Blood-brain barrier permeable ROCK2 protein kinase selective inhibitors, and their use

Abstract

The present invention relates to novel blood-brain barrier (BBB) ​​permeable substituted bicyclic derivatives capable of selectively inhibiting myosin light chain phosphate phosphorylation mediated by ROCK2 and / or Rho kinase, compositions comprising such derivatives, methods for preparing such derivatives and / or compositions, and methods for using such derivatives and / or compositions.

Description

Cross-reference to Related Applications

[0001] This application claims the priority of U.S. Provisional Application No. 63 / 496,836, filed on April 18, 2023, the entire disclosure of which is incorporated herein by reference.

Technical Field

[0002] The present invention relates to novel substituted bicyclic derivatives capable of selectively inhibiting the phosphorylation of myosin light chain mediated by ROCK2 and / or Rho kinase, methods for preparing the same, formulations thereof, and their use for the manufacture of pharmaceuticals, as well as pharmaceutically acceptable salts, diastereomers, enantiomers, and racemates.

Background Art

[0003] Rho-related coiled-coil protein kinases (ROCKs / Rho kinases / Rho-associated kinases) are downstream effectors of the small GTPase Rho (Rho A, Rho B, Rho C, and Rho E) and belong to the serine / threonine kinase family. Active GTP-bound Rho mediates several biological functions, including smooth muscle contraction, cell motility, and cell division, through the action of ROCKs. ROCK proteins were identified in 1996 as proteins that bind to Rho GTPases. Two proteins were isolated independently as p160 and p164. Later, these were recognized as ROCK-1 and ROCK-2, respectively, and were found to be isoforms of Rho-associated kinases. The two isoforms, ROCK-1 (ROCK-b / p160) and ROCK-2 (ROCK-a / p164), share 92% homology in their amino acid sequences. These structures consist of a catalytic kinase domain located at the N-terminus, a coiled-coil region (600 amino acids) followed by a Rho-binding domain, and a plextrin homology (PH) domain at the C-terminus. They are expressed in different sites, and distinct physiological roles have been identified for each. ROCK-1 transcript (a gene on chromosome 18) is widely expressed throughout the body, particularly prominently in the liver, kidneys, spleen, testes, thymus, and blood cells, while ROCK-2 mRNA (on chromosome 2) is more abundantly expressed in skeletal muscle and the brain, suggesting specialized roles in these regions.

[0004] ROCK inhibitors have been investigated for use in numerous diseases, including cerebral ischemia, hypertension, erectile dysfunction, glaucoma, osteoporosis, cardiac hypertrophy, diabetic cardiomyopathy, retinopathy, pulmonary hypertension, and atherosclerosis. However, their practical application is limited due to a lack of knowledge regarding the involvement of specific ROCK isoforms. It remains unclear whether isoform-specific targeting or inhibition of ROCK as a whole leads to superior therapeutic effects. Despite incomplete specificity to ROCK isoforms, as well as incomplete specificity to other serine / threonine kinases such as PRK2, PKC, cAMP-dependent protein kinases, and citron kinase, some nonspecific ROCK2 inhibitors have shown promising results in certain conditions such as glaucoma and hypertension. However, although some research-based findings have elucidated many unknowns regarding the specific functions of ROCK1 and ROCK2, further research is needed before isoform-selective ROCK2 inhibitors can be clinically used. Since ROCK plays a central role in the organization of the actin cytoskeleton, complete inhibition of both isoforms is likely to cause adverse events in patients. Therefore, selective inhibition of ROCK2 may have a higher specificity index than dual inhibition of ROCK1 and ROCK2. Thus, understanding the individual functions of each isoform in specific diseases will help improve safety and specificity, as well as expand the therapeutic range of ROCK inhibitors. [Overview of the Initiative]

[0005] In one aspect of the present invention, a novel compound represented by the following formula (1) is provided, which has the ability to inhibit Rho-related coiled-coil forming protein serine / threonine kinase (ROCK).

[0006] [ka] Here, X, Y, Z 1 , Z 2 , Z3 , R 1 , R 2 , R 3 and R 4 This is defined in the detailed description of the present invention, which will be described later.

[0007] In other embodiments, the present invention provides pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs of novel compounds. The present invention also provides pharmaceutically acceptable salts, hydrates, or solvates of diastereomers, enantiomers, or racemates.

[0008] In yet another embodiment, the present invention provides pharmaceutical compositions each comprising a compound, a salt, a diastereomer, an enantiomer, a racemate, a hydrate, a solvate, a prodrug, or a combination thereof.

[0009] In yet another embodiment, the present invention provides methods for treating or alleviating specific ROCK-mediated diseases or disorders using compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or compositions. Non-limiting examples of diseases or disorders include cardiovascular, pulmonary, inflammatory, nervous system, or proliferative diseases or disorders.

[0010] In a further aspect, the present invention provides methods for preparing compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs. [Modes for carrying out the invention]

[0011] 1.Compound In one embodiment, the present invention provides a compound represented by formula (1), a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, hydrate, solvate, or prodrug of the compound.

[0012] [ka] Here, X is CH2 or O, Y is N or CH, Z 1 and Z 2 and Z 3 are each independently N or CH, n is 0, 1, 2 or 3, R 1 is H, heterocycloalkyl, C3-C7 cycloalkyl, or C1-C6 alkyl, the nitrogen of the heterocycloalkyl may be optionally substituted with C1-C3 alkyl, and the C3-C7 cycloalkyl or C1-C6 alkyl may be optionally substituted with one or more suitable substituents such as C1-C6 alkyl or OH, R 2 is H, an amino group, NR 6 R 7 or NR 8 R 9 , R 3 is 5-6 member heteroaryl or bicyclic heteroaryl, the heteroaryl or bicyclic heteroaryl may be optionally substituted with one or more suitable substituents such as halogen, CN, CHF2, CF3, C1-C3 alkyl, or amino, the 5-6 member heteroaryl or bicyclic heteroaryl has 1-3 heteroatoms selected from the group consisting of oxygen and nitrogen, R 4 and R 5 are each independently H, Cl, F, OH, OCD 3 , C1-C3 alkyl, or C1-C3 alkoxy, the C1-C3 alkyl or C1-C3 alkoxy may be optionally substituted with one or more suitable substituents such as amino, OH, OMe, OEt, or OPr i etc., R 6 and 7 are each independently H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, the C1-C6 alkyl or C3-C7 cycloalkyl may be optionally substituted with one or more suitable substituents such as hydroxyl or C1-C3 alkoxy, R 8 and R 9 These, along with the nitrogen atom to which they are bonded, R 8 and R 9 This forms a 4-6 member saturated monocyclic group that does not have heteroatoms other than the bonded nitrogen atom, and this 4-6 member saturated or partially saturated monocyclic group may be optionally substituted at one or two carbon atoms with a halogen, amino, hydroxyl, or C1-C3 alkoxy.

[0013] In some embodiments, R 1 may be H, a heterocycloalkyl, a C3-C7 cycloalkyl, or a C1-C6 alkyl, where the nitrogen of the heterocycloalkyl may optionally be substituted with methyl or ethyl, and the C3-C7 cycloalkyl or C1-C6 alkyl may optionally be substituted with one or more suitable substituents, such as a C1-C3 alkyl or OH.

[0014] In some embodiments, R 3 It may be one of the following groups.

[0015] [ka]

[0016] In some embodiments, R 4 and R 5 These are H, Cl, F, OH, CH3, methoxy, and OCD, respectively, independently. 3 It is either ethoxy or isopropoxy. In some embodiments, R 6 and R 7 Each of these may independently be H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, and the C1-C6 alkyl or C3-C7 cycloalkyl may be optionally substituted with hydroxyl, methoxy, or ethoxy.

[0017] In some embodiments, R 8 and R9 Along with the nitrogen atom to which they are bonded, R 8 and R 9 This forms a 4-6 member saturated monocyclic group that does not have heteroatoms other than the nitrogen atom to which it is bonded, and this 4-6 member saturated or partially saturated monocyclic group may be optionally substituted at one or two carbon atoms with a halogen, amino, hydroxyl, or methoxy.

[0018] In this disclosure, the articles "a" and "an" are used to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, "an element" means one or more elements.

[0019] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise specified. The term "or" means "and / or" unless it explicitly refers to an option only or the options are mutually exclusive, but this disclosure supports both the definition referring to an option only and the definition referring to "and / or".

[0020] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and the description includes both the cases in which such event or situation occurs and the cases in which it does not. For example, "optionally substituted aryl" includes both "aryl" and "substituted aryl" as defined herein. Those skilled in the art will understand that there is no intention to introduce any substitution or substitution pattern for any group containing one or more substituents that is sterically unrealizable, synthetically impractical, and / or inherently unstable.

[0021] Unless otherwise specified, the term “optionally substituted” means that the group is either unsubstituted or substituted with one or more of the substituents listed for that group (e.g., 0, 1, 2, 3, 4, or 5 or more, or any number derivable therefrom), and these substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In another embodiment, an optionally substituted group has five substituents. For example, an 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 can be bonded at any position on the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical structure portion may contain other functional groups, but does not necessarily have additional functional groups.

[0022] The term "alkyl," when used alone or as part of a larger group such as "arylalkyl" or "cycloalkyl," refers to a linear or branched hydrocarbon group having 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms (unless otherwise specified), including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents.

[0023] The term "cycloalkyl" refers to monocyclic or polycyclic hydrocarbon ring groups having 3 to 10 or 3 to 7 carbon atoms in the hydrocarbon ring (unless otherwise specified), including, for example, cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Cycloalkyl groups may be unsubstituted or substituted with one or more suitable substituents.

[0024] The term "hetero" refers to the substitution of at least one carbon atom in a ring system with at least one heteroatom, such as nitrogen, sulfur, sulfoxide, sulfone, or oxygen.

[0025] The term "heterocycloalkyl" refers to a monocyclic or polycyclic ring, either unaromatic, saturated or unaromatic, having 2 to 9 carbon atoms or 2 to 7 carbon atoms in the ring (unless otherwise specified), and having at least one heteroatom, preferably 1 to 4 heteroatoms selected from nitrogen, sulfur (including sulfur oxides such as sulfones and sulfoxides), and oxygen. The ring or ring system of a heterocycloalkyl group may be linked to other parts of a compound via carbon or nitrogen atoms, if present. A heterocycloalkyl group may have a total of 3 to 10 atoms, or 3 to 8 atoms, or 5 to 8 atoms in the ring system (unless otherwise specified). A heterocycloalkyl group may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the cyclic group, provided that the cyclic group is not aromatized by their presence.

[0026] Examples of heterocycloalkyl groups include azetidinyl, azilidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, tetrahydrofuranil, tetrahydrothiofuranil, tetrahydropyranil, and pyranyl. Heterocycloalkyl groups may be unsubstituted or substituted with one or more suitable substituents.

[0027] In this specification, the term "halo" includes fluorine, chlorine, bromine, and iodine. In this specification, "alkoxy" refers to the alkyl groups linked via oxygen, examples of which include methoxy, ethoxy, isopropoxy, and tert-butoxy. Furthermore, alkoxy also refers to polyethers such as -O-(CH2)2-O-CH3. The alkoxy may be unsubstituted or substituted with one or more suitable substituents.

[0028] In this specification, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group, including, for example, carbocyclic aromatic groups such as phenyl and naphthyl, and heteroaromatic groups such as pyridyl, furanyl, and thiophenyl. The term "aryl" also includes aromatic rings (such as phenyl and pyridyl rings) fused to nonaromatic carbocyclic or heterocyclic rings. The term "aryl" is interchangeable 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 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. Aryl or heteroaryl can be monocyclic or bicyclic aromatic groups. Typical aryl and heteroaryl groups include, for example, phenyl, quinolineyl, indazoyl, indolyl, dihydrobenzodioxynyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, pyrimidinyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, pyrrole, pyrazole, imidazole, and thiazole. The aryl or heteroaryl may be unsubstituted or substituted with one or more suitable substituents.

[0029] In this specification, the terms "hydroxyl" or "hydroxy" refer to -OH. In this specification, the term "amino" refers to -NH2.

[0030] In this specification, the term "hydroxyalkyl" refers to any hydroxyl derivative of an alkyl group. The term "hydroxyalkyl" includes alkyl groups in which one or more hydrogen atoms are substituted with a hydroxyl group. In this specification, the term "arylalkyl" includes alkyl groups in which one or more hydrogen atoms are substituted with an aryl group, such as a benzyl group or a phenethyl group.

[0031] In this specification, “substituent” refers to a molecular portion covalently bonded to an atom within the molecule in question. For example, a cyclic substituent may be a halogen, alkyl group, haloalkyl group, or other group covalently bonded to an atom constituting the ring (preferably a carbon or nitrogen atom). Substituents of aromatic groups are generally covalently bonded to the ring carbon atom. The term “substitution” refers to replacing a hydrogen atom in a molecular structure with a substituent so that the valence of the specified atom is not exceeded and a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) is obtained from the substitution.

[0032] As described above, certain groups are either unsubstituted or substituted with one or more suitable substituents (identical or different groups) other than hydrogen at one or more available positions, usually positions 1, 2, 3, 4, or 5. When a particular group is substituted, it is substituted with one, two, three, or four substituents independently selected. Suitable substituents include halo, alkyl, haloalkyl, aryl, hydroxy, alkoxy, hydroxyalkyl, and amino groups.

[0033] In this specification, the term "pharmaceutically acceptable" refers to substances such as carriers or diluents that do not impair the biological activity or properties of the compounds described herein. Such substances, when administered to an organism, do not cause undesirable biological effects and do not interact harmfully with any of the components of the composition they contain.

[0034] In this specification, “pharmaceutically acceptable salt” means a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound described herein. Pharmacologically 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).

[0035] Pharmaceutically acceptable acidic / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, acidic tartrate, bromide, calcium edetate, camusylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrulate, esylate, fumarate, glyceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinolate, hydrobromide, hydrochloride, and hydroxynaphthatoethate. These include iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucinate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, succinate, sulfate, bisulfate, tannate, tartrate, theocrate, tosylate, and triiodide salts. Pharmaceutically acceptable basic / cationic salts include sodium salt, potassium salt, calcium salt, magnesium salt, diethanolamine salt, N-methyl-D-glucamine salt, L-lysine salt, L-arginine salt, ammonium salt, ethanolamine salt, piperazine salt, and triethanolamine salt.

[0036] Pharmaceutically acceptable salts are formed by the reaction of the free base form of the compound of Formula 1 with an appropriate inorganic or organic acid, including but not limited to acids such as 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, 2-naphthalenesulfonic acid, or hexanoic acid. pharmaceutically acceptable acid addition salts of the 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-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), or hexanoates, or may be salts thereof.

[0037] The free acid form or free base form of the compound according to the present invention is obtained by methods known to those skilled in the art (for example, for details, see "Excavatorio of Bigley, S.M. Berg, and D.C. Monkhouse"). See "Pharmaceutical Technology," edited by J. Swarbrick and JC Boylan, Vol. 13, Marcel Dekker, Inc., 1995, pp. 453–499. The full disclosure thereof is incorporated herein by reference.) The compounds can be prepared from the form of the corresponding base addition salt or acid addition salt. For example, the compounds of the present invention in the form of an acid addition salt can be converted to the form of the corresponding free base by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds of the present invention in the form of a base addition salt can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).

[0038] Prodrug derivatives of the compounds of the present invention can be prepared by methods known to those skilled in the art (for example, see Saulnier et al., Bioorg. Med. Chem. Letters, 1994, Vol. 4, p. 1985; and Daniela Hartmann Jornada et al., Molecules, 2016, Vol. 21, p. 42 for details; the entire contents of these documents are incorporated herein by reference). Protected derivatives of the compounds of the present invention can be prepared by methods well known to those skilled in the art. A detailed description of the techniques applicable to the formation and removal of protecting groups is found in "Green's Protective Groups in Organic Chemistry" by TW Greene (4th edition, John Wiley and Sons, Inc., 2006), the entire teachings of which are incorporated herein by reference.

[0039] The compounds of the present invention can be prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomer compounds, and then separating the diastereomers to recover the optically pure enantiomers. The separation of the enantiomers can be performed using a covalent diastereomer derivative or a dissociable complex (e.g., a crystalline diastereomer salt) of the compound of the present invention. Each diastereomer has different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences can be easily utilized for separation. The diastereomers can be separated by chromatography or by separation / resolving techniques based on differences in solubility. The optically pure enantiomers are then recovered together with the resolving agent by practical means that do not cause racemization. A detailed description of the techniques applicable to separating stereoisomers from a racemic mixture of the compound can be found in Jean Jacques, Andre Collet, and Samuel H. Wilen, "Enantiomers, Racemates and This is described in "Resolutions" (John Wiley And Sons, Inc., 1981), and the full disclosures of that document are incorporated herein by reference.

[0040] In this specification, the term “solvate” refers to a stoichiometrically variable complex formed by a solute (in this invention, the compound of Formula 1 or a pharmaceutically acceptable salt thereof) and a solvent. For the purposes of this invention, such a solvent must not inhibit 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.

[0041] 2. Composition In other embodiments, the present invention provides pharmaceutical compositions comprising compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or pharmaceutically acceptable combinations thereof. The compositions may further contain additional components. Non-limiting examples of additional components include pharmaceutically acceptable carriers, diluents, excipients, and combinations thereof.

[0042] In this specification, the term "pharmaceutical composition" refers to a mixture of the compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In this specification, the term "combined pharmaceutical product" means a product obtained by mixing or combining multiple active ingredients.

[0043] In this specification, the term “acceptable” with respect to a formulation, composition, or component means that it does not have a sustained adverse effect on the overall health of the person being treated. In this specification, the term "carrier" refers to a compound or agent that facilitates the uptake of the compounds described herein into cells or tissues. In this specification, the term "diluent" refers to a compound used to dilute the compounds described herein before administration. Diluents may also be used to stabilize the compounds described herein.

[0044] Suitable pharmaceutically acceptable carriers, diluents, auxiliaries, or excipients used in the pharmaceutical compositions of the present invention include, for example, tablets (coated tablets), capsules (gelatin), solutions (aqueous or aqueous-ethanol solutions), syrups, emulsions, or inhalable powders containing the active ingredient (various sugars such as lactose and glucose, salts, and mixtures thereof of these excipients), and aerosols (inhalation solutions with or without propellants).

[0045] Suitable excipients include pharmaceutically acceptable organic solvents such as carriers, including, for example, water, paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monohydric or polyhydric alcohols (e.g., ethanol or glycerol), natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersible silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite solution, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, sodium lauryl sulfate).

[0046] 3. Method of using the compound or composition In other embodiments, the present invention provides methods for treating or alleviating specific protein kinase-mediated diseases or conditions by administering a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition to a subject or patient in a therapeutically effective amount. In some embodiments, the present invention provides methods for treating or alleviating specific ROCK-mediated diseases or disorders by administering a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition to a subject or patient in a therapeutically effective amount. In some embodiments, the present invention provides methods for treating or alleviating diseases or disorders in which ROCK is known to be involved.

[0047] In a further embodiment, the present invention provides a method for inhibiting enzyme activity, particularly ROCK1, ROCK2, PKCδ, PKCθ, PRK1, GSK3, PRK2, NEK1, and NEK4 kinase activity, by administering a therapeutically effective amount of a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition to a subject or patient.

[0048] In yet another embodiment, the present invention provides a method for inhibiting protein kinase activity in a biological sample, such as ROCK kinase activity, by contacting the biological sample with a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or composition.

[0049] In this specification, the term "inhibitor" refers to a compound that inhibits one or more kinases described herein. For example, the term "ROCK inhibitor" refers to a compound that inhibits the ROCK receptor or reduces its signaling effect.

[0050] In this specification, the terms “protein kinase-mediated disease” or “disorder, disease, or condition mediated by inappropriate protein kinase activity” refer to disease conditions mediated or regulated by protein kinases as described herein. Such disease conditions include fibrous diseases; pulmonary fibrosis including cystic pulmonary fibrosis and idiopathic pulmonary fibrosis, radiation-induced lung injury, hepatic fibrosis including cirrhosis, arterial fibrosis, endocardial fibrosis, cardiac fibrosis including former myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, arthral fibrosis, Crohn's disease, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive widespread fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic 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 disease, for example. This includes, but is not limited to, chronic renal failure, chronic nephritis, diabetic nephropathy, and IgA nephropathy; neurological disorders or conditions such as spinal cord injury, Alzheimer's disease, multiple sclerosis, and neuropathic pain; and proliferative disorders such as retinopathy, fibrosis, and invasive / metastatic cancer. Such cancers include adenocarcinoma, adrenocortical carcinoma; bladder cancer, bone cancer; brain tumors; breast cancer; oral cancer; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine cancer, squamous cell carcinoma, esophageal cancer, eye cancer, follicular carcinoma, gallbladder cancer, digestive tract cancer, genitourinary tract cancer, glioblastoma, hairy cell carcinoma, head and neck cancer, liver cancer, hepatocellular carcinoma, Hodgkin's disease, keratosacral cell carcinoma, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer; liver cancer; lung cancers such as lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, 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 intestine cancer; stomach cancer; testicular cancer; thyroid cancer and vulvar cancer. In certain embodiments, the cancers to be treated are melanoma, breast cancer, colon cancer, or pancreatic cancer.

[0051] In this specification, the terms “to treat,” “to treat,” or “treatment” mean a method of alleviating, reducing or improving the symptoms of a disease or condition, preventing additional symptoms, improving or preventing the underlying metabolic cause of symptoms, suppressing a disease or condition, stopping the progression of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0052] In this specification, the terms “subject” or “patient” include mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish.

[0053] In this specification, "administration" or "administration" of the target compound means providing the compound of the present invention and / or its prodrug to a subject in need of treatment.

[0054] In this specification, the terms “effective dose” or “therapeutic effective dose” refer to the amount of a compound described herein administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. As a result, there may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desirable changes in the biological system. For example, “effective dose” in therapeutic use is the amount of a composition containing the compounds disclosed herein that is required to produce a clinically significant reduction in the symptoms of the disease. The appropriate “effective” dose in individual cases can be determined using techniques such as dose escalation studies. As an example only, therapeutic effective doses of the compounds of the present invention may range, for example, from about 0.01 mg / kg / day to about 1000 mg / kg / day, from about 0.1 mg / kg / day to about 500 mg / kg / day, or from about 0.1 mg(x2) / kg / day to about 500 mg(x2) / kg / day.

[0055] The compounds of the present invention were screened against a kinase panel and inhibited the activity of at least one kinase on the panel. Examples of kinases include, but are not limited to, ROCK1 and ROCK2.

[0056] The compounds described herein are inhibitors of ROCK kinase activity and have therapeutic effects in the treatment of diseases associated with inappropriate kinase activity, particularly in the treatment and prevention of kinase-mediated disease conditions, including ROCK kinase. Therefore, the present invention provides methods for modulating, and in particular inhibiting, kinase-mediated signaling cascades. These methods generally involve administering an effective amount of the compounds described herein, their salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, and / or compositions thereof, to a subject or contacting kinase-expressing cells in order to modulate or inhibit a signaling cascade. These methods are also used to modulate, and in particular inhibit, downstream processes or cellular responses induced by the activation of specific kinase signaling cascades. These methods can also be implemented in vitro or in vivo as therapeutic approaches toward the treatment or prevention of diseases characterized by, caused by, or associated with the activation of kinase-dependent signaling cascades.

[0057] In the therapeutic applications of compounds provided herein, including compounds of Formula 1, salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs thereof, these compounds are administered alone or as part of a pharmaceutical composition in therapeutically effective amounts. Accordingly, this specification provides pharmaceutical compositions comprising at least one of the compounds described herein, including at least one compound of Formula 1, a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, hydrate, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, or excipients.

[0058] Furthermore, these compounds and compositions are administered alone or in combination with one or more additional therapeutic agents. Non-limiting examples of additional therapeutic agents include immune checkpoint inhibitors and immunogenic cell death (ICD) inducing chemotherapeutic agents. Non-limiting examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. Non-limiting examples of immunogenic cell death (ICD) inducing chemotherapeutic agents may include doxorubicin, idarubicin, mitoxantrone, tautomycin, calculin A, salbrinal, oxaliplatin, bleomycin, and cyclophosphamide. Methods of administration of these compounds and compositions include, but are not limited to, intravenous administration, inhalation, oral administration, rectal administration, parenteral administration, intravitreal administration, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, topical administration, intraocular administration, oral administration, intratracheal administration, bronchial administration, sublingual administration, or optic nerve administration. The compounds provided herein are administered by known pharmaceutical formulations, including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and lotions, gels, ointments, or creams for topical administration. In some embodiments, these pharmaceutical compositions are formulated as tablets, pills, capsules, liquids, inhalants, nasal sprays, suppositories, solutions, gels, emulsions, ointments, eye drops, or ear drops.

[0059] The effective therapeutic dose varies depending particularly on the target disease, its severity, the patient's age and relative health status, the efficacy of the compound administered, the method of administration, and the desired treatment. The required dose also differs depending on the method of administration, the specific condition being treated, and the desired effect.

[0060] The compound of Formula 1 inhibits one or more protein kinases and is useful in treating protein kinase-mediated diseases and disorders such as cancer, autoimmune diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases.

[0061] As used herein, the term “biological specimen” means a specimen taken outside of an animal body, and includes, but is not limited to, cell cultures or their extracts, biopsy material taken from an animal or its extracts, and blood, saliva, urine, feces, semen, tears, other bodily fluids or their extracts. Inhibition of kinase activity in biological specimens, particularly ROCK kinase activity, is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the preservation of biological specimens and biological assays.

[0062] In this specification, “ROCK-mediated disease” or “condition” means any disease or other adverse condition in which ROCK is known to be involved. ROCK is involved in various important physiological functions in the vascular system, including smooth muscle contraction, cell proliferation such as the proliferation of vascular smooth muscle cells, cell adhesion, and cell migration (Hu & Lee, Expert Opin. Ther. Targets, 9 (4):715-36, 2005; Shimokawa & Takeshita, Arterioscler). See Thromb. Vase. Biol. 25(9):1767-75, 2005). ROCK is also involved in inflammatory responses mediated by leukocyte migration, such as in autoimmune diseases and allergic reactions (see Wettschureck et al., J. Mol. Med. 80:629-38, 2002). Abnormal activation of the Rho / ROCK pathway has been observed in various central nervous system diseases (see Mueller et al., Nature Rev., 4:387-98, 2005). Furthermore, ROCK is involved in tumor cell migration and invasion (see Riento & Ridley, Nature Rev. 4:446-56, 2004) and osteoporosis (Ohnaka et al., Biochem. He has also been involved in Biophys., Res. Commun. 287(2):337-4, 2001).

[0063] Specifically, the present invention relates to methods for treating or alleviating the severity of cardiovascular diseases or disorders such as cerebral vasospasm, hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemia / reperfusion injury, stroke, and bronchial asthma; glaucoma, premature birth, erectile dysfunction; or kidney diseases such as chronic renal failure, chronic nephritis, diabetic nephropathy, and IgA nephropathy; neurological diseases or neuropathy such as spinal cord injury, Alzheimer's disease, multiple sclerosis, and neuropathic pain; and proliferative diseases such as retinopathy, fibrosis, or invasive / metastatic cancer. These cancers include adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain tumor, breast cancer, oral cancer, cervical cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, squamous cell carcinoma, esophageal cancer, ocular cancer, follicular carcinoma, gallbladder cancer, gastrointestinal cancer, genitourinary cancer, glioblastoma, hairy cell carcinoma, head and neck cancer, liver cancer, hepatocellular carcinoma, Hodgkin's disease, keratospermatoma, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, lung cancer such as lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, non-small cell lung cancer, malignant 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 intestine cancer, stomach cancer, testicular cancer, thyroid cancer, and vulvar cancer. In certain embodiments, the cancers to be treated are melanoma, breast cancer, colorectal cancer, or pancreatic cancer.

[0064] In another embodiment, the present invention provides a method for treating a fibrous disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula 1 to the subject. Non-limiting examples of fibrous diseases include pulmonary fibrosis, including cystic pulmonary fibrosis and idiopathic pulmonary fibrosis; radiation-induced lung injury; hepatic fibrosis, including cirrhosis; cardiac fibrosis, including arterial fibrosis; endocardial fibrosis; former myocardial infarction; arteriosclerosis; atherosclerosis; restenosis; arthritis fibrosis; Crohn's disease; myelofibrosis; Peyronie's disease; nephrogenic systemic fibrosis; progressive extensive fibrosis; retroperitoneal fibrosis; scleroderma / systemic sclerosis; mediastinal fibrosis; keloids and hypertrophic scars; glial scars; or renal fibrosis.

[0065] In one embodiment, the present invention provides a method for treating a cell proliferation disorder or condition, such as cancer, including, for example, lymphoma, osteosarcoma, melanoma, breast cancer, kidney cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, nerve cancer, lung cancer, uterine cancer, or gastrointestinal cancer, by administering a therapeutically effective amount of a compound of Formula 1, a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, prodrug, or any combination thereof, or a pharmaceutical composition or drug thereof, to a subject in need of treatment. In one embodiment, the present invention provides a method for inhibiting the proliferation of cancer cells using a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or any combination thereof, or a composition described herein.

[0066] In certain embodiments, the protein kinase-mediated diseases or conditions are inflammatory diseases or conditions, respiratory diseases, or autoimmune diseases or conditions, 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.

[0067] In other embodiments, the present invention provides a method for treating a neurological / neurodegenerative disease or condition by administering to a subject a therapeutically effective amount of a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or combination thereof, or a composition described herein. In certain embodiments, such neurological / neurodegenerative diseases or conditions include, for example, Alzheimer's disease, cerebral edema, cerebral ischemia, multiple sclerosis, cavernous hemangioma (CCM), neuropathy, Parkinson's disease, blunt trauma or surgical trauma (including postoperative cognitive impairment and spinal cord or brainstem injury), as well as neurological manifestations of disorders such as intervertebral disc degeneration and sciatica.

[0068] In other embodiments, the present invention provides a method for treating cardiovascular disease by administering to a subject a therapeutically effective amount of a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or combination thereof, or composition described herein. Such cardiovascular diseases affect the heart or blood vessels and include, for example, atherosclerosis, arrhythmia, angina pectoris, myocardial ischemia, myocardial infarction, aneurysm of the heart or blood vessels, vasculitis, stroke, peripheral occlusive arterial disease of the limbs, organs or tissues, post-ischemia-reperfusion injury of organs or tissues, endotoxin shock, surgical shock or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vasoconstriction, vascular abnormalities, or inflammation.

[0069] In other aspects, the present invention comprises administering to a target subject in need a composition comprising a therapeutically effective amount of at least one of the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs thereof, and a therapeutically effective amount of at least one immune checkpoint inhibitor, for cancers including adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, oral cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, squamous cell carcinoma, esophageal cancer, eye cancer, This invention provides methods for treating cancers such as follicular carcinoma, gallbladder cancer, gastrointestinal cancer, genitourinary cancer, glioblastoma, hairy cell carcinoma, head and neck cancer, liver cancer, hepatocellular carcinoma, Hodgkin's disease, keratosacral cell carcinoma, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, squamous cell carcinoma of the lung, 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 intestine cancer, gastric cancer, testicular cancer, thyroid cancer, vulvar cancer, or combinations thereof. Examples of checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

[0070] In other embodiments, the present invention comprises administering to a subject in need a composition comprising a therapeutically effective amount of at least one of the compounds described herein, a salt thereof, a diastereomer, an enantiomer, a racemate, a hydrate, a solvate, or a prodrug, and at least one immunogenic cell death (ICD) inducing chemotherapeutic agent, such that 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, squamous cell carcinoma, esophageal cancer, etc. The present invention provides a method for treating cancer, which is cancer of the eye, follicular carcinoma, gallbladder cancer, digestive tract cancer, genitourinary tract cancer, glioblastoma, hairy cell carcinoma, head and neck cancer, liver cancer, hepatocellular carcinoma, Hodgkin's disease, keratospermum acanthoma, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, 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 intestine cancer, stomach 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, tautomycin, calculin A, salvulinal, oxaliplatin, bleomycin, and cyclophosphamide.

[0071] In the above-described method using the compounds of the present invention, the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs described herein are administered to a system including cells or tissues. In certain embodiments, the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or any combination thereof described herein are administered to a target human or animal. In even more specific 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 target human or animal.

[0072] 4. Method for preparing the compound In further embodiments, the present invention provides methods for preparing compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs. In some embodiments, 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 methods. (a) If necessary, convert the compound of the present invention into a pharmaceutically acceptable salt. (b) Convert the salt form of the compound of the present invention to the non-salt form as necessary. (c) If necessary, convert the non-oxidized form of the compound of the present invention to a pharmaceutically acceptable N-oxide. (d) Separating individual isomers of the compound of the present invention from a stereoisomer mixture, if necessary. (e) If necessary, convert the non-derivative compound of the present invention into a pharmaceutically acceptable prodrug derivative, and (f) If necessary, convert the prodrug derivative of the compound of the present invention into its non-derivative form.

[0073] Exemplary methods for preparing the compounds of the present invention are described herein, including examples that are described in detail below. Some embodiments of the invention provide processes for preparing the compounds of the present invention, as shown in Method 1 or Method 2 below.

[0074] [ka]

[0075] A bicyclic acid (2) was reacted with thionyl chloride or oxalyl chloride in dichloromethane in the presence of a catalytic amount of GMF to obtain acylchloride (3). The obtained acylchloride (3) was coupled with a bicyclic heteroaryl compound (4) by a Friedel-Crafts acylation reaction in an organic solvent (dichloromethane or dichloroethane) in the presence of a Lewis acid (aluminum chloride, titanium chloride, or stannous chloride) to obtain ketone (5). The obtained ketone (5) was reacted with an alkyl bromide, alkyl chloride, or alkyl epoxide in an organic solvent (dimethylformamide, acetone, dioxane, acetonitrile, dichloromethane, or dichloroethane) and reacted at room temperature (RT) to 150°C for 5 to 24 hours in the presence of an inorganic base (NaHCO3, Na2CO3, K2CO3, CS2CO3, K2HPO4, or K3PO4) to obtain an N-alkylated compound (6).

[0076] The N-alkylated compound (6) was also prepared by using a bicyclic heteroaryl compound (4) as a starting material, performing N-alkylation under the aforementioned reaction conditions to obtain (7), and then carrying out a Friedel-Crafts acylation reaction using acylchloride (3).

[0077] The N-alkylated compound (6) was reacted under Suzuki reaction conditions using a palladium catalyst (Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, or Pd(dppf)Cl2.DCM) to obtain compound (1) in the presence of an inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, CsF, K2HPO4, or K3PO4) at room temperature (RT) to 150°C for 5 to 24 hours.

[0078] Alternatively, the N-alkylated compound (6) could also be prepared starting from a bicyclic compound, as shown in Method 2 below.

[0079] [ka]

[0080] Bicyclic heteroaryl compound (4) was reacted with N-iodosuccinimide (NIS) in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane, or dichloroethane) at room temperature (RT) for 2 to 24 hours to obtain iodized bicyclic heteroaryl compound (8). Iodobicyclic heteroaryl compound (8) was reacted with alkyl bromide alkyl chloride or alkyl epoxide in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane, or dichloroethane), and an inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, K2HPO4, or K3PO4) was added, and the reaction was carried out for 5 to 24 hours under conditions of room temperature (RT) to -150°C. The N-alkylated compound (10) was alternatively prepared by N-alkylating the bicyclic heteroaryl compound (4) to obtain (9), and then iodizing (9) using N-iodosuccinimide (NCI) as described above. The bicyclic acid (2) was bonded with N-methoxymethanamine hydrochloride in an organic solvent (DMF, tetrahydrofuran, dichloromethane, or dichloroethane) using a coupling reagent (DCC, EDCI, HATU, HBTU, PyBop, or PyBrop) at room temperature for 2 to 24 hours to obtain winerebamide (11). This winerebamide (11) was converted to ketone (6) by reacting with the bicyclic heteroaryl iodide compound (10) in THF at a low temperature (-78 to 0°C) in the presence of a Grignard reagent.

[0081] Non-limiting examples of compounds described herein include: (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone dihydrochloride, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone dimethanesulfonic acid, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone hydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (6-chlorochroman-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]-(6-methoxychroman-3-yl)methanone, [1-(azetidine-3-yl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)pyrrolo[2,3-b]pyridine-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]methanone, [1-(azetidine-3-yl)-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[(1-methylpyrrolidine-2-yl)methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(1-methylpyrrolidine-2-yl)methyl]indole-3-yl]methanone, [1-(azetidine-3-ylmethyl)-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(azetidine-3-ylmethyl)-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]methanone, (S)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]methanone, (R)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazole-4-yl)-1-[(1-methylpyrrolidine-2-yl)methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[[(1R)-1-methylpyrrolidine-2-yl]methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)(6-(5-methoxy-1H-pyrazole-4-yl)-1-(((S)-1-methylpyrrolidine-2-yl)methyl)-1H-indole-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[2-(5-chloro-1H-pyrazole-4-yl)-7-[2-(dimethylamino)ethyl]pyrrolo[2,3-d]pyrimidine-5-yl]methanone, (6-chlorochroman-3-yl)-[7-[2-(dimethylamino)ethyl]-2-(5-fluoro-1H-pyrazole-4-yl)pyrrolo[2,3-d]pyrimidine-5-yl]methanone, (1-(((R)-azetidine-2-yl)methyl)-6-(5-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (1-(((S)-azetidine-2-yl)methyl)-6-(5-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, [1-[[(2S)-azetidine-2-yl]methyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[[(2R)-azetidine-2-yl]methyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (1-(((S)-azetidine-2-yl)methyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, (1-(((R)-azetidine-2-yl)methyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(2-aminopropyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2R)-2-aminopropyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(3-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, [1-[(2R)-2-aminobutyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2S)-2-(dimethylamino)propyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[[1-(dimethylamino)cyclopropyl]methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[(2R)-2-(dimethylamino)propyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2R)-2-(dimethylamino)propyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2R)-2-(dimethylamino)propyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazole-4-yl)-1-[(1-methylazetidine-3-yl)methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[(1-methylazetidine-3-yl)methyl]indole-3-yl]methanone, [6-(5-fluoro-1H-pyrazole-4-yl)-1-[[(2R)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1S)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-Methoxychroman-3-yl)-[6-(5-Methoxy-1H-pyrazole-4-yl)-1-[[(1S)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [6-(5-fluoro-1H-pyrazole-4-yl)-1-[[(2S)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-Methoxychroman-3-yl)-[6-(5-Methoxy-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [1-[[(1R)-1-ethylazetidine-2-yl]methyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1R)-1-ethylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[2-(azetidine-1-yl)ethyl]-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[2-(azetidine-1-yl)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[3-(dimethylamino)propyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (S)-(6-chlorochroman-3-yl)(1-(3-(dimethylamino)propyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, (R)-(6-chlorochroman-3-yl)(1-(3-(dimethylamino)propyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-[ethyl(methyl)amino]ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(diethylamino)ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(diethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(diethylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[2-(diethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-fluoro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[2-[ethyl(methyl)amino]ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(1-aminocyclopropyl)methyl]-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-fluorochroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, 2,3-dihydro-1,4-benzodioxin-3-yl-[1-[2-(dimethylamino)ethyl]-6-(1H-pyrazole-4-yl)indole-3-yl]methanone, Croman-3-yl-[1-[2-(dimethylamino)ethyl]-6-(1H-pyrazole-4-yl)indole-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (R)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluoro-2,3-dihydro-1,4-benzodioxin-3-yl)methanone, (6-chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone, (R)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone dimethanesulfonic acid, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazol-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazole-3-yl)indole-3-yl]methanone, [6-(2-amino-4-pyridyl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazol-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazole-3-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (R)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (S)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (R)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone dihydrochloride, (R)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (R)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, 1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(6-methoxychroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-methoxychroman-3-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, Croman-3-yl(1-(2-(dimethylamino)ethyl)-6-(5-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-(3-fluoro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (6-(3-fluoro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indazole-3-yl)((S)-6-fluorochroman-3-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(7-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(7-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dichloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-ethylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-ethylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrobromide, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-ethylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonic acid, ((S)-6-chlorochroman-3-yl)(1-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, ((S)-6-chlorochroman-3-yl)(1-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone hydrobromide, (S)-(6-chlorochroman-3-yl)(1-(2-(diethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, (S)-(6-chlorochroman-3-yl)(1-(2-(diethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone dihydrochloride, (S)-(6-chlorochroman-3-yl)(1-(2-(diethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone dimethanesulfonic acid, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone hydrochloride, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dibromide, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone hydrobromide, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (6-(3-chloro-1H-pyrazole-4-yl)-1-(((R)-1-(2-fluoroethyl)azetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(((R)-1-(2,2-difluoroethyl)azetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(((R)-1-(2,2,2-trifluoroethyl)azetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(2-fluoroethyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(1-(2-(bis(2-fluoroethyl)amino)ethyl)-6-(3-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone hydrochloride, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone hydrobromide, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone dimethanesulfonic acid, (6-(3-fluoro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indazole-3-yl)((S)-6-fluorochroman-3-yl)methanone dihydrobromide, It may include.

[0082] (Examples) The present invention is further embodied by the following examples illustrating methods for preparing the compounds shown in Figure 1. These examples are for illustrative purposes only and are not intended to limit the present invention in any way, nor should they be interpreted as limiting it. Those skilled in the art will understand that various changes and modifications are possible without altering the scope of the present invention.

[0083] The nuclear magnetic resonance (NMR) and mass spectrometry (MS) spectra obtained for the following examples and the compounds described herein were consistent with the spectra of the compounds according to the formulas described herein.

[0084] Liquid chromatography-mass spectrometry (LC-MS) method: 1. Samples were analyzed at room temperature at a flow rate of 1.5 mL / min using an Agilent Technologies 6120 MSD system equipped with a Zorbax Eclipse XDB-C18 (3.5 μm) reversed-phase column (4.6 × 50 mm). 2. The mobile phase was prepared by using solvent A (water / 0.1% formic acid) and solvent B (acetonitrile / 0.1% formic acid) for 5 minutes, and then diluting them by 95% / 5% to 0% / 100% (A / B). 3. The mass spectrum (m / z) was recorded using electro-spray ionization (ESI). 4. Ionization data was rounded to the nearest integer.

[0085] Proton NMR spectrum: Unless otherwise noted, all NMR spectra were measured using a Varian series Mercury 400 or 500 MHz NMR spectrometer. All observed protons are reported in ppm values ​​at low magnetic fields from tetramethylsilane, using abbreviations conventionally used to denote major peaks, such as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and brs (broad singlet).

[0086] Example 1: Preparation of the compound [ka] Compound 1-1: (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone (continues in step 5a.)

[0087] [ka]

[0088] Step 1: A mixture of 6-chlorochroman-3-carboxylic acid (6.0 g, 28.2 mmol), thionyl chloride (21.0 mL, 282.2 mmol), and DMF (0.1 mL, catalyst) was heated under reflux in toluene (60 mL) 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 obtain 1a as a light brown oily substance. 1a was used in the next step without purification.

[0089] 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. At ℃ After stirring for 1 hour, saturated ammonium chloride aqueous solution (100 mL) was added at 0°C to stop the reaction and generate a solid precipitate. The mixture was then warmed to room temperature and stirred for a further 2 hours. The solid was collected by filtration and washed with methanol. The resulting solid was dried under high vacuum to obtain 1b as a white solid in 80% yield (7.4 g). LC / MS yielded 391.0 and 393.0 [M+H] + Detected.

[0090] 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-dimethylethanamine hydrochloride (690 mg, 6.4 mmol) was heated in DMF (20 mL) at 70°C for 16 hours. The mixture was poured into water (100 mL) and extracted with siRNA (100 mL). The organic layer was separated, washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on a silica gel column by gradient elution of 20–100% siRNA in hexane to obtain 1c as a white solid in 20% yield (202 mg). LC / MS analysis yielded 463.1 and 465.0 [M+H]+ It was detected.

[0091] Step 4: Intermediate 1c (202 mg, 43 μmol), a mixture of [3-methoxy-1-(p-toluylsulfonyl)pyrazole-4-yl]boronic acid (190 mg, 65 μmol), potassium carbonate (2 M aqueous solution, 54 μL), and tetrakis(triphenylphosphine)palladium (25.0 mg, 22 μmol) in 1,4-dioxane (10 mL), was degassed with argon gas for 5 minutes. The resulting 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 ethyl acetate (50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain 1d. The residue was used in the next step without purification.

[0092] Step 5a for tosyl (Ts) protected pyrazole compound: A solution of 1d (crude, 230 mg) in THF (1 mL) was cooled on an ice bath and treated with 2N sodium hydroxide solution (2.0 mL). After stirring the solution at 0°C for 30 minutes, it was neutralized with 1N hydrochloric acid solution (4.0 mL) and diluted with  (30 mL) and saturated Na₂CO₃ solution (30 mL). The aqueous layer was separated and extracted with Â. The combined organic layers were dried over Na₂SO₄, filtered, treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain compound 1-1(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone (101 mg, 210 μmol, 58% yield of Steps 4, 5a) as a white solid. LC / MS analysis showed 480.2[M+H] + It was detected.

[0093] Compound 1-2: ((6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-pyrrolo[3,2-c]pyridine-3-yl)methanone dihydrochloride) Step 6a: To a 1 mL solution of 1-1 (50 mg, 104 mmol) in acetone, 55 mL of 4 M dioxane hydrochloride solution was slowly added at room temperature to form a solid precipitate. After stirring for another hour at room temperature, 2 mL of ter-butyl ethyl ether was added and the mixture was completely precipitated. The solid was collected by filtration under a nitrogen atmosphere, washed with ter-butyl ethyl ether, and dried under reduced pressure to obtain a white powder of 1-2 (47.5 mg, 82%). LC / MS analysis revealed a concentration of 480.2 [M+H]. + It was detected.

[0094] Compounds 1-3: ((6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-pyrrolo[3,2-c]pyridine-3-yl)methanone dimethanesulfonic acid) Step 6a: A 1 M acetone solution (220 mL) of methanesulfonic acid was slowly added to a 1 mL solution of 1-1 (50 mg, 104 mmol) at room temperature to form a solid precipitate. After stirring for a further 1 hour at room temperature, ter-butyl ethyl ether (2 mL) was added and the mixture was completely precipitated. The resulting solid was collected by filtration under a nitrogen atmosphere, washed with ter-butyl ethyl ether, and dried under reduced pressure to obtain a white powder of 1-3 (60.3 mg, 90%). LC / MS analysis detected 480.2 [M+H]+.

[0095] The following compounds 1-4 to 1-51 shown in Table 1 are suitable boronic acid / ester (R 3 ) and appropriate R 1 R 2 Compounds 1-1, 1-2, and 1-3 were prepared using a suitable substituent (4) in the same manner as described for the preparation of compounds 1-1, 1-2, and 1-3 (general formula 1).

[0096] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0097] [ka]

[0098] Compound 2-1: [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-chlorochroman-3-yl)methanone [ka]

[0099] Step 1: A mixture of 1b (80 mg, 213 μmol), potassium carbonate (176.8 mg, 1.3 mmol, 77 μL), and 2-bromoethane-1-ol (87 mg, 639 μmol) in DMF (2 mL) was heated to 70°C and stirred overnight. This mixture was poured into water (10 mL) and extracted with toluene (10 mL). The organic layer was separated, washed with saturated brine (10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column flash chromatography with gradient elution of 10–100% toluene in hexane to obtain [6-bromo-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridine-3-yl]-(6-chlorochroman-3-yl)methanone as a white solid (2a, 68 mg, yield 68%). LC / MS analysis yielded 435.1 and 437.0 [M+H] + It was detected.

[0100] Step 2: A mixture of 2a (56 mg, 129 μmol) and triethylamine (27 μL, 193 μmol) in DCM (3 mL) was cooled in an ice bath, treated with MsCl (15 μL, 193 μmol), and stirred at 0°C for 1 hour. The solution was diluted with DCM (10 mL), washed sequentially with water and saturated saline (10 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain 2-(6-bromo-3-(6-chlorochroman-3-carbonyl)-1H-pyrrolo[3,2-c]pyridine-1-yl)ethylmethanesulfonate (2b, 59 mg, 115 μmol, yield 89%) as a clear oil. LC / MS showed 513.0, 515.1 [M+H] + Detected.

[0101] Step 3: A mixture of 2b (29 mg, 56 μmol) and sodium azide (46 mg, 113 μmol) in DMF (2 mL) was heated to 60°C and shaken overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed sequentially with water and saturated saline (10 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain (1-(2-azidoethyl)-6-bromo-1H-pyrrolo[3,2-c]pyridine-3-yl)(6-chlorochroman-3-yl)methanone (2c, 19 mg, 41 μmol, yield 73%) as a white solid. LC / MS analysis yielded 460.2,462.2[M+H] + It was detected.

[0102] Step 4: A mixture of 2c (19 mg, 41 μmol), triphenylphosphan (14 mg, 54 mmol), and water (2-3 drops) dissolved in THF (1.5 mL) was heated to 55°C and shaken overnight. The mixture was concentrated, poured into water (10 mL), and extracted with ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (5 mL). The organic layers were combined, treated with silica gel and dried, then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (1-(2-aminoethyl)-6-bromo-1H-pyrrolo[3,2-c]pyridine-3-yl)(6-chlorochroman-3-yl)methanone (2d, 16 mg, 37 μmol, yield 89%) as a white solid. LC / MS analysis revealed 434.0,436.0[M+H] + It was detected.

[0103] Step 5: A mixture of 2d (16 mg, 37 μmol), tert-butyl 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (24 mg, 72 μmol), potassium carbonate (2 M aqueous solution, 53 μL), and tetrakis(triphenylphosphine)palladium (2.5 mg, 2.1 μmol) dissolved in 1,4-dioxane (2 mL) was degassed by aeration with argon or nitrogen for 5 minutes, heated to 70°C, and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (5 mL), and extracted twice with ethyl acetate (5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain tert-butyl4-(1-(2-aminoethyl)-3-(6-chlorochroman-3-carbonyl)-1H-pyrrolo[3,2-c]pyridine-6-yl)-5-chloro-1H-pyrazole-1carboxylate 2e, which was used in the next step without purification.

[0104] Step 6: A solution of 2e (21 mg) of the crude product in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at room temperature. After stirring at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure to obtain a residue. This residue was dissolved in Depositphotos (10 mL) and washed with 2 M sodium carbonate solution (10 mL). The aqueous layer was separated and extracted with Depositphotos (5 mL). The combined organic layers were dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain (1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)-1H-pyrrolo[3,2-c]pyridine-3-yl)(6-chloro-2H-chromen-3-yl)methanone (2-1, 8.3 mg, 18.2 μmol; 25% yield from Steps 5 and 6) as a white solid. LC / MS analysis revealed 456.1 [M+H] + It was detected.

[0105] Compound 2-12: (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2S)-2-(dimethylamino)propyl]indole-3-yl]methanone [ka]

[0106] Step 1: A mixture of [1-[(1-aminocyclopropyl)methyl]-6-bromo-indole-3-yl]-(6-chlorochroman-3-yl)methanone (2f, 22 mg, 48 μmol), formaldehyde (36 μL, 479 μmol), and acetic acid (12 μL, 210 μmol) prepared in the same manner as in Step 2d was stirred in THF (1 mL) at room temperature. After about 30 minutes, the reaction mixture was cooled in an ice bath and treated with sodium borocyanide (6.6 mg, 105 μmol). The reaction mixture was stirred for a further 30 minutes, and then the reaction was stopped with saturated NH4Cl aqueous solution (1 mL). The mixture was concentrated, diluted with HCl (15 mL), washed sequentially with water and saturated brine (15 mL each), dried (Na2SO4), treated with silica gel, and then evaporated under reduced pressure. The obtained substance was purified by silica gel column chromatography to obtain (6-bromo-1-((S)-2-(dimethylamino)propyl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone (2 g, 23 mg, 47 μmol, yield 98%) as a light brown solid. LC / MS analysis revealed 475.1,477.2[M+H] + It was detected.

[0107] Step 2: A mixture of 1,4-dioxane (2 mL) containing 2 g (23 mg, 48 μmol) of tert-butyl 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (25 mg, 73 μmol), potassium carbonate (2 M aqueous solution, 60 μL, 121 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (2.0 mg, 2.4 μmol) was degassed by passing it through with argon or nitrogen gas for 5 minutes, then heated to 70°C and shaken overnight. The mixture was cooled to room temperature, concentrated, and then poured into water (5 mL) and extracted twice with SiO2 (5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain tert-butyl3-chloro-4-(3-(6-chlorochroman-3-carbonyl)-1-((S)-2-(dimethylamino)propyl)-1H-indole-6-yl)-1H-pyrazole-1-carboxylate 2h, which was used in the next step without purification.

[0108] Step 3a for obtaining the Boc-protected pyrazole compound: A solution of 2h (29 mg) of the crude product in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at room temperature. After about 1.5 hours, the solvent was evaporated under reduced pressure, dissolved in siRNA (10 mL), and washed with 2M Na2CO3 solution (10 mL). The aqueous layer was separated and extracted with siRNA (5 mL). The combined organic layers were dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-chloro-4-(3-(6-chlorochroman-3-carbonyl)-1-((S)-2-(dimethylamino)propyl)-1H-indole-6-yl)-1H-pyrazole-1 carboxylic acid ester (2-12, 21 mg, 42 μmol; 87% yield from Steps 2 and 3a) as a light brown solid. LC / MS analysis yielded 497.3 [M+H] + It was detected.

[0109] The following compounds 2-2 to 2-16 shown in Table 2 are suitable 2a (azaindole / indole skeleton) and suitable boronic acid / ester (R 3Compound 2-1 or Compound 2-12 was prepared using the method described (General Scheme 2) above.

[0110] [Table 2-1] [Table 2-2] [Table 2-3]

[0111] [ka]

[0112] Compound 3-1:[1-[2-(azetidine-1-yl)ethyl]-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone [ka]

[0113] Step 1: A mixture of 3a[6-bromo-1-(2-hydroxyethyl)pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone (85.0 mg, 203 μmol) and triethylamine (56.5 μL, 405 μmol) prepared in the same manner as in Scheme 2 was cooled in an ice bath and treated with methanesulfonyl chloride (15 μL, 193 μmol), and stirred at 0°C for 1 hour. The solution was diluted with DCM (10 mL), washed sequentially with water and saturated saline (10 mL each), dried with (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The obtained substance was purified by silica gel column chromatography to obtain 2-(6-bromo-3-(6-fluorochroman-3-carbonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl)ethylmethanesulfonate (3b, 86 mg, 173 μmol, yield 85%) as a light brown oily substance. LC / MS analysis showed 497.1,499.2 [M+H] + It was detected.

[0114] Step 2: A mixture of 3b (20 mg, 40 μmol), potassium carbonate (25 mg, 181 μmol), and azetidine hydrochloride (11 mg, 121 μmol) in DMF (1 mL) was heated at 50°C and shaken overnight. The reaction mixture was diluted with RINKAN (10 mL), washed sequentially with water and saturated saline (10 mL each), dried (Na₂SO₄), treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (1-(2-(azetidine-1-yl)ethyl)-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)(6-fluorochroman-3-yl)methanone (3c, 4.7 mg, 10 μmol, yield 25%) as a light brown solid. LC / MS analysis yielded 458.2,460.1[M+H] + It was detected.

[0115] Step 3: The mixture of 3c (4.7 mg, 10 μmol), tert-butyl 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (6.1 mg, 18 μmol) or 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrazole, potassium carbonate (2 M aqueous solution, 13 μL), and tetrakis(triphenylphosphine)palladium (3.5 mg, 2.1 μmol) in 1,4-dioxane (2 mL) was degassed by aeration with argon or nitrogen gas for 5 minutes, then heated to 70°C and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (5 mL), and extracted twice with SiO2 (twice). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the intermediates 3d-Boc(Boc(tert-butyl4-(1-(2-(azetidine-1-yl)ethyl)-3-(6-fluorochroman-3-carbonyl)-1H-pyrrolo[2,3-b]pyridine-6-yl)-5-chloro-1H-pyrazole-1-carboxylate) or 3d-Ts([1-[2-(azetidine-1-yl)ethyl]-6-[3-methoxy-1-(p-toluylsulfonyl)pyrazole-4-yl]indole-3-yl]-(6-chlorochroman-3-yl)methanone). The intermediates 3d-Boc or 3d-Ts were used in the next step without further purification.

[0116] Step 4a: A solution of crude 3d-Boc (6.5 mg) in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at room temperature. After about 1.5 hours, the solvent was evaporated under reduced pressure to obtain the residue. This substance was dissolved in toluene (10 mL) and washed with 2 M Na2CO3 solution (10 mL). The aqueous layer was separated and extracted with toluene (5 mL). The combined organic layers were dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain [1-[2-(azetidine-1-yl)ethyl]-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone (3-1, 2.1 mg, 4.4 μmol; 42% yield from Steps 3 and 4a) as a light brown solid. LC / MS analysis showed 480.2[M+H] + It was detected.

[0117] Step 4b: A solution of crude 3d-Ts (30 mg) in THF (1 mL) was cooled on an ice bath and then treated with 2 N NaOH aqueous solution (0.20 mL). The solution was stirred at 0°C for 30 minutes, neutralized with 1 N HCl aqueous solution (0.40 mL), and then diluted with siRNA (10 mL) and saturated Na2CO2 aqueous solution (10 mL). The aqueous layer was separated and extracted with siRNA (twice). The combined organic layers were dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. This substance was purified by silica gel column chromatography to obtain [1-[2-(azetidine-1-yl)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone (3-4, 4.0 mg, 8.5 μmol, 17% yield from Steps 3 and 4b) as a white solid. LC / MS analysis showed 491.2[M+H] + It was detected.

[0118] The following compounds 3-2 to 3-19 shown in Table 3 are suitable (7) (azaindole / indole skeleton), suitable boronic acid / ester (R 3 ), and appropriate R 1Compounds 3-1 or 3-4 were prepared using substituents in the same manner as described in the preparation method (General Scheme 3).

[0119] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0120] [ka]

[0121] Compound 4-1[1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone [ka]

[0122] Step 1: A mixture of (6-bromo-1H-indole-3-yl)-(6-chlorochroman-3-yl)methanone 1b (300 mg, 768 μmol), potassium carbonate (318 mg, 2.3 mmol), and methyl 1-(bromomethyl)cyclopropanecarboxylate (445 mg, 2.3 mmol) in DMF (4 mL) was heated to 70°C and shaken overnight. The reaction mixture was diluted with ₹ (15 mL), washed sequentially with water and saturated saline (15 mL each), dried with (Na₂SO₄), treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain methyl 1-((6-bromo-3-(6-chlorochroman-3-carbonyl)-1H-indole-1-yl)methyl)cyclopropane-1-carboxylate (4a, 380 mg, 756 μmol, 98% yield) as a light brown solid. LC / MS analysis showed 502.2, 504.3 [M+H] + It was detected.

[0123] Step 2: A mixture of 4a (380 mg, 756 μmol) and LiOH·H2O (2 M, 3.8 mL, 7.6 mmol) in THF (4 mL) was stirred overnight at room temperature. The mixture was acidified to pH 3-4 with 1 N aqueous HCl, the resulting precipitate was vacuum filtered, washed with water, and dried overnight under vacuum to obtain 1-((6-bromo-3-(6-chlorochroman-3-carbonyl)-1H-indole-1-yl)methyl)cyclopropane-1-carboxylic acid (4b 290 mg, 593 μmol, yield 78%) as a light brown solid. LC / MS analysis revealed 487.1,489.1[M+H] - It was detected.

[0124] Step 3: A mixture of 4b (290 mg, 593 μmol), triethylamine (165 μL, 1.19 mmol), and [azido(phenoxy)phosphoryl]oxybenzene (218 μL, 1.01 mmol) in THF (3 mL) was shaken overnight at room temperature. The reaction mixture was diluted with  (10 mL), washed sequentially with water and saturated saline (10 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain 1-((6-bromo-3-(6-chlorochroman-3-carbonyl)-1H-indole-1-yl)methyl)cyclopropane-1-carbonyl azide (4c, 225 mg, 438 μmol, yield 73%) as a light brown solid. LC / MS analysis yielded 513.2,513.2[M+H] + It was detected.

[0125] Step 4: A solution of 4c (215 mg, 418 μmol) of tert-butanol (1 mL) and toluene (2 mL) was heated to 100°C and shaken overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate (10 mL), washed sequentially with water (10 mL) and saturated saline (10 mL), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain tert-butyl(1-((6-bromo-3-(6-chlorochroman-3-carbonyl)-1H-indole-1-yl)methyl)cyclopropyl)carbamate (4d, 170 mg, 304 μmol, yield 72%) as a light brown solid. LC / MS analysis revealed [M+H] + It was detected (but not detected by LCMS).

[0126] Step 5: The mixture of 4d (45 mg, 80 μmol), tert-butyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (42 mg, 129 μmol), potassium carbonate (2 M aqueous solution, 100 μL), and cyclopentyl (diphenyl)phosphan, dichloromethane, dichloropalladium, and iron (3.3 mg, 4.0 μmol) in 1,4-dioxane (2 mL) was degassed by aeration with argon or nitrogen for 5 minutes, then heated to 70°C and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (5 mL), and extracted twice with ethyl acetate (5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain tert-butyl 4-(1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-(6-chlorochroman-3-carbonyl)-1H-indole-6-yl)-3-methoxy-1H-pyrazole-1-carboxylate 4e, which was used in the next step without purification.

[0127] Step 6: A solution of 4e (54 mg) of the crude product in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at room temperature. After approximately 1.5 hours, the solvent was evaporated under reduced pressure to obtain the residue. This substance was dissolved in  (10 mL) and washed with 2 M Na₂CO₃ solution (10 mL). The aqueous layer was separated and extracted with  (5 mL). The combined organic layers were dried over Na₂SO₄, filtered, treated with silica gel, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain [1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone (4-1.25 mg, 52 μmol; 65% yield from Steps 5 and 6) as a light brown solid. LC / MS yielded 480.2 [M + H]. + It was detected.

[0128] The following compounds 4-2 to 4-6 shown in Table 4 are suitable 1b (azaindole / indole skeleton) and suitable boronic acid / ester (R 3 ), and appropriate R1 R 2 Compound 4-1 was prepared using substituents in the same manner as described in the preparation method (general scheme 4).

[0129] [Table 4]

[0130] [ka]

[0131] Compound 5-1: (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methyl-1H-pyrazole-4-yl)indole-3-yl]methanone [ka]

[0132] Step 1: A solution of 6-bromo-1H-indole (5.00 g, 25.5 mmol) in DMF (150 mL) was treated in small increments with sodium hydride (60% dispersion in mineral oil; 3.08 g, 77.0 mmol). After stirring the solution at room temperature for 30 minutes, 2-dimethylaminoethyl chloride hydrochloride (4.83 g, 33.5 mmol) was added, and the mixture was stirred at 70°C for 5 hours. The mixture was diluted with  (500 mL), washed sequentially with water (3 × 500 mL) and saturated saline (300 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(6-bromo-1H-indole-1-yl)-N,N-dimethylethane-1-amine (5a, 5.93 g, 22.2 mmol, yield 87%) as a yellow liquid. LC / MS analysis showed 267.1,269.1[M+H] + It was detected.

[0133] Step 2: A solution of 5a (2.51 g, 9.39 mmol) in DMF (90 mL) was cooled on an ice bath, then treated with N-iodosuccinimide (2.22 g, 9.9 mmol), and the ice bath was removed. After stirring for 90 minutes, the reaction mixture was diluted with Depositphotos (500 mL) and washed with water (500 mL). The aqueous layer was extracted with Depositphotos (150 mL), the combined organic layers were washed with saline (2 × 450 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(6-bromo-3-iodoindole-1-yl)-N,N-dimethylethanamine (5b, 2.12 g, 5.38 mmol, yield 57%) as a red liquid. This liquid solidified upon standing. LC / MS analysis yielded 393.0,395.0[M+H] + It was detected.

[0134] Step 3: 5b (2.75 g, 7.00 mmol) was placed in a 250 mL round-bottom flask and THF (100 mL) was added under a nitrogen atmosphere. The solution was cooled in a dry ice / acetonitrile bath (approximately -42°C), and isopropyl magnesium chloride (2 M THF solution, 4.90 mL) was added dropwise (for 3 minutes). After 3 minutes, the cooling bath was replaced with an ice bath, and the mixture was stirred for 60 minutes. The reaction mixture was cooled again to -42°C, and a THF (27 mL) solution of 6-chloro-N-methoxy-N-methylchroman-3-carboxamide (6-16, 2.68 g, 10.49 mmol) was added dropwise (for 3 minutes). The cooling bath was removed, and the reaction mixture was stirred for 3 hours. 25% NH4Cl aqueous solution (20 mL) was added to stop the reaction, and the mixture was stirred for 10 minutes. THF was removed under reduced pressure. The residue was diluted with 200 mL of water and extracted with DCM (200 mL). The organic layer was washed with saturated brine (150 mL), dried over Na2SO4, treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [6-bromo-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-chlorochroman-3-yl)methanone (5c, 1.02 g, 2.2 mmol, yield 32%) as a yellow solid. LC / MS analysis yielded 461.1,463.1[M+H]. + It was detected.

[0135] Step 4: Suspension 5c (143.5 mg, 310.8 μmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (146.7 mg, 476.0 μmol), PdCl2(dppf)-CH2Cl2 (39.1 mg, 47.88 μmol), and tribasic potassium phosphate (198.2 mg, 933.7 μmol) in a 40 mL vial of dioxane (5 mL) and water (0.3 mL) was bubbling with nitrogen gas for 12 minutes and then shaken overnight at 70°C. The solution was evaporated under reduced pressure, the residue was dissolved in Â1 (30 mL), washed sequentially with water (10 mL) and saturated saline (10 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain impure tert-butyl 4-[3-(6-chlorochroman-3-carbonyl)-1-[2-(dimethylamino)ethyl]indole-6-yl]-3-methylpyrazole-1-carboxylate (5d, 290.7 mg) as a brown solid. The resulting residue was used without further purification. LC / MS analysis yielded 563.3 [M+H] + It was detected.

[0136] Step 5: An impure solution of 5d (290.7 mg) in DCM (2 mL) and MeOH (0.1 mL) was treated with TFA (2 mL). The solution was stirred at room temperature for 25 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in MeOH (10 mL) and evaporated in two portions. The residue was dissolved in  (30 mL), washed sequentially with aqueous NaOH (1 M, 5 mL) and saturated saline (5 mL), dried over Na2SO4, treated with silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methyl-1H-pyrazole-4-yl)indole-3-yl]methanone (5-1, 99.3 mg, 214.48 μmol; 69% yield from Steps 4 and 5) as a brown solid. LC / MS analysis yielded 463.3 [M+H] + It was detected.

[0137] Compound 5-29: (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone [ka]

[0138] Step 1: 2-chloro-N,N-dimethylethane-1-amine hydrochloride (479 mg, 3.33 mmol) was added to a mixture of 6-bromo-3-iodo-1H-indazole (973 mg, 3.01 mmol), potassium carbonate (1.25 g, 9.04 mmol), and sodium iodide (98 mg, 0.65 mmol) in acetone (15 mL). The mixture was heated under reflux overnight with stirring, cooled to room temperature, poured into H2O, and extracted with siRNA. The combined organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (gradient elution of 10-40% siRNA in heptane) to obtain 2-(6-bromo-3-iodo-1H-indazole-1-yl)-N,N-dimethylethane-1-amine as a slightly white solid in 81% yield (5 e, 965 mg, 2.5 mmol). LC / MS analysis showed 394.0[M+H] + It was detected.

[0139] Step 2: To a solution of 5e (542 mg, 1.38 mmol) in dry THF (10 mL) cooled to -40°C, isopropyl magnesium chloride (2.0 M in THF, 0.96 mL, 1.9 mL) was added dropwise. The mixture was stirred at this temperature for 1 hour, and then a solution of 6-chloro-N-methoxy-N-methylchroman-3-carboxamide (6-16, 459 mg, 1.80 mmol) in dry THF (4 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. The reaction was stopped by adding saturated NH4Cl aqueous solution, and the mixture was extracted with Â(2 times). The combined organic layers were washed with saturated brine, dried over Na2SO4, concentrated, and dried. The residue was purified by silica gel column chromatography using a gradient of 50–100% ethyl acetate in heptane to obtain (6-bromo-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-chlorochroman-3-yl)methanone as a white solid in 11% yield (5 f, 72 mg, 0.16 mmol). LC / MS analysis revealed a concentration of 462.1 [M+H]. + It was detected.

[0140] Step 3: Starting from 5f and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrazole, the Suzuki protocol of Step 4 of Scheme 5 was used to obtain (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1-tosyl-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone (5g, 47mg, 69μmol) as a light brown solid. LC / MS analysis revealed a concentration of 635.3[M+H]. + It was detected.

[0141] Step 4: Starting with 5 g of (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1-tosyl-1H-pyrazole-4-yl)-1H-indazole-3-yl), the yellow (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone (5-29, 11 mg, 23 μmol) was obtained using the general deprotection step 5a of Scheme 1. LC / MS analysis yielded 480.2 [M+H] + It was detected.

[0142] Compound 5-34: (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone [ka]

[0143] Step 1: A 40 mL vial, dried in an oven equipped with a stirring rod, was filled with [6-bromo-1-[2-(dimethylamino)ethyl]indazole-3-yl]-(6-chlorochroman-3-yl)methanone (5h, 399 mg, 0.86 mmol), bis(pinacolate)diborone (329 mg, 1.30 mmol), potassium acetate (170 mg, 1.73 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (35 mg, 42 μmol). The vial was sealed with a septum cap. 1,4-dioxane (9 mL) was added by syringe. The mixture was aerated with nitrogen gas for 10 minutes, then heated with stirring at 100°C overnight. The mixture was cooled to room temperature, filtered through a diatomaceous earth plug, and the filtrate was concentrated and dried. The residue was purified by silica gel column chromatography using gradient elution of 1-7% CH3OH in CH2Cl2 to obtain 5i(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-yl)methanone in quantitative yield as a sticky brown solid. LC / MS analysis revealed a concentration of 510.3[M+H]. + It was detected.

[0144] Step 2: Using tert-butyl 4-bromo-3-fluoro-1H-pyrazole-1-carboxylate and 5a as starting materials, a general Suzuki reaction was performed, and deprotection was carried out according to steps 4 and 5a of Scheme 5 to obtain (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone as a slightly brown solid (5-34, 127 mg, yield 31%). LC / MS analysis revealed 468.3[M+H] + It was detected.

[0145] Alternatively, racemic mixtures of compounds were separated by the following supercritical fluid chromatography. Compound 5-19: [(3S)-6-chlorochroman-3-yl]-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]methanone, and Compound 5-20: [(3R)-6-chlorochroman-3-yl]-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]methanone

[0146]

Chem.

[0147] A sample of the racemic mixture 5-18 was separated by supercritical fluid chromatography under the following conditions. Column: NanoMicro UniChiral AS-5H21x250mm, Mobile phase: 45% 2-propanol and 0.25% diethylamine in CO2, Flow rate: 70 mL / min, Sample: 149.5 mg dissolved in 6 mL of methanol and 6 mL of dichloromethane, Injection volume: 1.0 mL, Detection wavelength: 254 nm.

[0148] Compound 5-19: Second elution peak, 64.7 mg, purity 100%, ee 97.4%, LC / MS detected value 479.2 [M+H] + . Compound 5-20: First elution peak, 66.0 mg, purity 100%, ee 100%. LC / MS detected value 479.2 [M+H] + .

[0149] Compound 5-22: (S)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6-chlorochroman-3-yl)methanone and Compound 5-23: (R)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6-chlorochroman-3-yl)methanone

Chem.

[0150] Samples of racemic compound 5-21 were separated by supercritical fluid chromatography under the following conditions. Column: ChiralPakIC-H21x250mm, Mobile phase: 40% methanol in CO2, Flow rate: 70 mL / min, Sample: 19.4 mg dissolved in 2.0 mL of methanol and 2.0 mL of dichloromethane, Injection volume: 0.75 mL, Detection wavelength: 220 nm.

[0151] Compound 5-22: Second elution peak, 80.2 mg, purity 100%, ee 96.4%. LC / MS detection value 452.2 [M+H] + . Compound 5-23: First elution peak, 77.5 mg, purity 100%, ee 100%. LC / MS detection value 452.2 [M+H] + .

[0152] Compound 5-25: [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-[(3R)-6-fluorochroman-3-yl]methanone and Compound 5-27: [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-[(3S)-6-fluorochroman-3-yl]methanone [ka]

[0153] Samples of semi-compound 5-24 were separated by supercritical fluid chromatography under the following conditions. Column: ChiralPakAD-H21x250mm, Mobile phase: CO2 solution containing 40% 2-propanol and 0.25% diethylamine, Flow rate: 70 mL / min, Sample: 82.0 mg dissolved in 4.0 mL of methanol and 4.0 mL of dichloromethane, Injection volume: 2.0 mL, Detection wavelength: 254 nm.

[0154] Compound 2-25: The second eluting peak, 31.2 mg, purity 100%, ee 100%. LC / MS detected value: 463.3 [M+H] + . Compound 5-27: The first eluting peak, 29.2 mg, purity 100%, ee value 100%. LC / MS detected value: 463.3 [M+H] + .

[0155] The following compounds 5-2 to 5-18 and 5-28 to 5-51 shown in Table 5 were prepared in a similar manner to the method described for the preparation of compounds 5-1, 5-29, and 5-34 using appropriate boronic acids / esters and Weinreb amides.

[0156]

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

[0157] [ka]

[0158] Weinlev intermediate 6-1:6-chloro-N-methoxy-N-methylchroman-3-carboxamide [ka]

[0159] A suspension of 6-chlorochroman-3-carboxylic acid (964.5 mg, 4.54 mmol), N,O-dimethylhydroxylamine hydrochloride (665.3 mg, 6.82 mmol), and HBTU (2.15 g, 5.67 mmol) in DMF (33 mL) was treated with N,N-diisopropylethylamine (18.4 mmol, 3.2 mL). The solution was stirred overnight at room temperature. The solution was diluted with ₹ (300 mL), washed sequentially with water (3 × 300 mL) and saturated saline (300 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The resulting substance was purified by silica gel column chromatography to obtain 6-chloro-N-methoxy-N-methyl-chroman-3-carboxamide (Weinlev intermediate 9-1; 1.06 g, 4.15 mmol, yield 91%) as a colorless, transparent oil. LC / MS analysis yielded 256.0 [M+H] + Detected. The following wine rebamide intermediates 6-2 to 6-21, shown in Table 6, were prepared using appropriate carboxylic acids in the same manner as the preparation method for intermediate 6-1.

[0160] [Table 6-1] [Table 6-2] [Table 6-3]

[0161] Example 2: ROCK Inhibition Assay Kinase IC 50 LANCE Ultra The activity was measured by an in vitro assay based on the TR-FRET (time-resolved fluorescence resonance energy transfer) homogeneous technique (Perkin Elmer). Recombinant ROCK1 (amino acids 1-477) and ROCK2 (amino acids 5-554) proteins were purchased from Carna Biosciences and SignalChem. Compound activity was measured by Envision and IC50. 50 The following was calculated. The assay was performed using a white LUMITRAC® 2009 6-well half-area microplate 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) ATP. After the kinase reaction was carried out for 1 hour, a stop buffer was added, and 10 mM EDTA and 0.6 nM LANCE Ultra Europium antiphosphorylated CREB (Ser133) antibody (PerkinElmer) were added to the LANCE detection buffer. TRF0200 was added. All assay incubations were performed at room temperature, during which time the microplates were sealed with polyester film. After incubating the reaction for 1 hour, the signal was measured using Envision's TR-FRET mode (excitation wavelength 320 nm, emission wavelength 615 / 665 nm).

[0162] Compound (1) exhibited useful pharmacological properties. In this specification, the method for expressing the inhibitory potency (nM) is the 50% inhibitory activity value (IC2). 50 ) The results are shown in Table 7 below. IC 50We define "A" as less than 20 nM, "B" as 21 nM or more and less than 200 nM, "C" as 201 nM or more and less than 500 nM, and "D" as greater than 501 nM. Table 7 shows the inhibitory activity of ROCK1 and ROCK2 by representative compounds of (1).

[0163] Table 7. Inhibitory activity of ROCK1 and ROCK2 in 1 mM ATP [Table 7-1] [Table 7-2] [Table 7-3]

[0164] Example 3: Blood-brain barrier (BBB) ​​permeability in rats and mice Compound (1) exhibited useful blood-brain barrier (BBB) ​​permeability. Compound (1) was administered intravenously (IV) at a dose of 1 mg / kg to CD-1 mice and Sprague-Dawley rats (n=3), and blood and brain concentrations of compound (1) were measured. After euthanasia of the mice and rats, blood and brain tissue were collected by cardiac puncture. Plasma or brain homogenate was treated with an internal standard in a methanol / acetonitrile (1:1, v / v) mixture in a vortex mixer for 1 minute, and then centrifuged at 4000-4500 rpm for 15 minutes at room temperature to precipitate proteins. The supernatant was then introduced into an LC / MS / MS system. Quantitative analysis was performed using an AB Sciex API 5500 mass spectrometer system (Sciex, USA).

[0165] The concentrations of compound (1) in plasma and brain samples were measured using a standard calibration curve, and the brain / plasma concentration ratio was calculated. Table 8 shows the blood-brain barrier (BBB) ​​ratios for representative compounds of compound (1).

[0166] Table 8. Blood-brain barrier (BBB) ​​ratio [Table 8]

Claims

1. A compound represented by formula (1), a pharmaceutically acceptable salt of the compound, or a prodrug of the compound or salt thereof, 【Chemistry 24】 Here, X is either CH2 or O. Y is CH, Z1, Z2, and Z3 are each independently N or CH. n is 0, 1, 2, or 3. R1 is H, heterocycloalkyl, C3-C7 cycloalkyl, or C1-C6 alkyl, and the nitrogen of the heterocycloalkyl may be optionally substituted with a C1-C3 alkyl, and the C3-C7 cycloalkyl or the C1-C6 alkyl may be optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl and OH. R2 is H, amino, NR6R7, or NR8R9. R3 is a 5-6 membered heteroaryl or a bicyclic heteroaryl, wherein the 5-6 membered heteroaryl or the bicyclic heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogens, CN, CHF2, CF3, C1-C3 alkyl, and amino, and the 5-6 membered heteroaryl or the bicyclic heteroaryl has 1 to 3 heteroatoms selected from the group consisting of oxygen and nitrogen. R4 and R5 are each independently H, Cl, F, OH, CD3, C1-C3 alkyl, or C1-C3 alkoxy, and the C1-C3 alkyl or C1-C3 alkoxy is optionally substituted with one or more substituents selected from the group consisting of amino, OH, and C1-C3 alkoxy. R6 and R7 are each independently H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, and the C1-C6 alkyl or C3-C7 cycloalkyl is optionally substituted with hydroxyl or C1-C3 alkoxy. R7 and R8, together with the nitrogen atom to which they are bonded, may form a 4-6 member saturated monocyclic group having no heteroatoms other than the nitrogen atom, wherein the 4-6 member saturated or partially saturated monocyclic group is optionally substituted at one or two carbon atoms with a halogen, amino, hydroxyl, or C1-C3 alkoxy, in a compound, salt, or prodrug.

2. The compound, salt, or prodrug according to claim 1, wherein R1 is H, a heterocycloalkyl, a C3-C7 cycloalkyl, or a C1-C6 alkyl, the nitrogen on the heterocycloalkyl is optionally substituted with methyl or ethyl, and the C3-C7 cycloalkyl or the C1-C6 alkyl is optionally substituted with one or more suitable substituents selected from methyl, ethyl, and OH.

3. The compound, salt, or prodrug according to claim 1, wherein R3 is selected from the following group. 【Chemistry 25】

4. The compound, salt, or prodrug according to claim 1, wherein R4 and R5 are each independently H, Cl, F, OH, CH3, methoxy, OCD3, ethoxy, or isopropoxy.

5. The compound, salt, or prodrug according to claim 1, wherein R6 and R7 are each independently H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, and the C1-C6 alkyl or the C3-C7 cycloalkyl is optionally substituted with hydroxyl, methoxy, or ethoxy.

6. The compound, salt, or prodrug according to claim 1, wherein R8 and R9, together with the nitrogen atom to which they are bonded, form a 4-6 member saturated monocyclic group that does not contain any heteroatoms other than the nitrogen atom to which R8 and R9 are bonded, and the 4-6 member saturated or partially saturated monocyclic group is optionally substituted with one or two carbon atoms selected from the group consisting of halogens, hydroxyls, and methoxyls.

7. 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, auxiliaries, and combinations thereof.

8. The compounds listed below, their pharmaceutically acceptable salts, or prodrugs of those compounds or salts. (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (6-chlorochroman-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]-(6-methoxychroman-3-yl)methanone, [1-(azetidine-3-yl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)pyrrolo[2,3-b]pyridine-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]methanone, [1-(azetidine-3-yl)-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[(1-methylpyrrolidine-2-yl)methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(1-methylpyrrolidine-2-yl)methyl]indole-3-yl]methanone, [1-(azetidine-3-ylmethyl)-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(azetidine-3-ylmethyl)-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]methanone, (S)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]methanone, (R)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazole-4-yl)-1-[(1-methylpyrrolidine-2-yl)methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[[(1R)-1-methylpyrrolidine-2-yl]methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)(6-(5-methoxy-1H-pyrazole-4-yl)-1-(((S)-1-methylpyrrolidine-2-yl)methyl)-1H-indole-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[2-(5-chloro-1H-pyrazole-4-yl)-7-[2-(dimethylamino)ethyl]pyrrolo[2,3-d]pyrimidine-5-yl]methanone, (6-chlorochroman-3-yl)-[7-[2-(dimethylamino)ethyl]-2-(5-fluoro-1H-pyrazole-4-yl)pyrrolo[2,3-d]pyrimidine-5-yl]methanone, (1-(((R)-azetidine-2-yl)methyl)-6-(5-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (1-(((S)-azetidine-2-yl)methyl)-6-(5-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, [1-[[(2S)-azetidine-2-yl]methyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-(azetidine-2-ylmethyl)-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[[(2R)-azetidine-2-yl]methyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (1-(((S)-azetidine-2-yl)methyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, (1-(((R)-azetidine-2-yl)methyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-chlorochroman-3-yl)methanone, [1-(2-aminopropyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2R)-2-aminopropyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(3-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminopropyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(2S)-2-aminobutyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, [1-[(2R)-2-aminobutyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2S)-2-(dimethylamino)propyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[[1-(dimethylamino)cyclopropyl]methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[(2R)-2-(dimethylamino)propyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2R)-2-(dimethylamino)propyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[(2R)-2-(dimethylamino)propyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazole-4-yl)-1-[(1-methylazetidine-3-yl)methyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[(1-methylazetidine-3-yl)methyl]indole-3-yl]methanone, [6-(5-fluoro-1H-pyrazole-4-yl)-1-[[(2R)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1S)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-methoxychroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[[(1S)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [6-(5-fluoro-1H-pyrazole-4-yl)-1-[[(2S)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-methoxychroman-3-yl)-[6-(5-methoxy-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [1-[[(1R)-1-ethylazetidine-2-yl]methyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazole-4-yl)-1-[[(1R)-1-methylazetidine-2-yl]methyl]indole-3-yl]methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[[(1R)-1-ethylazetidine-2-yl]methyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[2-(azetidine-1-yl)ethyl]-6-(3-chloro-1H-pyrazole-4-yl)pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]pyrrolo[3,2-c]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]pyrrolo[2,3-b]pyridine-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[2-(azetidine-1-yl)ethyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[3-(dimethylamino)propyl]-6-(3-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (S)-(6-chlorochroman-3-yl)(1-(3-(dimethylamino)propyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, (R)-(6-chlorochroman-3-yl)(1-(3-(dimethylamino)propyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-[ethyl(methyl)amino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazole-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(diethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)-yl)-1-[2-(diethylamino)ethyl]indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(diethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(diethylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[2-(diethylamino)ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-fluoro-1H-pyrazole-4-yl)-1-[2-(methylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [6-(5-chloro-1H-pyrazole-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[2-[ethyl(methyl)amino]ethyl]-6-(5-fluoro-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, [1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[(1-aminocyclopropyl)methyl]-6-(5-chloro-1H-pyrazole-4-yl)indole-3-yl]-(6-chlorochroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-fluorochroman-3-yl)methanone, (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, 2,3-dihydro-1,4-benzodioxin-3-yl-[1-[2-(dimethylamino)ethyl]-6-(1H-pyrazole-4-yl)indole-3-yl]methanone, Chroman-3-yl-[1-[2-(dimethylamino)ethyl]-6-(1H-pyrazole-4-yl)indole-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (R)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluoro-2,3-dihydro-1,4-benzodioxin-3-yl)methanone, (6-chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone, [6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone hydrochloride, (S)-[6-(3-chloro-1H-pyrazole-4-yl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-fluorochroman-3-yl)methanone dimethanesulfonic acid, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazole-4-yl)indole-3-yl]methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazole-3-yl)indole-3-yl]methanone, [6-(2-amino-4-pyridyl)-1-[2-(dimethylamino)ethyl]indole-3-yl]-(6-chlorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazole-3-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (R)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (S)-(6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (R)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-chlorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, (S)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone dihydrochloride, (R)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-fluorochroman-3-yl)methanone, [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]-(6-methoxychroman-3-yl)methanone, (6-chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazole-4-yl)indole-3-yl]methanone, (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (R)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(6-methoxychroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-methoxychroman-3-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, Chroman-3-yl(1-(2-(dimethylamino)ethyl)-6-(5-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-(3-fluoro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (6-(3-fluoro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indazole-3-yl)((S)-6-fluorochroman-3-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)(6-fluorochroman-3-yl)methanone, (7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1H-pyrazole-4-yl)-1H-indazole-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone, (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (1-(2-(dimethylamino)-6-(3-methoxy-1H-pyrazole-4-yl)-1H-indazole-3-yl)(7-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indazole-3-yl)(7-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone hydrochloride, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-methylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-ethylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-ethylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrobromide, (6-(5-chloro-1H-pyrazole-4-yl)-1-(((R)-1-ethylazetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonic acid, ((S)-6-chlorochroman-3-yl)(1-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, ((S)-6-chlorochroman-3-yl)(1-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone hydrobromide, (S)-(6-chlorochroman-3-yl)(1-(2-(diethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone, (S)-(6-chlorochroman-3-yl)(1-(2-(diethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone dihydrochloride, (S)-(6-chlorochroman-3-yl)(1-(2-(diethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone dimethanesulfonic acid, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone hydrochloride (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(diethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone hydrobromide, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dihydrochloride, (S)-(6-(5-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(methyl)amino)ethyl)-1H-indole-3-3-yl)methanone dimethanesulfonic acid, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone hydrobromide, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone dimethanesulfonic acid, (6-(3-chloro-1H-pyrazole-4-yl)-1-(((R)-1-(2-fluoroethyl)azetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(((R)-1-(2,2-difluoroethyl)azetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (6-(3-chloro-1H-pyrazole-4-yl)-1-(((R)-1-(2,2,2-trifluoroethyl)azetidine-2-yl)methyl)-1H-indole-3-yl)((S)-6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(2-fluoroethyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone,-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-(3-chloro-1H-pyrazole-4-yl)-1-(2-(ethyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(1-(2-(bis(2-fluoroethyl)amino)ethyl)-6-(3-chloro-1H-pyrazole-4-yl)-1H-indole-3-yl)(6-methoxychroman-3-yl)methanone, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone hydrochloride, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone hydrobromide, (S)-(6-chlorochroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazole-4-yl)-1H-indole-3-yl)methanone dimethanesulfonic acid, (6-(3-fluoro-1H-pyrazole-4-yl)-1-(((S)-1-methylazetidine-2-yl)methyl)-1H-indazole-3-yl)((S)-6-fluorochroman-3-yl)methanone hydrobromide.

9. Use of the compound, salt, or prodrug according to claim 1 for preparing a pharmaceutical for treating a disease treatable by inhibition of the ROCK enzyme.

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

11. The use according to claim 10, wherein the fibrous disease is selected from the group consisting of cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, hepatic fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endocardial myocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, arthritis fibrosis, Crohn's disease, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive extensive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scars, and renal fibrosis.

12. The use according to claim 10, wherein the cardiovascular disease or disorder 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 disorder, premature birth, Raynaud's disease, renal disease, and stroke.

13. The use according to claim 10, wherein the proliferative disorder or disorder 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, squamous cell carcinoma, esophageal cancer, eye cancer, follicular carcinoma, gallbladder cancer, digestive tract cancer, genitourinary tract cancer, glioblastoma, hairy cell carcinoma, head and neck cancer, liver cancer, hepatocellular carcinoma, Hodgkin's disease, keratotic leukemia, kidney cancer, large cell carcinoma, colorectal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, non-small cell lung cancer, melanoma, myeloproliferative disorder, neuroblastoma, ovarian cancer, papillary carcinoma, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, small cell carcinoma, small intestine cancer, gastric cancer, testicular cancer, thyroid cancer, and vulvar cancer.

14. The use according to claim 10, wherein the neurological disease or disorder is selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Batten's disease, dementia, spinal muscular atrophy, motor neuron disease, cavernous vascular malformation (CCM), spinocerebellar degeneration, acute or chronic pain, dementia, neurodegeneration, spinal cord injury, cerebral vasospasm, and multiple sclerosis.

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