[0103] Step 2: Isopropyl magnesium chloride (2 M in THF, 0.76 mL) was added dropwise to a solution of 6-bromo-3-iodo-1-(2-methoxyethyl)indazole (3a, 485.8 mg, 1.3 mmol) in 20 mL of THF at -78 °C. After stirring at -78 °C for 35 minutes, the solution was added dropwise. N -Methoxy- N A solution of methyl-chroman-3-carboxamide (4-3, 443.2 mg, 2.00 mmol) in THF (5 mL). After 1 hour and 45 minutes, the reaction was quenched by dropwise addition of water (3 mL), and the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (40 mL) and washed successively with aqueous ammonium chloride solution (12%, 20 mL) and brine (40 mL). The organic layer was dried (Na2SO4), decanted, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide [6-bromo-1-(2-methoxyethyl)indazole-3-yl]-chroman-3-yl-methyl ketone (3b, 50.7 mg, 122.1 μmol, 10% yield) as an oil. LC / MS values: 415.1, 417.1 [M+H] + .

[0104] Step 3: The suspension of [6-bromo-1-(2-methoxyethyl)inzol-3-yl]-chroman-3-yl-methyl ketone (3b, 50.7 mg, 122.1 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (71.8 mg, 244.1 μmol), PdCl2(dppf)-CH2Cl2 (15.2 mg, 18.61 μmol) and tripotassium phosphate (79.1 mg, 372.64 μmol) in dioxane (1.85 mL) and water (0.21 mL) was bubbled with nitrogen for 5 minutes and shaken overnight at 65°C. The residue was dissolved in EtOAc (10 mL), washed with brine (10 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure to provide an impure tert-butyl 4-[3-(chroman-3-carbonyl)-1-(2-methoxyethyl)indazole-6-yl]pyrazole-1-carboxylate (3c, 119.6 mg) as a red oil. The material was used without further purification. LC / MS result: 503.2 [M+H] + .

[0105] Step 4: The crude solution of tert-butyl 4-[3-(chroman-3-carbonyl)-1-(2-methoxyethyl)indazole-6-yl]pyrazole-1-carboxylate (3c, 119.6 mg) in DCM (1.0 mL) and MeOH (0.05 mL) was treated with TFA (0.5 mL) and shaken for 15 min. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (10 mL), washed successively with 1M NH4OH and brine (10 mL each), dried (Na2SO4), decanted, treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide chroman-3-yl-[1-(2-methoxyethyl)-6-(1-... H [-pyrazol-4-yl)indazole-3-yl]methyl ketone (2-24, 28.3 mg, 70.32 μmol; yields of steps 3 and 4 were 58%). LC / MS 403.2 [M+H + .

[0106] The following compounds 2-3 to 2-35 shown in Table 2 were prepared by a method similar to that described for the preparation of compounds 2-1, 2-2, or 2-24, using appropriate boric acid / esters and Weinreb amides.

[0107] Table 2 Alternatively, racemic mixtures of compounds can be separated by supercritical fluid chromatography as follows.

[0108] Compound 2-18: [(3 S )-6-chloro-3-yl]-[6-(5-methoxy-1 H -pyrazol-4-yl)-1-(2-oxoyl)indol-3-yl] ketone and compound 2-19: [(3 R )-6-chloro-3-yl]-[6-(5-methoxy-1 H [-pyrazol-4-yl)-1-(2-oxoethyl)indol-3-yl] methyl ketone s Samples of racemic compound 2-17 were separated by supercritical fluid chromatography under the following conditions: column, ChiralPak IC-H 21 x 250 mm; mobile phase, CO2 solution of 40% methanol; flow rate, 70 mL / min; sample, 19.4 mg dissolved in 2.0 mL methanol and 2.0 mL dichloromethane; injection volume, 0.75 mL; detection: 220 nm.

[0109] Compound 2-18: [(3 S )-6-chloro-3-yl]-[6-(5-methoxy-1 H [-pyrazol-4-yl)-1-(2-oxoethyl)indol-3-yl]methyl ketone: first elution peak, 8.4 mg, 100% purity, 97.9% ee. LC / MS result: 452.2 [M+H] + .

[0110] Compound 2-19: [(3 R )-6-chloro-3-yl]-[6-(5-methoxy-1 H [-pyrazol-4-yl)-1-(2-oxoethyl)indol-3-yl]methyl ketone: second elution peak, 8.7 mg, 100% purity, 96.4% ee. LC / MS result: 452.2 [M+H] + .

[0111] Compound 2-21: [(3 S )-6-Fluoro-3-yl]-[1-(2-hydroxyethyl)-6-(5-methoxy-1 H-pyrazol-4-yl)indol-3-yl]methyl ketone and compound 2-22: [(3 R )-6-Fluoro-3-yl]-[1-(2-hydroxyethyl)-6-(5-methoxy-1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone Samples of racemic compound 2-20 were separated by supercritical fluid chromatography under the following conditions: column, ChiralPak IC-H 21 x 250 mm; mobile phase, CO2 solution of 35% methanol; flow rate, 70 mL / min; sample, 25.5 mg dissolved in 2.0 mL methanol and 2.0 mL dichloromethane; injection volume, 1.0 mL; detection, 254 nm.

[0112] Compound 2-21: [(3 S )-6-Fluoro-3-yl]-[1-(2-hydroxyethyl)-6-(5-methoxy-1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone: first elution peak, 10.9 mg, 100% purity, 98.5% ee. LC / MS result: 436.2 [M+H] + .

[0113] Compound 2-22: Compound 2-22: [(3 R )-6-Fluoro-3-yl]-[1-(2-hydroxyethyl)-6-(5-methoxy-1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone: second elution peak, 10.8 mg, 100% purity, 97.7% ee. LC / MS result: 436.2 [M+H] + .

[0114] Compound 3-1: Chrom-3-yl-[1-(2-methoxyethyl)-6-(1 H [-pyrazole-4-yl)indazole-3-yl] methyl ketone Step 1: Add 6-bromo-1 HA mixture of 1-indazole (985 mg, 5.00 mmol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazole (2.09 g, 7.50 mmol), tris(dibenzylacetone)dipalladium, tri-tert-butylphosphonium tetrafluoroborate (4 mol%) and Na₂CO₃ (3 equivalents) in a 1:1 ethanol / water mixture (10 mL) was degassed by N jet for 5 min and heated to 100 °C overnight with stirring. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography using 50–100% EtOAc / heptane to provide 4a, i.e., 6-(1-(tetrahydro-2-yl)pyrazole, as a white foamy solid. H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H -Indazole, yield 90% (4a, 1.21 g, 4.51 mmol). LC / MS result 269.2 [M+H] + .

[0115] Step 2: To 6-(1-(tetrahydro-2-) H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H -Indazole (4a, 1.01 g, 3.76 mmol) was added to a solution of potassium carbonate (1.04 g, 7.53 mmol) in DMF (10 mL), followed by the addition of N 3-Iodosuccinimide (1.02 g, 4.52 mmol). The mixture was stirred overnight at room temperature and poured into a 10% aqueous solution of NaHSO3. The mixture was extracted with EtOAc, and the combined organic layers were washed with water, washed with brine, dried over Na2SO4, filtered, and then concentrated to provide 3-iodo-6-(1-(tetrahydro-2-iodosuccinimide) as a white solid. H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H -Indazole, yield 86% (4b, 1.27 g, 3.22 mmol). LC / MS result 395.1 [M+H] + The crude product is used without further purification.

[0116] Step 3: To 3-iodine-6-(1-(tetrahydro-2-) H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H-Indazole (4b, 1.27 g, 3.22 mmol) was added to a solution of potassium carbonate (888 mg, 6.43 mmol) in acetonitrile (32 mL), followed by the addition of ethylene oxide (2.9 M in THF, 2.2 mL, 6.4 mmol). The mixture was heated to 80 °C overnight with stirring. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography using a 50-100% EtOAc / heptane gradient to provide 4c as a solid, namely 2-(3-iodo-6-(1-(tetrahydro-2-)- H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H (-Indazole-1-yl)ethyl-1-ol, yield 32% (450 mg, 1.03 mmol). LC / MS result 439.1 [M+H] + .

[0117] Step 4: Add 2-(3-iodine-6-(1-(tetrahydro-2-)) to the solution cooled to 0°C. H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H 1-Indazole-1-yl)ethyl-1-ol (4c, 437 mg, 1.00 mmol) and imidazole (140 mg, 2.06 mmol) in a solution of DMF (4 mL) were added to tert-butyldimethylchlorosilane (170 mg, 1.13 mmol). The mixture was heated to room temperature and stirred overnight. The mixture was poured into water and extracted with 1:1 EtOAc / hexane. The combined organic layers were washed with water (3x), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a 1-10% EtOAc / hexane gradient to provide 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-iodo-6-(1-(tetrahydro-2-)- ... H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H -Indazole, yield 88% (4 days, 487 mg, 0.88 mmol). LC / MS result 553.3 [M+H] + .

[0118] Step 5: Add 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-iodine-6-(1-(tetrahydro-2-yl ...-3-iodine-6-(1-(tert-butyldimethylsilyl)oxy)ethyl)-3-iodine-6-(1-(tetrahydro-2-yl)-3-iodine-6- H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H-Indazole (4d, 85 mg, 0.15 mmol) was added dropwise to a solution of anhydrous THF (2 mL) with magnesium isopropyl chloride (2.0 M in THF, 0.11 mL, 0.22 mmol). After 5 minutes, the mixture was heated to 0°C and stirred at that temperature for 45 minutes. The mixture was then cooled back to -40°C, and 6-fluoroalkyl (fluoranyl) was added dropwise. N -Methoxy- N A solution of methyl-chromium-3-carboxamide (62 mg, 0.26 mmol) in anhydrous THF (1 mL). The mixture was heated back to 0 °C and stirred for 2 hours. The reaction was quenched by adding water and extracted with EtOAc. The combined organic layers were washed with 10% NH4Cl aqueous solution, washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography using a 1-10% EtOAc / heptane gradient to provide (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(1-(tetrahydro-2-ethyl)-ethyl) as a white solid. H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)(6-Fluorochrom-3-yl)methyl ketone, yield 38% (4e, 35 mg, 59 μmol).

[0119] Step 6: To (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(1-(tetrahydro-2-ethyl ...tetrahydro-2-ethyl)oxy)ethyl)-6-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazole-4-yl)-1 H (-Indazole-3-yl)(6-fluorochromium-3-yl)methyl ketone (4e, 35 mg, 59 μmol) was added to a solution of p-toluenesulfonic acid monohydrate (11 mg) in a 1:1 THF / water mixture (2 mL), and the mixture was heated to 60 °C overnight with stirring. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a 1-10% CH3OH / CH2Cl2 gradient to provide (6-fluorochromium-3-yl)(1-(2-hydroxyethyl)-6-(1-)methyl ketone as a white solid. H -pyrazole-4-yl)-1 H (-Indazole-3-yl)methyl ketone, yield 24% (3-1, 5.7 mg, 14 μmol). LC / MS result 407.1 [M+H] + .

[0120] The following compounds 3-2 to 3-4 shown in Table 3 were prepared using a method similar to that described for the preparation of compound 3-1, with the use of a suitable Weinreb amide and a suitable R 2 Preparation of borate esters.

[0121] Table 3 Intermediate 4-1: 6-chloro- N -Methoxy- N -Methyl-chroman-3-carboxamide 6-Chlorochrome-3-carboxylic acid (964.5 mg, 4.54 mmol), N , O -Dimethylhydroxylamine hydrochloride (665.3 mg, 6.82 mmol) and 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxid hexafluorophosphate), N -[(dimethylamino)-1 H -1,2,3-triazolo-[4,5- b ]pyridin-1-ylmethylene]- N methylmethylammonium hexafluorophosphate N - The suspension of HATU oxide (2.15 g, 5.67 mmol) in DMF (33 mL) was used N , N 6-Diisopropylethylamine (18.4 mmol, 3.2 mL) was used to treat the solution. The solution was stirred overnight at ambient temperature. The solution was diluted with EtOAc (300 mL), washed sequentially with water (3 x 300 mL) and brine (300 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide 6-chloro- N -Methoxy- N 3-Methyl-chroman-3-carboxamide (Weinreb intermediate 4-1; 1.06 g, 4.15 mmol, 91% yield). LC / MS result: 256.0 [M+H] + .

[0122] The following Weinerb amide intermediates 4-2 to 4-23 shown in Table 4 were prepared using appropriate carboxylic acids by a method similar to that described for the preparation of intermediate 4-1.

[0123] Table 4 Example 2: ROCK Inhibition Measurement The kinase IC50 was determined by in vitro assay using a homogeneous technique based on LANCE Ultra TR-FRET (time-resolved fluorescence resonance energy transfer) (Perkin Elmer). 50 Recombinant ROCK1 (amino acids 1-477) and ROCK2 (amino acids 5-554) proteins were purchased from Carna Biosciences and SignalChem. Compound activity was measured using Envision and IC50 was calculated. 50 The assays were performed in white LUMITRAC™ 200 96-well half-area microplates from Greiner Bio-One. The kinase reaction buffer consisted of 50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, and 0.01% Tween-20. The kinase was incubated with 50 nM (ULight-CREBtide) substrate in the presence of 1 mM (ROCK1) or 1 mM (ROCK2). The kinase reaction was allowed to proceed for 1 hour, after which a stop buffer was added to the final 10 mM EDTA and 0.6 nM LANCE Ultra Europium antiphosphorylated CREB (Ser133) antibody (PerkinElmerTRF0200) in the LANCE assay buffer. All assay incubations were performed at room temperature, and the microplates were sealed with a polyester membrane during this period. The reaction was incubated for 1 hour, and the signal was read out in Envision in TR-FRET mode (excited at 320 nm and emitted at 615 / 665 nm).

[0124] Compounds of formula (1) exhibit useful pharmacological properties. As used herein, the inhibitory potency (nM) is described as the inhibitory activity value at 50% (IC50). 50 The results are shown in Table xx below, where ICs less than 10 nM are... 50 Defined as "A", ICs between 11 nM and 50 nM 50 Defined as "B", ICs between 51 nM and 500 nM 50ICs defined as "C" and greater than 501nM 50 Defined as "D". Table 5 illustrates the inhibition of ROCK1 and ROCK2 by representative compounds of (1).

[0125] Table 5. Inhibitory activities of ROCK1 and ROCK2 at ATP Km

Claims

1. A compound of formula (1), a pharmaceutically acceptable salt of said compound, or a prodrug of said compound or said salt: in: X is CH2 or O; Y is either N or CH; Z 1 Z 2 and Z 3 Each can be either N or CH independently; n is 0, 1, 2, or 3; R 1 H, C2-C6 alkyl or CH2C3-C8 cycloalkyl, wherein the C2-C6 alkyl or CH2C3-C8 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of C1-C3 alkyl, hydroxyl, CN and C1-C3 alkoxy; R 2 It is a heteroaryl or bicyclic heteroaryl, wherein the heteroaryl or bicyclic heteroaryl is optionally substituted by one or more suitable substituents selected from the group consisting of halogens, CN, CHF2, CF3, C1-C3 alkyl and amino groups, wherein the heteroaryl or bicyclic heteroaryl has 1-3 heteroatoms selected from the group consisting of oxygen and nitrogen; and R 3 and R 4 Independently, H, Cl, F, OH, OCD 3 C1-C3 alkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy is optionally replaced by one or more suitable substituents, such as OH or OMe, OEt, OPr i replace.

2. The compound, salt, or prodrug according to claim 1, wherein R 2 Selected from the following group: 。 3. The compound, salt, or prodrug according to claim 1, wherein R 3 and R 4 Independently, H, Cl, F, OH, OMe, OCD 3 、OEt、OPr i Or a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally selected from one or more suitable free radicals selected from OH, OMe, OEt, and OPr. i Substituents in the group are substituted.

4. A pharmaceutical composition comprising a compound, salt or prodrug according to claim 1, and an additional component selected from the group consisting of pharmaceutically acceptable carriers, diluents, excipients, adjuvants, and combinations thereof.

5. A compound represented by the following list, a pharmaceutically acceptable salt of said compound, or a prodrug of said compound or said salt: (6-Chlorochrome-3-yl)-[1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] ketone; (6-Chloro-2H-chromen-3-yl)-[6-(3-Chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(6-fluorochroman-3-yl) methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[2,3-b]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-b]pyridin-3-yl] methyl ketone; (6-Chloro-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)pyrrolo[3,2-c]pyridin-3-yl]methyl ketone (6-Chlorochrome-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-[(2R)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-((S)-2-hydroxypropyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-chlorochroman-3-yl) methyl ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-((S)-2-hydroxypropyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((R)-6-chlorochroman-3-yl) methyl ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-((S)-2-hydroxypropyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-chloro-seromon-3-yl)methyl ketone methanesulfonate; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; (6-Fluorochrome-3-yl)-[1-(2-hydroxyethyl)-6-(3-methyl-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl]methyl ketone hydrochloride; [6-(3-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; [[6-(3-chloro-1H-pyrazol-4-yl)-1-[(2R)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[2,3-b]pyridin-3-yl]-(6-methoxy-chroman-3-yl) ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-chroman-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [6-(5-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [(3S)-6-chloro-3-yl]-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxypropyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [(3S)-6-chloro-3-yl]-[6-(5-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] ketone; [(3S)-6-chloro-3-yl]-[6-(5-chloro-1H-pyrazol-4-yl)-1-(2-hydroxy-2-methyl-propyl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [(3S)-6-chloro-3-yl]-[1-[(2S)-2-hydroxypropyl]-6-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [(3R)-6-chloro-3-yl]-[1-[(2R)-2-hydroxypropyl]-6-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxybutyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(2S)-2-hydroxybutyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(3-hydroxycyclobutyl)methyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(3-hydroxycyclobutyl)methyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)indol-3-yl] methyl ketone; (6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)-1H-indol-3-yl)((S)-6-chlorochrome-3-yl) methyl ketone; (6-(3-chloro-1H-pyrazol-4-yl)-1-(2-hydroxypropyl)-1H-indol-3-yl)((S)-6-chlorochrome-3-yl) methyl ketone; ((S)-6-chloro-3-yl)(1-(2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; (6-Chlorochrome-3-yl)-[1-[(2S)-2-hydroxypropyl]-6-(3-methoxy-1H-pyrazol-4-yl)indol-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[1-[(2R)-2-hydroxypropyl]-6-(3-methoxy-1H-pyrazol-4-yl)indol-3-yl] methyl ketone; (6-Chlorochrome-3-yl)-[2-(5-chloro-1H-pyrazol-4-yl)-7-[(2S)-2-hydroxypropyl]pyrrolo[2,3-d]pyrimidin-5-yl] methyl ketone; (2-(5-chloro-1H-pyrazol-4-yl)-7-((S)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-chlorochroman-3-yl) methyl ketone; (6-Chlorochrome-3-yl)-[2-(5-fluoro-1H-pyrazol-4-yl)-7-[(2S)-2-hydroxypropyl]pyrrolo[2,3-d]pyrimidin-5-yl] methyl ketone; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(6-fluorochroman-3-yl) methyl ketone; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-fluorochroman-3-yl) methyl ketone; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-fluorosom-3-yl) methyl ketone hydrochloride; (2-(5-fluoro-1H-pyrazol-4-yl)-7-((R)-2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)((S)-6-fluorosomn-3-yl)methyl ketone methanesulfonate; (6-Fluorochroman-3-yl)(7-(2-hydroxy-2-methylpropyl)-2-(5-methoxy-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) methyl ketone; (6-Chlorochrome-3-yl)-[7-[(2S)-2-hydroxypropyl]-2-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-5-yl] methyl ketone; (6-Chlorochrome-3-yl)-[2-(5-fluoro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methyl-propyl)pyrrolo[2,3-d]pyrimidin-5-yl] ketone; (S)-(6-chloro-3-yl)(2-(5-fluoro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) methyl ketone; (S)-(6-chloro-3-yl)(2-(5-fluoro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) methyl ketone methanesulfonate; (6-Chlorochrome-3-yl)-[2-(5-chloro-1H-pyrazol-4-yl)-7-(2-hydroxy-2-methyl-propyl)pyrrolo[2,3-d]pyrimidin-5-yl] ketone; (6-Chlorochrome-3-yl)-[7-(2-hydroxy-2-methyl-propyl)-2-(5-methoxy-1H-pyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-5-yl] ketone; (6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl) methyl ketone hydrochloride; (6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl) methyl ketone methanesulfonate; (2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-hydroxyethyl)-6-(1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; Chromium-3-yl-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; 2,3-Dihydro-1,4-benzodioxin-3-yl-[1-(2-hydroxyethyl)-6-(1 H -pyrrolo[2,3- b [Pyridin-3-yl]indol-3-yl]methyl ketone; [6-(3-chloro-1] H [-pyrazol-4-yl)-1-(2-hydroxyethyl)indol-3-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl) methyl ketone; Chromium-3-yl-[1-(2-hydroxyethyl)-6-(1 H -pyrrolo[2,3- b [Pyridin-3-yl]indol-3-yl]methyl ketone; [6-(3-chloro-1] H -pyrazol-4-yl)-1-(2-hydroxyethyl)indol-3-yl]-chroman-3-yl-methyl ketone; (6-Fluorochrome-3-yl)-[1-(2-hydroxyethyl)-6-(1-) H [-pyrazol-4-yl)indol-3-yl]methyl ketone; [1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]-(7-methoxychroman-3-yl)methyl ketone; (6-Fluoro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6-Chloro-2,3-dihydro-1,4-benzodioxin-2-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6-Fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6,7-Dichloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (6-Chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]methyl ketone; [1-(2-hydroxyethyl)-6-(1 H [-pyrazol-4-yl)indol-3-yl]-(6-methoxy-2,3-dihydro-1,4-benzodioxin-3-yl)methyl ketone; [6-(3-chloro-1] H [-pyrazol-4-yl)-1-(2-hydroxyethyl)indol-3-yl]-(6-methoxychroman-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(6-(3-fluoro-1H-pyrazol-4-yl)-1-(2-hydroxyethyl)-1H-indol-3-yl) methyl ketone; (6-Chlorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; (S)-(6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; (R)-(6-chloro-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; (6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; (S)-(6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; (R)-(6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indol-3-yl)methyl ketone; Chromium-3-yl(1-(2-hydroxyethyl)-6-(1H-pyrazol-4-yl)-1H-indol-3-yl) methyl ketone; Chromium-3-yl(1-(2-methoxyethyl)-6-(1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-methoxyethyl)-6-(1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(3-(trifluoromethyl)-1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-Fluoro-3-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-Fluoro-3-yl)(1-(2-hydroxyethyl)-6-(3-isopropyl-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; 2-(3-(6-chloro-3-carbonyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-1-yl)acetonitrile (2,3-Dihydrobenzofuran-2-yl)(1-(2-hydroxyethyl)-6-(3-methoxy-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (1-(2-hydroxyethyl)-6-(3-methoxy-1) H -pyrazole-4-yl)-1 H -Indazol-3-yl)(2-methyl-2,3-dihydrobenzo[ b [1,4]dioxin-2-yl)methyl ketone; Benzofurano-3-yl(1-(2-hydroxyethyl)-6-(3-methoxy-1) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(1-(2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(1-((R)-2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (6-Chlorochrome-3-yl)(1-((S)-2-hydroxypropyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (6-Fluorochrome-3-yl)(1-(2-hydroxyethyl)-6-(1-) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (chroman-3-yl(1-(2-hydroxyethyl)-6-(1) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (7-Fluoro-2,3-dihydrobenzo[ b [1,4]Dioxin-2-yl)(1-(2-hydroxyethyl)-6-(1 H -pyrazole-4-yl)-1 H -indazole-3-yl)methyl ketone; and (7-Chloro-2,3-dihydrobenzo[ b [1,4]Dioxin-2-yl)(1-(2-hydroxyethyl)-6-(1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone.

6. Use of the compound, salt, or prodrug according to claim 1 in the preparation of a medicament for treating diseases that can be treated by inhibiting ROCK enzymes.

7. Use of the compound, salt, or prodrug according to claim 1 for the treatment or relief of fibrotic disorders, cardiovascular diseases or disorders, inflammatory diseases or disorders, or proliferative diseases or disorders.

8. The use according to claim 7, wherein the fibrotic disorder is pulmonary fibrosis selected from the group consisting of cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis and endocardial myocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, joint fibrosis, Crohn's disease, myelofibrosis, Peroni disease, renal systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scars, and renal fibrosis.

9. The use according to claim 7, wherein the cardiovascular disease or ailment is selected from the group consisting of: angina pectoris, atherosclerosis, cerebral vasospasm, cerebral vasoconstriction, coronary vasospasm, endothelial dysfunction, erectile dysfunction, glaucoma, hypertension, ischemia / reperfusion injury, myocardial hypertrophy, myocardial infarction, peripheral circulatory disorders, premature birth, Raynaud's disease, nephropathy, and stroke.

10. The use according to claim 7, wherein the proliferative disease or lesion is an invasive or metastatic cancer selected from the group consisting of: adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, oral cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, epidermoid carcinoma, esophageal cancer, eye cancer, follicular carcinoma, gallbladder cancer, gastrointestinal cancer, urogenital tract cancer, glioblastoma, pilocarcinoma, head and neck cancer, liver tumor, hepatocellular carcinoma, Hodgkin's disease, keratoacanthoma, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, squamous cell lung cancer, non-small cell lung cancer, melanoma, myeloproliferative disorders, neuroblastoma, ovarian cancer, papillary carcinoma, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, small cell carcinoma, small bowel cancer, gastric cancer, testicular cancer, thyroid cancer, and vulvar cancer.

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