Blood brain barrier penetrability selective inhibitors of ROCK2 protein kinase and uses thereof

Abstract

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

Description

[0001] Cross Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 496,836, filed April 18, 2023, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present invention relates to novel substituted bicyclic derivatives that can selectively inhibit ROCK2 and / or Rho kinase-mediated phosphorylation of myosin light chain phosphate, processes for their production, formulations thereof and their use for the manufacture of medicaments, as well as pharmaceutically acceptable salts, diastereomers, enantiomers, racemates. BACKGROUND

[0003] Rho-associated coiled-coil containing protein kinases (ROCK / Rho kinases / Rho-associated kinases) are downstream effectors of the small GTPases Rho (RhoA, RhoB, RhoC and RhoE) and belong to the serine / threonine kinase family. The active GTP-bound form of Rho mediates several biological functions, including smooth muscle contraction, cell motility and cytokinesis, through the action of ROCK. The ROCK proteins were identified in 1996 as proteins that bind to Rho GTPases. Two proteins were independently isolated as pl60 and pl64. Later, these proteins were identified as ROCK-1 and ROCK-2, respectively, and are isoforms of Rho-associated kinases. The two isoforms, ROCK-1 (ROCK-b / pl60) and ROCK-2 (ROCK-a / pl64), share 92% similarity in their amino acid sequences. Their structure contains a catalytic kinase domain at the N-terminus, followed by a region containing coiled-coils (600 amino acids), and at the C-terminus, a Rho-binding domain and a pleckstrin homology (PH) domain. They have different localizations and distinct physiological roles have been identified for each. The ROCK-1 transcript (gene on chromosome 18) is ubiquitous, with more prominent expression in the liver, kidney, spleen, testis, thymus and blood cells, while the ROCK-2 mRNA (chromosome 2) has more abundant expression in skeletal muscle and brain, suggesting specialized roles for them in these locations.

[0004] ROCK inhibitors have been considered for a variety of diseases such as cerebral ischemia, hypertension, erectile dysfunction, glaucoma, osteoporosis, cardiac hypertrophy, diabetic cardiomyopathy, retinopathy, pulmonary hypertension, and atherosclerosis. However, their implementation has been limited due to lack of knowledge about the involvement of specific ROCK isoforms. Whether isoform-specific targeting or combination of ROCK inhibition would provide better therapeutic outcome remains to be verified. Although they are not completely specific for ROCK isoforms and other serine / threonine kinases (e.g. PRK2, PKC, cAMP-dependent protein kinase, and citron kinase), some non-specific ROCK2 inhibitors have shown promising results in certain pathological conditions (e.g. glaucoma and hypertension). However, further work is needed for isoform-selective ROCK2 inhibitors to be used in the clinic, but some research-based studies have helped to a great extent in resolving the ambiguity of ROCK-1 and ROCK-2 specific functions. Since ROCK plays a critical role in the organization of the actin cytoskeleton, it is foreseeable that complete inhibition of both isoforms can cause adverse events in patients. Therefore, selective ROCK2 inhibition can have a greater therapeutic index of specificity than dual inhibition of ROCK1 and ROCK2. Thus, understanding the individual functions of each isoform in a particular disorder can help to improve safety and specificity and expand the therapeutic applications of ROCK inhibitors. SUMMARY

[0005] In one aspect, the present application provides novel compounds capable of inhibiting Rho-associated coiled-coil forming protein serine / threonine kinase (ROCK) represented by (1) below: wherein X, Y, Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 and R 4 are defined in the detailed description below.

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

[0007] In yet another aspect, the present application provides pharmaceutical compositions each comprising the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or combinations thereof.

[0008] In still another aspect, the present application provides methods for treating or alleviating certain ROCK-mediated diseases or conditions by using the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or compositions. Non-limiting examples of the diseases or conditions include cardiovascular, pulmonary, inflammatory, neurological, or proliferative diseases or conditions.

[0009] In additional aspects, the present application provides methods for preparing the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs. DETAILED DESCRIPTION

[0010] 1. Compounds In one aspect, the present application provides a compound represented by Formula (1), a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, hydrate, solvate, or prodrug thereof: wherein: X is CH2or O; Y is N or CH; Z 1 , Z 2 , and Z 3 are each independently N or CH; n is 0, 1, 2, or 3; R 1 is H, heterocycloalkyl, C3-C7cycloalkyl, or C1-C6alkyl, wherein the nitrogen of the heterocycloalkyl can be optionally substituted with C1-C3alkyl, and wherein the C3-C7cycloalkyl or C1-C6alkyl can be optionally substituted with one or more suitable substituents, such as C1-C6alkyl or OH; R 2 is H, amino, NR 6 R 7 , or NR 8 R 9 ; R 3 is 5-6 membered heteroaryl or bicyclic heteroaryl, wherein the heteroaryl or bicyclic heteroaryl can be optionally substituted with one or more suitable substituents, such as halogen, CN, CHF2, CF3, C1-C3alkyl, or amino, wherein the 5-6 membered heteroaryl or bicyclic heteroaryl has 1-3 heteroatoms selected from the group consisting of oxygen and nitrogen; R 4 and R5 each independently H, Cl, F, OH, OCD 3 , C1-C3 alkyl or C1-C3 alkoxy, wherein C1-C3 alkyl or C1-C3 alkoxy can be optionally substituted with one or more suitable substituents, such as amino, OH, or OMe, OEt, or OPr i ; R 6 and R 7 each independently H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, wherein C1-C6 alkyl or C3-C7 cycloalkyl can be optionally substituted with one or more suitable substituents, such as hydroxyl or C1-C3 alkoxy; and R 7 and R 8 together with the nitrogen atom to which they are bonded form a 4-6 membered saturated monocyclic group, which monocyclic group has no heteroatoms other than the nitrogen atom to which R 7 and R 8 are bonded, wherein the 4-6 membered saturated or partially saturated monocyclic group is optionally substituted on one or two carbon atoms with halogen, amino, hydroxyl, or C1-C3 alkoxy.

[0011] In some embodiments, R 1 may be H, heterocycloalkyl, C3-C7 cycloalkyl, or C1-C6 alkyl, wherein the nitrogen on heterocycloalkyl can be optionally substituted with methyl or ethyl, wherein C3-C7 cycloalkyl or C1-C6 alkyl can be optionally substituted with one or more suitable substituents, such as C1-C3 alkyl or OH.

[0012] In some embodiments, R 3 may be one of the following group: In some embodiments, R 4 and R 5 each can independently be H, Cl, F, OH, CH3, methoxy, OCD 3 , ethoxy, or isopropoxy.

[0013] In some embodiments, R 6 and R 7 each can independently be H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, wherein C1-C6 alkyl or C3-C7 cycloalkyl is optionally substituted with hydroxyl, methoxy, or ethoxy.

[0014] In some embodiments, R 7 and R 8 together with the nitrogen atom to which they are bonded form a 4-6 membered saturated monocyclic group, which monocyclic group has no heteroatoms other than the nitrogen atom to which R 7and R 8 heteroatoms other than the nitrogen atom to which the group is bound, wherein the 4-6 membered saturated or partially saturated monocyclic group is optionally substituted on one or two carbon atoms with halogen, amino, hydroxyl, or methoxyl.

[0015] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0016] The term "and / or" used in the disclosure is used to mean "and" or "or", unless expressly stated otherwise. The use of the term "or" is used to refer to "and / or" unless expressly stated otherwise, but the disclosure supports definitions that are the only alternatives, and "and / or."

[0017] "Optional" or "optionally" mean that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" encompasses "aryl" as defined herein and "substituted aryl." It will be understood by those of ordinary skill in the art that, for any group containing one or more substituents, such group does not thereby include any sterically impractical, synthetically infeasible, and / or inherently unstable moieties or modes of substitution.

[0018] The term "optionally substituted" means that the group can be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group, which can be the same or different. In one embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents. In another embodiment, an optionally substituted group has 3 substituents. In another embodiment, an optionally substituted group has 4 substituents. In another embodiment, an optionally substituted group has 5 substituents. For example, an optionally substituted alkyl can be a completely saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl can have a substituent other than hydrogen. For example, it can be bonded at any point along 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 moiety has the potential to contain additional functional groups, but does not necessarily have any additional functional groups.

[0019] The term "alkyl" used alone or as part of a larger moiety (e.g., "arylalkyl" or "cycloalkyl") refers to a straight or branched chain hydrocarbon group having from 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, unless otherwise indicated, and includes, by way of example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, and the like. Alkyl groups can be unsubstituted or substituted with one or more suitable substituents.

[0020] The term "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring group having from 3 to 10 carbon atoms, or 3 to 7 carbon atoms, in the hydrocarbon ring, unless otherwise indicated, and includes, by way of example, cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, cyclopentyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one or more suitable substituents.

[0021] The term "hetero" refers to replacement of at least one member of the carbon atom members of the ring system with at least one heteroatom such as nitrogen, sulfur, sulfoxide, sulfone, and oxygen.

[0022] The term "heterocycloalkyl" means a non-aromatic saturated or non-aromatic unsaturated monocyclic or non-aromatic saturated or non-aromatic unsaturated polycyclic ring having from 2 to 9 carbon atoms or 2 to 7 carbon atoms in the ring, unless otherwise indicated, and at least one heteroatom, preferably 1 to 4 heteroatoms selected from nitrogen, sulfur (including oxidized sulfur, e.g., sulfone or sulfoxide), and oxygen. The ring or ring system of the heterocycloalkyl group can be attached to another fragment of the compound through a carbon atom or a nitrogen atom, if such an atom is present. The heterocycloalkyl group can have a total of 3-10, or 3-8, or 5-8 atoms in the ring system, unless otherwise indicated. The heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring group, as long as the ring group does not become aromatic as a result of their presence.

[0023] Examples of heterocycloalkyl groups include azetidinyl, aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, and the like. Heterocycloalkyl groups can be unsubstituted or substituted with one or more suitable substituents.

[0024] The term "halo" as used herein includes fluoro, chloro, bromo, and iodo.

[0025] As used herein, the term "alkoxy" refers to an alkyl radical above bonded through an oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy also refers to polyethers such as -0-(CH2)2-0-CH3, and the like. The alkoxy group can be unsubstituted or substituted with one or more suitable substituents.

[0026] As used herein, the term "aryl" refers to an unsubstituted or substituted aromatic monocyclic or polycyclic group and includes, for example, carbocyclic aromatic groups (e.g., phenyl, naphthyl, and the like) as well as heteroaromatic groups (e.g., pyridyl, furanyl, thiophenyl, and the like). The term "aryl" also includes aromatic rings fused to non-aromatic carbocyclic or heterocyclic rings (e.g., phenyl or pyridyl rings). The term "aryl" can be used interchangeably with "aryl ring," "aromatic group," and "aromatic ring." Heteroaryl groups have 4 to 14 atoms in the heteroaromatic ring, 1 to 9 of the atoms being independently selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl groups have 1-3 heteroatoms in 5-8 membered aromatic groups. The aryl or heteroaryl group can be a monocyclic or bicyclic aromatic group. Typical aryl and heteroaryl groups include, for example, phenyl, quinolinyl, indazolyl, indolyl, dihydrobenzodioxynyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, pyrimidinyl, 3-methylpyridyl, benzothiophenyl, 2,4,6-tribromophenyl, 4-ethylbenzothiophenyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, pyrrole, pyrazole, imidazole, thiazole, and the like. The aryl or heteroaryl group can be unsubstituted or substituted with one or more suitable substituents.

[0027] As used herein, the term "hydroxyl" or "hydroxy" refers to -OH.

[0028] As used herein, the term "amino" refers to -NH2.

[0029] As used herein, the term "hydroxyalkyl" refers to any hydroxy derivative of an alkyl radical. The term "hydroxyalkyl" includes any alkyl group having one or more hydrogen atoms replaced by a hydroxyl group.

[0030] As used herein, the term "arylalkyl" includes any alkyl group having one or more hydrogen atoms replaced by an aryl group (e.g., benzyl, phenethyl, and the like).

[0031] As used herein, "substituent" refers to a fragment of a molecule covalently bonded to an atom within a molecule of interest. For example, a ring substituent can be a fragment covalently bonded to an atom that is a ring member, preferably a carbon or nitrogen atom, such as a halogen, alkyl, haloalkyl, or other group. Substituents of aromatic groups are typically covalently bonded to a ring carbon atom. The term "substituted" means that a hydrogen atom in a molecule is replaced with a substituent group, such that the valency of the designated atom is not exceeded, and such that a chemically stable compound results from the substitution (i.e., a compound that can be isolated, characterized, and tested for biological activity).

[0032] As noted above, certain groups can be unsubstituted, or substituted at one or more available positions with one or more suitable substituents other than hydrogen, typically with one or more suitable groups (which can be the same or different) at 1, 2, 3, 4, or 5 positions. Certain groups, when substituted, are substituted with 1, 2, 3, or 4 independently selected substituents. Suitable substituents include halo, alkyl, haloalkyl, aryl, hydroxy, alkoxy, hydroxyalkyl, amino, and the like.

[0033] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which they are contained.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.

[0035] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid / anionic or base / cationic salts (UK Journal of Pharmaceutical and Biosciences Vol. 2(4), 01-04, 2014, which is incorporated herein by reference). Pharmaceutically acceptable acid / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, bisulfate, tannate, tartrate, teoclate, tosylate, and triethiodide. Pharmaceutically acceptable base / cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine salts.

[0036] Pharmaceutically acceptable acid salts are formed by reaction of a free base form of a compound of Formula 1 with a suitable inorganic or organic acid, including but not limited to hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid (e.g., 2-naphthalenesulfonic acid), or hexanoic acid. Pharmaceutically acceptable acid addition salts of a compound of Formula 1 can include or be, for example, a 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 hexanoate.

[0037] The free acid or free base form of a compound of the present application can be prepared from the corresponding base or acid addition salt form, respectively, by a method known to those of ordinary skill in the art (see, e.g., more details in L. D. Bigley, S. M. Berg, D. C. Monkhouse, “ Encyclopedia of Pharmaceutical Technology ”.J. Swarbrick and J. C. Boylan, Eds., Vol. 13, Marcel Dekker, Inc., 1995, pp. 453-499; the entire teachings of this document are incorporated herein by reference). For example, the acid addition salt form of a compound of the present application can be converted to the corresponding free base form by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of a compound of the present application can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).

[0038] Prodrug derivatives of a compound of the present application can be prepared by a method known to those of ordinary skill in the art (see, e.g., more details in Saulnier et al., Bioorg.Med.Chem.Letters , 1994, 4, 1985; Daniela Hartmann Jornada at. Al., Molecules 2016, 21, 42; the entire teachings of these documents are incorporated herein by reference). Protected derivatives of a compound of the present application can be prepared by a method known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation and removal of protecting groups can be found in T. W. Greene, “ Green’s Protective Groups in Organic Chemistry ,” 4th Ed., John Wiley and Sons, Inc., 2006; the entire teachings of this document are incorporated herein by reference.

[0039] The compounds of the present application 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 diastereoisomeric compounds, separating the pair of diastereoisomers, and recovering the optically pure enantiomer of the compound. The separation of the pair of diastereoisomers can be carried out by any method known or hereafter developed for chemical resolution of stereoisomers, such as preferential crystallization. The optically pure enantiomer can be recovered by any Enantiomers, Racemates and Resolutions ,” John Wiley And Sons, Inc., 1981, the entire teachings of which are incorporated herein by reference.

[0040] As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this application, a compound of Formula 1 or a pharmaceutically acceptable salt thereof) and a solvent. Such a solvent for the purposes of the present application can not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include water, acetone, methanol, ethanol, and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid.

[0041] 2. Compositions In another aspect, the present application provides a pharmaceutical composition comprising the compound, salt, diastereoisomer, enantiomer, racemate, hydrate, solvate, prodrug, or pharmaceutical combination thereof. The composition can further comprise additional components. Non-limiting examples of the additional components include pharmaceutically acceptable carriers, diluents, excipients, and combinations thereof.

[0042] As used herein, the term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients.

[0043] As used herein, the term “pharmaceutical combination” means a product that results from the mixing or combining of more than one active ingredient.

[0044] As used herein, the term "acceptable," with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effects on the general health of the subject being treated.

[0045] As used herein, the term "carrier" refers to a compound or agent that aids in the incorporation of a compound described herein into a cell or tissue.

[0046] As used herein, the term "diluent" refers to a compound used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize a compound described herein.

[0047] Suitable pharmaceutically acceptable carriers, diluents, adjuvants, or excipients for pharmaceutical compositions of the present application include tablets (coated tablets), capsules (gelatin), solutions (aqueous or water-alcohol), syrups containing the active ingredient, emulsions or inhalable powders (containing various sugars, such as lactose or glucose, salts and mixtures of these excipients with one another) and aerosols (inhalation solutions with or without propellant) made of, for example, collidone or shellac, gum arabic, talc, titanium dioxide or sugars.

[0048] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., high- silica or kaolin), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, spent sulphite liquor, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium dodecyl sulphate).

[0049] 3. Methods of using the compounds or compositions In another aspect, the present application provides methods of treating or reducing certain protein kinase-mediated diseases or disorders by administering to a subject or patient a therapeutically effective amount of the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or compositions. In some embodiments, the present application provides methods of treating or reducing certain ROCK-mediated diseases or conditions by administering to a subject or patient a therapeutically effective amount of the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or compositions. In some embodiments, the present application provides methods of treating or reducing diseases or conditions in which ROCK is known to play a role.

[0050] In yet another aspect, the present application provides a method of inhibiting an enzyme activity, particularly ROCK1, ROCK2, PKC5, PKC0, PRK1, GSK3, PRK2, NEK1 and NEK4 kinase activity, by administering to a subject or patient a therapeutically effective amount of the compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug or composition.

[0051] In yet another aspect, the present application provides a method of inhibiting a protein kinase activity (e.g., ROCK kinase activity) in a biological sample by contacting the biological sample with the compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug or composition.

[0052] As used herein, the term "inhibitor" refers to a compound that inhibits one or more of the kinases described herein. For example, the term "ROCK inhibitor" refers to a compound that inhibits a ROCK receptor or reduces a signaling effect.

[0053] As used herein, the term "protein kinase-mediated disease" or "disorder or disease or condition mediated by inappropriate protein kinase activity" refers to any disease state mediated or modulated by a protein kinase described herein. Such disease states include, but are not limited to, fibrotic disorders; pulmonary fibrosis including cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, joint fibrosis, Crohn's disease, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scarring, 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 renal diseases, such as chronic renal failure, chronic nephritis, diabetic nephropathy, and IgA nephropathy; neurological diseases or disorders, such as spinal cord injury, Alzheimer's disease, multiple sclerosis, or neuropathic pain; and proliferative disorders, such as retinopathy, fibrosis, or invasive / metastatic cancer. Such cancers include adenocarcinoma, adrenocortical carcinoma; bladder cancer; bone cancer; brain cancer; breast cancer; oral cancer; cervical cancer; colon cancer; colorectal cancer; endometrial cancer or uterine cancer; epidermoid carcinoma; esophageal cancer; eye cancer; follicular carcinoma; gall bladder cancer; gastrointestinal cancer; genitourinary tract cancer; glioblastoma; hairy cell cancer; head and neck cancer; hepatoma; hepatocellular carcinoma; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; large intestine cancer; laryngeal cancer; liver cancer; lung cancer, 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 particular embodiments, the cancer treated is melanoma, breast cancer, colon cancer, or pancreatic cancer.

[0054] As used herein, the term "treat," "treating," or "treatment" refers to a method for preventing and / or therapeutically reducing, alleviating, or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing underlying metabolic causes of symptoms, inhibiting a disease or condition, arresting the development of a disease or condition, relieving a disease or condition, causing a regression of a disease or condition, relieving a condition caused by a disease or condition, or stopping a symptom of a disease or condition.

[0055] As used herein, the term "subject" or "patient" includes mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, simians, cows, horses, sheep, goats, pigs; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like.

[0056] As used herein, the term "administration" or "administering" of a subject compound refers to providing a compound of the application and / or a prodrug thereof to a subject in need of treatment.

[0057] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound described herein being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case can be determined using techniques, such as a dose escalation study. By way of example only, a therapeutically effective amount of a compound of the application can range, e.g., 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, from about 0.1 mg (x2) / kg / day to about 500 mg (x2) / kg / day.

[0058] The compounds of the application are screened against a panel of kinases and inhibit the activity of at least one kinase on the panel. Examples of kinases include, but are not limited to, ROCK1 and ROCK2.

[0059] The compounds described herein are inhibitors of ROCK kinase activity and have therapeutic benefits in treating conditions associated with inappropriate kinase activity, particularly in treating and preventing disease states mediated by kinases, including ROCK kinases. Accordingly, the present application provides methods of modulating, particularly inhibiting, the signal transduction cascade in which the kinases act. The methods generally involve administering to a subject, or contacting a cell expressing a kinase, an effective amount of a compound described herein, a salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, and / or composition thereof, to modulate or inhibit the signal transduction cascade. The methods are also useful for modulating, particularly inhibiting, downstream processes or cellular responses that result from the activation of the particular kinase signal transduction cascade. The methods are also practiced in an in vitro setting or in an in vivo setting as a method of treatment for a disease characterized by, resulting from, or associated with the activation of a kinase-dependent signal transduction cascade.

[0060] For therapeutic uses of the compounds provided herein, including a compound of Formula 1, a salt, diastereomer, enantiomer, racemate, hydrate, solvate, or prodrug thereof, such compounds are administered in a therapeutically effective amount, alone or as part of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions comprising at least one compound provided 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.

[0061] In addition, such compounds and compositions are administered alone or in combination with one or more additional therapeutic agents. Non-limiting examples of the additional therapeutic agents can include immune checkpoint inhibitors and chemotherapeutics that induce immunogenic cell death (ICD). Non-limiting examples of immune checkpoint inhibitors can include PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. Non-limiting examples of chemotherapeutics that induce immunogenic cell death (ICD) can include doxorubicin, idarubicin, mitoxantrone, tautomycin, calyculin A, salubrinal, oxaliplatin, bleomycin, and cyclophosphamide. Methods of administration of such compounds and compositions include, but are not limited to, intravenous administration, inhalation administration, oral administration, rectal administration, parenteral administration, intravitreal administration, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, topical administration, ophthalmic administration, buccal administration, tracheal administration, bronchial administration, sublingual administration, or ocular administration. The compounds provided herein are administered 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, lotions, gels, ointments, or creams for topical administration, and the like. In some embodiments, such pharmaceutical compositions are formulated as tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, solutions, gels, emulsions, ointments, eye drops, or ear drops.

[0062] The therapeutically effective amount will depend on the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired. The dose desired will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.

[0063] Compounds of Formula 1 are useful for inhibiting one or more protein kinases and for treating diseases and conditions mediated by protein kinases, such as cancer, autoimmune diseases, fibrotic conditions, cardiovascular diseases, and neurodegenerative diseases.

[0064] The term "biological sample" as used herein means an in vitro sample of an animal and includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from an animal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Inhibition of kinase activity, particularly ROCK kinase activity, in a biological sample can be useful for a variety of purposes known to those of skill in the art. Examples of such purposes include, without limitation, biological sample storage and biological assays.

[0065] As used herein, the terms “ROCK-mediated disease” or “symptom” refer to any disease or other harmful condition in which ROCK is known to play a role. ROCK is involved in a variety of important physiological functions in the vascular system, including smooth muscle contraction; cell proliferation, such as vascular smooth muscle cell proliferation; and cell adhesion and migration (see Hu and Lee, Expert Opin.Ther.Targets, 9(4):715-36, 2005; Shimokawa and Takeshita, Arterioscler. Thromb. Vase. Biol. 25(9):1767-75, 2005). ROCK is involved in inflammatory responses due to leukocyte migration, such as autoimmune diseases and allergic reactions (see Wettschureck et al., J. Mol.Med .80:629-38, 2002). Aberrant activation of the Rho / ROCK pathway has been observed in various disorders of the central nervous system (see Mueller et al., .80:629-38, 2002). Nature Rev ., 4:387-98, 2005). Furthermore, ROCK has been involved in tumor cell migration and invasion ((Riento and Ridley, 4:387-98, 2005). Nature Rev . 4:446-56, 2004) and osteoporosis (Ohnaka et al., Biochem. Biophys., Res. Commun . 287(2):337-4, 2001).

[0066] In particular, the present application relates to a method of treating or lessening the severity of a cardiovascular disease or condition, such as cerebral vasospasm, hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemia / reperfusion injury, stroke, bronchial asthma; glaucoma, premature birth, erectile dysfunction, or a kidney disease, such as chronic renal failure, chronic nephritis, diabetic nephropathy, and IgA nephropathy; a nervous system disease or condition, such as spinal cord injury, Alzheimer's disease, multiple sclerosis, or neuropathic pain; and a proliferative condition, such as retinopathy, fibrosis, or an invasive / metastatic cancer. Such cancers include adenocarcinoma, adrenocortical carcinoma; bladder cancer; bone cancer; brain cancer; breast cancer; oral cancer; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine cancer; epidermoid cancer; esophageal cancer; eye cancer; follicular cancer; gallbladder cancer; gastrointestinal cancer; genitourinary tract cancer; glioblastoma; hairy cell cancer; head and neck cancer; hepatoma; hepatocellular carcinoma; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell cancer; large intestine cancer; laryngeal cancer; liver cancer; lung cancer, such as lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, non-small cell lung cancer; melanoma; myeloproliferative disorders; neuroblastoma; ovarian cancer; papillary cancer; pancreatic cancer; peritoneal cancer; prostate cancer; rectal cancer; salivary gland cancer; sarcoma; squamous cell cancer; small cell cancer; small intestine cancer; stomach cancer; testicular cancer; thyroid cancer; and vulvar cancer. In particular embodiments, the cancer treated is melanoma, breast cancer, colon cancer, or pancreatic cancer.

[0067] In another aspect, the present application provides a method of treating a fibrotic condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Non-limiting examples of fibrotic conditions are pulmonary fibrosis including cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, joint fibrosis, Crohn's disease, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scarring, or renal fibrosis.

[0068] In one aspect, the present application provides a method of treating a cell proliferative disease or disorder, e.g., cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula 1, a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or a pharmaceutical composition or medicament thereof, wherein the cell proliferative disease or disorder includes, e.g., lymphoma, osteosarcoma, melanoma, breast cancer, renal cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, neuronal cancer, lung cancer, uterine cancer, or gastrointestinal cancer. In one aspect, the present application provides a method of inhibiting the growth of cancer cells with a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or any combination thereof described herein, or a composition described herein.

[0069] In certain embodiments, the protein kinase-mediated disease or disorder is an inflammatory disease or disorder, a respiratory disease or an autoimmune disease or disorder, e.g., 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 disease, or lupus.

[0070] In another aspect, the present application provides a method of treating a neurological / neurodegenerative disease or disorder by administering to a subject a therapeutically effective amount of a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or any combination thereof described herein, or a composition described herein. In certain embodiments, such neurological / neurodegenerative disease or disorder includes, e.g., Alzheimer's disease, cerebral edema, cerebral ischemia, multiple sclerosis, cerebral cavernous malformation (CCM), neuropathy, Parkinson's disease, blunt or surgical trauma (including post-operative cognitive dysfunction and spinal cord or brain stem injury), and the neurological aspects of conditions such as degenerative disc disease and sciatica.

[0071] In another aspect, the present application provides a method of treating a cardiovascular disease by administering to a subject a therapeutically effective amount of a compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, prodrug, or any combination thereof described herein, or a composition described herein. Such cardiovascular diseases affect the heart or blood vessels and include, for example, atherosclerosis, arrhythmia, angina, myocardial ischemia, myocardial infarction, aneurysm of the heart or blood vessels, vasculitis, stroke, peripheral occlusive arterial disease of a limb, organ or tissue, reperfusion injury following ischemia of an organ or tissue, endotoxic, surgical or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vasoconstriction, abnormal blood vessels, or inflammation.

[0072] In another aspect, the present application provides a method of treating a cancer, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound described herein, a salt, diastereomer, enantiomer, racemate, hydrate, solvate, or prodrug thereof, and a therapeutically effective amount of at least one immune checkpoint inhibitor, wherein the cancer is adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, oral cavity cancer, cervical cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, epidermoid cancer, esophageal cancer, eye cancer, follicular carcinoma, gall bladder cancer, gastrointestinal cancer, genitourinary tract cancer, glioblastoma, hairy cell cancer, head and neck cancer, hepatoma, hepatocellular cancer, Hodgkin's disease, keratoacanthoma, kidney cancer, large cell carcinoma, large intestinal cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, lung squamous carcinoma, non-small cell lung cancer, melanoma, myelodysplastic syndromes, neuroblastoma, ovarian cancer, papillary carcinoma, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland carcinoma, sarcoma, squamous cell carcinoma, small cell carcinoma, small intestinal cancer, stomach cancer, testicular cancer, thyroid cancer, vulvar cancer, or any combination thereof. Examples of the checkpoint inhibitor include, but are not limited to, a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor.

[0073] In another aspect, the present application provides a method of treating cancer, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound described herein, a salt, diastereomer, enantiomer, racemate, hydrate, solvate, or prodrug thereof, and a therapeutically effective amount of at least one chemotherapeutic agent that induces immunogenic cell death (ICD), wherein the cancer is adenocarcinoma, adrenocortical carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, oral cavity cancer, cervical cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, epidermoid carcinoma, esophageal cancer, eye cancer, follicular carcinoma, gall bladder cancer, gastrointestinal cancer, genitourinary tract cancer, glioblastoma, hairy cell cancer, head and neck cancer, liver tumor, hepatocellular cancer, Hodgkin's disease, keratoacanthoma, kidney cancer, large cell carcinoma, large bowel cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, lung squamous carcinoma, non-small cell lung cancer, melanoma, myeloproliferative disorders, neuroblastoma, ovarian cancer, papillary carcinoma, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland carcinoma, sarcoma, squamous cell carcinoma, small cell carcinoma, small bowel 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, bleomycin, and cyclophosphamide.

[0074] In the above methods using the compounds of the present application, the compounds described herein, salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs thereof are administered to a system comprising cells or tissues. In certain embodiments, the compounds described herein, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or any combination thereof are administered to a human or animal subject. In yet certain embodiments, a pharmaceutical composition or medicament comprising at least one of the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, prodrugs, or any combination thereof is administered to a human or animal subject.

[0075] 4. A method of making a compound In additional aspects, the present application provides methods of making the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, and prodrugs. In some embodiments, the compounds, salts, diastereomers, enantiomers, racemates, hydrates, solvates, or prodrugs can be made by a method comprising, but not limited to, one or more of the following methods: (a) optionally converting a compound of the present application to a pharmaceutically acceptable salt; (b) optionally converting a salt form of a compound of the present application to a non-salt form; (c) optionally converting an unoxidized form of a compound of the application to a pharmaceutically acceptable N-oxide; (d) optionally resolving an individual stereoisomer of a compound of the application from a mixture of stereoisomers; (e) optionally converting a non-derivatized compound of the application to a pharmaceutically acceptable prodrug derivative; and (f) optionally converting a prodrug derivative of a compound of the application to its non-derivatized form.

[0076] In this document, illustrative of the methods used to prepare the compounds of the application are described in the examples, which will be described in detail below. Some embodiments of the application provide methods of preparing the compounds of the application, as shown in Method 1 or Method 2 below.

[0077] Bicyclic acid (2) is reacted with thionyl chloride or oxalyl chloride in dichloromethane in the presence of catalytic amount of GMF to provide its acid chloride (3). The resulting acid chloride (3) is coupled with bicyclic heteroaryl compound (4) in Friedel-Crafts acylation reaction in the presence of Lewis acid (aluminum chloride, titanium chloride or stannous chloride) in organic solvent (dichloromethane or dichloroethane) to provide ketone (5). The resulting ketone (5) is reacted with alkyl bromide, alkyl chloride or alkyl epoxide using inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, K2HPO4or K3PO4) in organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane or dichloroethane) at room temperature (RT) - 150 °C for 5-24 hours to get N -alkylated compound (6).

[0078] N -alkylated compound (6) is also prepared starting from bicyclic heteroaryl compound (4) by carrying out N -alkylation under the reaction conditions mentioned above to get (7) followed by Friedel-Crafts acylation reaction with acid chloride (3) instead.

[0079] -alkylated compound (6) is also prepared starting from bicyclic heteroaryl compound (4) by carrying out N -alkylation under the reaction conditions mentioned above to get (7) followed by Friedel-Crafts acylation reaction with acid chloride (3) instead. . DCM), using Suzuki reaction conditions to react N -alkylated compound (6) with boronic acid or boronic acid ester in the presence of inorganic base (NaHCO3, Na2CO3, K2CO3, Cs2CO3, CsF, K2HPO4or K3PO4) at room temperature (RT) - 150 °C for 5-24 hours to provide compound (1).

[0080] N - Alkylated compound (6) is also prepared alternatively from bicyclic starting as shown below in Method 2.

[0081] Bicyclic heteroaryl compound (4) is reacted with N - Iodine succinimide (NIS) in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane or dichloroethane) at room temperature for 2-24 h to provide iodo bicyclic heteroaryl compound (8). Iodo bicyclic heteroaryl compound (8) is reacted with alkyl bromide, alkyl chloride or alkyl epoxide using inorganic base (NaHC03, Na2C03, K2C03, Cs2C03, K2HPO4or K3PO4) in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane or dichloroethane) at room temperature (RT) - 150 °C for 5-24 hours to get N - Alkylated compound (10). Starting from bicyclic heteroaryl compound (4), (9) is obtained by N-alkylation followed by iodination of (9) using N - Iodine succinimide (NCI) in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane or dichloroethane) at room temperature for 2-24 h to provide iodo bicyclic heteroaryl compound (8). Iodo bicyclic heteroaryl compound (8) is reacted with alkyl bromide, alkyl chloride or alkyl epoxide using inorganic base (NaHC03, Na2C03, K2C03, Cs2C03, K2HPO4or K3PO4) in an organic solvent (DMF, acetone, dioxane, acetonitrile, dichloromethane or dichloroethane) at room temperature (RT) - 150 °C for 5-24 hours to get N - Alkylated compound (10). Bicyclic acid (2) is coupled with N - Methoxymethylamine hydrochloride in an organic solvent (DMF, tetrahydrofuran, dichloromethane or dichloroethane) using coupling reagent (DCC, EDCI, HATU, HBTU, PyBop or PyBrop) at room temperature for 2-24 h to provide Weinreb amide (11). Weinreb amide (11) is converted to ketone (6) by reaction with iodo bicyclic heteroaryl compound (10) in the presence of Grignard reagent in THF at low temperature (-78-0 °C).

[0082] Non-limiting examples of compounds described herein can include: (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methoxy-lH-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]methanone; (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methoxy-lH-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]methanone dihydrochloride; (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methoxy-lH-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]methanone dimethanesulfonate; (6-(5-chloro-1H-pyrazol-4-yl)-1-(((S)-1-methylazacyclobutane-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-methoxychroman-3-yl) ketone; (6-(5-chloro-1H-pyrazol-4-yl)-1-(((S)-1-methylazacyclobutane-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-methoxy-som-3-yl)methyl ketone dihydrochloride; (6-(5-chloro-1H-pyrazol-4-yl)-1-(((S)-1-methylazacyclobutane-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-methoxysom-3-yl)methyl ketone dihydrobromide; (6-(5-chloro-1H-pyrazol-4-yl)-1-(((S)-1-methylazacyclobutane-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)((S)-6-methoxy-seroton-3-yl)methyl ketone dimethyl sulfonate; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl] methyl ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6-fluorosom-3-yl) ketone; (6-Chlorochrome-3-yl)-[6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridin-3-yl] methyl ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6-methoxy-chroman-3-yl) ketone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridin-3-yl]-(6-methoxy-sem-3-yl) ketone; [1-(azacyclobutane-3-yl)-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorosom-3-yl) methyl ketone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; [ 1 -(Azetidin-3 -ylmethyl)-6-(5 -chloro- 1 H-pyrazol-4-yl)indol-3 -yl] -(6-chlorochroman- 3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; [ 1 -(Azetidin-3 -ylmethyl)-6-(5 -chloro- 1 H-pyrazol-4-yl)indol-3 -yl] -(6-chlorochroman- 3-yl)methanone; [ 1 -(Azetidin-3 -ylmethyl)-6-(5 -chloro- 1 H-pyrazol-4-yl)indol-3 -yl] -(6-chlorochroman- 3-yl)methanone; [ 1 -(Azetidin-3 -ylmethyl)-6-(5 -chloro- 1 H-pyrazol-4-yl)indol-3 -yl] -(6-chlorochroman- 3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; (S)-(6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin- 2-yl)methyl]indol-3-yl]methanone; (R)-(6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin- 2-yl)methyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2- yl)methyl]indol-3-yl]methanone; (6-chromanyl-3-yl)-[2-(5-chloro-lH-pyrazol-4-yl)-7-[2-(dimethylamino)ethyl]pyrrolo[2,3- d]pyrimidin-5-yl]methanone; [1 -(azetidin-2-ylmethyl)-6-(5-chloro- 1 H-pyrazol-4-yl)indol-3-yl]-(6-chromanyl-3- yl)methanone; [1 -(azetidin-2-ylmethyl)-6-(5-chloro- 1 H-pyrazol-4-yl)indol-3-yl]-(6-chromanyl-3- yl)methanone; [1 -(azetidin-2-ylmethyl)-6-(5-chloro- 1 H-pyrazol-4-yl)indol-3-yl]-(6-chromanyl-3- yl)methanone; (6-chromanyl-3-yl)-[2-(5-chloro-lH-pyrazol-4-yl)-7-[2-(dimethylamino)ethyl]pyrrolo[2,3- d]pyrimidin-5-yl]methanone; (6-chromanyl-3-yl)-[2-(5-chloro-lH-pyrazol-4-yl)-7-[2-(dimethylamino)ethyl]pyrrolo[2,3- d]pyrimidin-5-yl]methanone; (1-(((R)-azetidin-2-yl)methyl)-6-(5-chloro-lH-pyrazol-4-yl)-lH-indol-3-yl)(6-methoxy- chroman-3-yl)methanone; (1-(((S)-azetidin-2-yl)methyl)-6-(5-chloro-lH-pyrazol-4-yl)-lH-indol-3-yl)(6-methoxy- chroman-3-yl)methanone; [1 -[[(2S)-azetidin-2-yl]methyl]-6-(5-fluoro- 1 H-pyrazol-4-yl)indol-3-yl]-(6-methoxy- chroman-3-yl)methanone; [1 -(azetidin-2-ylmethyl)-6-(5-chloro- 1 H-pyrazol-4-yl)indol-3-yl]-(6-chromanyl-3- yl)methanone; [1 -[[(2R)-azetidin-2-yl]methyl]-6-(5-fluoro- 1 H-pyrazol-4-yl)indol-3-yl]-(6-chromanyl-3- yl)methanone; (1-(((S)-azetidin-2-yl)methyl)-6-(5-chloro-lH-pyrazol-4-yl)-lH-indol-3-yl)(6-chromanyl- 3-yl)methanone; (1-(((R)-azetidin-2-yl)methyl)-6-(5-chloro-lH-pyrazol-4-yl)-lH-indol-3-yl)(6-methoxy- chroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; (6-(5-chloro- 1 H-pyrazol-4-yl)- 1 -(((S)- 1 -methylazetidin-2-yl)methyl)- 1 H-indol-3- yl)((S)-6-methoxychroman-3-yl)methanone; [1 -(2-aminopropyl)-6-(3-chloro- 1 H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-chloro- 1 H-pyrazol-4-yl)- 1 -[(2S)-2-(dimethylamino)propyl] indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro- 1 H-pyrazol-4-yl)- 1 -[[ 1 -(dimethylamino)cyclopropyl] methyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[1-[(2R)-2-(dimethylamino)propyl]-6-(5-methoxy-1H- pyrazol-4-yl)indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2R)-2- (dimethylamino)propyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2R)-2- (dimethylamino)propyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(1- methylazetidin-3-yl)methyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[(1- methylazetidin-3-yl)methyl]indol-3-yl]methanone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[[(2R)-1-methylazetidin-2-yl]methyl]indol-3-yl]- (6-methoxychroman-3-yl)methanone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[[(1S)-1-methylazetidin-2-yl]methyl]indol-3-yl]- (6-methoxychroman-3-yl)methanone; (6-methoxychroman-3-yl)-[6-(5-methoxy-1H-pyrazol-4-yl)-1-[[(1S)-1- methylazetidin-2-yl]methyl]indol-3-yl]methanone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[[(2S)-1-methylazetidin-2-yl]methyl]indol-3-yl]- (6-methoxychroman-3-yl)methanone; (6-methoxychroman-3-yl)-[6-(5-methoxy-1H-pyrazol-4-yl)-1-[[(1R)-1- methylazetidin-2-yl]methyl]indol-3-yl]methanone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[[(1R)-1-methylazetidin-2-yl]methyl]indol-3-yl]- (6-methoxychroman-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[[(1R)-1- methylazetidin-2-yl]methyl]indol-3-yl]methanone; [1-[[(1R)-1-ethylazetidin-2-yl]methyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6- methoxychroman-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-fluoro-1H-pyrazol-4-yl)-1-[[(1R)-1-methylazetidin-2- yl]methyl]indol-3-yl]methanone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[[(1R)-1-ethylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; [1-[2-(azetidin-1-yl)ethyl]-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridin-3-yl]-(6- fluochroman-3-yl)methanone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(methylamino)ethyl]pyrrolo[3,2-c]pyridin-3-yl]-(6- fluochroman-3-yl)methanone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(methylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6- fluochroman-3-yl)methanone; [1-[2-(azetidin-1-yl)ethyl]-6-(3-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3- yl)methanone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(methylamino)ethyl]indol-3-yl]-(6-fluorochroman-3- yl)methanone; (6-chlorochroman-3-yl)-[1-[3-(dimethylamino)propyl]-6-(3-methoxy-1H-pyrazol-4- yl)indol-3-yl]methanone; (S)-(6-chlorochroman-3-yl)(1-(3-(dimethylamino)propyl)-6-(3-methoxy-1H-pyrazol-4- yl)-1H-indol-3-yl)methanone; (R)-(6-chlorochroman-3-yl)(1-(3-(dimethylamino)propyl)-6-(3-methoxy-1H-pyrazol-4- yl)-1H-indol-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[2-(methylamino)ethyl]indol-3- yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indol- 3-yl]methanone; (6-chlorochroman-3-yl)-[1-[2-[ethyl(methyl)amino]ethyl]-6-(5-methoxy-1H- pyrazol-4-yl)indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[2-(diethylamino)ethyl]indol- 3-yl]methanone; (6-chlorochroman-3-yl)-[1-[2-(diethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol- 3-yl]methanone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[2-(diethylamino)ethyl]indol-3-yl]-(6-methoxychroman- 3-yl)methanone; [1-[2-(diethylamino)ethyl]-6-(5-fluoro-1H-pyrazol-4-yl)indol-3-yl]-(6-methoxychroman- 3-yl)methanone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[2-(methylamino)ethyl]indol-3-yl]-(6-methoxychroman- 3-yl)methanone; [6-(5-fluoro-1H-pyrazol-4-yl)-1-[2-(methylamino)ethyl]indol-3-yl]-(6-methoxychroman- 3-yl)methanone; [6-(5-chloro-1H-pyrazol-4-yl)-1-[2-[ethyl(methyl)amino]ethyl]indol-3-yl]-(6-methoxychroman-3-yl)methanone; [1-[2-[ethyl(methyl)amino]ethyl]-6-(5-fluoro-1H-pyrazol-4-yl)indol-3-yl]-(6-methoxychroman-3-yl)methanone; [1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; [1-[(1-aminocyclopropyl)methyl]-6-(5-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-chloro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6-methoxychroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6-chlorochroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6-fluorochroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; 2,3-dihydro-1,4-benzodioxin-3-yl-[1 -[2-(dimethylamino)ethyl]-6-(1 H -pyrazol-4-yl)indol-3-yl]methanone; chroman-3-yl-[1 -[2-(dimethylamino)ethyl]-6-(1 H -pyrazol-4-yl)indol-3-yl]methanone [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrochloride; (R)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; [6-(3-chloro-1 H -pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-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-1 H -pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]methanone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(2,3-dihydro-1,4- benzodioxin-3-yl)methanone; [6-(3-chloro-1 H -pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorochroman-3-yl)methanone; (S)-[6-(3-chloro-1 H -pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorochroman-3-yl)methanone; (R)-[6-(3-chloro-1H -pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorosomn-3-yl)methyl ketone dimethyl sulfonate; (6-Chlorochrome-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazol-4-yl)indol-3-yl]methyl ketone; (6-Chlorochrome-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazol-3-yl)indol-3-yl] methyl ketone; [6-(2-amino-4-pyridyl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-chlorochrome-3-yl)methyl ketone; [1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazol-4-yl)indol-3-yl]-(6-fluorosom-3-yl)methyl ketone; [1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazol-3-yl)indol-3-yl]-(6-fluorochroman-3-yl)methyl ketone; (6-Chlorochrome-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1-yl) H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (R)-(6-chloro-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1-yl) H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (S)-(6-chloro-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1-yl) H [-pyrazol-4-yl)indol-3-yl]methyl ketone; (R)-(6-(5-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6-chlorochrome-3-yl) methyl ketone; (S)-(6-(5-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6-chlorochrome-3-yl) methyl ketone; [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-fluorosom-3-yl)methyl ketone; (S)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-fluorosom-3-yl)methyl ketone; (S)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-fluorosom-3-yl)methyl ketone dihydrochloride; (R)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-fluorosom-3-yl)methyl ketone; [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-methoxychroman-3-yl)methyl ketone; (6-Chloro-2,3-dihydro-1,4-benzodioxin-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl] methyl ketone; (2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(1H-pyrazol-4-yl)-1H-indazol-3-yl)methyl ketone; (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (6-Chlorochrome-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (S)-(6-chloro-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (R)-(6-chloro-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (6-Chlorochrome-3-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1-yl) H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H -pyrazole-4-yl)-1 H -Indazol-3-yl)(6-methoxychroman-3-yl)methyl ketone; (6-(3-chloro-1) H -pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1 H-Indazol-3-yl)(6-methoxychroman-3-yl)methyl ketone; (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H -pyrazole-4-yl)-1 H -Indazol-3-yl)(6-Fluorochrom-3-yl)methyl ketone; (6-(3-chloro-1) H -pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1 H -Indazol-3-yl)(6-Fluorochrom-3-yl)methyl ketone; (S)-(6-(3-chloro-1) H -pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1 H -Indazol-3-yl)(6-Fluorochrom-3-yl)methyl ketone; Chromium-3-yl(1-(2-(dimethylamino)ethyl)-6-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-3-yl) methyl ketone; (6-(3-fluoro-1H-pyrazol-4-yl)-1-(((S)-1-methylazacyclobutane-2-yl)methyl)-1H-indazol-3-yl)(6-fluorochroman-3-yl) methyl ketone; (6-(3-fluoro-1H-pyrazol-4-yl)-1-(((S)-1-methylazacyclobutane-2-yl)methyl)-1H-indazol-3-yl)((S)-6-fluorochroman-3-yl) methyl ketone; (1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1) H -pyrazole-4-yl)-1 H -Indazol-3-yl)(6-Fluorochrom-3-yl)methyl ketone; (7-Chloro-2,3-dihydrobenzo[ b [1,4]Dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (7-Chloro-2,3-dihydrobenzo[ b [1,4]Dioxin-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1 H -pyrazole-4-yl)-1 H -Indazole-3-yl)methyl ketone; (6-(3-chloro-1) H -pyrazole-4-yl)-1-(2-(dimethylamino)ethyl)-1 H- indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b ][1,4]dioxan-2-yl)methanone; (1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H -pyrazol-4-yl)-1 H - indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b ]oxepin-4-yl)methanone ((1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H -pyrazol-4-yl)-1 H - indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b ]oxepin-4-yl)methanone ((1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 (6-(3-chloro-1 H -pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b ]oxepin-4-yl)methanone ((1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 (6-(3-chloro-1 H -pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b ]oxepin-4-yl)methanone ((1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 (6-(3-chloro-1 H -pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b ]oxepin-4-yl)methanone ((1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 (6-(5-chloro-1H-pyrazol-4-yl)-1-(((R)-1-methylazetidin-2-yl)methyl)-1H-indol-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrobromide; (6-(5-chloro-1H-pyrazol-4-yl)-1-(((R)-1-methylazetidin-2-yl)methyl)-1H-indol-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrobromide; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ((S)-6-chlorochroman-3-yl)(l-((R)-2-(dimethylamino)propyl)-6-(5-fluoro-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(diethylamino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(diethylamino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethanesulfonate; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethanesulfonate; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethanesulfonate; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide; (6-(3-chloro-lH-pyrazol-4-yl)-l-(((R)-l-(2,2-difluoroethyl)azetidin-2-yl)methyl)-lH- indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; (6-(3-chloro-lH-pyrazol-4-yl)-l-(((R)-l-(2,2-difluoroethyl)azetidin-2-yl)methyl)-lH- indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; (6-(3-chloro-lH-pyrazol-4-yl)-l-(((R)-l-(2,2-difluoroethyl)azetidin-2-yl)methyl)-lH- indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)- lH-indol-3-yl)(6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)- lH-indol-3-yl)(6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)- lH-indol-3-yl)(6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)- lH-indol-3-yl)(6-methoxychroman-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH-pyrazol-4- yl)-lH-indol-3-yl)methanone hydrochloride; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH-pyrazol-4- yl)-lH-indol-3-yl)methanone dihydrobromide; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH-pyrazol-4- yl)-lH-indol-3-yl)methanone dimethanesulfonate; (6-(3-fluoro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-indazol-3-yl)((S)- 6-fluorochroman-3-yl)methanone dihydrobromide.

[0083] Examples The present application is further illustrated by the following examples, which illustrate the preparation of the compounds of Figure 1 according to the present application. The examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the application in any way. It will be understood by those skilled in the art that variations and modifications can be made without changing the scope of the application.

[0084] The nuclear magnetic resonance (NMR) and mass spectrometry (MS) spectra of the compounds obtained in the following examples and the compounds described herein are consistent with the NMR and MS spectra of the compounds of the formulae described herein.

[0085] Liquid chromatography-mass spectrometry (LC-MS) method: 1. The samples were run on an Agilent Technologies 6120 MSD system with a Zorbax Eclipse XDB-C18 (3.5 ) reversed-phase column (4.6 x 50 mm) run at room temperature with a flow rate of 1.5 mL / min.

[0086] 2. The mobile phase used solvent A (water / 0.1% formic acid) and solvent B (acetonitrile / 0.1% formic acid): 95% / 5% to 0% / 100% (A / B) for 5 minutes.

[0087] 3. Mass spectra (m / z) were recorded using electrospray ionization (ESI).

[0088] 4. Ionization data was rounded to the nearest whole number.

[0089] Proton NMR spectra: Unless otherwise indicated, all 1 H NMR spectra were run on a Varian Series Mercury 400 or 500 MHz. The conventional abbreviations used for designating multiplet peaks are used: e.g., s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br s (broad singlet), all observed protons are reported as parts per million (ppm) from the low field of tetramethylsilane.

[0090] Example 1: Preparation of Compounds Compound 1-1: (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H- pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]methanone (Step 5a) 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) in toluene (60 mL) was heated to reflux with stirring for 3 hours. The mixture was cooled to room temperature and concentrated to remove the volatile organic solvent. The crude product was dissolved in acetonitrile (100 mL) and concentrated to provide 1a as a light brown oil. 1a was used in the next step without further purification.

[0091] 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. After stirring at 0 °C for 1 h, the reaction was quenched with saturated aqueous NH4Cl (100 mL) at 0 °C to form a solid precipitate. The mixture was then warmed to room temperature and stirred for an additional 2 h. The solid was collected by filtration and then rinsed with methanol. The resulting solid was dried under high vacuum to provide 1b as a white solid in 80% yield (7.4 g). LC / MS found 391.0 and 393.0 [M+H] + .

[0092] 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) in DMF (20 mL) was heated to 70 °C for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on a silica gel column using a 20-100% EtOAc / hexanes gradient to give 1c as a white solid in 20% yield (202 mg). LC / MS found 463.1 and 465.0 [M+H] + .

[0093] Step 4: A mixture of intermediate 1c (202 mg, 43 μmol), [3-methoxy-1-(p- toluenesulfonyl)pyrazol-4-yl]boronic acid (190 mg, 65 μmol), potassium carbonate (2 M in water, 54 μL), and tetrakis(triphenylphosphine)palladium (25.0 mg, 22 μmol) in 1,4-dioxane (10 mL) was degassed by sparging with argon for 5 min, and 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 with EtOAc (50 mL) twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 1d, and the residue was used in the next step without further purification.

[0094] Step 5a, 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). The solution was stirred at 0 °C for 30 minutes and it was neutralized with 1N HC1 solution (4.0 mL), diluted with EtOAc (30 mL) and saturated Na2C03solution (30 mL). The aqueous phase was separated and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, treated with silica gel and evaporated under reduced pressure. The material was purified by silica gel column chromatography to afford compound 1-1 (6-chloro-chroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methoxy-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]methanone as a white solid (101 mg, 210 μmol, 58% yield for steps 4 and 5a). LC / MS found 480.2 [M+H] + .

[0095] Compound 1-2: ((6-chloro-chroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone dihydrochloride Step 6a: To a solution of 1-1 (50 mg, 104 μmol) in acetone (1 mL) was slowly added 4M HC1 in dioxane (55 μL) at room temperature to form a solid precipitate. After stirring at room temperature for an additional hour, tert-butyl methyl ether (2 mL) was added to completely precipitate. The solid was collected by filtration under a nitrogen atmosphere, rinsed with tert-butyl methyl ether, and dried under vacuum to give 1-2 as a white powder (47.5 mg, 82%). LC / MS found 480.2 [M+H] + .

[0096] Compound 1-3: ((6-chloro-chroman-3-yl)(1-(2-(dimethylamino)ethyl)-6-(5-methoxy-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone dimethanesulfonate Step 6a: To a solution of 1-1 (50 mg, 104 μmol) in acetone (1 mL) was slowly added 1M methanesulfonic acid in acetone (220 μL) at room temperature to form a solid precipitate. After stirring at room temperature for an additional hour, tert-butyl methyl ether (2 mL) was added to completely precipitate. The resulting solid was collected by filtration under a nitrogen atmosphere, rinsed with tert-butyl methyl ether, and dried under vacuum to give 1-3 as a white powder (60.3 mg, 90%). LC / MS found 480.2 [M+H] +.

[0097] The following compounds 1-4 to 1-51 shown in Table 1 were prepared by analogous methods (General Scheme 1) to those described for the preparation of compounds 1-1, 1-2 or 1-3, using the appropriate (4) with the appropriate boronic acid / ester (R 3 ) and the appropriate R 1 R 2 substituent.

[0098] Table 1 Compound 2-1: [1-(2-aminoethyl)-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]-(6-chloro-chroman-3-yl)methanone Step 1: A mixture of 1b (80 mg, 213 μmol), potassium carbonate (176.8 mg, 1.3 mmol, 77 μL), and 2-bromoethan-1-ol (87 mg, 639 μmol) in DMF (2 mL) was heated to 70 °C and stirred overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on a silica gel column using 10-100% EtOAc / hexanes gradient to give ([6-bromo-1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-3-yl]-(6-chloro-chroman-3- yl)methanone) (2a, 68 mg, 68% yield) as a white solid. LC / MS found 435.1 and 437.0 [M+H] + .

[0099] 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 h. The solution was diluted with DCM (10 mL), washed sequentially with water and brine (10 mL each), dried (Na2S04), treated with silica gel, and evaporated under reduced pressure. The material was purified by column chromatography on silica gel to provide 2-(6-bromo-3-(6-chlorochroman-3- carbonyl)-lH-pyrrolo[3,2-c]pyridin-l-yl)ethyl methanesulfonate (2b, 59 mg, 115 μmol, 89% yield) as a clear oil. LC / MS found 513.0, 515.1 [M+H] + .

[0100] 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 EtOAc (10 mL), washed sequentially with water and brine (10 mL each), dried (Na2S04), treated with silica gel, and evaporated under reduced pressure. The material was purified by column chromatography on silica gel to provide (l-(2-azidoethyl)-6-bromo-lH-pyrrolo[3,2-c]pyridin-3-yl)(6-chlorochroman-3- yl)methanone (2c, 19 mg, 41 μmol, 73% yield) as a white solid. LC / MS found 460.2, 462.2 [M+H] + .

[0101] Step 4: A mixture of 2c (19 mg, 41 μmol), triphenylphosphane (14 mg, 54 mmol), and water (2-3 drops) 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 EtOAc (10 mL). The aqueous layer was separated and extracted with EtOAc (5 mL). The organic layers were combined, dried, treated with silica gel, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to provide (l-(2-aminoethyl)-6-bromo-lH-pyrrolo[3,2-c]pyridin-3-yl)(6-chlorochroman-3- yl)methanone (2d, 16 mg, 37 μmol, 89% yield) as a white solid. LC / MS found 434.0, 436.0 [M+H] + .

[0102] 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 in water, 53 μL), and tetrakis(triphenylphosphine)palladium (2.5 mg, 2.1 μmol) in 1,4-dioxane (2 mL) was degassed by sparging with argon or nitrogen for 5 min, heated to 70 °C and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (5 mL) and extracted twice with EtOAc (5 mL). The combined organic layers were dried over Na2S04, filtered and concentrated to give tert-butyl 4-(1 -(2-aminoethyl)-3-(6-chlorochroman-3- carbonyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)-5-chloro-1 H-pyrazole-1 -carboxylate 2e which was used in the next step without further purification.

[0103] Step 6: A solution of crude 2e (21 mg) in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at ambient temperature. After stirring at room temperature for 1.5 h, the mixture was concentrated under reduced pressure to provide a residue. The material was dissolved in EtOAc (10 mL) and washed with 2 M sodium carbonate solution (10 mL). The aqueous layer was separated and extracted with EtOAc (5 mL), the combined organics were dried over Na2S04, filtered, treated with silica gel and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide (1 -(2-aminoethyl)-6-(3-chloro-1 H-pyrazol-4-yl)-1 H-pyrrolo[3,2- c]pyridin-3-yl)(6-chloro-2H-chromen-3-yl)methanone (2-1, 8.3 mg, 18.2 μmol; 25% yield over steps 5 and 6) as a white solid. LC / MS found 456.1 [M+H] + .

[0104] Compound 2-12: (6-Chlorochroman-3-yl)-[6-(5-chloro-1 H-pyrazol-4-yl)-1 - [(2S)-2-(dimethylamino)propyl]indol-3-yl]methanone Step 1 : A mixture of [l-[(l-aminocyclopropyl)methyl]-6-bromo-indol-3-yl]-(6- chlorochroman-3-yl)methanone (2f, 22 mg, 48 μmol), formaldehyde (36 μL, 479 μmol) and acetic acid (12 μL, 210 μmol) in THF (1 mL) prepared in a similar manner to 2d was stirred at room temperature. At ca. 30 min, the reaction mixture was cooled in an ice bath and treated with sodium cyanoborohydride (6.6 mg, 105 μmol). The reaction mixture was stirred for an additional 30 min and quenched with saturated aqueous NH4Cl (1 mL). The mixture was concentrated, diluted with EtOAc (15 mL), washed sequentially with water and brine (15 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide (6-bromo-l-((S)-2-(dimethylamino)propyl)-lH-indol-3-yl)(6-chlorochroman-3- yl)methanone (2g, 23 mg, 47 μmol, 98% yield) as a light brown solid. LC / MS found 475.1, 477.2 [M+H] + .

[0105] Step 2: A mixture of 2g (23 mg, 48 μmol), 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]dichloropalladium(ll) (2.0 mg, 2.4 μmol) in 1,4-dioxane (2 mL) was degassed by sparging with argon or nitrogen for 5 min, heated to 70 °C and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (5 mL), and extracted twice with EtOAc (5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl 3-chloro-4-(3-(6-chlorochroman-3- carbonyl)- 1 -((S)-2-(dimethylamino)propyl)- 1 H-indol-6-yl)- 1 H-pyrazole- 1 -carboxylate 2h which was used without further purification in the next step.

[0106] Step 3a, Boc-protected pyrazole compound: A solution of crude 2h (29 mg) in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at room temperature. At ~1.5 h, the solvent was evaporated under reduced pressure, dissolved in EtOAc (10 mL), and washed with 2 M Na2C03solution (10 mL). The aqueous layer was separated and extracted with EtOAc (5 mL), the combined organic layers were dried over Na2S04, filtered, treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 3-chloro-4-(3-(6-chloro-chroman-3-ylcarbonyl)-1-((S)-2-(dimethylamino)propyl)-1H- indol-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2-12, 21 mg, 42 μmol; 87% yield for steps 2 and 3a) as a light brown solid. LC / MS found 497.3 [M+H] + .

[0107] The following compounds 2-2 to 2-16 shown in Table 2 were prepared by similar methods (general scheme 2) to those described for the preparation of compound 2-1 or 2-12, using the appropriate 2a (azaindole / indole core) and the appropriate boronic acid / ester (R 3 ) as described.

[0108] Table 2 Compound 3-1 : [1-[2-(azetidin-1-yl)ethyl]-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridin-3-yl]-(6-fluorochroman-3-yl)methanone Step 1 : A mixture of 3a [6-bromo-l-(2-hydroxyethyl)pyrrolo[2,3-b]pyridin-3-yl]-(6- fluorochroman-3-yl)methanone (85.0 mg, 203 μmol) and triethylamine (56.5 μL, 405 μmol) prepared by a similar method in Scheme 2 in DCM (1.5 mL) was cooled in an ice bath, treated with methanesulfonyl chloride (15 μL, 193 μmol), and stirred at 0 °C for 1 h. The solution was diluted with DCM (10 mL), washed sequentially with water and brine (10 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide 2-(6-bromo-3-(6-fluorochroman-3- carbonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)ethyl methanesulfonate (3b, 86 mg, 173 μmol, 85% yield) as a light brown oil. LC / MS found 497.1, 499.2 [M+H] + .

[0109] 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 to 50 °C and shaken overnight. The reaction mixture was diluted with EtOAc (10 mL), washed sequentially with water and brine (10 mL each), dried (Na2SO4), treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide (l-(2-(azetidin-l-yl)ethyl)-6-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)(6- fluorochroman-3-yl)methanone (3c, 4.7 mg, 10 μmol, 25% yield) as a light brown solid. LC / MS found 458.2, 460.1 [M+H] + .

[0110] Step 3: A mixture of 3c (4.7 mg, 10 μmol), 3-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (6.1 mg, 18 μmol) or 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- toluenesulfonyl-1H-pyrazole, potassium carbonate (2 M in water, 13 μL), and tetrakis(triphenylphosphine)palladium (3.5 mg, 2.1 μmol) in 1,4-dioxane (2 mL) was degassed by sparging with argon or nitrogen for 5 min, heated to 70 °C and shaken overnight. The mixture was cooled to room temperature, concentrated, poured into water (5 mL), and extracted twice with EtOAc (x2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give intermediate 3d-Boc (Boc (4-(1-(2-(azetidin-1-yl)ethyl)-3-(6-fluorotetralin-3- carbonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-5-chloro-1H-pyrazole-1-carboxylic acid tert-butyl ester) or 3d-Ts ([1-[2-(azetidin-1-yl)ethyl]-6-[3-methoxy-1-(p-tolylsulfonyl)pyrazol-4-yl]indol-3-yl]-(6-chlorotetralin-3-yl)methanone). Intermediate 3d-Boc or 3d-Ts was used in the next step without further purification.

[0111] 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 ambient temperature. At ~1.5 h, the solvent was evaporated under reduced pressure to provide a residue. The material was dissolved in EtOAc (10 mL) and washed with 2 M Na2CO3solution (10 mL). The aqueous layer was separated and extracted with EtOAc (5 mL), and the combined organics were dried over Na2SO4, filtered, treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide [1-[2-(azetidin-1-yl)ethyl]-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridin-3-yl]-(6-fluorotetralin-3-yl)methanone (3-1, 2.1 mg, 4.4 μmol; 42% yield for steps 3 and 4a) as a light brown solid. LC / MS found 480.2 [M+H] + .

[0112] Step 4b: A solution of 3d-Ts (crude, 30 mg) in THF (1 mL) was cooled on an ice bath and then treated with 2N aqueous NaOH (0.20 mL). The solution was stirred at 0 °C for 30 min and it was neutralized with 1N aqueous HC1 (0.40 mL), diluted with EtOAc (10 mL) and saturated aqueous Na2C03(10 mL). The aqueous phase was separated and extracted with EtOAc (x2). The combined organic layers were dried over Na2S04, filtered, treated with silica gel and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide [1-[2-(azetidin-1-yl)ethyl]-6-(3-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-chloro-chroman-3-yl)methanone (3-4, 4.0 mg, 8.5 μmol; 17% yield for steps 3 and 4b) as a white solid. LC / MS found 491.2 [M+H] + .

[0113] The following compounds 3-2 to 3-19 shown in Table 3 were prepared by analogous methods to those described for the preparation of compound 3-1 or 3-4 (general scheme 3), using the appropriate (7) (azaindole / indole core), the appropriate boronic acid / ester (R 3 ) and the appropriate R 1 substituent.

[0114] Table 3 Compound 4-1 [1-[(1-Aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-chloro-chroman-3-yl)methanone Step 1: A mixture of (6-bromo-lH-indol-3-yl)-(6-chlorochroman-3-yl)methanone lb (300 mg, 768 pmol), potassium carbonate (318 mg, 2.3 mmol), and 1- (bromomethyl)cyclopropane carboxylate (445 mg, 2.3 mmol) in DMF (4 mL) was heated to 70 °C and shaken overnight. The reaction mixture was diluted with EtOAc (15 mL), washed sequentially with water and brine (15 mL each), dried (Na2S04), treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide methyl l-((6-bromo-3-(6-chlorochroman-3- carbonyl)-lH-indol-l-yl)methyl)cyclopropane-l-carboxylate (4a, 380 mg, 756 pmol, 98% yield) as a light brown solid. LC / MS found 502.2, 504.3 [M+H] + .

[0115] Step 2: A mixture of 4a (380 mg, 756 pmol) and LiOH H20 (2 M, 3.8 mL, 7.6 mmol) in THF (4 mL) was stirred at room temperature overnight. The mixture was acidified to pH 3-4 with IN aqueous HC1 and the resulting precipitate was vacuum filtered, washed with water, and dried under vacuum overnight to provide l-((6-bromo-3-(6-chlorochroman-3- carbonyl)-lH-indol-l-yl)methyl)cyclopropane-l-carboxylic acid (4b 290 mg, 593 pmol, 78% yield) as a light brown solid. LC / MS found 487.1, 489.1 [M+H] - .

[0116] Step 3: A mixture of 4b (290 mg, 593 pmol), triethylamine (165 pL, 1.19 mmol), and [azido(phenyloxy)phosphoryl]oxybenzene (218 pL, 1.01 mmol) in THF (3 mL) was shaken at room temperature overnight. The reaction mixture was diluted with EtOAc (10 mL), washed sequentially with water and brine (10 mL each), dried (Na2S04), treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide l-((6-bromo-3-(6-chlorochroman-3- carbonyl)-lH-indol-l-yl)methyl)cyclopropane-l-carbonyl azide (4c, 225 mg, 438 pmol, 73% yield) as a light brown solid. LC / MS found 513.2, 513.2 [M+H] + .

[0117] Step 4: A solution of 4c (215 mg, 418 pmol) in t-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 EtOAc (10 mL), washed sequentially with water and brine (10 mL each), dried (Na2S04), treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide tert-butyl (1-((6-bromo-3-(6-chloro-chroman-3-carbonyl)-1H-indol-1- yl)methyl)cyclopropyl)carbamate (4d, 170 mg, 304 pmol, 72% yield) as a light brown solid. LC / MS found [M+H] 540.2 + .

[0118] Step 5: A mixture of 4d (45 mg, 80 pmol), tert-butyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (42 mg, 129 pmol), potassium carbonate (2 M in water, 100 pL), and cyclopentyl(diphenyl)phosphane; dichloromethane; palladium dichloride; iron (3.3 mg, 4.0 pmol) in 1,4-dioxane (2 mL) was degassed by sparging 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 EtOAc (5 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give tert-butyl 4-(1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-(6-chloro-chroman-3-carbonyl)-1H-indol-6-yl)-3-methoxy-1H-pyrazole-1-carboxylate 4e, which was used in the next step without further purification.

[0119] Step 6 A solution of crude 4e (54 mg) in DCM (1.0 mL) was treated with TFA (0.5 mL) and stirred at ambient temperature. At about 1.5 hours, the solvent was evaporated under reduced pressure to provide a residue. The material was dissolved in EtOAc (10 mL) and washed with 2 M Na2C03solution (10 mL). The aqueous layer was separated and extracted with EtOAc (5 mL), and the combined organics were dried over Na2S04, filtered, treated with silica gel, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide [1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone (4-1, 25 mg, 52 pmol; 65% yield for steps 5 and 6) as a light brown solid. LC / MS found 480.2 [M+H] +.

[0120] The following compounds 4-2 to 4-6 shown in Table 4 were prepared using a method similar to that described for the preparation of compound 4-1 (General Scheme 4), using a suitable 1b (azaindole / indole core), a suitable borate / ester (R... 3 ) and appropriate R 1 R 2 Preparation of substituents.

[0121] Table 4 Compound 5-1: (6-chloro-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methyl-1H-pyrazol-4-yl)indol-3-yl] methyl ketone Step 1: Add 6-bromo-1 H A solution of indole (5.00 g, 25.5 mmol) in DMF (150 mL) was fractionally treated with sodium hydride (60% dispersion in mineral oil; 3.08 g, 77.0 mmol). The solution was stirred at ambient temperature for 30 min, 2-dimethylaminoethyl chloride hydrochloride (4.83 g, 33.5 mmol) was added, and the mixture was stirred at 70 °C for 5 h. The mixture was diluted with EtOAc (500 mL), washed successively with water (3 x 500 mL) and brine (300 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 2-(6-bromo-1-dimethylaminoethyl ... H -indol-1-yl)- N , N -Dimethylethyl-1-amine (5a, 5.93 g, 22.2 mmol, 87% yield). LC / MS values: 267.1, 269.1 [M+H] + .

[0122] Step 2: Cool the solution of 5a (2.51 g, 9.39 mmol) in DMF (90 mL) on an ice bath, then use... NTreatment with iodosuccinimide (2.22 g, 9.9 mmol) followed by removal from the ice bath. After stirring for 90 min, the reaction mixture was diluted with EtOAc (500 mL) and washed with water (500 mL). The aqueous phase was extracted with EtOAc (150 mL), and the combined organic layers were washed with brine (2 x 450 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide 2-(6-bromo-3-iodo-indole-1-yl)- N , N -Dimethyl-ethylamine (5b, 2.12 g, 5.38 mmol, 57% yield). LC / MS values: 393.0, 395.0 [M+H] + .

[0123] Step 3: Under nitrogen atmosphere, add 100 mL of THF to 5b (2.75 g, 7.00 mmol). Cool the solution in a dry ice / acetonitrile bath (approximately -42°C) and treat dropwise with isopropyl magnesium chloride (2 M in THF, 4.90 mL) (3 min). After three min, replace the cooling bath with an ice bath and stir the mixture for 60 min. Cool the reaction mixture back to -42°C and add 6-chloro- N -Methoxy- N A solution of methyl-chroman-3-carboxamide (6-16, 2.68 g, 10.49 mmol) in THF (27 mL) for 3 min. The cooling bath was removed, and the reaction mixture was stirred for 3 h. The reaction was quenched by adding 25% NH4Cl aqueous solution (20 mL) and stirred for 10 min. THF was removed under reduced pressure. The aqueous residue was diluted with water to 200 mL and extracted with DCM (200 mL). The organic layer was washed with 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 provide [6-bromo-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-chlorochroman-3-yl) methyl ketone as a yellow solid (5c, 1.02 g, 2.2 mmol, 32% yield). LC / MS 461.1, 463.1 [M+H] + .

[0124] Step 4: A suspension of 5c (143.5 mg, 310.8 μmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-l-carboxylate (146.7 mg, 476.0 μmol), PdCl2(dppf)-CH2Cl2(39.1 mg, 47.88 μmol), and potassium phosphate tribasic (198.2 mg, 933.7 μmol) in dioxane (5 mL) and water (0.3 mL) in a 40 mL vial was bubbled with nitrogen for 12 min and shaken at 70 °C overnight. The solution was evaporated under reduced pressure, and the residue was dissolved in EtOAc (30 mL), washed sequentially with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give impure tert-butyl 4-[3-(6-chloro-chroman-3-ylcarbonyl)-l-[2-(dimethylamino)ethyl]indol-6-yl]-3-methyl-pyrazole-l-carboxylate (5d, 290.7 mg) as a brown solid. The resulting residue was used without further purification. LC / MS found 563.3 [M+H] + .

[0125] Step 5: A solution of impure 5d (290.7 mg) in DCM (2 mL) and MeOH (0.1 mL) was treated with TFA (2 mL). The solution was stirred at ambient temperature for 25 min. The solvent was evaporated under reduced pressure. The residue was dissolved in MeOH (10 mL) and evaporated twice. The residue was dissolved in EtOAc (30 mL), washed sequentially with aqueous NaOH (1 M, 5 mL) and brine (5 mL), dried over Na2SO4, treated with silica gel, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methyl-lH-pyrazol-4-yl)indol-3-yl]methanone (5-1, 99.3 mg, 214.48 μmol; 69% yield over steps 4 and 5) as a tan solid. LC / MS found 463.3 [M+H] + .

[0126] Compound 5-29: (6-Chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(3-methoxy-lH-pyrazol-4-yl)-lH-indazol-3-yl)methanone Step 1: To a solution of 6-bromo-3-iodo-l H- 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) was added 2-chloro- N , N - dimethyl-ethylamine hydrochloride (479 mg, 3.33 mmol). The mixture was heated to reflux with stirring overnight, cooled to room temperature, poured into H2O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using a 10-40% EtOAc / heptane gradient to provide 2-(6-bromo-3-iodo-l H - indazol-l-yl)- N , N - dimethyl-ethylamine hydrochloride (479 mg, 3.33 mmol). The mixture was heated to reflux with stirring overnight, cooled to room temperature, poured into H2O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using a 10-40% EtOAc / heptane gradient to provide 2-(6-bromo-3-iodo-l + .

[0127] Step 2: To a solution of 5e (542 mg, 1.38 mmol) in dry THF (10 mL) cooled to -40 °C was added isopropylmagnesium chloride (2.0 M in THF, 0.96 mL, 1.9 mL) dropwise. The mixture was stirred at this temperature for 1 hour, then 6-chloro- N - methoxy- N - methyl-chromane-3-carboxamide (6-16, 459 mg, 1.80 mmol) in dry THF (4 mL). The mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over Na2SO4, then concentrated to dryness. The residue was purified by column chromatography on silica gel using a 50-100% EtOAc / heptane gradient to provide (6-bromo-l-(2-(dimethylamino)ethyl)-l H - indazol-l-yl)- + .

[0128] Step 3: Starting with 5f and 3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 -toluenesulfonic acid, (6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(3- methoxy-lH-pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol) was obtained as a light brown solid by using the Suzuki protocol Step 4 in Scheme 5. LC / MS obsd. 635.3 [M+H] H - pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol). LC / MS obsd. 635.3 [M+H] H - pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol). LC / MS obsd. 635.3 [M+H] + .

[0129] Step 4: Starting with 5g (6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(3- methoxy-lH-pyrazol-4-yl)-lH-indazol-3-yl)methanone, (6-chlorochroman-3-yl)(l-(2- (dimethylamino)ethyl)-6-(3-fluoro-lH-pyrazol-4-yl)-lH-indazol-3-yl)methanone (5-29, 11 mg, 23 μmol) was obtained as a yellow solid by using the general deprotection Step 5a in Scheme 1. H - pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol). LC / MS obsd. 635.3 [M+H] H - pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol). LC / MS obsd. 635.3 [M+H] H - pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol). LC / MS obsd. 635.3 [M+H] H - pyrazol-4-yl)-lH-indazol-3-yl)methanone (5g, 47 mg, 69 μmol). LC / MS obsd. 635.3 [M+H] + .

[0130] Compound 5-34: (6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(3-fluoro-lH- pyrazol-4-yl)-lH-indazol-3-yl)methanone Step 1 : Into a tared 40 mL vial equipped with a stir bar was charged with [6-bromo-l-[2-(dimethylamino)ethyl]indazol-3-yl]-(6-chlorochroman-3-yl)methanone (5h, 399 mg, 0.86 mmol), bis(pinacolato)diboron (329 mg, 1.30 mmol), potassium acetate (170 mg, 1.73 mmol), and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (35 mg, 42 μmol). The vial was capped with a septum cap. 1,4-Dioxane (9 mL) was added via syringe. The mixture was purged with N2for 10 minutes and heated to 100 °C with stirring overnight. The mixture was cooled to room temperature and filtered through a plug of celite, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography using a 1-7% CH3OH / CH2Cl2gradient to provide 5i (6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-3-yl)methanone in quantitative yield as a viscous brown solid. LC / MS found 510.3 [M+H] H - indazol-3-yl)methanone. LC / MS found 510.3 [M+H] + .

[0131] Step 2: Starting with tert-butyl 4-bromo-3-fluoro-l H - pyrazol-l-yl)indazol-3-yl)methanone (5-34, 127 mg, 31% yield). LC / MS found 468.3 [M+H] H - pyrazol-l-yl)indazol-3-yl)methanone (5-34, 127 mg, 31% yield). LC / MS found 468.3 [M+H] + . H

[0132] Alternatively, the racemic mixture of compounds was separated by supercritical fluid chromatography as follows.

[0133] Compound 5-19: [(3 S )-6-chlorochroman-3-yl]-[l-[2-(dimethylamino)ethyl]-6-(5-methoxy-l H - pyrazol-l-yl)indazol-3-yl)methanone and Compound 5-20: [(3 R )-6-chlorochroman-3-yl]-[l-[2-(dimethylamino)ethyl]-6-(5-methoxy-l H - pyrazol-l-yl)indazol-3-yl)methanone ​ A sample of racemic compound 5-18 was separated by supercritical fluid chromatography under the following conditions: column, NanoMicro UniChiral AS-5H 21 x 250 mm; mobile phase, 45% 2-propanol and 0.25% diethylamine in CO2; flow rate, 70 mL / min; sample, 149.5 mg dissolved in 6 mL methanol and 6 mL dichloromethane; injection volume, 1.0 mL; detection: 254 nm.

[0134] Compound 5-19: second eluting peak, 64.7 mg, 100% purity, 97.4% ee. LC / MS found 479.2 [M+H] + .

[0135] Compound 5-20: first eluting peak, 66.0 mg, 100% purity, 100% ee. LC / MS found 479.2 [M+H] + .

[0136] Compound 5-22: (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2- (dimethylamino)ethyl)-lH-indol-3-yl)(6-chlorochroman-3-yl)methanone and Compound 5-23: (R)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2- (dimethylamino)ethyl)-lH-indol-3-yl)(6-chlorochroman-3-yl)methanone and A sample of racemic compound 5-21 was separated by supercritical fluid chromatography under the following conditions: column, "ChiralPak IC-H 21 x 250 mm; mobile phase, 40% methanol in CO2; flow rate, 70 mL / min; sample, 19.4 mg dissolved in 2.0 mL methanol and 2.0 mL dichloromethane; injection volume, 0.75 mL; detection: 220 nm."

[0137] Compound 5-22: second eluting peak, 80.2 mg, 100% purity, 96.4% ee. LC / MS found 452.2 [M+H] + .

[0138] Compound 5-23: first eluting peak, 77.5 mg, 100% purity, 100% ee. LC / MS found 452.2 [M+H] + .

[0139] Compound 5-25: [l-[2-(dimethylamino)ethyl]-6-(5-methoxy-l H-pyrazole-4-yl)indol-3-yl]-[(3 R [1-[2-(dimethylamino)ethyl]-6-(5-methoxy-1-ethyl] ketone and compound 5-27: H -pyrazole-4-yl)indol-3-yl]-[(3 S )-6-Fluorochrome-3-yl]methyl ketone Samples of racemic compound 5-24 were separated by supercritical fluid chromatography under the following conditions: column, ChiralPak AD-H 21 x 250 mm; mobile phase, CO2 solution of 40% 2-propanol and 0.25% diethylamine; flow rate, 70 mL / min; sample, 82.0 mg dissolved in 4.0 mL methanol and 4.0 mL dichloromethane; injection volume, 2.0 mL; detection, 254 nm.

[0140] Compound 2-25: Second elution peak, 31.2 mg, 100% purity, 100% ee. LC / MS measured 463.3 [M+H] + .

[0141] Compound 5-27: First elution peak, 29.2 mg, 100% purity, 100% ee. LC / MS measured 463.3 [M+H] + .

[0142] The following compounds 5-2 to 5-18 and 5-28 to 5-51 shown in Table 5 were prepared by a method similar to that described for the preparation of compounds 5-1, 5-29, or 5-34, using appropriate boric acid / esters and Weinreb amides.

[0143] Table 5 Weinreb intermediate 6-1: 6-chloro- N -Methoxy- N -Methyl-chroman-3-carboxamide 6-Chlorochrome-3-carboxylic acid (964.5 mg, 4.54 mmol), N , O A suspension of dimethylhydroxylamine hydrochloride (665.3 mg, 6.82 mmol) and HBTU (2.15 g, 5.67 mmol) in DMF (33 mL) was used N , N 6-Diisopropylethylamine (18.4 mmol, 3.2 mL) was used to treat the solution. The solution was stirred overnight at ambient temperature. The solution was diluted with EtOAc (300 mL), washed sequentially with water (3 x 300 mL) and brine (300 mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The material was purified by silica gel column chromatography to provide 6-chloro- N -Methoxy- N 3-Methyl-chroman-3-carboxamide (Weinreb intermediate 9-1; 1.06 g, 4.15 mmol, 91% yield). LC / MS result: 256.0 [M+H] + .

[0144] The following Weinerb amide intermediates 6-2 to 6-21 shown in Table 6 were prepared using appropriate carboxylic acids by a method similar to that described for the preparation of intermediate 6-1.

[0145] Table 6 Example 2: ROCK Inhibition Measurement The kinase IC50 was determined by in vitro assay using a homogeneous technique based on LANCE Ultra TR-FRET (time-resolved fluorescence resonance energy transfer) (Perkin Elmer). 50 Recombinant ROCK1 (amino acids 1-477) and ROCK2 (amino acids 5-554) proteins were purchased from Carna Biosciences and SignalChem. Compound activity was measured using Envision and IC50 was calculated. 50The assay was performed in white LUMITRAC™ 200 96-well half-area microplate from Greiner Bio-One. The kinase reaction buffer consists of 50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT and 0.01% Tween-20. The kinases were incubated with 50 nM (ULight-CREBtide) substrate in the presence of 1 mM (ROCK1) or 1 mM (ROCK2) ATP. The kinase reaction was allowed to proceed for 1 hour, after which the stop buffer was added to a final 10 mM EDTA and 0.6 nM LANCE Ultra Europium Anti-phosphorylated CREB (Ser133) antibody (PerkinElmer TRF0200) in LANCE detection buffer. All assay incubations were performed at room temperature and during this time the microplate was sealed with a polyester film. The reaction was incubated for 1 hour and the signal was read in Envision in TR-FRET mode (excitation at 320 nm and emission at 615 / 665 nm).

[0146] The compounds of (1) exhibit useful pharmacological properties. As used herein, the manner in which potency of inhibitory activity (nM) is described is the value of inhibitory activity at 50% (IC 50 ). The results are shown in Table 7 below, where IC 50 defined as "A", IC 50 defined as "B", IC 50 defined as "C", and IC 50 defined as "D". Table 7 illustrates the inhibition of ROCK1 and ROCK2 for representative compounds of (1).

[0147] Table 7. Inhibitory activity of ROCK1 and ROCK2 at 1 mM ATP Example 3: Blood brain barrier (BBB) penetration properties in rats and mice Compounds of (1) exhibited useful blood brain barrier (BBB) penetration properties. Concentrations of compounds of (1) in blood and brain were measured from plasma and brain samples taken at 0.25 and 2 hours after intravenous (IV) administration of compounds of (1) at 1 mg / kg in CD-1 mice and Sprague-Dawley rats (n=3). After euthanasia of mice and rats, blood samples from cardiac puncture and brain tissue were collected. Plasma or brain homogenate was vortexed with internal standard in methanol / acetonitrile (1:1, v / v) for 1 min and centrifuged at 4000-4500 rpm for 15 min at room temperature to precipitate proteins. Subsequently, the supernatant was introduced into the LC / MS / MS system. Quantitative analysis was performed using an AB Sciex API 5500 mass spectrometer system (Sciex, USA).

[0148] Concentrations of compounds of (1) in plasma and brain samples were determined using standard calibration curves and brain-plasma concentration ratios were calculated. Table 8 shows blood brain barrier (BBB) ratios for representative compounds of (1).

[0149] Table 8. Blood brain barrier (BBB) ratios

Claims

1. A compound of Formula (1), a pharmaceutically acceptable salt of the compound, or a prodrug of the compound or the salt: wherein: X is CH2or O; Y is or CH; n is 0, 1, 2, or 3; and m is 0, 1, 2, or 3.

7. A pharmaceutical composition comprising a compound, salt, or prodrug of claim 1 and an additional component selected from the group consisting of a pharmaceutically acceptable carrier, diluent, excipient, adjuvant, and combinations thereof.

8. A compound represented by the following list, a pharmaceutically acceptable salt of the compound, or a prodrug of the compound or the salt: (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methoxy-lH-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]methanone; Z 1 , Z 2 and Z 3 are each independently N or CH; (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methoxy-lH-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]methanone; R 1 H, heterocycloalkyl, C3-C7cycloalkyl, or Ci-C6alkyl, wherein the nitrogen on the heterocycloalkyl is optionally substituted with Ci-C3alkyl, wherein the C3-C7cycloalkyl or Ci-C6alkyl is optionally substituted with one or more substituents selected from the group consisting of Ci-C6alkyl and OH; R 2 R is H, amino, NR 6 R 7 or NR 8 R 9 ; R 3 is 5-6 membered heteroaryl or bicyclic heteroaryl, wherein the heteroaryl or bicyclic heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, CHF2, CF3, C1-C3 alkyl and amino, wherein the 5-6 membered heteroaryl or bicyclic heteroaryl has 1-3 heteroatoms selected from the group consisting of oxygen and nitrogen; R 4 and R 5 each independently is H, Cl, F, OH, CD 3 , C1-C3 alkyl, or C1-C3 alkoxy, wherein said 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; R 6 and R 7 each independently is H, CD3, C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C1-C6 alkyl or C3-C7 cycloalkyl is optionally substituted with hydroxyl or C1-C3 alkoxy; and R 7 and R 8 together with the nitrogen atom to which they are bound form a 4-6 membered saturated monocyclic group, which does not have a heteroatom other than the nitrogen atom to which R 7 and R 8 are bound, wherein the 4-6 membered saturated or partially saturated monocyclic group is optionally substituted on one or two carbon atoms with halogen, amino, hydroxyl or C1-C3alkoxy.

2. The compound, salt, or prodrug of claim 1, wherein R 1 is H, heterocycloalkyl, C3-C7cycloalkyl, or C1-C6alkyl, wherein the nitrogen on the heterocycloalkyl is optionally substituted with a methyl or ethyl group, wherein the C3-C7cycloalkyl or C1-C6alkyl is optionally substituted with one or more suitable substituents selected from the group consisting of methyl, ethyl, and OH.

3. The compound, salt, or prodrug of claim 1, R 3 selected from the group consisting of: 。 4. The compound, salt, or prodrug of claim 1, wherein R 4 and R 5 are each independently H, Cl, F, OH, CH3, methoxy, OCD 3 , ethoxy, or isopropoxy.

5. The compound, salt, or prodrug of claim 1, wherein R 6 and R 7 each independently is H, CD3, C1-C6 alkyl, or C3-C7 cycloalkyl, wherein the C1-C6 alkyl or C3-C7 cycloalkyl is optionally substituted with hydroxyl, methoxy, or ethoxy.

6. The compound, salt, or prodrug of claim 1, wherein R 8 and R 9 together with the nitrogen atom to which they are bonded form a 4-6 membered saturated monocyclic group, which monocyclic group has no heteroatoms other than the nitrogen atom to which R 8 and R 9 are bonded, wherein the 4-6 membered saturated or partially saturated monocyclic group is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halogen, hydroxyl, and methoxyl. (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(3-methoxy-lH-pyrazol-4-yl)pyrrolo[3,2- c]pyridin-3-yl]methanone; (6-(5-chloro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-pyrrolo[3,2- c]pyridin-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrobromide; (6-(5-chloro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-pyrrolo[3,2- c]pyridin-3-yl)((S)-6-methoxychroman-3-yl)methanone dihydrobromide; (6-(5-chloro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-pyrrolo[3,2- c]pyridin-3-yl)((S)-6-methoxychroman-3-yl)methanone dimethanesulfonate; (6-chlorochroman-3-yl)-[6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]pyrrolo[2,3- b]pyridin-3-yl]methanone; [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6- fluorochroman-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]pyrrolo[3,2- c]pyridin-3-yl]methanone; ​ ​ ​ ​ ​ [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridin-3-yl]-(6- fluorochroman-3-yl)methanone; [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6- methoxychroman-3-yl)methanone; [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]pyrrolo[3,2-c]pyridin-3-yl]-(6- methoxychroman-3-yl)methanone; [l-(azetidin-3-yl)-6-(3-chloro-lH-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorochroman-3- yl)methanone; (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5-fluoro-lH-pyrazol-4-yl)pyrrolo[2,3- b]pyridin-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(dimethylamino)ethyl]indol-3- yl]methanone; [l-(azetidin-3-yl)-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2-yl)methyl] indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2-yl)methyl] indol-3-yl]methanone; [l-(azetidin-3-ylmethyl)-6-(5-chloro-lH-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3- yl)methanone; [l-(azetidin-3-ylmethyl)-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3- yl)methanone; [l-[2-(dimethylamino)ethyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6-fluorochroman-3- yl)methanone; (6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol-3- yl]methanone; (S)-(6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol- 3-yl]methanone; (R)-(6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol- 3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylpyrrolidin-2-yl)methyl] indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-methoxy-lH-pyrazol-4-yl)-l-[[(lR)-l- methylpyrrolidin-2-yl]methyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)(6-(5-methoxy-lH-pyrazol-4-yl)-l-(((S)-l- methylpyrrolidin-2-yl)methyl)-lH-indol-3-yl)methanone; [l-(azetidin-2-ylmethyl)-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; [l-(azetidin-2-ylmethyl)-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; [l-(azetidin-2-ylmethyl)-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; (6-Chlorochroman-3-yl)-[2-(5-chloro-lH-pyrazol-4-yl)-7-[2- (dimethylamino)ethyl]pyrrolo[2,3-d]pyrimidin-5-yl]methanone; (6-Chlorochroman-3-yl)-[7-[2-(dimethylamino)ethyl]-2-(5-fluoro-lH- pyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-5-yl]methanone; (l-(((R)-azetidin-2-yl)methyl)-6-(5-chloro-lH-pyrazol-4-yl)-lH-indol-3- yl)(6-methoxychroman-3-yl)methanone; (l-(((S)-azetidin-2-yl)methyl)-6-(5-chloro-lH-pyrazol-4-yl)-lH-indol-3- yl)(6-methoxychroman-3-yl)methanone; [l-[[(2S)-azetidin-2-yl]methyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6- methoxychroman-3-yl)methanone; [l-(azetidin-2-ylmethyl)-6-(5-chloro-lH-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; [l-[[(2R)-azetidin-2-yl]methyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; (l-(((S)-azetidin-2-yl)methyl)-6-(5-methoxy-lH-pyrazol-4-yl)-lH-indol-3- yl)(6-chlorochroman-3-yl)methanone; (l-(((R)-azetidin-2-yl)methyl)-6-(5-methoxy-lH-pyrazol-4-yl)-lH-indol-3- yl)(6-methoxychroman-3-yl)methanone; [l-(2-aminoethyl)-6-(3-chloro-lH-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6- chlorochroman-3-yl)methanone; [1-(2-aminopropyl)-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorochroman-3-yl)methanone; [1-(2-aminopropyl)-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorochroman-3-yl)methanone; [1-(2-aminopropyl)-6-(3-chloro-1H-pyrazol-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-(6-fluorochroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; (6-(5-chloro-1H-pyrazol-4-yl)-1-(((S)-1-methylazetidin-2-yl)methyl)-1H-indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; [1-[(2R)-2-aminopropyl]-6-(3-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6-chlorochroman-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2S)-2-(dimethylamino)propyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[[1-(dimethylamino)cyclopropyl]methyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[1-[(2R)-2-(dimethylamino)propyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2R)-2-(dimethylamino)propyl]indol-3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-1H-pyrazol-4-yl)-1-[(2R)-2-(dimethylamino)propyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (6-Chlorochroman-3-yl)-[6-(5-fluoro-lH-pyrazol-4-yl)-l-[(l-methylazetidin-3- yl)methyl]indol-3-yl]methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; [6-(5-Fluoro-lH-pyrazol-4-yl)-l-[[(2S)-l-methylazetidin-2-yl]methyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(methylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6- fluorochroman-3-yl)methanone; [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(methylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6- fluorochroman-3-yl)methanone; [6-(3-chloro-lH-pyrazol-4-yl)-l-[2-(methylamino)ethyl]pyrrolo[2,3-b]pyridin-3-yl]-(6- fluorochroman-3-yl)methanone; (6-chlorochroman-3-yl)-[l-[3-(dimethylamino)propyl]-6-(3-methoxy-lH-pyrazol-4-yl)indol- 3-yl]methanone; (S)-(6-chlorochroman-3-yl)(l-(3-(dimethylamino)propyl)-6-(3-methoxy-lH-pyrazol-4-yl)- lH-indol-3-yl)methanone; (R)-(6-chlorochroman-3-yl)(l-(3-(dimethylamino)propyl)-6-(3-methoxy-lH-pyrazol-4-yl)- lH-indol-3-yl)methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-lH-pyrazol-4-yl)-l-[2-(methylamino)ethyl]indol-3-yl] methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-lH-pyrazol-4-yl)-l-[2-[ethyl(methyl)amino]ethyl]indol- 3-yl]methanone; (6-chlorochroman-3-yl)-[l-[2-[ethyl(methyl)amino]ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol- 3-yl]methanone; (6-chlorochroman-3-yl)-[6-(5-chloro-lH-pyrazol-4-yl)-l-[2-(diethylamino)ethyl]indol-3-yl] methanone; (6-chlorochroman-3-yl)-[l-[2-(diethylamino)ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl] methanone; [6-(5-chloro-lH-pyrazol-4-yl)-l-[2-(diethylamino)ethyl]indol-3-yl]-(6-methoxychroman-3- yl)methanone; [l-[2-(diethylamino)ethyl]-6-(5-fluoro-lH-pyrazol-4-yl)indol-3-yl]-(6-methoxychroman-3- yl)methanone; [6-(5-chloro-lH-pyrazol-4-yl)-l-[2-(methylamino)ethyl]indol-3-yl]-(6-methoxychroman-3- yl)methanone; [6-(5-fluoro-lH-pyrazol-4-yl)-l-[2-(methylamino)ethyl]indol-3-yl]-(6-methoxychroman-3- yl)methanone; [6-(5-chloro-lH-pyrazol-4-yl)-l-[2-[ethyl(methyl)amino]ethyl]indol-3-yl]-(6-methoxychroman- 3-yl)methanone; [1-[2-[ethyl(methyl)amino]ethyl]-6-(5-fluoro-1H-pyrazol-4-yl)indol-3-yl]-(6- methoxychroman-3-yl)methanone; [1-[(1-aminocyclopropyl)methyl]-6-(5-methoxy-1H-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; [1-[(1-aminocyclopropyl)methyl]-6-(5-chloro-1H-pyrazol-4-yl)indol-3-yl]-(6- chlorochroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-chloro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6- chlorochroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6- fluorochroman-3-yl)methanone; (1-((1-aminocyclopropyl)methyl)-6-(5-fluoro-1H-pyrazol-4-yl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; 2,3-dihydro-1,4-benzodioxin-3-yl-[1 -[2-(dimethylamino)ethyl]-6-(1 H - pyrazol-4-yl)indol-3-yl]methanone; Chroman-3-yl-[1-[2-(dimethylamino)ethyl]-6-(1 H - pyrazol-4-yl)indol-3-yl]methanone; [6-(3-chloro-1 H - pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6- methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrochloride; (R)-(6-(3-chloro-1H-pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)(6- methoxychroman-3-yl)methanone; [6-(3-chloro-1 H - pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-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-1 H - pyrazol-4-yl)-1 -[2-(dimethylamino)ethyl]indol-3-yl]methanone; [6-(3-chloro-1H-pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(2,3-dihydro-1,4- benzodioxin-3-yl)methanone; [6-(3-chloro-1 H - pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorochroman-3- yl)methanone; (S)-[6-(3-chloro-1 H - pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorobenzofuran-3- yl)methanone; (S)-[6-(3-chloro-1 H - pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorochroman-3-yl)methanone hydrochloride; (S)-[6-(3-chloro-1 H - pyrazol-4-yl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-fluorochroman-3- yl)methanone dimethanesulfonate; (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazol-4-yl)indol-3- yl]methanone; (6-chlorochroman-3-yl)-[1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazol-3-yl)indol-3- yl]methanone; [6-(2-amino-4-pyridyl)-1-[2-(dimethylamino)ethyl]indol-3-yl]-(6-chlorochroman-3- yl)methanone; [1-[2-(dimethylamino)ethyl]-6-(3-methylisoxazol-4-yl)indol-3-yl]-(6-fluorochroman-3- yl)methanone; [1-[2-(dimethylamino)ethyl]-6-(2-methylpyrazol-3-yl)indol-3-yl]-(6-fluorochroman-3- yl)methanone; (6-chloro-chroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5-methoxy-l H pyrazol-4-yl)indol-3-yl]methanone; (R)-(6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5- methoxy- 1 H - pyrazol-4-yl)indol-3-yl]methanone; (S)-(6-chlorochroman-3-yl)-[l-[2-(dimethylamino)ethyl]-6-(5- methoxy- 1 H - pyrazol-4-yl)indol-3-yl]methanone; (R)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(dimethylamino)ethyl)-lH-indol-3-yl)(6- chlorochroman-3-yl)methanone; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(dimethylamino)ethyl)-lH-indol-3-yl)(6- chlorochroman-3-yl)methanone; [ l-[2-(Dimethylamino)ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6- fluorochroman-3-yl)methanone; (S)-[ l-[2-(Dimethylamino)ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6- fluorochroman-3-yl)methanone; (S)-[ l-[2-(Dimethylamino)ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6- fluorochroman-3-yl)methanone dihydrochloride; (R)-[ l-[2-(Dimethylamino)ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6- fluorochroman-3-yl)methanone; [ l-[2-(Dimethylamino)ethyl]-6-(5-methoxy-lH-pyrazol-4-yl)indol-3-yl]-(6- fluorochroman-3-yl)methanone; (6-chloro-2,3-dihydro-l,4-benzodioxin-3-yl)-[ l-[2-(dimethylamino)ethyl]-6-(5- methoxy- lH-pyrazol-4-yl)indol-3-yl]methanone; (2,3-dihydrobenzo[b][l,4]dioxin-2-yl)(l-(2-(dimethylamino)ethyl)-6-(lH-pyrazol-4-yl)- lH-indazol-3-yl)methanone (S)-(2,3-dihydrobenzo[b][l,4]dioxin-2-yl)(l-(2-(dimethylamino)ethyl)-6-(lH-pyrazol-4- yl)-lH-indazol-3-yl)methanone; (6-chlorochroman-3-yl)(1 -(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(3-methoxy-lH-pyrazol-4- yl)-lH-indazol-3-yl)methanone; (R)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(3-methoxy-lH-pyrazol-4- yl)-lH-indazol-3-yl)methanone; (6-chlorochroman-3-yl)(1 -(2-(dimethylamino)ethyl)-6-(3-fluoro-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)methanone; (1 -(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)(6-methoxychroman-3-yl)methanone; (6-(3-chloro-1 H - pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(6-methoxychroman-3-yl)methanone; (1 -(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)(6-fluorochroman-3-yl)methanone; (6-(3-chloro-1 H - pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(6-fluorochroman-3-yl)methanone; (S)-(6-(3-chloro-1 H - pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(6-fluorochroman-3-yl)methanone; Chroman-3-yl(l-(2-(dimethylamino)ethyl)-6-(5-(trifluoromethyl)-lH-pyrazol-4-yl)-lH- indazol-3-yl)methanone; (6-(3-fluoro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-indazol-3-yl)(6- fluorochroman-3-yl)methanone; (6-(3-fluoro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-indazol-3-yl)((S)- 6-fluorochroman-3-yl)methanone; (1 -(2-(dimethylamino)ethyl)-6-(3-fluoro-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)(6-fluorochroman-3-yl)methanone; (7-chloro-2,3-dihydrobenzo[ b ][1,4]dioxan-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)methanone; (7-chloro-2,3-dihydrobenzo[ b ][1,4]dioxan-2-yl)(1-(2-(dimethylamino)ethyl)-6-(3-fluoro-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)methanone; (6-(3-chloro-1 H - pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(7-chloro-2,3-dihydrobenzo[ b - [1,4]dioxin-2-yl)methanone; (1 -(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)(7-fluoro-2,3,4,5-tetrahydrobenzo[ b ]oxepin-4-yl)methanone; (6-(3-chloro-1 H - pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(7-fluoro-2,3,4,5-tetrahydrobenzo[ b ]oxepin-4-yl)methanone; (1 -(2-(dimethylamino)ethyl)-6-(3-methoxy-1 H - pyrazol-4-yl)-1 H - indazol-3-yl)(7-methoxy-2,3,4,5-tetrahydrobenzo[ b ]oxepin-4-yl)methanone; (6-(3-chloro-1 H - pyrazol-4-yl)-1-(2-(dimethylamino)ethyl)-1 H - indazol-3-yl)(7-methoxy-2,3,4,5-tetrahydrobenzo[ b ]oxepin-4-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH- pyrazol-4-yl)-lH-indol-3-yl)methanone; ​ ​ ​ (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(diethylamino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(diethylamino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethosulfonate; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethosulfonate; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethosulfonate; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dihydrobromide; (S)-(6-(5-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(methyl)amino)ethyl)-lH-indol-3-yl)(6- methoxychroman-3-yl)methanone dimethosulfonate; (6-(3-chloro-lH-pyrazol-4-yl)-l-(((R)-l-(2,2-difluoroethyl)azetidin-2-yl)methyl)-lH- indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; (6-(3-chloro-lH-pyrazol-4-yl)-l-(((R)-l-(2,2-difluoroethyl)azetidin-2-yl)methyl)-lH- indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; (6-(3-chloro-lH-pyrazol-4-yl)-l-(((R)-l-(2,2,2-trifluoroethyl)azetidin-2-yl)methyl)-lH- indol-3-yl)((S)-6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(2-fluoroethyl)amino)ethyl)-lH-indol-3- yl)(6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-((2,2-difluoroethyl)(ethyl)amino)ethyl)-lH-indol- 3-yl)(6-methoxychroman-3-yl)methanone; (S)-(6-(3-chloro-lH-pyrazol-4-yl)-l-(2-(ethyl(2,2,2-trifluoroethyl)amino)ethyl)- lH-indol-3-yl)(6-methoxychroman-3-yl)methanone; (S)-(l-(2-(bis(2-fluoroethyl)amino)ethyl)-6-(3-chloro-lH-pyrazol-4-yl)-lH-indol-3- yl)(6-methoxychroman-3-yl)methanone; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH-pyrazol-4- yl)-lH-indol-3-yl)methanone hydrochloride; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH-pyrazol-4- yl)-lH-indol-3-yl)methanone dihydrobromide; (S)-(6-chlorochroman-3-yl)(l-(2-(dimethylamino)ethyl)-6-(5-methoxy-lH-pyrazol-4- yl)-lH-indol-3-yl)methanone dimesylate; (6-(3-fluoro-lH-pyrazol-4-yl)-l-(((S)-l-methylazetidin-2-yl)methyl)-lH-indazol-3-yl)((S)- 6-fluorochroman-3-yl)methanone dihydrobromide.

9. Use of a compound, salt, or prodrug of claim 1 for the manufacture of a medicament for the treatment of a disease that can be treated by inhibition of ROCK enzymes.

10. Use of a compound, salt, or prodrug of claim 1 for the treatment or alleviation of a fibrotic disorder, a cardiovascular disease or disorder, an inflammatory disease or disorder, a nervous system disease or disorder, or a proliferative disease or disorder.

11. The use of claim 10, wherein the fibrotic disorder is pulmonary fibrosis selected from the group consisting of cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, old myocardial infarction, arteriosclerosis, atherosclerosis, restenosis, joint fibrosis, Crohn's disease, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scarring, and renal fibrosis.

12. The use of claim 10, wherein the cardiovascular disease or disorder is selected from the group consisting of angina, atherosclerosis, cerebral vasospasm, cerebral vasoconstriction, coronary vasospasm, endothelial dysfunction, erectile dysfunction, glaucoma, hypertension, ischemia / reperfusion injury, myocardial hypertrophy, myocardial infarction, peripheral circulation disorder, premature birth, Raynaud's disease, renal disease, and stroke.

13. The use of claim 10, wherein the proliferative disease 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, buccal cancer, cervical cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, epidermoid cancer, esophageal cancer, eye cancer, follicular cancer, gall bladder cancer, gastrointestinal cancer, genitourinary tract cancer, glioblastoma, hairy cell cancer, head and neck cancer, hepatoma, hepatocellular cancer, Hodgkin's disease, keratoacanthoma, kidney cancer, large cell cancer, large intestine cancer, laryngeal cancer, liver cancer, lung adenocarcinoma, small cell lung cancer, lung squamous cell cancer, non-small cell lung cancer, melanoma, myeloproliferative disorders, neuroblastoma, ovarian cancer, papillary cancer, pancreatic cancer, peritoneal cancer, prostate cancer, rectal cancer, salivary gland cancer, sarcoma, squamous cell cancer, small cell cancer, small intestine cancer, stomach cancer, testicular cancer, thyroid cancer, and vulvar cancer.

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

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