Azaindole rock inhibitors with advantageous properties

Abstract

This invention provides azaindole rho-associated protein kinase (ROCK) inhibiting compounds for treating disorders mediated by ROCK1 and / or ROCK2, such as a neurodegenerative disease or disorder, a kidney disease, a cancer, or a fibrotic disease or disorder, in a subject in need thereof. Specifically disclosed are compounds with a pyrrolo[2,3- b]pyridine-2-carboxamide structural backbone comprising a substituted pyrazolyl moiety at the 6-position.

Description

[0001] AZAINDOLE ROCK INHIBITORS WITH ADVANTAGEOUS PROPERTIES CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application 63 / 667,610, filed July 3, 2024. The entirety of this application is hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides rho-associated protein kinase (ROCK) inhibiting compounds for therapeutic applications as described further herein. BACKGROUND ROCK (Rho-associated protein kinase) is a kinase belonging to the AGC (cAMP- dependent protein kinase (PKA) / protein kinase G (PKG) / protein kinase C (PKC)) family of serine- threonine kinases and is activated by the GTP-bound form of RhoA. Two isoforms of mammalian Rho kinase, ROCK1 and ROCK2, have been described. They are approximately 160-kDa in weight proteins consisting of 1354 and 1388 amino acids, respectively, and contain an N- terminally located kinase domain, followed by a coiled-coil region containing the Rho-binding domain (RBD), a Pleckstrin homology domain (PH), and a cysteine-rich region at the C-terminus. The RBD binds exclusively to GTP-bound active RhoA and RhoC. The two ROCK isoforms share approximately 60% overall amino acid identity and approximately 90% identity within the N- terminal kinase domain. The carboxyl-terminal region comprises two cysteine-rich zinc finger- like motif domains and a split pleckstrin homology domain, which plays a role in the stabilization of the membrane binding of ROCK. (See, S. Hartmann, A. J. Ridley, and S. Lutz. “The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease” Frontiers in Pharmacology, November 2015, Vol.6, Art.276; J. C. Koch, L. Tatenhorst, A.-E. Roser, K.-A. Saal, L. Tönges, P. Lingor. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation” Pharmacology & Therapeutics 189 (2018) 1–21; Y. Feng, P. V. LoGrasso, O. Defert, and R. Li. “Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential” J. Med. Chem.2016, 59, 2269−2300). In its native form, ROCK is enzymatically inactive. This is caused by an auto-inhibition of the ROCK kinase domain by the carboxyl-terminal region of ROCK. The best-characterized upstream activators of ROCK are Rho-GTPase proteins RhoA and RhoC. In the activated GTP- bound state, they interact with the Rho-binding domain of ROCK and induce conformational changes that disrupt the autoinhibitory function of the carboxyl-terminal region. (J. C. Koch, L. Tatenhorst, A.-E. Roser, K.-A. Saal, L. Tönges, P. Lingor. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation” Pharmacology & Therapeutics 189 (2018) 1–21). There are a large number of downstream targets that are phosphorylated by ROCK. Activation of ROCK leads to the phosphorylation of several central regulator proteins resulting in diverse cellular responses like autophagy, cell survival and apoptosis, vesicle dynamics, cytoskeleton regulation, cell growth and regeneration, as well as cell shape and motility. In response to activators of Rho, which stimulate Rho-guanine nucleotide exchange factor (GEF) and lead to the formation of active GTP-bound Rho, ROCKs mediate a broad range of cellular responses that involve the actin cytoskeleton. For example, they control assembly of the actin cytoskeleton and cell contractility by phosphorylating a variety of proteins, such as myosin light chain (MLC) phosphatase, LIM-kinases, adducin and Ezrin / Radixin / Moesin (ERM) proteins. ROCK2 can alter the sensitivity of smooth muscle cell contraction to Ca2+, since MLCK is Ca2+sensitive. ROCKs are important regulators of cellular growth, migration, metabolism and apoptosis, through control of the actin cytoskeletal assembly and cell contraction. ROCK1 expression tends to be more ubiquitous (ROCK1 messenger RNA and protein are highly expressed in the lung, liver, spleen, kidney, and testis), while ROCK2 is most highly expressed in cardiac and brain tissues. ROCKs regulate cell polarity and migration, predominantly through enhancing actomyosin contraction and focal adhesions. Increased ROCK activity is observed in tumor metastasis and overexpression of constitutively activated ROCK promotes tumor invasion (Y. Rikitake et al., “ROCKs as therapeutic targets in cardiovascular diseases” Expert. Rev. Cardiovasc. Ther., 2005 May; 3(3): 441–451. doi:10.1586 / 14779072.3.3.441; A. V. Schofield and O. Bernard, “Rho-associated coiled-coil kinase (ROCK) signaling and disease” Crit. Rev. Biochem. Mol. Biol. 2013 Jul-Aug; 48(4): 301-16). Pharmacologic inhibitors of ROCKs, such as Y-27632, Fasudil (HA1077) and hydroxyfasudil, which target their ATP-dependent kinase domains, can inhibit both ROCK1 and ROCK2. ROCK inhibitors have been investigated for the treatment of a variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration and osteoporosis. To date, three ROCK inhibitors are approved for clinical use: Fasudil for the treatment of cerebral vasospasm, Ripasudil for the treatment of glaucoma and Belumosudil for the treatment of graft versus host disease. Fasudil (an isoquinoline derivative) was shown to effectively inhibit ROCK and other kinases like PKA, PKG, PKC, and MLCK (J. C. Koch et al., “Compassionate use of the ROCK inhibitor Fasudil in three patients with amyotrophic lateral sclerosis” Front. Neurol. March 2020, Volume 11, Article 173). Fasudil has been the subject of multiple clinical trials for the treatment of amyotrophic lateral sclerosis (ALS) (Wolff, Andreas W., et al. “SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants” CNS drugs 38.4 (2024): 291-302; Lingor, Paul, et al. “ROCK-ALS: protocol for a randomized, placebo-controlled, double-blind phase IIa trial of safety, tolerability and efficacy of the rho kinase (ROCK) inhibitor Fasudil in amyotrophic lateral sclerosis” Frontiers in neurology 10 (2019): 293). Several synthetic ROCK inhibitors identified by researchers at Scripps Research Institute based on indole, 5-azaindole, and 7-azaindole heterocyclic systems have been described in literature (S. Chowdhury et al., “Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)” Bioorg. Med. Chem. Lett.21 (2011) 7107–7112; E. H. Sessions et al., “Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (Part-II)” Bioorg. Med. Chem. Lett.21 (2011) 7113–7118.) Synthesis and inhibitory activity of some benzothiazole derivatives against ROCK have also been previously disclosed (Y. Yin et al., “Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors” Bioorg. Med. Chem. Lett. 19 (2009) 6686–6690.). Additional ROCK inhibitors are described in WO 2011 / 050245 which was filed by researchers at Scripps Research Institute. The ROCK inhibitory activity of these indole, azaindole and benzothiazole compounds varies significantly depending on substituents attached to the heterocyclic ring. Avicenna Biosciences, Inc. describes ROCK inhibitors and their uses in WO 2024 / 145569. Additional patent applications describing ROCK inhibitors and their uses include WO 2024 / 110851, WO 2024 / 023276, WO 2023 / 209692, WO 2023 / 139379, WO 2023 / 110700, WO 2022 / 020381, WO 2022 / 150676, WO 2022 / 042712, WO 2022 / 012409, WO 2021 / 214200, WO 2021 / 095945, WO 2020 / 177292, WO 2020 / 094111, WO 2019 / 000683, WO 2019 / 000682, WO 2018 / 130178, WO 2018 / 108156, WO 2014 / 177699, WO 2013 / 112722, WO 2011 / 050245, WO 2010 / 065907, WO 2010 / 065907, WO 2010 / 032875, WO 2009 / 155209, WO 2007 / 026920, and WO 2006 / 088088. Despite these efforts, there remains a need for new ROCK inhibiting compounds to treat disorders mediated by ROCK1 and / or ROCK2 in a subject in need thereof for example a human. SUMMARY OF THE INVENTION Azaindole compounds and their pharmaceutically acceptable salts, uses, and manufacture are provided that inhibit a rho-associated protein kinase (ROCK). It has been discovered that several of these compounds have advantageous ADME (absorption, distribution, metabolism, and excretion) properties. For example, when administered to Sprague-Dawley rats (Example 21) all of the tested azaindole compounds of Formula I had half-lives of more than two hours and eleven of the thirteen tested compounds had bioavailability values (%F) of greater than 10% (see Table 10). Advantages were also seen in chemical properties including solubility. Eight of the thirteen tested compounds had kinetic solubilities of greater than 10 ^M (see Table 6). An effective amount of a compound of the present invention provided herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable composition can be used to treat a disorder that is mediated by ROCK1 and / or ROCK2. In some embodiments, a method to treat a subject with a disorder mediated by ROCK1 and / or ROCK2 is provided that includes administering an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, to the subject, typically a human, optionally in a pharmaceutically acceptable composition. In certain embodiments the disorder is mediated by ROCK1. In additional embodiments the disorder is mediated by ROCK2. In other embodiments the disorder is mediated by PRKX. In certain embodiments, the disorder is mediated by ROCK1 and PRKX. In certain aspects a compound of Formula I is provided: or a pharmaceutically acceptable salt thereof; wherein: R1is selected from the group consisting of -CH2OC(O)R2, -CH2OP(O)(OR4)(OR5), -C(O)R3, -C(=NH)NR4R5, and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; in certain embodiments R1is -CH2OP(O)(OH)(OR5); in certain embodiments R1is C(=NH)NR4R5; in certain embodiments R1is R2is C1-C6alkyl, C2-C6alkenyl, or aryl; each of which is optionally substituted with -C(O)OR4; in certain embodiments R2is ; in certain embodiments R2is R3is C1-C6alkyl, -OR4, or a 4-, 5-, or 6-m embered heterocycle with 1 or 2 nitrogen or oxygen atoms; in certain embodiments R3is propyl; in certain embodiments R3is butyl; in certain embodiments R3is -OR4; in certain embodiments R3is piperazinyl; R4and R5are independently hydrogen or C1-C6 alkyl; R6and R7are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen; in certain embodiments R6and R7are hydrogen; in other embodiments R6is hydrogen and R7is methyl; R8is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; in certain embodiments R8is H or CH3; and R9and R10are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and halogen. Every combination of variables, substituents, embodiments, and the compounds that result from these combinations, is deemed specifically and individually disclosed, as such depiction is for convenience of space only and not intended to describe only a genus or even a subgenus of compounds. In certain embodiments the compound of Formula I is of structure or a pharmaceutically acceptable salt thereof. In other embodiments the compound of Formula I is of structure or a pharmaceutically acceptable salt thereof. In certain aspects a compound of the present invention is used to treat a ROCK1 or ROCK2 mediated disorder in the central nervous system (CNS). In other aspects a compound of the present invention is used to treat a peripheral disorder that is mediated by ROCK1 or ROCK2. Non-limiting examples of compounds of Formula I include:

[0002] or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the present invention has sufficient properties to penetrate the blood brain barrier. Adequate levels of blood brain barrier penetration are important for the treatment of neurodegenerative disorders. For example, blood brain barrier penetration is required to treat amyotrophic lateral sclerosis because this disease primarily affects nerve cells in the brain. In other embodiments a compound of the present invention is used to treat stroke, spinal cord injury, Alzheimer’s, disease, Parkinson’s disease, Levodopa-induced dyskinesia, diabetic nephropathy, or polycystic kidney disease. In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof to a subject in need thereof, for example, a human, optionally in a pharmaceutically acceptable composition. For example, in certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human to treat a neurodegenerative disorder, for example amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (PD). In other embodiments, an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a human to treat a kidney disorder, for example diabetic nephropathy or polycystic kidney disease. In certain embodiments, an effective amount of a compound of the present invention is used to treat ALS. For example, in certain embodiments, an effective amount of a compound of the present invention is used to treat bulbar, respiratory, flail arm, classical, pyramidal, or flail leg ALS. In certain embodiments, an effective amount of a compound of the present invention is used to treat Parkinson’s disease. For example, in certain embodiments, an effective amount of a compound of the present invention is used to treat motor-cognitive, cognitive dominant or motor dominant Parkinson’s disease. In certain embodiments, a compound of the present invention is used to treat levodopa-induced dyskinesia (LID). For example, in certain embodiments, a compound of the present invention is used to treat peak-dose dyskinesia, wearing-off / off-period dyskinesia, or diphasic dyskinesia of LID. In other embodiments, an effective amount of a compound of the present invention is used to treat a disorder selected from cerebral vasospasm, pulmonary hypertension, acute lung injury exfoliation syndrome, ocular hypertension, glaucoma (for example exfoliative glaucoma), Levodopa-induced dyskinesia, Huntington's disease, traumatic brain injuries, polycystic kidney disease, renal fibrosis, renal failure, diabetic nephropathy (kidney disease), benign prostatic hyperplasia, urinary bladder dysfunction, motor neuron disease, diabetic retinopathy, sarcoidosis, scleroderma, focal segmental glomerulosclerosis, and cancers. Alternatively, an effective amount of a compound of the present invention can be used to treat an edema (for example pulmonary edema), inflammatory bowel disease, or inflammation. In certain embodiments, the selected compound of Formula I or a pharmaceutically acceptable salt thereof, has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments, the compound of Formula I or its pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. For example, in certain embodiments a compound of Formula I or a pharmaceutically acceptable salt thereof has one or more deuterium substitutions at a site of metabolism. In other embodiments a compound of Formula I or a pharmaceutically acceptable salt thereof has one or more deuterium substitutions next to the site of metabolism. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A compound of the present invention as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A method to treat a ROCK1 and / or ROCK2 mediated disorder, such as a neurodegenerative disorder, including for example ALS or Parkinson’s disease, comprising administering an effective amount of a compound of the present invention or pharmaceutically acceptable salt thereof, to a subject in need thereof; (c) The method of (b) wherein the ROCK1 and / or ROCK2 mediated disorder is a kidney disease, including for example diabetic nephropathy or polycystic kidney disease; (d) The method of (b) wherein the ROCK1 and / or ROCK2 mediated disorder is levodopa-induced dyskinesia; (e) The method of (b) wherein the ROCK1 and / or ROCK2 mediated disorder is a fibrotic disorder, including for example a fibrotic disorder of the lung, kidney, liver or skin; (f) A compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by ROCK1 and / or ROCK2, for example a neurodegenerative disorder, including for example ALS or Parkinson’s disease; (g) The compound of (f) wherein the ROCK1 and / or ROCK2 mediated disorder is a kidney disease, including for example diabetic nephropathy or polycystic kidney disease; (h) The compound of (f) wherein the ROCK1 and / or ROCK2 mediated disorder is levodopa-induced dyskinesia; (i) The compound of (f) wherein the ROCK1 and / or ROCK2 mediated disorder is a fibrotic disorder, including for example a fibrotic disorder of the lung, kidney, liver or skin; (j) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a subject in need thereof, typically a human, with a ROCK1 and / or ROCK2 mediated disorder, for example a neurodegenerative disorder, including for example ALS or Parkinson’s disease; (k) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated disorder, for example a neurodegenerative disorder, including for example ALS or Parkinson’s disease; (l) The use of (j) or (k) wherein the ROCK1 and / or ROCK2 mediated disorder is a kidney disease, including for example diabetic nephropathy or polycystic kidney disease; (m) The use of (j) or (k) wherein the ROCK1 and / or ROCK2 mediated disorder is levodopa-induced dyskinesia; (n) The use of (j) or (k) wherein the ROCK1 and / or ROCK2 mediated disorder is a fibrotic disorder, including for example a fibrotic disorder of the lung, kidney, liver or skin; (o) A pharmaceutical composition comprising an effective subject-treating amount of a compound of the present invention, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. The present invention includes a compound of Formula I or its pharmaceutically acceptable salt thereof, with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine and iodine such as2H,3H,11C,13C,14C,15N,17O,18O,18F,36Cl, and125I respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided in a compound of Formula I or a pharmaceutically acceptable salt thereof optionally in a metabolically labile position, or a position in close proximity to a metabolically labile position. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). In certain aspects a compound of the present invention may form a solvate with a solvent (including for example water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non- limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D2O, d6- acetone, d6-DMSO (dimethyl sulfoxide). A solvate can be in a liquid or solid form. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through carbon of the carbonyl (C=O) group. “Alkyl” is a straight, branched, or cyclic saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl is C1-C2, C1-C3, or C1-C4,and where the alkyl is cyclic, it may be, for example a C3-C4moiety.The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1-C4 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. In certain embodiments “alkyl” is a C1-C4alkyl, C1-C3alkyl, or C1-C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, and butyl. Additional non-limiting examples of “alkyl” include: isopropyl and isobutyl. Additional non-limiting examples of “alkyl” include: sec-butyl and tert-butyl. In certain embodiments “cycloalkyl” is a C3-C4cycloalkyl. In certain embodiments “cycloalkyl” has three carbons. In certain embodiments “cycloalkyl” has four carbons. Non-limiting examples of “cycloalkyl” include: cyclopropyl and cyclobutyl. “Halo” and “Halogen” refers independently to fluorine, chlorine, bromine or iodine. “Haloalkyl” is a straight, branched or cyclic alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to trifluoromethyl and pentafluoroethyl. In certain embodiments “haloalkyl” is a C1-C4haloalkyl, C1-C3haloalkyl, or C1-C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” is perhaloalkyl. Non-limiting examples of “haloalkyl” include: , , and Additional non-limiting examples of “haloalkyl” include: , , Additional non-limiting examples of “haloalkyl” include: , , andAdditional non-limiting examples of “haloalkyl” include: , , and “Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon- carbon double bonds that may occur at a stable point along the chain. Unless denoted otherwise, “alkenyl” is typically a C2-C8alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. In certain non-limiting embodiments, the alkenyl contains from 2 to 12 carbon atoms, from 2 to 6 carbon atoms or from 2 to 4 carbon atoms. In certain embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6alkenyl. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. The term “Alkenyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4- to 7- or 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group. In certain embodiments, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. The term “heterocycle” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole-2(3H)-onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2- piperazinonyl, indolinyl, and dihydrothiazolyl. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused / condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. For example, ocycle” group. However, ” group. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. “Parenteral” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques. A “patient” or “subject” is a human or domesticated animal in need of treatment for any of the disorders as specifically described herein and unless otherwise specified, refers to a human. Non-limiting examples of domesticated animals include dogs, cats, horses, and livestock. As described further herein, the words patient or subject typically refers to a human patient or subject, and unless otherwise indicated by the text is assumed to refer to a human. In an alternative embodiment, the patient or subject is a domesticated animal in need of such therapy and responsive thereto. "Livestock" refers to animals that are generally kept for agricultural purposes, including, for example, cows, sheep, goats, and pigs. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. II. COMPOUNDS OF FORMULA I In certain aspects, the present invention provides a compound of Formula: or a pharmaceutically acceptable salt thereof. In other aspects, the present invention provides a compound of Formula: or a pharmaceutically acceptable salt thereof. Additional examples of Formulas of the present invention include: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is of Formula or a pharmaceutically acceptable salt thereof. Other Formulas of the present invention include: or a pharmaceutically acceptable salt thereof.

[0003] Non-limiting examples of compounds of Formula I include:

[0004] or a pharmaceutically acceptable salt thereof. Additional non-limiting examples of compounds of Formula I include:

[0005] or a pharmaceutically acceptable salt thereof. Embodiments of R1In certain embodiments R1is -CH2OC(O)R2. In certain embodiments R1is -CH2OP(O)(OR4)(OR5). In certain embodiments R1is -CH2OP(O)(OH)(OH). In certain embodiments R1is -C(O)R3. In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is -C(=NH)NR4R5. In certain embodiments R1is In certain embodiments R1is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. In certain embodiments R1is Embodiments of R2In certain embodiments R2is C1-C6 alkyl optionally substituted with -C(O)OR4. In certain embodiments R2is In certain embodiments R2is In certain embodiments R2is In certain embodiments R2is In certain embodiments R2is C2-C6alkenyl optionally substituted with -C(O)OR4. In certain embodiments R2is In certain embodiments R2is an aryl optionally substituted with -C(O)OR4. In certain embodiments R2is in certain embodiments R2is methyl substituted with -C(O)OR4. in certain embodiments R2is ethyl substituted with -C(O)OH. in certain embodiments R2is propyl substituted with -C(O)OH. in certain embodiments R2is ethyl substituted with -C(O)OMe. in certain embodiments R2is ethylene substituted with -C(O)OH. in certain embodiments R2is phenyl substituted with -C(O)OH. Embodiments of R3In certain embodiments R3is C1-C6alkyl. In certain embodiments R3is -CH3. In certain embodiments R3is -C2H5. In certain embodiments R3is -CH2CH2CH3. In certain embodiments R3is -CH(CH3)2. In certain embodiments R3is -CH2CH2CH2CH3. In certain embodiments R3is -C(CH3)3. In certain embodiments R3is -OR4. In certain embodiments R3is In certain embodiments R3is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. In certain embodiments R3is piperazinyl. In certain embodiments R3is Embodiments of R4In certain embodiments R4is hydrogen. In certain embodiments R4is C1-C6 alkyl. In certain embodiments R4is -CH3. In certain embodiments R4is -C2H5. In certain embodiments R4is -CH2CH2CH3. In certain embodiments R4is -CH(CH3)2. In certain embodiments R4is -CH2CH2CH2CH3. In certain embodiments R4is -C(CH3)3. Embodiments of R5In certain embodiments R5is hydrogen. In certain embodiments R5is C1-C6 alkyl. In certain embodiments R5is -CH3. In certain embodiments R5is -C2H5. In certain embodiments R5is -CH2CH2CH3. In certain embodiments R5is -CH(CH3)2. In certain embodiments R5is -CH2CH2CH2CH3. In certain embodiments R5is -C(CH3)3. Embodiments of R6In certain embodiments R6is hydrogen. In certain embodiments R6is CH3. In certain embodiments R6is C2H5. In certain embodiments R6is CH2CH2CH3. In certain embodiments R6is isopropyl. In certain embodiments R6is F. In certain embodiments R6is Cl. In certain embodiments R6is Br. In certain embodiments R6is CF3. In certain embodiments R6is CH2F. In certain embodiments R6is CH2CF3. Embodiments of R7In certain embodiments R7is hydrogen. In certain embodiments R7is CH3. In certain embodiments R7is C2H5. In certain embodiments R7is CH2CH2CH3. In certain embodiments R7is isopropyl. In certain embodiments R7is F. In certain embodiments R7is Cl. In certain embodiments R7is Br. In certain embodiments R7is CF3. In certain embodiments R7is CH2F. In certain embodiments R7is CH2CF3. Embodiments of R8In certain embodiments R8is hydrogen. In certain embodiments R8is CH3. In certain embodiments R8is C2H5. In certain embodiments R8is CH2CH2CH3. In certain embodiments R8is isopropyl. In certain embodiments R8is CF3. In certain embodiments R8is CH2F. In certain embodiments R8is CH2CF3. Embodiments of R9In certain embodiments R9is hydrogen. In certain embodiments R9is CH3. In certain embodiments R9is C2H5. In certain embodiments R9is CH2CH2CH3. In certain embodiments R9is isopropyl. In certain embodiments R9is F. In certain embodiments R9is Cl. In certain embodiments R9is Br. In certain embodiments R9is CF3. In certain embodiments R9is CH2F. In certain embodiments R9is CH2CF3. Embodiments of R10In certain embodiments R10is hydrogen. In certain embodiments R10is CH3. In certain embodiments R10is C2H5. In certain embodiments R10is CH2CH2CH3. In certain embodiments R10is isopropyl. In certain embodiments R10is F. In certain embodiments R10is Cl. In certain embodiments R10is Br. In certain embodiments R10is CF3. In certain embodiments R10is CH2F. In certain embodiments R10is CH2CF3. The structure of the compound of the present invention is typically selected such that it is sufficiently stable to sustain a shelf life of at least two, three, four, or five months under ambient conditions. One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions. Illustrative Embodiments 1. A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: R1is selected from the group consisting of -CH2OC(O)R2, -CH2OP(O)(OR4)(OR5), -C(O)R3, -C(=NH)NR4R5, and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R2is C1-C6 alkyl, C2-C6 alkenyl, or aryl; each of which is optionally substituted with -C(O)OR4; R3is C1-C6 alkyl, -OR4, or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R4and R5are independently hydrogen or C1-C6alkyl; R6and R7are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R8is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; and R9and R10are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4 alkyl, and halogen. 2. The compound of embodiment 1, wherein R10is hydrogen. 3. The compound of embodiment 1, wherein R10is halogen. 4. The compound of embodiment 1, wherein R10is fluoro. 5. The compound of embodiment 1, wherein R10is chloro. 6. The compound of embodiment 1, wherein R10is methyl. 7. The compound of embodiment 1, wherein R10is ethyl. 8. The compound of any one of embodiments 1-7, wherein R6is hydrogen. 9. The compound of any one of embodiments 1-7, wherein R6is halogen. 10. The compound of any one of embodiments 1-7, wherein R6is methyl. 11. The compound of any one of embodiments 1-10, wherein R7is hydrogen. 12. The compound of any one of embodiments 1-10, wherein R7is halogen. 13. The compound of any one of embodiments 1-10, wherein R7is methyl. 14. The compound of any one of embodiments 1-10, wherein R7is C1-C2haloalkyl. 15. The compound of any one of embodiments 1-14, wherein R8is hydrogen. 16. The compound of any one of embodiments 1-14, wherein R8is methyl. 17. The compound of any one of embodiments 1-16, wherein R9is hydrogen. 18. The compound of any one of embodiments 1-16, wherein R9is halogen. 19. The compound of any one of embodiments 1-16, wherein R9is fluoro. 20. The compound of any one of embodiments 1-16, wherein R9is chloro. 21. The compound of any one of embodiments 1-16, wherein R9is C1-C2haloalkyl. 22. The compound of embodiment 1 of Formula or a pharmaceutically acceptable salt thereof. 23. The compound of embodiment 1 of Formula or a pharmaceutically acceptable salt thereof. 24. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 25. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 26. The compound of any one of the embodiments 1-25, wherein R5is hydrogen. 27. The compound of any one of the embodiments 1-25, wherein R5is C1-C6 alkyl. 28. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 29. The compound of embodiment 28, wherein R2is C1-C6 alkyl optionally substituted with -C(O)OR4. 30. The compound of embodiment 28, wherein R2is . 31. The compound of embodiment 28, wherein R2is . 32. The compound of embodiment 28, wherein R2is 33. The compound of embodiment 28, wherein R2is C2-C6alkenyl optionally substituted with -C(O)OR4. 34. The compound of embodiment 28, wherein R2is . 35. The compound of embodiment 28, wherein R2is aryl optionally substituted with -C(O)OR4. 36. The compound of embodiment 28, wherein R2is . 37. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 38. The compound of embodiment 37, wherein R3is -OR4. 39. The compound of any one of embodiments 1-38, wherein R4is hydrogen. 40. The compound of any one of embodiments 1-38, wherein R4is C1-C6alkyl. 41. The compound of any one of embodiments 1-38, wherein R4is methyl. 42. The compound of any one of embodiments 1-38, wherein R4is iso-propyl. 43. The compound of embodiment 37, wherein R3is C1-C6 alkyl. 44. The compound of embodiment 37, wherein R3is iso-propyl. 45. The compound of embodiment 37, wherein R3is tert-butyl. 46. The compound of embodiment 37, wherein R3is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. 47. The compound of embodiment 37, wherein R3is . 48. A compound selected from:

[0006] or a pharmaceutically acceptable salt thereof. 49. A compound selected from: or a pharmaceutically acceptable salt thereof.

[0007] 50. A compound selected from: or a pharmaceutically acceptable salt thereof. 51. A pharmaceutical composition comprising a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 52. The pharmaceutical composition of embodiment 51, wherein the pharmaceutical composition is suitable for oral administration. 53. The pharmaceutical composition of embodiment 51, wherein the pharmaceutical composition is suitable for parenteral administration. 54. The pharmaceutical composition of embodiment 51, wherein the pharmaceutical composition is suitable for intravenous administration. 55. A method of treating a ROCK1 or ROCK2 mediated disorder comprising administering an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a subject in need thereof. 56. The method of embodiment 55, wherein the subject is a human. 57. The method of embodiment 55 or 56, wherein the disorder is a neurodegenerative disorder. 58. The method of embodiment 57, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis. 59. The method of embodiment 57, wherein the neurodegenerative disorder is Parkinson’s disease. 60. The method of embodiment 57, wherein the neurodegenerative disorder is Huntington’s disease. 61. The method of embodiment 57, wherein the neurodegenerative disorder is Alzheimer’s disease. 62. The method of embodiment 55 or 56, wherein the disorder is a kidney disease. 63. The method of embodiment 62, wherein the kidney disease is diabetic nephropathy. 64. The method of embodiment 62, wherein the kidney disease is polycystic kidney disease. 65. The method of embodiment 62, wherein the kidney disease is focal segmental glomerulosclerosis. 66. The method of embodiment 55 or 56, wherein the disorder is Levodopa-induced dyskinesia. 67. The method of embodiment 55 or 56, wherein the disorder is a bladder dysfunction. 68. The method of embodiment 67, wherein the bladder dysfunction is interstitial cystitis. 69. The method of embodiment 67, wherein the bladder dysfunction is bladder inflammation. 70. The method of embodiment 67, wherein the bladder dysfunction is overactive bladder. 71. The method of embodiment 67, wherein the bladder dysfunction is bladder fibrosis. 72. The method of embodiment 67, wherein the bladder dysfunction is neurogenic bladder. 73. The method of embodiment 67, wherein the bladder dysfunction is a lower urinary tract symptom. 74. The method of embodiment 55 or 56, wherein the disorder is a cancer. 75. The method of embodiment 74, wherein the cancer is breast cancer. 76. The method of embodiment 74, wherein the cancer is prostate cancer. 77. The method of embodiment 74, wherein the cancer is melanoma. 78. The method of embodiment 74, wherein the cancer is a desmoplastic disorder. 79. The method of embodiment 55 or 56, wherein the disorder is a traumatic brain injury. 80. The method of embodiment 55 or 56, wherein the disorder is diabetic retinopathy. 81. The method of embodiment 55 or 56, wherein the disorder is idiopathic pulmonary fibrosis. 82. The method of embodiment 55 or 56, wherein the disorder is a pulmonary sarcoidosis. 83. The method of embodiment 55 or 56, wherein the disorder is a neurosarcoidosis. 84. The method of embodiment 55 or 56, wherein the disorder is scleroderma. 85. The method of embodiment 55 or 56, wherein the disorder is a fibrotic disorder. 86. The method of embodiment 85, wherein the disorder is a fibrotic disorder of the lung. 87. The method of embodiment 85, wherein the disorder is a fibrotic disorder of the kidney. 88. The method of embodiment 85, wherein the disorder is a fibrotic disorder of the liver. 89. The method of embodiment 85, wherein the disorder is a fibrotic disorder of the skin. 90. The method of any one of embodiments 55-89, wherein the disorder is mediated by ROCK1. 91. The method of any one of embodiments 55-89, wherein the disorder is mediated by ROCK2. 92. Use of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated disorder. 93. Use of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated disorder. III. METHODS OF TREATMENT Rho-associated coiled-coil kinase (ROCK) isoforms 1 and 2 are downstream targets of GTP-bound and activated Rho GTPase proteins that phosphorylate a number of substrates involved in myosin-actin-cytoskeletal architecture, actin-filament dynamics, neurofilament, and actin-binding proteins. ROCK1 is expressed in a variety of human tissues including the heart, pancreas, lung, liver, skeletal muscle, and kidney, but is not substantially expressed in the brain (Fujisawa, K. et al. Identification of the rho-binding domain of p160ROCK, a rho-associated coiled-coil containing protein kinase. J Biol Chem.271:23022-8(1996)). ROCK2 is preferentially expressed in the brain and skeletal muscle (Nakagawa, O. et al. ROCK-I and ROCK-II, two isoforms of rho-associated coiled-coil forming protein serine / threonine kinase in mice. FEBS Lett. 395:189-93(1996)). Increased activity of ROCK2 is implicated in defects on dendritic spine structure and function in several model systems (Swanger, S.A. et al. ROCK1 and ROCK2 inhibition alters dendritic spine morphology in hippocampal neurons. Cell Logist. 5:e1133266(2015); Sellers, K.J. et al. Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by Fasudil. Alzheimer’s Dement. 14:306-17(2018); Henderson et al. Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against beta-amyloid. Sci Signal. 12:eaaw9318(2019)). Indeed, ROCK2 is implicated in a number of neurodegenerative and neurological disorders including Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), spinal cord injury, stroke, and neuroinflammation (Weber, A.J. et al. Perspectives on ROCK2 as a Therapeutic Target for Alzheimer’s Disease. Front in Cell Neurosci. 15:636017(2021)). ROCK2 is shown to regulate several complex neuronal processes associated with neurodegenerative disorders. For example, AAV.shRNA-mediated downregulation of ROCK2 rescued dopaminergic neurons in the substantia nigra (SN) and preserves motor behavior in a 6- hydroxydopamine (6-OHDA)-induced Parkinson mouse model (Saal, K. et al. Neurobiol Dis. 73:150-62(2015)). ROCK inhibition can be used to modulate these neuronal processes. For example, in a study in mice ROCK inhibition led to decreased midbrain alpha-synuclein pathology and improved motor and cognitive function in a mouse model expressing human mutant alpha- synuclein (aSynA53T) (Tatenhorst et al. Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease. Acta Neuropathol Commun.4:39(2016)). ROCK proteins are present in many types of nerve cells in the CNS. Excess activity of ROCK proteins in the CNS leads to oxidative stress, uncontrolled inflammation, immune abnormality, energy metabolism disorders, neuronal cell loss, reactive gliosis, and / or impaired synaptic transmission, thus promoting the development of neurodegenerative diseases. ROCK protein overexpression has been detected in the lesions of Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), revealing that ROCK proteins are involved in the pathology of these diseases and might be important initiators of pathogenesis. Inhibition of ROCK proteins has been shown to cause several biological events, such as increased neurite outgrowth, axonal regeneration, and activation of prosurvival protein kinase B (AKT). (Q. Wang et al. “Advantages of Rho-associated kinases and their inhibitor Fasudil for the treatment of neurodegenerative diseases”, Neural Regen. Res.2022, 17(12):2623-2631.) Because of ROCK’s role in neuronal processes, its over activity or increased concentration is associated with various neurological defects. For example, increased levels of ROCK2 protein are observed in progressive stages of AD (Herskowitz et al.2013). While increased ROCK activity is observed in SOD1G93AALS mutant model mice (Gunther, R. et al. Rho Kinase Inhibition with Fasudil in the SOD1G93AMouse Model of Amyotrophic Lateral Sclerosis – Symptomatic Treatment Potential After Disease Onset. Front Pharmacol.8:17(2017)). Thus, a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in an effective amount to treat a neurological disease. Non-limiting examples of neurological diseases include amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Huntington's Disease (HD), Alzheimer’s disease (AD), and neurological deficiencies caused by spinal cord injuries. Based on the above-described roles of ROCK1 and ROCK2 in central nervous system disorders, methods and uses to treat subjects such as humans afflicted with such disorders are provided herein. In certain embodiments a method of treating a subject with a ROCK1 and / or ROCK2 mediated disorder is provided comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject. Non-limiting examples of disorders mediated by ROCK1 and / or ROCK2 are provided below. In certain aspects the compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a ROCK1 mediated disorder. In certain aspects the compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a ROCK2 mediated disorder. Specific examples of disorders that can be treated with the compounds described herein or their pharmaceutically acceptable salts are described below. Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disease that affects an estimated million individuals (Hardiman, O. et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 3(17071):1-19(2017)), with different risk levels geographically. ALS is characterized by degeneration of upper motor neurons and lower motor neurons that contribute to both motor and non-motor symptoms. Several subtypes of ALS have been identified including bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat ALS. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat bulbar, respiratory, flail arm, classical, pyramidal, or flail leg ALS. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with ALS or a secondary condition associated with ALS. Parkinson disease (PD) Parkinson disease (PD) is the second-most common neurodegenerative disorder following Alzheimer disease, with an estimated 2 to 3 cases per 100,000 individuals worldwide (Parkinson’s Foundation. Statistics. 2022). PD is characterized by several dysregulated mechanisms and pathways which contribute to neuronal loss in the substantia nigra (SN), including alpha-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation (Poewe, W. et al. Parkinson disease. Nat Rev Dis Primers. 3(17013):1- 21(2017)). Intracellular alpha-synuclein aggregates are a hallmark of PD, as well as SN neuronal loss and striatal dopamine deficiency. Subjects are diagnosed with PD based on the presence of bradykinesia and other motor defects, as well as non-motor symptoms. Several subtypes of PD have been identified including motor-cognitive, cognitive dominant and motor dominant PD. There is presently no cure for PD and treatments focus on slowing the progression and / or decreasing the symptoms of PD. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat PD. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat motor-cognitive, cognitive dominant or motor dominant PD. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with PD or a secondary condition associated with PD. Alzheimer disease (AD) Alzheimer disease (AD) is the most common cause of dementia affecting over 40 million people in 2016 (GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol.18(1):88-106(2019)) and is expected to increase to 150 million by 2050 worldwide. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 7(2):e105-e125(2022)). AD is a neurodegenerative disorder characterized by extracellular plaques comprising amyloid beta and intracellular neurofibrillary tangles comprising tau leading to neuronal loss (Knopman, D.S. et al. Alzheimer disease. Nat Rev Dis Primers. 7(33):1-21(2021)). Subjects with AD present with cognitive impairment and dementia. Symptoms of cognitive impairment include loss in short-term memory, expressive speech, visuospatial processing, and executive functioning. AD risk factors include rare, dominantly inherited mutations in APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) causing autosomal dominant forms of AD. Much more common is the development of sporadic late-onset AD which is influenced by more common but incompletely penetrant genetic polymorphisms in genes such as APOE. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat AD. AD treatments can be beneficial at several stages in the progression of the disease. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a subject with no cognitive impairment but high levels of amyloid beta and / or tau biomarkers, subjective cognitive decline in the absence of impaired cognitive testing scoring, mild cognitive impairment, clinically confirmed AD, or autosomal dominant AD. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with AD or a secondary condition associated with AD. Spinal cord injury Spinal cord injuries can trigger complex and varied neurological effects including axon degeneration and mild to severe loss of cognitive function. In certain embodiments a compound described herein is used to treat a spinal cord injury. For example, a compound of the present invention or a pharmaceutically acceptable salt thereof may be used to promote axon regeneration and functional recovery in a subject who has had a spinal cord injury. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a spinal cord injury or a secondary condition associated with a spinal cord injury. Stroke Stroke is a neurological disorder that occurs when one or more blood vessels that supply blood to the brain are blocked or rupture. The depletion of blood in the brain causes damage to the brain tissue in the area where the blood vessel previously delivered blood. There are two common categories of stroke: ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when the brain tissue is ischemic due to a decrease in the supply of blood caused by a blockage. Hemorrhagic stroke instead occurs due to hemorrhage when a blood vessel ruptures. Ischemic stroke is the most common form of stroke. When an ischemic stroke occurs, cells cannot obtain sufficient oxygen and nutrients due to the interruption of blood flow. In certain embodiments a compound described herein is used to treat a stroke. Non-limiting examples of strokes include ischemic stroke, acute ischemic stroke, thrombosis, embolism, transient ischemic attack, leukoplakia, and infarction. In other embodiments a compound herein is used to prevent a stroke or provide neuroprotection, for example acute neuroprotection. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human who has had a stroke or a secondary condition associated with a stroke. Other Neurodegenerative Disorders In addition to ROCKs important role in the regulation of several complex neuronal processes research has identified ROCK as a regulator of reactive oxygen species (ROS). This biological function allows ROCK inhibition to modulate additional neurodegenerative disorders (Kang H. et al. Chemical Screening Identifies ROCK as a Target for Recovering Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome. Aging Cell 16:541-50(2017) and Sheng W. et al. Reactive Oxygen Species from Human Astrocytes Induce Functional Impairment and Oxidative Damage. Neurochem. Res.38:2148-59(2013)). Non-limiting examples of neurodegenerative diseases including ataxia, Huntington's disease, motor neuron disease, multiple system atrophy, Creutzfeldt-Jakob disease, dementia, non- dementia cognitive impairment, and progressive supranuclear palsy. Non-limiting examples of dementia include senile dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumors, and dementia caused by chronic subdural hematoma. Additional non- limiting examples of neurodegenerative diseases including corticobasal degeneration, spinocerebellar ataxia, frontotemporal dementia and CMT2A (Charcot-Marie-Tooth disease type 2A). In certain embodiments the neurodegenerative disease is corticobasal degeneration. In certain embodiments the neurodegenerative disease is spinocerebellar ataxia. In certain embodiments the neurodegenerative disease is frontotemporal dementia. In certain embodiments the neurodegenerative disease is CMT2A (Charcot-Marie-Tooth disease type 2A). In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof is used to reduce inflammation. For example, a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a subject in need thereof to reduce inflammation in the brain. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a neurodegenerative disorder such as one of those listed above or a secondary condition associated with the neurodegenerative disorder. ROCK has recently emerged as a novel therapeutic target for neurodegenerative disorders (J. C. Koch, L. Tatenhorst, A.-E. Roser, K.-A. Saal, L. Tönges, P. Lingor. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation”, Pharmacology & Therapeutics 189 (2018) 1–21). While ROCK1 is expressed preferentially in peripheral tissue, ROCK2 is highly expressed in the central nervous system (CNS). Axonal growth inhibitory molecules (e.g., Nogo, MAG, OMgp, ephrins, semaphorins) bind to specific extracellular receptors and signal via ROCK to trigger axonal degeneration, growth cone collapse, and impaired axonal regeneration. In non-neuronal structures, regulation of the actin cytoskeleton plasticity by ROCK also mediates vasoconstriction and vascular remodeling. Levels of ROCK increase with age and tissue of ALS patients shows increased levels of ROCK2 as well as its downstream targets LIMK1 and cofilin. Increased ROCK activity results in higher levels of phosphorylated adducin as well as activation of phosphatase and tensin homolog (PTEN) and decreased Akt activity. PTEN activation by ROCK exerts negative effects on cell growth, proliferation and metabolism. Inhibition of ROCK counteracts neuronal apoptosis and axonal degeneration and on the other hand fosters axonal regeneration and modulates microglia activation. (J. C. Koch et al., “Compassionate use of the ROCK inhibitor Fasudil in three patients with amyotrophic lateral sclerosis” Front. Neurol. March 2020, Volume 11, Article 173, doi: 10.3389 / fneur.2020.00173). Pain Disorders Pain is a subjective sensation reflecting a tissue damage and exhibits various forms. Pain is classified into somatic pain and psychogenic pain, and somatic pain is further classified into nociceptive pain and neuropathic pain. Nociceptive pain is caused by external stimulation or visceral pathology. Nociceptive pain is mainly acute, which disappears following cure of underlying disease, and plays a role as a biological signal generated by a disorder. Neuropathic pain is chronic pain caused by dysfunction of the peripheral or central nervous system and includes pain from various sources including pain due to diabetes, nerve compression and spinal cord injury. Psychogenic pain is chronic pain, which is due to mental disorder rather than physical disorder and cannot be explained by organic disorder, and includes chronic headache, abdominal pain of unknown cause and the like. Chronic pain can impart large distress to patients and thus, is an important target of treatment. Non-limiting examples of chronic pain include chronic pain associated with arthritis, diabetes, cancer and the like which requires pain treatment in addition to treatment of underlying disease. ROCK inhibitors have been shown to exert an analgesic effect on pain. In certain embodiments a compound described herein is used to treat a pain disorder. In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof may be used to treat somatic pain. For example, a compound of the present invention or a pharmaceutically acceptable salt thereof may be used to treat nociceptive pain or neuropathic pain. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat nociceptive pain. Non-limiting examples of nociceptive pain include acute pain arising from an underlying disease. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat neuropathic pain. Non-limiting examples of neuropathic pain include chronic pain caused by diabetes, nerve compression, or a spinal cord injury. In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof. is used to treat pain arising from arthritis, for example, osteoarthritis or rheumatoid arthritis. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a pain disorder such as one of those listed above or a secondary condition associated with the pain disorder. Cardiovascular Diseases Studies have demonstrated that the Rho / ROCK pathway is increased in hypertensive patients. For example, increased ROCK-dependent smooth muscle contraction is observed in the aorta in the early stage of atherosclerosis. During atherosclerosis lesion formation, ROCK activity, is increased in certain areas and cell types including endothelium, periadventitial adipocytes and macrophage foam cells, supporting a role of ROCK in the ERM phosphorylation-mediated macrophage infiltration and foam cell formation. ROCK has a role in cardiac ischemia / reperfusion injuries, where blood flow is restricted or cut off and then is reintroduced into the area. A deleterious role of RhoA / ROCK signaling in ischemia / reperfusion injury has been demonstrated in several in vivo models including mouse, rat and swine. (M. Surma et al., “Rho kinase as a therapeutic target in cardiovascular disease”, Future Cardiol. 2011 September; 7(5): 657–671. doi:10.2217 / fca.11.51). In certain embodiments a compound described herein is used to treat a cardiovascular disorder. Non-limiting examples of cardiovascular disorders include coronary heart disease, stroke, peripheral arterial disease, and aortic disease. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a cardiovascular disorder such as one of those listed above or a secondary condition associated with the cardiovascular disorder. Ocular Disorders The ability of ROCK proteins to mediate smooth muscle contractions in the eye has made ROCK a target for the treatment of ocular disorders. ROCK mediates calcium sensitization and smooth muscle contraction. The Ca2+-sensitizing effect of smooth muscle constricting agents has been ascribed to ROCK-mediated phosphorylation of MYPT-I, the regulatory subunit of myosin light chain phosphatase (MLCP). MYPT-1 is used by the body to inhibit the activity of MLCP. By inhibiting MLCP ROCK activated phosphorylation of MYPT-1 results in enhanced phosphorylation of the myosin light chain and smooth muscle contraction (WO 2005 / 003101 and WO 2005 / 034866). Glaucoma is an ophthalmic disease that leads to irreversible visual impairment. Glaucoma is characterized by a progressive optic neuropathy caused in part by deleterious effects resulting from increased intraocular pressure. In healthy individuals, intraocular pressures ranges from 12 to 20 mm Hg, averaging approximately 16 mm Hg. However, in individuals suffering from primary open angle glaucoma, intraocular pressures generally rise above 22 to 30 mm Hg. In angle closure or acute glaucoma intraocular pressure can reach as high as 70 mm Hg leading to blindness within only a few days. The loss of vision can also result from statistically normal intraocular pressures in individuals with unusually pressure-sensitive eyes; a condition known as normotensive glaucoma (See, e.g., P. L. Kaufman and T. W. Mittag, "Medical Therapy Of Glaucoma," Ch.9, Sec. II (pp.9.7-9.30) In P. L. Kaufman and T. W. Mittag (eds.): Glaucoma (Vol. 7 of S. M. Podos and M. Yanoff (eds): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994); A. C. Guyton, Textbook of Medical Physiology (W. B. Saunders Co., Sixth Ed.), pp. 386-89 (1981)). Open-angle glaucoma constitutes the majority of all primary glaucomas and is characterized by abnormally high resistance to fluid (aqueous humor) drainage from the eye. In the glaucomatous eye, the rate of aqueous humor production remains constant, while it is the increased resistance to outflow that is responsible for the elevated intraocular pressure. ROCK has also been implicated in the pathogeneses of vitreoretinal diseases caused by age and diabetic pathology. ROCK is involved in the ischemia response, angiogenesis, inflammation and membrane contraction, all key drivers of vitreoretinal diseases like age-related macular degeneration, diabetic retinopathy and proliferative vitreoretinopathies. (https: / / pmc.ncbi.nlm.nih.gov / articles / PMC5449758 / ). Diabetic retinopathy is a serious sight- threatening complication of diabetes. Diabetes damages small blood vessels throughout the body, including the retina. Diabetic retinopathy occurs when these tiny blood vessels leak blood and other fluids. This causes the retinal tissue to swell, resulting in cloudy or blurred vision. Diabetic retinopathy is classified into two types: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy (“Diabetic retinopathy” American Optometric Association). ROCK proteins have been studied in diabetic retinopathy (Wong, T., Cheung, C., Larsen, M. et al. “Diabetic retinopathy.” Nat Rev Dis Primers 2, 16012 (2016); Durham, Jennifer T., et al. “Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics.” American Journal of Physiology-Cell Physiology 307.9 (2014): C878-C892; Arita, Ryoichi, et al. “Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage.” Diabetes 58.1 (2009): 215-226; Nakagawa, Takahiko, et al. “Abnormal angiogenesis in diabetic nephropathy.” Diabetes 58.7 (2009): 1471; Singh, Kirti, and Arshi Singh. “Rho-kinase inhibitors in ocular diseases: a translational research journey.” Journal of current glaucoma practice 17.1 (2023): 44). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat diabetic retinopathy. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat non-proliferative diabetic retinopathy. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat proliferative diabetic retinopathy. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with diabetic retinopathy or a secondary condition associated with diabetic retinopathy. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat an ocular disorder. Non-limiting examples of ocular disorders include glaucoma (for example open angle glaucoma, angle closure glaucoma, acute glaucoma, and normotensive glaucoma) or intraocular pressure. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a human with glaucoma or a secondary condition associated with glaucoma. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat glaucoma. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat open angle glaucoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat angle closure glaucoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat acute glaucoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat normotensive glaucoma. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a human with diabetic macular edema (DME) or a secondary condition associated with diabetic macular edema (DME). For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat diabetic macular edema (DME).In additional embodiments, the disorder is a macular degeneration, for example age related macular degeneration, wet macular degeneration, or dry macular degeneration. In certain embodiments the disorder is age related macular degeneration. In certain embodiments the disorder is wet macular degeneration. In certain embodiments the disorder is dry macular degeneration. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with an ocular disorder such as one of those listed above or a secondary condition associated with the ocular disorder. Huntington's Disease (HD) Huntington's disease (HD) is a progressive brain disorder caused by a defective gene. This disease causes changes in the central area of the brain, which affect movement, mood and thinking skills. In Western populations HD has a prevalence of 10.6–13.7 individuals per 100 000 (McColgan, Peter, and Sarah J. Tabrizi. "Huntington's disease: a clinical review." European journal of neurology 25.1 (2018): 24-34). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat HD. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat Adult-onset Huntington's disease, or juvenile Huntington's disease. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with HD or a secondary condition associated with HD. Motor Neuron Diseases (MND) Motor neuron disease (MND) is an adult-onset neurodegenerative disorder characterized by loss of upper motor neurons and lower motor neurons (Bäumer, Dirk, Kevin Talbot, and Martin R. Turner. “Advances in motor neurone disease.” Journal of the Royal Society of Medicine 107.1 (2014): 14-21.). Nonlimiting examples of motor neuron disease include amyotrophic lateral sclerosis, primary lateral sclerosis, progressive bulbar palsy, pseudobulbar palsy, progressive muscular atrophy, spinal muscular atrophy, and Kennedy’s disease. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat motor neuron disease. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat amyotrophic lateral sclerosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat primary lateral sclerosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with motor neuron disease or a secondary condition associated with motor neuron disease. Polycystic Kidney Disease (PKD) Polycystic kidney disease (PKD) is a genetic disease that causes the growth of fluid-filled cysts in the kidneys. Autosomal recessive polycystic kidney disease (ARPKD) and Autosomal dominant polycystic kidney disease (ADPKD) are the two kinds of PKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common type of PKD and one of the most common genetic kidney diseases. About 9 out of every 10 people with PKD have ADPKD. It is characterized by relentless development of kidney cysts, hypertension, and eventually end-stage renal disease (ESRD). Clinical symptoms typically do not arise until adulthood. (Chebib, Fouad T., and Vicente E. Torres. “Autosomal dominant polycystic kidney disease: core curriculum 2016.” American Journal of Kidney Diseases 67.5 (2016): 792-810). In contrast to ADPKD, autosomal recessive polycystic kidney disease (ARPKD) is typically an infantile disease (Bergmann, Carsten. “ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies.” Pediatric Nephrology 30.1 (2015): 15- 30.). It is a rare genetic disorder that can cause palpable kidneys, enlarged liver, respiratory failure, hypertension, or urinary tract infections (Zerres, K., et al. “Autosomal recessive polycystic kidney disease.” Journal of molecular medicine 76 (1998): 303-309.). ROCK proteins have been studied in polycystic kidney disease (PKD) (Ma, Shenghong, and Kun-Liang Guan. “Polycystic kidney disease: a Hippo connection.” Genes & Development 32.11-12 (2018): 737-739; Cai, Jing, et al. “A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease.” Genes & development 32.11-12 (2018): 781-793). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat polycystic kidney disease (PKD). For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with PKD or a secondary condition associated with PKD. Diabetic Nephropathy Diabetic nephropathy is a serious complication of type 1 diabetes and type 2 diabetes. Diabetic nephropathy develops in approximately 40% of patients who are diabetic and is the leading cause of chronic kidney disease (CKD) worldwide (Alicic, Radica Z., Michele T. Rooney, and Katherine R. Tuttle. “Diabetic kidney disease: challenges, progress, and possibilities.” Clinical journal of the American Society of Nephrology 12.12 (2017): 2032-2045). ROCK proteins have been studied in diabetic nephropathy (Matoba, Keiichiro, et al. “Rho- kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia- inducible factor 1α.” Kidney international 84.3 (2013): 545-554; Gojo, Atsushi, et al. “The Rho- kinase inhibitor, Fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats.” European journal of pharmacology 568.1-3 (2007): 242-247; Knipe, Rachel S., Andrew M. Tager, and James K. Liao. “The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacological reviews 67.1 (2015): 103-117; Matoba, Keiichiro, et al. “ROCK inhibition may stop diabetic kidney disease.” JMA journal 3.3 (2020): 154-163; Matoba, Keiichiro, et al. “Renal ROCK activation and its pharmacological inhibition in patients with diabetes.” Frontiers in Pharmacology 12 (2021): 738121; Nath, Karl A. “Tubulointerstitial changes as a major determinant in the progression of renal damage.” American Journal of Kidney Diseases 20.1 (1992): 1-17; Matoba, Keiichiro, et al. “Rho-kinase blockade attenuates podocyte apoptosis by inhibiting the notch signaling pathway in diabetic nephropathy.” International Journal of Molecular Sciences 18.8 (2017): 1795). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat diabetic nephropathy. In other embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat kidney disease. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with diabetic nephropathy or a secondary condition associated with diabetic nephropathy. Kidney Failure Kidney failure (renal failure) means one or both of the kidneys no longer function well on their own. Kidney failure is also called end-stage renal disease (ESRD). Kidney failure is sometimes temporary and develops quickly (referred to as acute kidney injury (AKI)). Other times it’s a chronic (long-term) condition that slowly gets worse (chronic kidney disease (CKD)). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat kidney failure, end-stage renal disease (ESRD). For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat kidney failure caused by acute kidney injury (AKI) or kidney failure caused by chronic kidney disease (CKD). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with kidney failure or a secondary condition associated with kidney failure. Fibrotic disorders Non-limiting examples of fibrotic disorders include pulmonary fibrosis, renal fibrosis, liver fibrosis, heart fibrosis, and skin fibrosis (Antar SA, et. al. “Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation” Int J Mol Sci. 24.4 (2023): 4004). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a fibrotic disorder. Pulmonary fibrosis (fibrosis of the lungs) is lung disease that occurs when lung tissue becomes damaged and develops scars. A subtype of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) which is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation (Meltzer, Eric B., and Paul W. Noble. “Idiopathic pulmonary fibrosis.” Orphanet journal of rare diseases 3 (2008): 1-15). ROCK proteins have been studied in pulmonary fibrosis (Knipe, Rachel S., et al. “The Rho kinase isoforms ROCK1 and ROCK2 each contribute to the development of experimental pulmonary fibrosis.” American journal of respiratory cell and molecular biology 58.4 (2018): 471-481; Knipe, Rachel S., Andrew M. Tager, and James K. Liao. “The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacological reviews 67.1 (2015): 103-117; Li, Qingfang, et al. “Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarization through phosphorylation of STAT3.” Clinical and Translational Medicine 12.10 (2022): e1036; Wu, Xinhui, et al. “Rho-kinase 1 / 2 inhibition prevents transforming growth factor-β-induced effects on pulmonary remodeling and repair.” Frontiers in pharmacology 11 (2021): 609509). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat pulmonary fibrosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat idiopathic pulmonary fibrosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with pulmonary fibrosis or a secondary condition associated with pulmonary fibrosis. Renal fibrosis, characterized by tubulointerstitial fibrosis and glomerulosclerosis, is the final manifestation of chronic kidney disease. Renal fibrosis is characterized by an excessive accumulation and deposition of extracellular matrix components (Cho, Min Hyun. “Renal fibrosis.” Korean journal of pediatrics 53.7 (2010): 735). Rho-associated protein kinase (ROCK) inhibitor Fasudil has been studied for use in treating renal interstitial fibrosis (Baba, Itsuko, et al. “Inhibitory effects of Fasudil on renal interstitial fibrosis induced by unilateral ureteral obstruction.” Molecular Medicine Reports 12.6 (2015): 8010-8020). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat renal fibrosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat tubulointerstitial fibrosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat glomerulosclerosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with renal fibrosis or a secondary condition associated with renal fibrosis. Liver fibrosis is the excessive formation of scar tissue in the liver. It is a wound-healing response generated as a result of chronic liver injury and has the potential to progress into cirrhosis, and if not prevented, it may lead to liver cancer and liver failure (Aydın, M. Merve, and Kamil Can Akçalı. “Liver fibrosis” The Turkish Journal of Gastroenterology 29.1 (2018): 14). Studies have shown that ROCK proteins play a role in liver fibrosis (Xie, Y., et al. “Fasudil alleviates hepatic fibrosis in type 1 diabetic rats: involvement of the inflammation and RhoA / ROCK pathway.” European Review for Medical & Pharmacological Sciences 22.17 (2018); Murata, Toru, et al. “Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells.” Journal of hepatology 35.4 (2001): 474- 481; Zanin-Zhorov, Alexandra, et al. “Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism.” Communications biology 6.1 (2023): 1176; Tada, Seiya, et al. “A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.” Journal of hepatology 34.4 (2001): 529- 536). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with liver fibrosis or a secondary condition associated with liver fibrosis. Skin fibrosis is characterized by an excessive buildup of collagen and other connective tissues in the skin (Wang K, et al. “Extracellular matrix stiffness-The central cue for skin fibrosis” Front Mol Biosci.8.10 (2023): 1132353). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with skin fibrosis or a secondary condition associated with skin fibrosis. Heart fibrosis or myocardial fibrosis occurs when excessive extracellular matrix proteins are deposited in cardiac tissue (Frangogiannis NG. “Cardiac fibrosis” Cardiovasc Res. 25.117 (2021): 1450-1488). The association of ROCK protein and cardiovascular fibrosis has been explored (Yu B, et al. “Targeting Rho-associated coiled-coil forming protein kinase (ROCK) in cardiovascular fibrosis and stiffening” Expert Opin Ther Targets.24.1 (2020): 47-62) The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with myocardial fibrosis or a secondary condition associated with heart fibrosis. Levodopa-induced dyskinesia (LID) Levodopa is a used in the treatment of Parkinson's disease (PD), but its long-term use is complicated by motor fluctuations and dyskinesia. Different types of movement disorders are seen in levodopa-induced dyskinesia (LID) including chorea, ballism, dystonia, myoclonus, or combination of any of these movements. These dyskinesias are seen in the neck, facial muscles, jaw, tongue, hip, shoulder, trunk, and limb or may appear as involuntary flexion of toes (Pandey, Sanjay, and Prachaya Srivanitchapoom. “Levodopa-induced dyskinesia: clinical features, pathophysiology, and medical management.” Annals of Indian Academy of Neurology 20.3 (2017): 190-198.). There have been studies on the involvement of ROCK in the pathophysiology of LID (Lopez‐Lopez, Andrea, et al. “Rho kinase inhibitor Fasudil reduces L‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease.” British Journal of Pharmacology 177.24 (2020): 5622-5641; Lopez-Lopez, Andrea, et al. “Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia.” Antioxidants 12.7 (2023): 1454). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat LID. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat peak-dose dyskinesia, wearing-off / off-period dyskinesia, or diphasic dyskinesia of LID. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with LID or a secondary condition associated with LID. Traumatic Brain Injury (TBI) Traumatic brain injuries (TBIs) can affect people of all ages and are a major cause of death and disability, with an incidence of ∼10 million people worldwide (Blennow, Kaj, et al. “Traumatic brain injuries.” Nature reviews Disease primers 2.1 (2016): 1-19.). Traumatic brain injuries (TBIs) are clinically grouped by severity: mild, moderate and severe. Mild TBI (the least severe form) is synonymous with concussion and is typically caused by blunt non-penetrating head trauma. ROCK proteins have been studied in traumatic brain injuries (Fujita, Yuki, and Toshihide Yamashita. “Axon growth inhibition by RhoA / ROCK in the central nervous system.” Frontiers in neuroscience 8 (2014): 338; Lerouet, Dominique, Catherine Marchand‐Leroux, and Valérie C. Besson. “Neuropharmacology in traumatic brain injury: from preclinical to clinical neuroprotection?” Fundamental & clinical pharmacology 35.3 (2021): 524-538; Brabeck, Christine, et al. “Lesional expression of RhoA and RhoB following traumatic brain injury in humans.” Journal of neurotrauma 21.6 (2004): 697-706; Mulherkar, Shalaka, et al. “RhoA-ROCK inhibition reverses synaptic remodeling and motor and cognitive deficits caused by traumatic brain injury.” Scientific reports 7.1 (2017): 10689; Feng, Shi-jun, and Jian-guo Han. “Treatment of traumatic brain injury in rats by RhoA gene silencing combined with umbilical cord mesenchymal stem cell transplantation.” Chinese Journal of Tissue Engineering Research 17.1 (2013): 23.). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat TBI. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat mild TBI, moderate TBI or severe TBI. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with TBI or a secondary condition associated with TBI. Benign Prostatic Hyperplasia (BPH) Benign prostatic hyperplasia (BPH) results in a benign enlargement of the prostate gland due to unregulated hyperplastic growth of the epithelial andfibromuscular tissues of the transition zone (TZ) and periurethral area. (Devlin, Conor M., Matthew S. Simms, and Norman J. Maitland. “Benign prostatic hyperplasia–what do we know?” BJU international 127.4 (2021): 389-399.) Benign prostatic hyperplasia (BPH) is a major cause of lower urinary tract symptoms (LUTS) including nocturia, urinary frequency, urgency, decreased urine flow rates, incomplete bladder emptying, and hesitancy (Laborde, Eric E., and Kevin T. McVary. “Medical management of lower urinary tract symptoms.” Reviews in urology 11.Suppl 1 (2009): S19.). ROCK proteins have been studied in benign prostatic hyperplasia (Shan, Shidong, et al. “Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-β-catenin signaling axis and static & dynamic dual roles.” Molecular Medicine 29.1 (2023): 139; Takahashi, Ryosuke, et al. “RhoA / Rho kinase‐ mediated Ca2+sensitization in the contraction of human prostate.” Neurourology and urodynamics 26.4 (2007): 547-551; Morelli, Annamaria, et al. “BXL‐628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA / Rho kinase signaling in rat and human bladder.” The Prostate 67.3 (2007): 234-247; La Vignera, S., et al. “Endocrine control of benign prostatic hyperplasia.” Andrology 4.3 (2016): 404- 411). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat benign prostatic hyperplasia. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat lower urinary tract symptoms associated with benign prostatic hyperplasia. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with benign prostatic hyperplasia or a secondary condition associated with benign prostatic hyperplasia. Urinary bladder dysfunction Non-limiting examples of urinary bladder dysfunction include neurogenic bladder, interstitial cystitis / bladder pain syndrome, cystitis / bladder inflammation, overactive bladder, bladder fibrosis, and lower urinary tract symptoms (LUTS). Neurogenic bladder refers to a malfunctioning urinary bladder due to neurologic dysfunction or insult emanating from internal or external trauma, disease, or injury (Rackley, Raymond, S. P. Vasavada, and F. Firoozi. “Neurogenic bladder.” 2009). Interstitial cystitis / bladder pain syndrome is a condition that causes long-term pain or discomfort in the bladder and abdominal area, along with urinary frequency and urgency. Overactive bladder is a problem with bladder function that causes the sudden need to urinate. Bladder fibrosis refers to scarring and hardening of the tissue in the bladder. Lower urinary tract symptoms (LUTS) include nocturia, urinary frequency, urgency, decreased urine flow rates, incomplete bladder emptying, and hesitancy (Laborde, Eric E., and Kevin T. McVary. “Medical management of lower urinary tract symptoms.” Reviews in urology 11. Suppl 1 (2009): S19). ROCK proteins have been studied in urinary bladder dysfunctions (Oger, S., et al. “Rho-kinase inhibition relaxes detrusor from neurogenic patients.” European Urology Supplements 9.2 (2010): 112; Oudot, A., et al. “A new experimental rat model of erectile dysfunction and lower urinary tract symptoms associated with benign prostate hyperplasia: The testosterone-supplemented spontaneously hypertensive rat.” J Sex Med 7 (2010): 406-406; Peters, Stephan LM, Martina Schmidt, and Martin C. Michel. “Rho kinase: a target for treating urinary bladder dysfunction?” Trends in pharmacological sciences 27.9 (2006): 492-497; Yono, Makoto, et al. “Identification of potential therapeutic targets in hypertension‐associated bladder dysfunction.” BJU international 105.6 (2010): 877-883). The impact of ROCK inhibition on detrusor overactivity has also been conducted in chronic spinalized rats (Broqueres-You, Dong, et al. “Rho-Kinase Inhibition Impacts Neurogenic Detrusor Overactivity In Chronic Spinalized Rats.” The Journal of Urology 183.4S (2010): e76-e77). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat urinary bladder dysfunction. Non-limiting examples of urinary bladder dysfunction include neurogenic bladder, interstitial cystitis / bladder pain syndrome, cystitis / bladder inflammation, overactive bladder, bladder fibrosis and lower urinary tract symptoms (LUTS). In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat cystitis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with urinary bladder dysfunction or a secondary condition associated with urinary bladder dysfunction. Sarcoidosis Sarcoidosis is a multi-system disease characterized by the formation of granulomas in various organs. Sarcoidosis most commonly affects the lungs and lymph nodes, but it can affect any organ including the eyes, skin, heart and nervous system (Sève, Pascal, et al. “Sarcoidosis: a clinical overview from symptoms to diagnosis.” Cells 10.4 (2021): 766). ROCK proteins have been studied in sarcoidosis (Pehlivan, Yavuz, et al. “Investigation of the association between Rho / Rho-kinase gene polymorphisms and systemic sclerosis.” Rheumatology international 36 (2016): 421-427; Yuan, Ying, et al. “The role of the RhoA / ROCK signaling pathway in mechanical strain-induced scleral myofibroblast differentiation.” Investigative ophthalmology & visual science 59.8 (2018): 3619-3629; Li, Bo, et al. “Esophageal dysfunction in systemic sclerosis: an update.” Rheumatology and Therapy (2021): 1-15; Bei, Yihua, et al. “RhoA / Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis.” Experimental lung research 42.1 (2016): 44-55). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat pulmonary sarcoidosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat neurosarcoidosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with sarcoidosis or a secondary condition associated with sarcoidosis. Scleroderma Scleroderma is a rare, chronic autoimmune disease that affects skin and internal organs. Scleroderma results from the immune system and often causes inflammation and tissues changes leading to skin tightening and thickening. It can affect joints, muscles, heart, lungs, kidneys, blood vessels or intestines. (“Scleroderma” American College of Rheumatology, https: / / rheumatology.org / patients / scleroderma). ROCK proteins have been studied in scleroderma (Thompson‐Torgerson, Caitlin S., et al. “RhoA and Rho kinase activity is increased in scleroderma microvascular smooth muscle cells.” (2007): A1372-A1372). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat scleroderma. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with scleroderma or a secondary condition associated with scleroderma. Focal Segmental Glomerulosclerosis (FSGS) Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular lesion that includes several completely different clinicopathological diseases that share injury within the podocyte as a primary pathophysiological feature (Shabaka, Amir, Ana Tato Ribera, and Gema Fernández-Juárez. “Focal segmental glomerulosclerosis: state-of-the-art and clinical perspective.” Nephron 144.9 (2020): 413-427). According to the etiology, FSGS lesion has been classified into primary, genetic, and secondary forms that include maladaptive, virus-associated, and medication-induced FSGS. ROCK proteins have been studied in focal segmental glomerulosclerosis (Zhu, Lei, et al. “Activation of RhoA in podocytes induces focal segmental glomerulosclerosis.” Journal of the American Society of Nephrology 22.9 (2011): 1621-1630; Matoba, Keiichiro, et al. “Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis.” Communications Biology 7.1 (2024): 402; Asano-Matsuda, Kana, et al. “Role of Rho GTPase interacting proteins in subcellular compartments of podocytes.” International Journal of Molecular Sciences 22.7 (2021): 3656; Saleh, Mohamed A., et al. “RhoA / ROCK inhibition attenuates endothelin-1–induced glomerulopathy in the rats.” Life Sciences 323 (2023): 121687). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat focal segmental glomerulosclerosis. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat primary or secondary focal segmental glomerulosclerosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with focal segmental glomerulosclerosis or a secondary condition associated with FSGS. Cancer There has been early, basic research on the role of ROCK in cancer (Ridley, A. J. “RhoA, RhoB and RhoC have different roles in cancer cell migration.” Journal of microscopy 251.3 (2013): 242-249; Barcelo, Jaume, Remi Samain, and Victoria Sanz-Moreno. “Preclinical to clinical utility of ROCK inhibitors in cancer.” Trends in Cancer 9.3 (2023): 250-263; Chin, Venessa T., et al. “Rho-associated kinase signaling and the cancer microenvironment: novel biological implications and therapeutic opportunities.” Expert reviews in molecular medicine 17 (2015): e17). For example, in certain advanced stage breast cancer models, ROCK has been shown to be overexpressed or of higher activity (Guerra, Fabiana Sélos, et al. “ROCK inhibition with Fasudil induces beta-catenin nuclear translocation and inhibits cell migration of MDA-MB 231 human breast cancer cells.” Scientific reports 7.1 (2017): 13723). Likewise, an amplification of ROCK1 and ROCK2 expression was observed in selected pancreatic cancer models. (Kim, Seohyun, et al. “Rho-kinase as a target for cancer therapy and its immunotherapeutic potential.” International journal of molecular sciences 22.23 (2021): 12916). Additional studies on ROCK protein in pancreatic cancer include the papers by Whatcott, Clifford J., et al. “Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer.” PloS one 12.8 (2017): e0183871; Mu, Ganggang, et al. “Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12 / 13–RhoA–ROCK signaling pathway.” Experimental & Molecular Medicine 50.5 (2018): 1-14; Vennin, Claire, et al. “Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy.” Small GTPases 11.1 (2020): 45-52; Vennin, Claire, et al. “Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.” Science translational medicine 9.384 (2017): eaai8504; and Zhu, Shuai, et al. “ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca2+ / RhoA pathway.” Cell death & disease 8.5 (2017): e2806-e2806. ROCK proteins have also been researched in melanoma models (Chang, Fei, et al. “ROCK inhibitor enhances the growth and migration of BRAF‐mutant skin melanoma cells.” Cancer science 109.11 (2018): 3428-3437; Teiti, Iotefa, et al. “In vivo effects in melanoma of ROCK inhibition-induced FasL overexpression.” Frontiers in oncology 5 (2015): 156; and Kaczorowski, Maciej, et al. “ROCK1 and ROCK2 are down-regulated in aggressive and advanced skin melanomas–a clinicopathological perspective.” Anticancer Research 40.4 (2020): 1931-1942). Initial studies on the role of ROCK proteins in prostate cancer have also been reported (Chen, Weihua, et al. “The role of the RhoA / Rho kinase pathway in anti-angiogenesis and its potential value in prostate cancer.” Oncology letters 8.5 (2014): 1907-1911; Steurer, Stefan, et al. “Up regulation of Rho-associated coiled-coil containing kinase1 (ROCK1) is associated with genetic instability and poor prognosis in prostate cancer.” Aging (Albany NY) 11.18 (2019): 7859; Liu, Kang, et al. “Genetic variants in RhoA and ROCK1 genes are associated with the development, progression and prognosis of prostate cancer.” Oncotarget 8.12 (2017): 19298). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat pancreatic cancer. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat breast cancer. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat prostate cancer. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat melanoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat desmoplastic syndromes associated with cancer. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with cancer or a secondary condition associated with cancer. Non-limiting examples of cancer include pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer. Non-limiting examples of cancer include carcinomas, Kaposi’s sarcoma, melanoma, mesothelioma, soft tissue sarcoma, pancreatic cancer, lung cancer, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, and other), lymphoma (Hodgkin's and non- Hodgkin’s), multiple myeloma, adrenocortical carcinoma, cerebellar astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, Burkitt's lymphoma, carcinoid tumor, central nervous system lymphoma, cervical cancer, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, germ cell tumor, glioma,, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, retinoblastoma, islet cell carcinoma ( endocrine pancreas), laryngeal cancer, lip and oral cavity cancer, liver cancer, medulloblastoma, Merkel cell carcinoma, squamous neck cancer with occult mycosis fungoides, myelodysplastic syndromes, myelogenous leukemia, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma, soft tissue sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, Waldenström’s macroglobulinemia, and Wilms' tumor. Protein Kinase X (PRKX) PRKX, human protein kinase X, is an X chromosome encoded cAMP-dependent serine / threonine kinase. The cAMP-dependent protein kinases (cAPKs) play a key role in many signal transduction processes, mediating the majority of the known effects of cAMP in the eukaryotic cell. These multisubstrate enzymes regulate the activity of proteins involved in signal transduction, energy metabolism, cell proliferation, or differentiation by phosphorylation of Ser or Thr residues, which alters the biological properties of the target proteins. The human protein kinase PRKX is related to the catalytic subunit of cAMP-dependent protein kinases but is distinct from the isoforms Cα, Cβ, and Cγ. PRKX has 53.2% identity to the human Cα subunit of cAPK (PKA- Cα) in the catalytic core region. This degree of homology is much lower than the similarity of the two human isoforms Cα and Cβ (90.5% identity). PRKX mRNA is present in a variety of tissues, with the highest levels of expression in fetal and adult brain, kidney, and lung. (B. Zimmermann et al. “PRKX Is a Novel Catalytic Subunit of the cAMP-dependent Protein Kinase Regulated by the Regulatory Subunit Type I” Journal of Biological Chemistry, Vol. 274, No. 9, Issue of February 26, pp.5370-5378, 1999.) In contrast to the ubiquitously expressed Cα subunit, PRKX is mainly active during embryonic organ development and cellular differentiation in hematopoietic lineages. It was found to be crucial for macrophage and granulocyte maturation. PRKX was shown to be involved in renal development, regulating epithelial cell migration, ureteric bud branching, and induction of glomeruli formation (M. Diskar et al. “Regulation of cAMP-dependent protein kinases: the human protein kinase X (PrKX) reveals the role of the catalytic subunit αH – αI loop” Journal of Biological Chemistry, Vol.285, No.46, pp.35910 –35918, November 12, 2010). The role of PRKX in disease pathology is not well understood. However, a recent study identified the dysregulation of PRKX expression as a possible molecular cause for Mayer– Rokitansky–Küster–Hauser (MRKH) syndrome (P. Pontecorvi et al. “Altered Expression of Candidate Genes in Mayer–Rokitansky–Küster–Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X” Biology, 2021, 10, 450.). PRKX has also been indicated in the pathology of amyotrophic lateral sclerosis (ALS) (Oliverira G. et al., Early Gene Expression Changes in Skeletal Muscle from SOD1(G93A) Amyotrophic Lateral Sclerosis Animal Model). In certain embodiments a method of treating a subject with a PRKX mediated disorder is provided comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome PRKX has been implicated in the development of Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome (P. Pontecorvi et al. “Altered Expression of Candidate Genes in Mayer– Rokitansky–Küster–Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X” Biology, 2021, 10, 450). Thus, in certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat MRKH syndrome. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome or a secondary condition associated with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. Graft-vs-Host Disease ROCK is associated as a driver in the pathogenesis of corticosteroid-refectory acute graft- vs-host disease, and ROCK1 / 2 inhibition has been shown to reduce immune activation in both the innate and adaptive immune systems. In animal models and clinical trials of acute graft-vs-host disease (aGVHD), ROCK inhibitors have demonstrated the ability to reduce alloimmune activation at a variety of cellular and molecular levels (https: / / www.nature.com / articles / s41467- 024-44703-7). The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with graft-vs-host disease or a secondary condition associated with graft-vs-host disease. IV. PHARMACEUTICAL COMPOSITIONS A compound of Formula I or its pharmaceutically acceptable salt thereof, as described herein is typically administered as a pharmaceutical composition, that includes an effective amount for a subject, typically a human, in need of such treatment for a disorder described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable excipient for a use described herein. The pharmaceutical composition may contain the compound as the only active agent, or, in an alternative embodiment, the compound and at least one additional therapeutic agent. In general, the compositions of the disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease. In certain embodiments, the pharmaceutical composition is in a dosage form that contains from about 1 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional therapeutic agent in a unit dosage form. Examples are dosage forms with at least about 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. A pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject. The precise effective amount will vary from subject to subject, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation can be determined by routine experimentation. The subject can be administered as many doses as is required to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. In some embodiments, a compound or its pharmaceutically acceptable salt as disclosed herein or used as described is administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, compounds disclosed herein or used as described are administered QD, BID, or TID for at least 1 day, at least 2 days, at least 3 days, at least 7 days, at, at least 14 days, at least 21 days, or longer, including indefinitely. In certain embodiments, the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day. In certain embodiments, the compound of the present invention is administered orally once a day. In certain embodiments, the compound of the present invention is administered orally twice a day. In certain embodiments, the compound of the present invention is administered orally three times a day. In certain embodiments, the compound of the present invention is administered orally four times a day. In certain embodiments, the compound of the present invention is administered intravenously once a day. In some embodiments the compound of the present invention is administered with a treatment holiday in between treatment cycles. For example, the compound may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent. As non-limiting illustrative examples, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti-inflammatory or immunosuppressing agent. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound. In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: sodium, potassium, magnesium, zinc, lysine, meglumine, trimethylamine, and tromethamine salts. Additional non- limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). Thus, the selected compound of the present invention or pharmaceutically acceptable salt thereof can be administered as a pharmaceutical composition which is suitable for generally for systemic, parenteral or topical administration. Non-limiting examples include or oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, parenteral injection (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), inhalation or spray, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, or by other means of administration. A typical manner of administration is oral or intravenous, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. Oral pharmaceutical compositions include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier or excipient and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like. In certain aspects the term “carrier” applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. A “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” typically means a carrier or excipient that is useful in preparing a pharmaceutical composition / combination that is generally safe, suitably non-toxic and neither biologically nor otherwise inappropriate for administration to a subject, typically a human. Pharmaceutically acceptable excipients must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated. The pharmaceutically acceptable excipient can be inert or it can possess pharmaceutical benefits of its own. The amount of excipient employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of excipients include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material. Some excipients may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable excipients include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. Some excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. The compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy. Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in the pharmaceutical composition. A biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like. For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, referenced above. In yet another embodiment provided is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable inert excipient such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the active agent can be combined with any oral, non- toxic, pharmaceutically acceptable inert excipient such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device. Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable excipients, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in an acceptably nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained. Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a subject through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration. Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use. Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Alternatively, the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of the disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents. Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be affected using a transmucosal delivery system as known to those skilled in the art. The compounds of the disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated device can contain a single reservoir, or it can contain multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. V. COMBINATION THERAPY A compound of the present invention, or a pharmaceutically acceptable salt thereof can be used in an effective amount, either alone or in combination with other therapeutic agents, to treat a human with a ROCK1 and / or ROCK2 mediated disorder. For example, a compound of the present invention, or a pharmaceutically acceptable salt thereof can be used in an effective amount, either alone or in combination with a second therapeutic agent, to treat a human with a ROCK1 and / or ROCK2 mediated disorder. The term “second therapeutic agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In certain embodiments, the compound of the present invention and the second therapeutic agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter. In another embodiment, the compound of the present invention and the second therapeutic agent are administered to a subject in need thereof and they do not have overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic efficacy of the other. Non-limiting examples of second therapeutic agents include riluzole, edaravone, sodium phenyl butyrate, taurursodiol, levodopa, selegiline, rasagiline, safinamide, pramipexole, rotigotine, apomorphine, tolcapone, entacapone, trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, amantadine, and istradefylline. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with tiluzole, edaravone, or taurusodiol to treat ALS. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with levodopa, selegiline, rasagiline, safinamide, pramipexole, rotigotine, apomorphine, tolcapone, entacapone, trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, amantadine, and istradefylline to treat PD. In other embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with levodopa and carbidopa to treat PD. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with amantadine, donepezil, clozapine, quetiapine, olanzapine, and apomorphine, tetrabenazine, clonazepam, propranolol, branched-chain amino acids (BCAAs), ginkgo biloba, zonisamide, levetiracetam, melatonin, omega-3 fatty acids, piracetam, resveratrol, vitamin B6, or vitamin E to treat Levodopa-induced dyskinesia. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with dapagliflozin, finerenone, canagliflozin, angiotensin receptor blockers (ARBs), bexagliflozin, empagliflozin, ertugliflozin, ramipril, quinapril, or lisinopril to treat diabetic nephropathy. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with tolvaptan, dapagliflozin, finerenone, canagliflozin, angiotensin receptor blockers (ARBs), bexagliflozin, empagliflozin, ertugliflozin, ramipril, quinapril, or lisinopril to treat polycystic kidney disease. In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with another ROCK inhibitor. Non-limiting examples of ROCK inhibitors include fasudil, netarsudil, and ripasudil. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with fasudil to treat ALS, PD, Levodopa-induced dyskinesia, diabetic nephropathy, or polycystic kidney disease. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with netarsudil or ripasudil to treat an ocular disorder. VI. GENERAL SYNTHESIS The compounds described herein can be prepared by methods known by those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the schemes below. The abbreviations used in the synthetic procedures have the following definitions.

[0008] Example 1: Synthesis of (4-(2-((2-fluorobenzyl)carbamoyl)-1-methyl-1H-pyrrolo[2,3- b]pyridin-6-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (Compound 1) Di-tert-butyl [4-(2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methyl phosphate (1-2) To a solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (800 mg, 2.29 mmol, 1.00 equiv) in DMF (10 mL) was added Cs2CO3 (1.49 g, 4.58 mmol, 2.00 equiv) and the reaction was stirred at room temperature for 5 minutes. Followed by the addition of di-tert-butyl chloromethyl phosphate (1.18 g, 4.58 mmol, 2.00 equiv) in DMF (10 mL) dropwise at 0°C. The reaction mixture was stirred overnight at 25°C. The reaction was monitored on LCMS. After completion, the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers dried over anhydrous Na2SO4, filtered and concentrated. The crude was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford di-tert-butyl [4- (2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl phosphate (600 mg, 45.84%) as a yellow solid. MS (ESI) m / z: 572.3 [ M+H]+. [4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1- yl]methoxyphosphonic acid (Compound 1) A mixture of di-tert-butyl [4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl phosphate (500 mg, 0.87 mmol, 1.00 equiv) and TFA (0.46 mL, 6.21 mmol, 7.10 equiv) in DCM (2 mL). The reaction was continued stirring at room temperature for 2 hours. The reaction was monitored on LCMS. After completion, the solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase A:H2O (5 mM NH4HCO3), mobile phase B: CH3CN, 10% B to 50% B gradient in 10 min; detector, UV 220 nm, to afford [4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methoxyphosphonic acid (80 mg, 19.91%) as a white solid. MS (ESI) m / z: 460.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.10 (q, J = 11.8, 8.9 Hz, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 8.14 – 7.95 (m, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.46 – 7.38 (m, 1H), 7.37 – 7.23 (m, 1H), 7.24 – 6.99 (m, 3H), 5.83 (d, J = 9.8 Hz, 2H), 4.53 (d, J = 5.9 Hz, 2H), 4.05 (s, 3H) ppm. 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(2-((2-fluorobenzyl)carbamoyl)-1- methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate A solution of [4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin- 6-yl)pyrazol-1-yl]methoxyphosphonic acid (70 mg, 0.152 mmol, 1.0 equiv) and 2-amino-2- (hydroxymethyl)propane-1,3-diol (18.46 mg, 0.152 mmol, 1.0 equiv) in i-PrOH (3 mL) was stirred at room temperature for an hour. Then, the reaction was concentrated under reduced pressure to afford 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(2-((2-fluorobenzyl)carbamoyl)-1- methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate (63.7 mg, 71.29%) as a white solid. MS (ESI) m / z: 460.1 [M+H]+, Retention time: 1.32 min, 99.1% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.40 – 7.30 (m, 1H), 7.24 – 7.15 (m, 3H), 5.64 (d, J = 9.4 Hz, 2H), 4.53 (d, J = 5.8 Hz, 2H), 4.05 (s, 3H), 3.47 (s, 6H) ppm.19F NMR (376 MHz, DMSO-d6) δ -73.5 (s), -119.0 (s) ppm. The19F peak of δ -73.5 ppm and similar19F peaks in Compounds 3, 4, 5, and 6 have been attributed to small impurities of trifluoro acetic acid.31P NMR (162 MHz, DMSO-d6) δ -1.2 (s) ppm. Example 2: Synthesis of N-[(2-fluorophenyl)methyl]-1-methyl-6-[1-(2- methylpropanoyl)pyrazol-4-yl]pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 2) A solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (200.0 mg, 0.572 mmol, 1 equiv) in DCM (6 mL) was treated with Et3N (318.2 µL, 2.288 mmol, 4 equiv) for 5 minutes at 0°C followed by the addition of 2- methylpropanoyl chloride (179.9 µL, 1.716 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for 2 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 52% B to 72% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.5) to afford N-[(2-fluorophenyl)methyl]-1-methyl-6-[1-(2-methylpropanoyl)pyrazol- 4-yl]pyrrolo[2,3-b]pyridine-2-carboxamide (57.0 mg, 23.6%) as a white solid. MS (ESI) m / z: 420.35 [M+H]+. Retention time: 1.19 min, 99.6% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 5.9 Hz, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.44 (td, J = 7.7, 1.7 Hz, 1H), 7.33 (tdd, J = 7.3, 5.4, 1.8 Hz, 1H), 7.20 (q, J = 7.7, 6.6 Hz, 3H), 4.55 (d, J = 5.8 Hz, 2H), 4.08 (s, 3H), 3.94 – 3.76 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H) ppm.19F NMR (376 MHz, DMSO-d6) δ -118.9 (s) ppm. Example 3: Synthesis of N-(2-fluorobenzyl)-1-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 3) 1-(tert-butyl) 2-methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (3-1) Under nitrogen protection, MeCN (11.79 kg, 10.00 V) was charged into a reactor. The temperature was adjusted to 25 ± 5 °C after starting agitation, the above mixture was charged 2,6- dichloronicotinaldehyde (1.5 kg, 1.00 eq) in one portion, and the solid of feed port was sprayed with MeCN (2.358 kg, 2.00 V) at 25 ± 5 ^C. To this mixture was charged methyl 2-((tert- butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (2.787 kg, 1.1 eq), and the solid of feed port was sprayed with MeCN (2.358 kg, 2.00 V) at 25 ± 5 ^C. The temperature of mixture was controlled at 25 ± 5 °C.2,2-bipyridine (532.4 g, 0.4 eq) was then charged to the above reactor. K3PO4 (5.428 kg, 3.0 eq) was charged in 5 batches over 0.5 h into the reactor at 25 ± 5 °C, and the solid of feed port was sprayed with MeCN (5.895 kg, 5.00 V). The reaction solution was stirred for 0.5 h at 25 ± 5^C. While keeping the temperature of the mixture at 25 ± 5 °C, CuI (649.3 g, 0.4 eq) was charged to the above reactor, and the solid of feed port was sprayed with MeCN (1.179 kg, 1.00 V). The resulting mixture was heated up to 60 ^C and stirred for 18 h at 60 ± 5 ^C under nitrogen atmosphere when HPLC analysis showed the conversion was 100%. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The organic phase was concentrated under vacuum until the volume was 5 V at 35 ± 5 ^C. To this mixture was charged IPAc (10.0 V) and concentrated under vacuum until the volume was 5 V at 35 ± 5 ^C. The above reactor was charged with IPAc (10.0 V) and concentrated under vacuum until the volume is 5 V at 35 ± 5 ^C. IPAc (15 V) and 0.1 N HCl (10 V) were charged into the above mixture, stirred for 30 minutes at 25 ± 5 ^C, and the organic layers were collected. A solution of 10% NaCl (10 V) was charged into the above mixture, stirred for 30 min, and the organic layer was collected. The organic phase was concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. To the mixture was charged Heptane (10.0 V) and concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. The reactor was again charged with Heptane (10.0 V) and concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. Heptane (5.0 V) was again charged into the reactor and the mixture stirred for 2 h. The filter cake was collected by filtration, and washed with Heptane (1 V). The wet cake was dried under vacuum at 35 ^C for 12 hours. This resulted in 3-1 (2.12 kg, HPLC = 98.1 %, 80.1 % yield) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 3.94 (s, 3H), 1.66 (s, 9H) ppm. Methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3-2) Under nitrogen protection, DCM (5.62 kg, 2.00 V) was charged into a reactor. The temperature was adjusted to 25 ± 5 °C after starting agitation, the reactor was charged with 3-1 (2.12 kg, 1.00 eq) in one portion, and the solid feed port was sprayed with DCM (2.81 kg, 1.00 V) at 25 ± 5^C. The temperature of mixture was cooled to 0 ± 5 °C before TFA (4.88 kg, 1.50 V) was charged in one portion, then the solid feed port was sprayed with DCM (2.81 kg, 1.00 V) at 0 ± 5 ^C. After the addition, the above mixture was stirred for 18 h at 25 ± 5^C under nitrogen atmosphere, after which time HPLC showed the conversion was 100%. The temperature of mixture was cooled to 10 ± 5 °C, and the reactor was charged DCM (28.1 kg, 10.0 V) followed by an aqueous solution of 10% w / w K2HPO4 (21.2 L, 10.0 V). The mixture stirred for 30 min, then stood for 20 minutes to allow for phase separation, and the organic layers were collected. Another portion of 10% w / w K2HPO4(21.2 L, 10.0 V) was charged to the above mixture which stirred for 30 minutes and then stood for 20 minutes to allow for phase separation, and the organic layers were collected. A solution of 10% NaCl (21.2 L, 10.0 V) was charged, the mixture was stirred for 30 minutes and then stood for 20 minutes to allow for phase separation, and the organic layers were collected. The organic layer was filtered after drying over Na2SO4, and then concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. The product mixture was charged with Heptane (10.0 V) and concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. To the reactor was charged Heptane (10.0 V) and concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. The resulting mixture was charged again with heptane (5.0 V) and stirred for 2 h. The resulting filter cake was collected by filtration, and further washed with heptane (1 V). The wet cake was dried under vacuum at 35 ^C for 12 hours. This resulted in 3-2 (1.22 kg, HPLC=99.8 %, 84.8 % yield) as a yellow solid.1H NMR (300 MHz, Chloroform-d) δ 9.38 (s, 1H), 7.97 (dd, J = 8.3, 0.9 Hz, 1H), 7.20 – 7.13 (m, 2H), 3.97 (s, 3H) ppm. Methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3-3) Under nitrogen protection, DMF (8.10 kg, 7.00 V) was charged to a reactor. The temperature was adjusted to 25 ± 5 °C after starting agitation, then 3-2 (1.22 kg, 1.00 eq) was charged at 25 ± 5 °C, and the solid feed port was sprayed with DMF (1.16 kg, 1.00 V). To the above mixture was charged K2CO3 (2.0 kg, 2.50 eq) at 25 ± 5 °C, and the solid feed port was sprayed with DMF (1.16 kg, 1.00 V). The temperature of reactor was adjusted to 0 ± 5°C, then the mixture was charged with CH3I (904 g, 1.1 eq.) at 0 ± 5 °C. After the addition, the mixture was stirred 18 h at 25 ± 5 ^C under nitrogen atmosphere when HPLC showed the conversion was 99.8%. The temperature of the reactor was cooled to 10 ± 5 ℃, then IPAc (24 L, 20 V) and H2O (24 L, 20 V) were charged into the reactor. The mixture was stirred for 30 min, then the organic layer was collected. To this mixture was charged IPAc (6 L, 5 V), and stirred the mixture for 30 min, the organic layer was collected. The organic layers were combined, and a solution of 10% NaCl (12 L, 10 V) was charged, and the resulting mixture stirred for 30 mins before the organic layer was collected. A solution of 10% NaCl (12 L, 10 V) was charged again, and the resulting mixture stirred for 30 mins before the organic layer was collected. The organic layer was filtered after drying over Na2SO4. The organic phase was concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. Heptane (10.0 V) was charged into the reactor and concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. To this mixture was again charged heptane (10.0 V) and concentrated under vacuum at 35 ± 5 ^C until the volume was 5 V. To the above mixture was again charged heptane (5.0 V) and the mixture stirred for 2 hours. The filter cake was collected by filtration and washed with heptane (1 V). The wet cake was dried under vacuum at 35 ^C for 12 hours. This resulted in 3-3 (1.08 kg, HPLC = 99.8 %, 83 % yield) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.13 (s, 3H), 3.94 (s, 3H) ppm. Methyl 1-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxylate (3-4) Into a 20 L 4-necked round-bottom flask purged with and maintained under nitrogen was placed DMF / H2O (10:1) (12 L, 20 V). Then 3-3 (600 g, 1.0 eq.) was added, and the flask was maintained at 25 ± 5°C.1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (1301 g, 1.75 e q) and KOAc (788 g, 3.0 e q) were added into the flask in turns at 25 °C, and the reaction mixture was sparged with N2 for at least 10 min. Then to the mixture was charged catalytic PdCl2(dtbpf) (51.8 g, 0.03eq.), and the reaction mixture was sparged again with N2for at least 10 min. The temperature was then raised to 90 ± 5 °C, and the reaction stirred for 2 hours after which time HPLC indicated the reaction was complete. The reaction mixture was cooled to 25 ± 5 °C, and then to the mixture was charged H2O (9 L, 15V) and EtOAc (15 L, 25V). The resulting mixture stirred for at least 15 minutes and was then left to stand for at least 15 minutes. The resulting product mixture was filtered through a Celite pad (200 wt%), and the filtrate was collected. The biphasic filtrate was separated and the top phase collected. The aqueous layer was transferred to a reactor which was then charged with EtOAc (10.0 V). The resulting mixture was stirred for at least 15 minutes, and then left to stand at 25 ± 5 °C for at least 15 minutes to allow for phase separation, after which time the organic phase was collected. The organic phases of the two separations were combined in a single reactor and twice washed with 10% NaCl (12 L, 20 V each). To the organic phase was added activated carbon G60 (50%, 300 g) which was then stirred for 2 hours and filtered. The filtrate was collected and metal scavenger (silica thiol, 30%, 180 g) was then added, and the mixture stirred for at least 12 hours before being filtered. The temperature of the reactor was adjusted to 20 - 40 °C by water bath, and the organic filtrate was concentrated to 3 – 7 V. MTBE (10.0 V) was added to the reactor with the water bath at 20 - 40 °C, and the solution was again concentrated to 3 - 7 V. MTBE (10.0 V) was added to the reactor and stirred for at least 2 hours. The resulting solids were filtered and collected, affording 3-4 (674 g, 74% yield) as an off-white solid.1H NMR (300 MHz, Chloroform-d) δ 8.29 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 5.46 (dd, J = 8.8, 3.4 Hz, 1H), 4.20 (s, 3H), 4.16 – 4.06 (m, 1H), 3.93 (s, 3H), 3.82 – 3.69 (m, 1H), 2.29 – 1.95 (m, 3H), 1.78 – 1.64 (m, 3H) ppm. N-(2-fluorobenzyl)-1-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 3) In a 20 L reactor, (2-fluorophenyl)methanamine (485.3 g, 2.0 eq.) was added in THF (7.92 L, 12.0 V) at 25 ± 5 °C. The temperature of the reactor was adjusted to 0 °C before NaHMDS (2M, 2.0 eq.) was added dropwise into the reactor over 30 minutes at 0 °C. The reaction system was stirred for 40 minutes while the temperature was raised to 25 ± 5 °C. LCMS showed the reaction was completed. Then a solution of 3-4 (660 g, 1.0 eq.) in THF (5.28 L, 8.0 V) was added dropwise into the reactor over 30minutes at 25 ± 5 °C, and the reaction system was stirred for 40 minutes after which time HPLC showed nearly complete conversion of 3-4 (1.5% remaining). A solution of 7% NaHCO3 (13.2 L, 20.0 V) was charged to the reactor over 1 hour at 0 - 10 °C and then stirred for 30 minutes. To the mixture was charged ethyl acetate (13.2 L, 20.0V), and the product mixture stirred for 30 minutes at 25 ± 5 °C. The reactor settled for 30 minutes to allow for the phase separation before collecting the organic phase. A solution of 10 % sodium chloride (13.2 l ,20.0 V) was charged to the reactor and stirred for 30 minutes. The reactor settled for 30 minutes to allow for phase separation and the organic phase was again collected and concentrated under vacuum until the volume at 5 V. Ethyl acetate (6.6 L, 10.0 V) was charged into the reactor and again concentrated under vacuum until the volume at 5 V. Ethyl acetate (6.6 L, 10.0 V) was again charged into the reactor and concentrated under vacuum until the volume at 10 V. Finally, the reactor was charged with heptane (6.6 L, 10.0 V), and the product mixture was stirred for 15 hours at 25 ± 5 °C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate:heptane = 1:1 (2.64 L, 4.0 V) before collecting the filter cake. Drying afforded the title product N-(2-fluorobenzyl)-1-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (723 g, 86% yield) as a light yellow solid (99.3% purity).1H NMR (300 MHz, DMSO-d6) δ 9.12 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 0.7 Hz, 1H), 8.15 (d, J = 0.7 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.6, 1.7 Hz, 1H), 7.38 – 7.27 (m, 1H), 7.27 – 7.14 (m, 3H), 5.47 (dd, J = 10.0, 2.1 Hz, 1H), 4.54 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 3.97 (d, J = 11.9 Hz, 1H), 3.74 – 3.59 (m, 1H), 2.24 – 2.08 (m, 1H), 1.97 (d, J = 11.9 Hz, 2H), 1.81 – 1.63 (m, 1H), 1.56 (s, 2H) ppm.19F NMR (Chloroform-d, 376 MHz) δ -118.9 (s) ppm. Example 4: Synthesis of 6-[1-(2,2-Dimethylpropanoyl)pyrazol-4-yl]-N-[(2- fluorophenyl)methyl]-1-methylpyrrolo[2,3-b]pyridine-2-carboxamide (Compound 4) A solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (200 mg, 0.57 mmol, 1 equiv), DMAP (3.5 mg, 0.03 mmol, 0.05 equiv) and Et3N (239 uL, 1.7 mmol, 3 equiv) in DCM (3 mL) was stirred for 3 minutes at 0°C. To the above mixture was added 2,2-dimethylpropanoyl chloride (0.21 mL, 1.72 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for an additional 3 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 60% B to 80% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 12) to afford 6-[1-(2,2-dimethylpropanoyl)pyrazol-4-yl]-N-[(2- fluorophenyl)methyl]-1-methylpyrrolo[2,3-b]pyridine-2-carboxamide (100.1 mg, 40.18%) as a white solid. MS (ESI) m / z: 434.15 [M+H]+. Retention time: 1.33 min, 99.6% @ 254 nm.1H NMR (300 MHz, DMSO-d6) δ 9.17 (t, J = 5.9 Hz, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.32 (m, 1H), 7.26 – 7.15 (m, 3H), 4.55 (d, J = 5.8 Hz, 2H), 4.08 (s, 3H), 1.50 (s, 9H) ppm.19F NMR (282 MHz, DMSO-d6) δ -73.8 (s), -118.9 (s) ppm. Example 5: Synthesis of 4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3- b]pyridin-6-yl)pyrazole-1-carboxylate (Compound 5) A solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (200 mg, 0.57 mmol, 1 equiv) and pyridine (2 uL, 0.03 mmol, 0.04 equiv) in toluene (2 mL) was stirred for 10 h at 80°C. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 45% B to 65% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.85) to afford isopropyl 4-(2- {[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazole-1- carboxylate (111.4 mg, 44.46%) as a white solid. MS (ESI) m / z: 436.10 [M+H]+. Retention time: 1.04 min, 99.5% @ 254 nm.1H NMR (300 MHz, DMSO-d6) δ 9.16 (t, J = 6.0 Hz, 1H), 8.94 (d, J = 0.8 Hz, 1H), 8.50 (d, J = 0.8 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.33 (td, J = 5.6, 2.8 Hz, 1H), 7.24 – 7.15 (m, 3H), 5.24 – 5.17 (m, 1H), 4.54 (d, J = 5.8 Hz, 2H), 4.08 (s, 3H), 1.42 (d, J = 6.2 Hz, 6H) ppm.19F NMR (282 MHz, DMSO- d6) δ -73.4 (s), -118.9 (s) ppm. Example 6: Synthesis of 6-(1-carbamimidoylpyrazol-4-yl)-N-[(2-fluorophenyl)methyl]-1- methylpyrrolo[2,3-b]pyridine-2-carboxamide (Compound 6) A solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (180 mg, 0.51 mmol, 1 equiv) and cyanamide (32 mg, 0.77 mmol, 1.5 equiv) in HCl (gas) in 1,4-dioxane (2 mL) was stirred for 3 hours at 100°C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 25% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.72) to afford 6-(1-carbamimidoylpyrazol-4-yl)-N-[(2-fluorophenyl)methyl]-1- methylpyrrolo[2,3-b]pyridine-2-carboxamide (97.3 mg, 47.72%) as a white solid. MS (ESI) m / z: 392.10 [M + H]+. Retention time: 1.28 min, 98.9% @ 254 nm.1H NMR (300 MHz, DMSO-d6) δ 9.17 (t, J = 5.9 Hz, 1H), 9.08 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.49 – 7.40 (m, 1H), 7.34 (m , 1H), 7.21 (m, 3H), 4.54 (s, 2H), 4.08 (s, 3H) ppm.19F NMR (282 MHz, DMSO-d6) δ -73.5 (s), -118.9 (s) ppm.

[0009] Example 7: Synthesis of N-(2-fluorobenzyl)-1-methyl-6-(1-(piperazine-1-carbonyl)-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 7) tert-Butyl 4-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazole-1-carbonyl]piperazine-1-carboxylate (7-1) A solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (200 mg, 0.57 mmol, 1 equiv) and DIEA (598 uL, 3.43 mmol, 6 equiv) in DCM (5 mL) was stirred for 10 minutes at 0°C. To the above solution was added triphosgene (170 mg, 0.57 mmol, 1 equiv) in DCM (1 mL) dropwise at 0°C. Ten minutes later, tert-butyl piperazine-1-carboxylate (202 mg, 1.08 mmol, 1.9 equiv) in DCM (1 mL) was added into the solution. Then, the solution was stirred for additional 3 hours at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (3 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert- butyl 4-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazole-1-carbonyl]piperazine-1-carboxylate (203 mg, 63.14%) as a light yellow solid. N-(2-fluorobenzyl)-1-methyl-6-(1-(piperazine-1-carbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 7) A solution of tert-butyl 4-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazole-1-carbonyl]piperazine-1-carboxylate (203 mg, 0.361 mmol, 1 equiv) and TFA (268 uL, 3.61 mmol, 10 equiv) in DCM (2 mL) was stirred for 1 hour at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 23% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.25) to afford N-(2-fluorobenzyl)-1- methyl-6-(1-(piperazine-1-carbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide (80 mg, 51%) as a white solid. MS (ESI) m / z: 462.20 [M+H]+. Retention time: 1.13 min, 99.4% @ 254 nm.1H NMR (300 MHz, DMSO-d6) δ 9.17 (t, J = 5.9 Hz, 1H), 8.83 (d, J = 0.8 Hz, 1H), 8.43 (d, J = 0.7 Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.44 (td, J = 7.6, 1.7 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.27 – 7.13 (m, 3H), 4.55 (d, J = 5.9 Hz, 2H), 4.07 (s, 3H), 3.73 (d, J = 6.0 Hz, 4H), 2.91 (t, J = 5.0 Hz, 4H) ppm.19F NMR (376 MHz, Chloroform-d) δ -75.7 (s), -118.9 (s) ppm. Example 8: Synthesis of 4-([4-(2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3- b]pyridin-6-yl)pyrazol-1-yl]methoxy-4-oxobutanoic acid (Compound 8)

[0010] 1-tert-Butyl 4-[4-(2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methyl butanedioate (8-1) To a solution of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (300 mg, 0.859 mmol, 1 equiv) and Cs2CO3 (335.73 mg, 1.031 mmol, 1.2 equiv) in DMF (7 mL) was added 1-tert-butyl 4-chloromethyl butanedioate (210.33 mg, 0.945 mmol, 1.1 equiv) dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction was monitored on LCMS. After completion, the resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 1-tert-butyl 4-[4-(2-([(2- fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl butanedioate (290 mg, 63.06%) as a white semi-solid. MS (ESI) m / z: 536.4 [M+H]+. 4-([4-(2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1- yl]methoxy-4-oxobutanoic acid (Compound 8) To a solution of 1-tert-butyl 4-[4-(2-([(2-fluorophenyl)methyl]carbamoyl-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl butanedioate (180 mg, 0.336 mmol, 1 equiv) in DCM (4 mL) was added TFA (1 mL, 13.463 mmol, 40.06 equiv) at room temperature and was stirred for 2 hours. The reaction was monitored on LCMS. After completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, A: H2O (0.1% FA), mobile phase B: CH3CN, 10% B to 90% B gradient in 15 min; detector, UV 200 nm to afford 4-([4-(2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methoxy-4-oxobutanoic acid (65 mg, 39.53%) as a white solid. MS (ESI) m / z: 480.15 [M+H]+. Retention time: 1.30 min, 98.1% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 0.7 Hz, 1H), 8.23 (d, J = 0.7 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.7, 1.7 Hz, 1H), 7.33 (tdd, J = 7.3, 5.4, 1.9 Hz, 1H), 7.24 – 7.15 (m, 3H), 6.11 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H), 4.05 (s, 3H), 2.61 – 2.54 (m, 2H), 2.52 – 2.51 (m, 1H), 2.49 – 2.45 (m, 1H) ppm.19F NMR (376 MHz, DMSO-d6) δ -118.9 (s) ppm. Example 9: Synthesis of 2-(([4-(2-([(2-Fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3 -b]pyridin-6-yl)pyrazol-1-yl]methoxycarbonyl)benzoic acid (Compound 9)

[0011] 1-tert-Butyl 2-chloromethyl phthalate (9-1) To a stirred mixture of NaHCO3(1.51 g, 18.000 mmol, 4 equiv) and TBAHS (152.78 mg, 0.450 mmol, 0.10 equiv) in H2O (30 mL) was added 2-(tert-butoxycarbonyl)benzoic acid (1 g, 4.500 mmol, 1 equiv) dropwise at 0℃ under nitrogen atmosphere. The resulting mixture was stirred for 20 minutes at 0℃ under nitrogen atmosphere. To the above mixture was added chloromethyl sulfurochloridate (637.21 uL, 6.300 mmol, 1.4 equiv) dropwise at 0℃. The resulting mixture was stirred for additional 12 hours at room temperature. No signal was found on MS. Desired product was confirmed by1H NMR. The resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 1- tert-butyl 2-chloromethyl phthalate (1.1 g, 90.30%) as a light-yellow oil.1H NMR (300 MHz, DMSO-d6) δ 7.93 – 7.43 (m, 4H), 6.08 (s, 2H), 1.52 (s, 9H) ppm. 1-tert-Butyl 2-[4-(2-([(2-fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl) pyrazol-1-yl]methyl phthalate (9-2) To a stirred mixture of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (200 mg, 0.572 mmol, 1.00 equiv) and Cs2CO3(373.04 mg, 1.144 mmol, 2 equiv) in DMF (3 mL) was added 1-tert-butyl 2-chloromethyl phthalate (309.94 mg, 1.144 mmol, 2 equiv) in DMF (1 mL) dropwise at 0℃ under nitrogen atmosphere. The resulting mixture was stirred for 12 hours at room temperature under nitrogen atmosphere. Desired product was confirmed by LCMS. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (1 x 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-tert-butyl 2-[4-(2-([(2- fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl phthalate (300 mg, 89.79%) as a yellow solid. MS (ESI) m / z: 584.25 [M+H]+.

[0012] 2-(([4-(2-([(2-Fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol- 1-yl]methoxycarbonyl)benzoic acid (Compound 9) A mixture of 1-tert-butyl 2-[4-(2-([(2-fluorophenyl)methyl]carbamoyl-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl phthalate (100 mg, 0.171 mmol, 1 equiv) in TFA (1 mL) and DCM (2 mL) was stirred for 1h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 60% gradient over 10 min; detector, UV 254 nm. This resulted in 2-(([4-(2-([(2- fluorophenyl)methyl]carbamoyl-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1- yl]methoxycarbonyl)benzoic acid (61.9 mg, 68.48%) as an off-white solid. MS (ESI) m / z: 528.25 [M+H]+. LCMS was conducted on a Shimadzu LCMS-2020 system with PDA: SPD-M20A and MS: LCMS-2020 detectors. Column: Kinetex XB-C18, 2.0 *30 mm, mobile phase A: water (Water / 0.1%FA), mobile phase B: Acetonitrile / 0.07%FA; Flow rate: 1.0 mL / min; 5%B-100%B in 2.1 min; Rt: 1.709 min.1H NMR (400 MHz, DMSO-d6) δ: 13.37 (s, 1H), 9.12 (t, J = 6.0 Hz, 1H), 8.61 (s, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.83 – 7.74 (m, 1H), 7.70 – 7.62 (m, 3H), 7.55 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.6, 1.7 Hz, 1H), 7.38 – 7.28 (m, 1H), 7.25 – 7.15 (m, 3H), 6.31 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H), 4.07 (s, 3H) ppm.19F NMR (376 MHz, DMSO-d6) δ: -119.0 ppm. Example 10: Synthesis of 3-{[4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methoxy}-3-oxopropanoic acid (Compound 10) Chloromethyl 3,3-diethoxypropanoate (10-1) To a stirred mixture of K2CO3 (4.26 g, 30.830 mmol, 2.5 equiv) and n-Bu4NHSO4 (0.25 g, 0.740 mmol, 0.06 equiv) in H2O (8 mL) was added 3,3-diethoxypropanoic acid (2.0 g, 12.487 mmol, 1.0 equiv) in DCM (8 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at 0oC under nitrogen atmosphere. To the above mixture was added chloromethyl sulfurochloridate (2.28 g, 13.812 mmol, 1.12 equiv) dropwise at 0oC. The resulting mixture was stirred for an additional 3 hours at 0oC. The resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% MTBE in PE) to afford chloromethyl 3,3-diethoxypropanoate (900 mg, 34.65%) as a light-yellow oil.1H NMR (400 MHz, Chloroform-d) δ 5.70 (s, 1H), 4.98 – 4.90 (m, 1H), 4.19 – 4.09 (m, 1H), 3.67 (m, 2H), 3.62 – 3.47 (m, 2H), 2.73 (d, J = 5.9 Hz, 1H), 2.64 (d, J = 6.0 Hz, 1H), 1.21 – 1.15 (m, 6H) ppm. [4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1- yl]methyl 3,3-diethoxypropanoate (10-2) To a stirred mixture of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (300 mg, 0.859 mmol, 1.00 equiv) and Cs2CO3(335.73 mg, 1.031 mmol, 1.2 equiv) in DMF (4.5 mL) was added chloromethyl 3,3-diethoxypropanoate (180.88 mg, 0.859 mmol, 1.0 equiv) in DMF (1.0 ml) dropwise at 0oC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford [4-(2-{[(2- fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl 3,3- diethoxypropanoate (270 mg, 60.06%) as a white solid. MS (ESI) m / z: 524.25 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.14 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.45 (m, 1H), 7.35 – 7.27 (m, 2H), 7.18 – 7.06 (m, 2H), 6.78 (s, 1H), 6.54 (t, J = 6.2 Hz, 1H), 6.10 (s, 2H), 4.94 (t, J = 5.9 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.21 (s, 3H), 3.63 (m, 2H), 3.49 (m, 2H), 2.72 (d, J = 6.0 Hz, 2H), 1.14 (t, J = 7.0 Hz, 6H) ppm.19F NMR (377 MHz, Chloroform-d) δ -118.9 ppm. [4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1- yl]methyl 3-oxopropanoate (10-3) A mixture of [4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin- 6-yl)pyrazol-1-yl]methyl 3,3-diethoxypropanoate (250 mg, 0.477 mmol, 1.0 equiv) and HCl (aq., 2.5 mL, 1 mol / L) in dioxane (5.0 mL) was stirred for 10 h at 40oC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 10-3 (220 mg) was used in the next step directly without further purification. 3-{[4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol- 1-yl]methoxy}-3-oxopropanoic acid (Compound 10) To a mixture of [4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3- b]pyridin-6-yl)pyrazol-1-yl]methyl 3-oxopropanoate (250 mg, 0.556 mmol, 1.0 equiv) and 2- methylbut-2-ene (1560.44 mg, 22.240 mmol, 40 equiv) in THF (2.5 mL) was added Na2HPO4(789.63 mg, 5.560 mmol, 10 equiv) and NaClO2(162.53 mg, 2.780 mmol, 5.0 equiv) in H2O (2.5 mL) dropwise at 0oC. The resulting mixture was stirred for an additional 2 hours at room temperature. The aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 65% gradient over 30 min; detector, UV 254 nm. This resulted in 3-{[4-(2-{[(2- fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methoxy}-3- oxopropanoic acid (80 mg, 30.31%) as a light yellow solid. MS (ESI) m / z: 466.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.55 (s, 1H), 8.25 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.43 (m, 1H), 7.33 (m, 1H), 7.20 (m, 3H), 6.16 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.06 (s, 2H), 3.48 (s, 2H), 2.50 (m, 2H) ppm.19F NMR (377 MHz, DMSO-d6) δ -118.9 ppm. Example 11: Synthesis of 3-{[4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methoxy}-3-oxopropanoic acid (Compound 11) 1-tert-Butyl 5-chloromethyl pentanedioate (11-1) To a stirred mixture of K2CO3(3.70 g, 26.778 mmol, 2.52 equiv) and n-Bu4NHSO4(0.22 g, 0.638 mmol, 0.06 equiv) in H2O (15 mL) was added 5-(tert-butoxy)-5-oxopentanoic acid (2.0 g, 10.626 mmol, 1.0 equiv) in DCM (15 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at 0oC under nitrogen atmosphere. To the above mixture was added chloromethyl sulfurochloridate (1.96 g, 11.901 mmol, 1.12 equiv) dropwise at 0oC. The resulting mixture was stirred for additional 3 hours at 0oC. The resulting mixture was diluted with H2O (25 mL). The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% PE:MTBE). This resulted in 1-tert-butyl 5- chloromethyl pentanedioate (2.0 g, 79.52%) as a light yellow oil.1H NMR (400 MHz, Chloroform-d) δ 5.71 (s, 2H), 2.46 (t, J = 7.4 Hz, 2H), 2.30 (t, J = 7.3 Hz, 2H), 1.99 – 1.88 (m, 2H), 1.45 (s, 9H) ppm. 1-tert-Butyl 5-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methyl pentanedioate (11-2) To a stirred mixture of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (150 mg, 0.429 mmol, 1.0 equiv) and Cs2CO3 (167.87 mg, 0.515 mmol, 1.2 equiv) in DMF (2.0 mL) was added 1-tert-butyl 5-chloromethyl pentanedioate (223.57 mg, 0.944 mmol, 2.2 equiv) in DMF (1.0 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford 1-tert-butyl 5-[4-(2-{[(2- fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl pentanedioate (150 mg, 63.57%) as a white solid. MS (ESI) m / z: 550.25 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.11 (t, J = 5.9 Hz, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.46 – 7.37 (m, 1H), 7.37 – 7.27 (m, 1H), 7.25 – 7.13 (m, 3H), 6.11 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.05 (s, 3H), 2.39 (t, J = 7.4 Hz, 2H), 2.21 (t, J = 7.4 Hz, 2H), 1.80 – 1.65 (m, 2H), 1.36 (s, 9H) ppm.19F NMR (377 MHz, DMSO-d6) δ -119.0 ppm. 3-{[4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol- 1-yl]methoxy}-3-oxopropanoic acid (Compound 11) A mixture of 1-tert-butyl 3-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl propanedioate (150 mg, 0.288 mmol, 1.0 equiv) and TFA (0.3 mL) in DCM (3.0 mL) was stirred for 2 hours at room temperature under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 60% gradient over 25 min; detector, UV 254 nm. This resulted in 3-{[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1- yl]methoxy}-3-oxopropanoic acid (80 mg, 59.52%) as a white solid. MS (ESI) m / z: 494.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.12 (t, J = 6.1 Hz, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.33 (q, J = 7.2 Hz, 1H), 7.19 (q, J = 5.4, 4.6 Hz, 3H), 6.11 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H), 2.25 (t, J = 7.3 Hz, 2H), 1.74 (p, J = 7.5 Hz, 2H) ppm.19F NMR (377 MHz, DMSO) δ -118.9 ppm. Example 12: Synthesis of (2E)-4-{[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methoxy}-4-oxobut-2-enoic acid (Compound 12) 1-tert-Butyl 4-chloromethyl (2E)-but-2-enedioate (12-1) To a stirred mixture of K2CO3(4.05 g, 29.272 mmol, 2.52 equiv) and n-Bu4NHSO4(0.24 g, 0.697 mmol, 0.06 equiv) in H2O (15 mL) was added (2E)-4-(tert-butoxy)-4-oxobut-2-enoic acid (2.0 g, 11.616 mmol, 1.0 equiv) in DCM (15 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at 0oC under nitrogen atmosphere. To the above mixture was added chloromethyl sulfurochloridate (2.15 g, 13.010 mmol, 1.12 equiv) dropwise at 0oC. The resulting mixture was stirred for additional 3 hours at 0oC. The resulting mixture was diluted with H2O (25 mL). The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% MTBE in PE over 25 min; detector, UV 220 nm) to afford 1-tert-butyl 4-chloromethyl (2E)-but-2-enedioate (2.0 g, 78.03%) as a light yellow oil.1H NMR (400 MHz, Chloroform-d) δ 6.89 (d, J = 15.8 Hz, 1H), 6.77 (d, J = 15.8 Hz, 1H), 5.80 (s, 2H), 1.51 (s, 9H) ppm. 1-tert-Butyl 4-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methyl (2E)-but-2-enedioate (12-2) To a stirred mixture of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (150 mg, 0.429 mmol, 1 equiv) and Cs2CO3(167.87 mg, 0.515 mmol, 1.2 equiv) in DMF (3.0 mL) was added 1-tert-butyl 4-chloromethyl (2E)-but-2- enedioate (208.42 mg, 0.944 mmol, 2.2 equiv) in DMF (1 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0%-60%) to afford 1-tert-butyl 4-[4-(2-{[(2- fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl (2E)- but-2-enedioate (150 mg, 65.48%). MS (ESI) m / z: 534.25 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 9.12 (t, J = 6.0 Hz, 1H), 8.59 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.47 – 7.39 (m, 1H), 7.36 – 7.30 (m, 1H), 7.20 (dt, J = 11.3, 4.4 Hz, 3H), 6.71 (s, 2H), 6.25 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 1.44 (s, 9H) ppm.19F NMR (377 MHz, DMSO) δ -119.0 ppm. (2E)-4-{[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6- yl)pyrazol-1-yl]methoxy}-4-oxobut-2-enoic acid (Compound 12) A mixture of 1-tert-butyl 4-[4-(2-{[(2-fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl (2E)-but-2-enedioate (150 mg, 0.281 mmol, 1.0 equiv) and TFA (1.50 mL, 20.184 mmol, 71.83 equiv) in DCM (3.00 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 65% gradient over 25 min; detector, UV 254 nm. This resulted in (2E)-4-{[4-(2-{[(2- fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methoxy}-4- oxobut-2-enoic acid (100 mg, 74.28%) as a white solid. MS (ESI) m / z: 478.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.43 (td, J = 7.7, 1.7 Hz, 1H), 7.37 – 7.28 (m, 1H), 7.25 – 7.16 (m, 3H), 6.83 – 6.69 (m, 2H), 6.26 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.06 (s, 3H) ppm.19F NMR (377 MHz, DMSO) δ -118.9 ppm. Example 13: Synthesis of 1-[4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1- methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl 4-methyl butanedioate (Compound 13) 1-Chloromethyl 4-methyl butanedioate (13-1) To a stirred mixture of K2CO3 (1581.70 mg, 11.443 mmol, 2.52 equiv) and n-Bu4NHSO4 (92.52 mg, 0.272 mmol, 0.06 equiv) in H2O (6 mL) was added butanedioic acid, monomethyl ester (600 mg, 4.541 mmol, 1.0 equiv) in DCM (6 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at 0oC under nitrogen atmosphere. To the above mixture was added chloromethyl sulfurochloridate (839.17 mg, 5.086 mmol, 1.12 equiv) dropwise at 0oC. The resulting mixture was stirred for additional 3 hours at 0oC. The resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% PE in MTBE) to afford 1- chloromethyl 4-methyl butanedioate (400 mg, 48.77%) as a light-yellow solid.1H NMR (300 MHz, Chloroform-d) δ 5.74 (s, 2H), 3.73 (s, 3H), 2.84 – 2.59 (m, 4H) ppm. 1-[4-(2-{[(2-Fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol- 1-yl]methyl 4-methyl butanedioate (Compound 13) To a stirred mixture of N-[(2-fluorophenyl)methyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (80 mg, 0.229 mmol, 1 equiv) and Cs2CO3(89.53 mg, 0.275 mmol, 1.2 equiv) in DMF (2.0 mL) was added 1-chloromethyl 4-methyl butanedioate (90.97 mg, 0.504 mmol, 2.2 equiv) in DMF (1.0 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 5% to 60% gradient over 25 min; detector, UV 254 nm. The resulted in 1-[4-(2-{[(2- fluorophenyl)methyl]carbamoyl}-1-methylpyrrolo[2,3-b]pyridin-6-yl)pyrazol-1-yl]methyl 4- methyl butanedioate (80 mg, 70.09%) as a white solid. MS (ESI) m / z: 494.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J = 5.9 Hz, 1H), 8.53 (s, 1H), 8.24 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.43 (td, J = 7.7, 1.7 Hz, 1H), 7.33 (tdd, J = 7.3, 5.4, 1.8 Hz, 1H), 7.28 – 7.13 (m, 3H), 6.12 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H), 3.57 (s, 3H), 2.67 – 2.56 (m, 4H) ppm.19F NMR (377 MHz, DMSO) δ -119.0 ppm. Example 14: Synthesis of N-(2-fluorobenzyl)-1-methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (1-1, Compound 14) 6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (14-3) To a solution of 6-chloro-3-iodopyridin-2-amine (14-1) (9.00 g, 35.4 mmol), 2- oxopropanoic acid (14-2) (9.34 g, 106 mmol) and DABCO (11.9 g, 106 mmol) in N,N- dimethylformamide (255 mL) was added palladium(II) acetate (0.397 g, 1.77 mmol), and the reaction mixture was degassed three times and stirred under nitrogen atmosphere at 110oC for three hours until the reaction was completed, which was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (500 mL) and extracted with aq. sodium hydroxide (2 M, 500 mL × 3). The combined aqueous layer was concentrated to c.a.500 mL and acidified with aq. HCl (1 M) to pH 3. The mixture was filtered, and the filter-cake was collected, washed with water and dried to afford 14-3 (5.49 g, 74% yield) as a yellow solid. ESI m / z: 196.9 (M+H)+, retention time 1.23 min, 93.9% @ 254 nm.1H NMR (500 MHz, DMSOd6) δ 12.41 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H) ppm. Ethyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (14-4) To a solution of 14-3 (5.70 g, 35.4 mmol) in ethanol (170 mL) was added 98% sulfuric acid (14.5 g, 145 mmol) at 0oC, and the reaction mixture was stirred at 80oC for eighteen hours, which was monitored by LCMS. The resulting mixture was neutralized with sat. aq. sodium bicarbonate to pH 7-8 and then concentrated to remove ethanol. The residual aqueous mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 2) to give 14-4 (4.29 g, 66% yield) as a yellow solid. ESI m / z: 224.9 (M+H)+, retention time 1.82 min, 98.6% @ 254 nm.1H NMR (500 MHz, DMSOd6) δ 12.75 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H) ppm. Ethyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (14-5) To a suspension of 14-4 (1.03 g, 4.60 mmol) and potassium carbonate (2.54 g, 18.4 mmol) in N,N-dimethylacetamide (DMA, 21.0 mL) was added iodomethane (1.96 g, 13.8 mmol). The reaction mixture was stirred at room temperature for 72 hours, which was monitored by LCMS. The resulting mixture was poured into water (63 mL). The precipitate was filtered to collect, washed with water (5 mL × 2) and dried. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 2) to give 14-5 (766 mg, 70% yield) as a yellow solid. ESI m / z: 238.9 (M+H)+, retention time 2.02 min, 97.5% @ 214 nm.1H NMR (500 MHz, DMSOd6) δ 8.20 (d, J = 8.5 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H), 4.01 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H) ppm. Ethyl 1-methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (14-7) To a solution of 14-5 (766 mg, 3.22 mmol) in 1,4-dioxane (28.0 mL) and water (7.0 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14-6 (1.25 g, 6.44 mol), potassium phosphate (2.05 g, 9.66 mmol) and bis(tri-tert-butylphosphine)palladium (0.164 g, 0.322 mmol) under nitrogen gas. The reaction mixture was stirred under argon atmosphere at 100oC for two hours and the reaction progress was monitored by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol, v / v = 20) to give 14-7 (653 mg, 75.1% yield) as a light-yellow solid. ESI m / z: 271.0 (M+H)+, retention time 1.69 min, 98.3% @ 214 nm.1H NMR (500 MHz, DMSOd6) δ 13.03 (s, 1H), 8.29 (s, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.22 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 4.08 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H) ppm. 1-Methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (14-8) To a solution of compound 14-7 (400 mg, 1.48 mmol) in water (2.6 mL), tetrahydrofuran (THF, 7.8 mL) and methanol (2.6 mL) was added lithium hydroxide monohydrate (0.311 g, 7.41 mmol). The reaction mixture was stirred at 20oC for three hours and the reaction progress was monitored by LCMS. The reaction mixture was concentrated in vacuo and diluted with water (2 mL). The aqueous mixture was acidified with conc. aq. hydrochloride to pH 1 and then filtered. The filter-cake was dried in vacuo to give 14-8 (357 mg, 99.4% yield). ESI m / z: 243.1 (M+H)+, retention time 1.07 min, purity >99.9% @ 254 nm.1H NMR (400 MHz, DMSOd6) δ 8.30 (s, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 4.08 (s, 3H) ppm. N-(2-fluorobenzyl)-1-methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 14, 1-1) To a solution of 14-8 (5.9 g, 24.4 mmol) in N,N-dimethylformamide (236 mL) was added (2-fluorophenyl)methanamine 14-9 (3.66 g, 29.3 mmol, CAS: 89-99-6), EDCI (7.01 g, 36.6 mmol), HOBt (4.94 g, 36.6 mmol) and DIPEA (15.7 g, 122 mmol). The reaction was monitored by LCMS. After stirring at 25oC for eighteen hours, the reaction mixture was quenched with water (600 mL) and was then extracted with ethyl acetate (600 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-HPLC (5-95% acetonitrile in aq. ammonium bicarbonate (10 mM)) to give desired product 1-1 (Compound 14) (1.96 g, 23% yield) as a white solid. ESI m / z: 349.9 (M+H)+, retention time 1.59 min, purity >99.9% @ 254 nm.1H NMR (400 MHz, DMSOd6) δ 13.06 (s, 1H), 9.10 (t, J = 5.5 Hz, 1H), 8.26 (s, 2H), 8.05 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.36-7.29 (m, 1H), 7.24-7.13 (m, 3H), 4.54 (d, J = 5.5 Hz, 2H), 4.06 (s, 3H) ppm.19F NMR (376 MHz, DMSOd6) δ -118.97 ppm. Example 15: Synthesis of N-(2-fluorobenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 15) 6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (15-3) To a solution of 6-chloro-3-iodopyridin-2-amine (15-1) (9.00 g, 35.4 mmol), 2- oxopropanoic acid (15-2) (9.34 g, 106 mmol) and DABCO (11.9 g ,106 mmol) in N,N- dimethylformamide (255 mL) was added palladium(II) acetate (0.397 g,1.77 mmol). The reaction mixture was degassed three times and stirred under N2 atmosphere at 110oC for three hours. LCMS showed the reaction was completed. Then the mixture was concentrated under vacuum to remove the solvent. To the residue, ethyl acetate (500mL) was added, and the mixture was extracted with 2M aq. sodium hydroxide (500 mL ×3). The aqueous layer was concentrated under vacuum to 500 mL. Then the aqueous solution was acidified with HCl to pH=3. And the mixture was filtered. The filter-cake was washed and dried to afford 6-chloro-1H-pyrrolo[2,3-b] pyridine-2-carboxylic acid (5.49 g, 74.1%) as yellow solid. LCMS: ESI [M+H]+196.9 was found, retention time 1.23 min, purity 93.9 % at 254 nm.1H NMR (500 MHz, DMSOd6) δ 12.41 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H) ppm. Ethyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (15-4) To a solution of 15-3 (5.70 g, 35.4 mmol) in ethanol (170 mL) was added 98% sulfuric acid (14.5 g, 145 mmol). The reaction mixture was stirred at 80oC for eighteen hours. LCMS showed the reaction was completed. Then the mixture was alkalified with sodium bicarbonate and concentrated under vacuum to remove the ethanol. To the mixture, water (300 mL) was added, and the mixture was extracted with ethyl acetate (500 mL ×3). The organic phase was washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated under vacuum. The residue was purified with silica column (petroleum ether: ethyl acetate = 2:1) to afford ethyl 6- chloro-1H-pyrrolo [2,3-b]pyridine-2-carboxylate (15-4) (4.29 g, 65.9%) as yellow solid. LCMS: ESI: 224.9 [M+H]+, retention time 1.82 min, purity 98.6 % at 254 nm.1H NMR (500 MHz, DMSOd6) δ 12.75 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H) ppm. Ethyl 6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (15-5) To a solution of 15-4 (3.50 g, 15.6 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (6.5 g, 31.3 mol) and potassium phosphate (8.29 g 39.1 mmol) in 1,4-dioxane (70.0 mL) and water (17.5 mL) was added bis(tri-tert-butylphosphine)palladium (0.799 g,1.56 mmol). The reaction mixture was stirred under argon atmosphere at 100oC for eighteen hours. And the desired product was found by LCMS. Then water (100 mL) was added to the reaction mixture at 25oC. And the reaction mixture was extracted with ethyl acetate (200 mL×3), the organic phase was combined and washed with saturated sodium chloride solution (200 mL), then dried with sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified with silica column (dichloromethane: methanol = 20: 1) to give ethyl 6-(5-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (15-5) (1.14 g, 27.0%). LCMS: ESI [M+H]+271.0, retention time 1.65 min, purity 96.0% at 214 nm.1H NMR (500 MHz, DMSOd6) δ 12.73 (s, 1H), 12.26 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 2.61 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H) ppm. 6-(5-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (15-6) To a solution of 15-5 (1.14 g, 4.22 mmol) in water (3 mL), tetrahydrofuran (9 mL) and methanol (3 mL), lithium hydroxide monohydrate (0.886 g, 21.1 mmol) was added. The reaction mixture was stirred at 20oC for two hours. LCMS showed that the reaction was completed. The reaction mixture was concentrated under vacuum to remove tetrahydrofuran and methanol. Water (3 mL) was added and then 36.5% hydrochloric acid solution was added to adjust pH to 1, and then filtered. The filter-cake was dried under vacuum to give 6-(5-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxylic acid (15-6) (0.956 g, 93.7%). LCMS: ESI [M+H]+243.1, retention time 1.12 min, purity 100% at 254 nm.1H NMR (500 MHz, DMSOd6) δ 12.15 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 2.63 (s, 3H) ppm. N-(2-fluorobenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 15) To a solution of 15-6 (70.0 mg, 0.289 mmol) in N,N-dimethylformamide (3.00 mL), (2- fluorophenyl)methanamine (43.4 mg, 0.347 mmol), N-(3-(dimethylamino)propyl)propionamide dihydrochloride (83.2 mg, 0.434 mmol), 1-hydroxybenzotriazole (58.6 mg, 0.434 mmol) and N,N- diisopropylethylamine (187 mg, 1.45 mmol) was added. The reaction mixture was stirred at 25oC for eighteen hours. Then water (6 mL) was added to the reaction mixture. And then the reaction mixture was extracted with ethyl acetate (30 mL × 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL), and then dried with sodium sulfate and filtered. The filtrate was concentrated. The residue was purified with prep-HPLC to give N-(2- fluorobenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 15) as white solid. (29.9 mg, 29.6%) LCMS: ESI [M+H]+350.2, retention time 1.64 min, purity 100% at 254 nm.1H NMR (500 MHz, DMSOd6) δ 12.68 (s, 1H), 11.88 (s, 1H), 8.94 (t, J = 5.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.45–7.41 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.37– 7.30 (m, 1H), 7.24-7.17 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 2.60 (s, 3H) ppm. Example 16: Exemplary Compounds of the Present Invention Table 1 C C Example 17: ROCK1, ROCK2, PRKX, and PKA Inhibition Assay Compounds as a powder were dissolved in dimethyl sulfoxide to make a 10 mM stock. Compounds were tested in 10-dose IC50triplicate mode with a 3-fold serial dilution starting at 1 μM. The control compound, staurosporine, was tested in 10-dose IC50 mode with 4-fold serial dilution starting at 20 μM. The HotSpot kit employing33P-ATP was used with reactions conducted at 10 μM ATP for each tested enzyme. The percent activity relative to DMSO controls for each concentration was then fitted to a curve using GraphPad Prism to determine the IC50. Curve fits were performed where the enzyme activities at the highest concentration of compounds were less than 65%. The resulting data for the tested compounds is shown in Table 2A and Table 2B below. The data for Compound 14 and Compound 15 in Table 2B is the geometric mean of the IC50data from multiple enzyme inhibition experiments. Each experiment was run in the same lab with this p Table 2A – Inhibitory Activity of Compound 14 and Compound 15 Table 2B – Inhibitory Activity of Compound 14 and Compound 15 Through the in vivo cleavage of the moiety attached to the pyrazole (the R1position) the compounds of the present invention release an active agent which inhibits ROCK1, ROCK2, PRKX, and / or PKA. For example, Compound 14 is released in vivo by the cleavage of the R1moiety in Compounds 1-13. Once formed Compound 14 inhibits ROCK1, ROCK2, PRKX, and / or PKA. Example 18: MDCK-MDR1 Efflux Assay 1. Preparation of MDCKII-MDR1 Cells Cell culture medium (50 µL and 25 mL) was added to each well of the Transwell insert and reservoir, respectively. And then the HTS Transwell plates were incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. Afterwards, MDCKII-MDR1 cells were diluted to 1.56х106 cells / mL with culture medium and 50 µL of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. Cells were cultivated for 4-8 days in a cell culture incubator at 37 °C, 5% CO2, 95% relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating. 2. Preparation of Stock Solutions Stock solutions (10 mM) of test compounds were prepared in DMSO. The stock solutions of positive controls were prepared in DMSO at the concentration of 10 mM. Metoprolol, Digoxin, and Fasudil were used as control compounds in this assay. 3. Assessment of Cell Monolayer Integrity Medium was removed from the reservoir and each Transwell insert and replaced with prewarmed fresh culture medium. Then transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA). The plates were returned to the incubator once the measurement was done. The TEER value was calculated according to the following equation: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm•cm2) TEER value should be greater than 42 ohm•cm2, which indicates the well-qualified MDCKII- MDR1 monolayer. 4. Assay Procedures The MDCKII-MDR1 plate was removed from the incubator and washed twice with pre- warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of the control compounds and test compounds were diluted in DMSO to get 200 µM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 1 µM working solutions. The final concentration of DMSO in the incubation system is 0.5%. To determine the rate of drug transport in the apical to basolateral direction.125 µL of the working solution was added to the Transwell insert (apical compartment), and 50 µL of sample was transferred immediately from the apical compartment to 200 µL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96- well plate as the initial donor sample (A-B). The sample was vortexed at 1000 rpm for 10 minutes. The wells in the receiver plate (basolateral compartment) were filled with 235 µL of transport buffer. To determine the rate of drug transport in the basolateral to apical direction.285 μL of the working solution was added to the receiver plate wells (basolateral compartment), and 50 μL of sample was transferred immediately from the basolateral compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (B-A). The sample was vortexed at 1000 rpm for 10 minutes. The Transwell insert (apical compartment) was filled with 75 μL of transport buffer. The apical to basolateral direction and the basolateral to apical direction were done at the same time. Then, the plates were incubated at 37 °C for 2 hours. At the end of the incubation, 50 μL of samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) were transferred to wells of a new 96-well plate, followed by the addition of 4 volume of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide). Samples were vortexed for 10 minutes and then centrifuged at 3220 g for 40 minutes. An aliquot of 100 µL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC-MS / MS analysis. To determine the Lucifer Yellow leakage after 2-hour transport period, the stock solution of Lucifer Yellow was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 µM. Then, 100 µL of the Lucifer Yellow solution was added to each Transwell insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates were incubated at 37 °C for 30 minutes. Then, 80 μL samples were removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence was used to monitor monolayer integrity and its signal was measured in a fluorescence plate reader at 480 nM excitation and 530 nM emission. Detailed data are shown in Table 3. Table 3 – Permeability of Exemplary Compounds in MDR1-Transfected MDCK Cells C a Calculated as the ratio of Papp.,B→A / Papp.,A→B;bBLD: Below Limit of Detection;cNC: Not Calculated;dNT: Not tested;eCompound 1 was tested as a tromethamine salt Example 19: Metabolic Stability in Liver Microsomes of Selected Species (Mouse, Human and Rat) The master solution was prepared according to Table 4 and using the correct species’ microsomes. Table 4 – Preparation of master solution Two separate experiments were performed as follows. a) Cofactors (NADPH): 25 μL of 10 mM NADPH were added to the incubations. The final concentration of microsomes and NADPH was 0.5 mg / mL and 1 mM, respectively. b) Without Cofactors (NADPH): 25 μL of 100 mM Phosphate buffer was added to the incubations. The final concentration of microsomes was 0.5 mg / mL. The mixture was pre-warmed at 37 °C for 10 minutes. The reaction was started with the addition of 2.5 µL of 100 µM control compound or test compound solutions. Verapamil was used as positive control in this study. The final concentration of test compound or control compound was 1 μM. The incubation solution was incubated in water batch at 37 °C. Four Aliquots of 30 µL were taken from the reaction solution at 0.5, 5, 15, 30 and 60 minutes. The reaction was stopped by the addition of 5 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide). Samples were centrifuged at 3220 g for 40 minutes. Aliquot of 100 µL of the supernatant was mixed with 100 µL of ultra-pure H2O and then used for LC-MS / MS analysis. All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1 / 2) was determined from the slope value: in vitro t1 / 2=- (0.693 / k) Conversion of the in vitro t1 / 2 (min) into the in vitro intrinsic clearance (in vitro CLint, in µL / min / mg protein) was done using the following equation (mean of duplicate determinations): l f i i L ^^^ The resulting data is shown in Table 5 below. Table 5 – Mouse, Rat, and Human Live Microsome Data C

[0013] a NV: No value;bCompound 1 was tested as a tromethamine salt Example 20: Kinetic Solubility The stock solutions of test compounds and control compound progesterone were prepared in DMSO at the concentrations of 10 mM.15 µL of stock solution (10 mM) of each sample was placed in order into their proper 96-well rack.485 µL of PBS pH 7.4 was added into each vial of the cap-less solubility sample plate. The assay was performed in duplicate. One stir stick was added to each vial and sealed using a molded PTFE / Silicone plug. Then the solubility sample plate was transferred to the Eppendorf Thermomixer Comfort plate shaker and shook at 25 °C at 1100 rpm for 2 hours. After completion of the 2 hours, plugs were removed and the stir sticks were removed using a big magnet, the samples from the Solubility Sample plate were transferred into the filter plate. All the samples were filtered using the Vacuum Manifold. Aliquot of 5 µL DMSO were taken from the filtrate followed by addition of 490 µL of a mixture of H2O and acetonitrile containing internal standard (1:1). Ultrapure water was used to dilute the diluent according to the peak shape. The dilution factor was changed according to the solubility values and the LC-MS signal response. From the 10 mM DMSO STD plate, 6 µL was transferred into the remaining empty plate, and then 194 µL of DMSO was added to that plate to have a STD concentration of 300 µM. From the 300 µM DMSO STD plate, 5 µL DMSO STD and 5 µL PBS pH 7.4 were transferred into the remaining empty plate, and then 490 µL of a mixture of H2O and acetonitrile containing internal standard (1:1) was added to that plate to have a final STD concentration of 3 µM. A certain proportion of ultrapure water was used to dilute the diluent according to the peak shape. The concentrations of the standard samples were changed according to the LC-MS signal response. The plate was placed into the well plate autosampler. The samples were evaluated by LC-MS / MS analysis. All calculations were carried out using Microsoft Excel. The filtrate was analyzed and quantified against a standard of known concentration using LC coupled with mass spectral peak identification and quantitation. Solubility values of the test compound and control compound were calculated as follows: [Sample] The resulting data is shown in Table 6 below. Table 6 – Kinetic Solubility of Exemplary Compounds in Phosphate-Buffered Saline (PBS), pH 7.4 Cmp 1b2 3 4 5 6 7 8 9 10 11 12 13 a BLD: Below Limit of Detectio n;bCompound 1 was tested as a tromethamine salt Example 21: Pharmacokinetic Study via Intravenous and Oral Administration in male Sprague-Dawley rats Male Sprague-Dawley rats averaging 7-9 weeks of age and approximately 200-300g weight were separated into groups of three. The rats were then administered a test article at a dose of 3 mg / kg by IV or a dose of 10 mg / kg orally. The dose volume was 2 mL / kg by IV or 10 mL / kg orally. The intravenously administered test articles were formulated with 20% DMA, 20% PEG400, and 20% Kolliphor HS15, in saline and the orally administered test articles were formulated in a 1% DMSO and 0.5% methylcellulose in aqueous solution at room temperature. The solutions were prepared at a concentration of 1.5 mg / mL for intravenous administration and 1 mg / mL for oral administration. The dose formulations were kept stirred at room temperature for at least 2 minutes before dosing. For IV dosing, animals were administered intravenously via tail vein. For PO dosing, animals were administered via oral gavage. Blood samples were taken at 0.25, 0.5, 1, 2, 4, 8, 12 (optional) and 24 hours for the group of oral administration. Plasma samples were taken at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 (optional) and 24 hours for the group of intravenous administration. Acceptable time ranges for blood collection and blood sample collection and processing are shown in the table below. Table 7 – Acceptable Time Ranges for Blood Collection

[0014] Table 8 – Blood Sample Collection and Processing During the in-life phase, animals were evaluated by cage side observations twice daily, detailed clinical observation and body weight measurement were performed once prior to dosing. Unscheduled clinical observations (cage side or detailed) were also performed, as needed. Table 9 – Husbandry Information For PK samples analyses, concentrations of test articles in the plasma samples were analyzed using a LC-MS / MS method. WinNonlin (PhoenixTM, version 6.1) or other similar software was used for pharmacokinetic calculations. The following pharmacokinetic parameters were calculated, whenever possible from the plasma concentration versus time data: IV administration: T1 / 2, C0, AUClast, AUCinf, MRTinf, CL, Vss, number of points for regression. PO administration: Cmax, Tmax, MRTinf, AUCinf, AUClast, number of points for regression. The pharmacokinetic data were described using descriptive statistics such as mean, standard deviation. The resulting data is provided in the following table. Table 10 – In Vivo Pharmacokinetics in Male Sprague-Dawley Ratsa,b,cCaSingle oral dose via gavage; Parameters (including effective dose and apparent %F) were calculated based on thedetection of Compound 14;cCompounds were formulated in 0.5% methylcellulose + 1% v / v DMSO unless otherwise specified;dCompound 1 was tested as a tromethamine salt All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually incorporated. Although the foregoing invention has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teaching of this invention that certain changes and modification may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims. Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present application.

Claims

CLAIMS We claim:

1. A compound of Formula:or a pharmaceutically acceptable salt thereof; wherein: R1is selected from the group consisting of -CH2OC(O)R2, -CH2OP(O)(OR4)(OR5), -C(O)R3, -C(=NH)NR4R5, and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R2is C1-C6alkyl, C2-C6alkenyl, or aryl; each of which is optionally substituted with -C(O)OR4; R3is C1-C6 alkyl, -OR4, or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R4and R5are independently hydrogen or C1-C6alkyl; R6and R7are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R8is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; and R9and R10are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4 alkyl, and halogen.

2. The compound of claim 1, wherein R10is hydrogen.

3. The compound of claim 1, wherein R10is halogen.

4. The compound of claim 1, wherein R10is fluoro.

5. The compound of claim 1, wherein R10is chloro.

6. The compound of claim 1, wherein R10is methyl.

7. The compound of claim 1, wherein R10is ethyl.

8. The compound of any one of claims 1-7, wherein R6is hydrogen.

9. The compound of any one of claims 1-7, wherein R6is halogen.

10. The compound of any one of claims 1-7, wherein R6is methyl.

11. The compound of any one of claims 1-10, wherein R7is hydrogen.

12. The compound of any one of claims 1-10, wherein R7is halogen.

13. The compound of any one of claims 1-10, wherein R7is methyl.

14. The compound of any one of claims 1-10, wherein R7is C1-C2 haloalkyl.

15. The compound of any one of claims 1-14, wherein R8is hydrogen.

16. The compound of any one of claims 1-14, wherein R8is methyl.

17. The compound of any one of claims 1-16, wherein R9is hydrogen.

18. The compound of any one of claims 1-16, wherein R9is halogen.

19. The compound of any one of claims 1-16, wherein R9is fluoro.

20. The compound of any one of claims 1-16, wherein R9is chloro.

21. The compound of any one of claims 1-16, wherein R9is C1-C2 haloalkyl.

22. The compound of claim 1 of Formulaor a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 of Formulaor a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

26. The compound of any one of the claims 1-25, wherein R5is hydrogen.

27. The compound of any one of the claims 1-25, wherein R5is C1-C6 alkyl.

28. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

29. The compound of claim 28, wherein R2is C1-C6alkyl optionally substituted with -C(O)OR4.

30. The compound of claim 28, wherein R2is .

31. The compound of claim 28, wherein R2is .

32. The compound of claim 28, wherein R2is33. The compound of claim 28, wherein R2is C2-C6alkenyl optionally substituted with -C(O)OR4.

34. The compound of claim 28, wherein R2is .

35. The compound of claim 28, wherein R2is aryl optionally substituted with -C(O)OR4.

36. The compound of claim 28, wherein R2is37. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

38. The compound of claim 37, wherein R3is -OR4.

39. The compound of any one of claims 1-38, wherein R4is hydrogen.

40. The compound of any one of claims 1-38, wherein R4is C1-C6 alkyl.

41. The compound of any one of claims 1-38, wherein R4is methyl.

42. The compound of any one of claims 1-38, wherein R4is iso-propyl.

43. The compound of claim 37, wherein R3is C1-C6 alkyl.

44. The compound of claim 37, wherein R3is iso-propyl.

45. The compound of claim 37, wherein R3is tert-butyl.

46. The compound of claim 37, wherein R3is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms.

47. The compound of claim 37, wherein R3is .

48. A compound selected from:or a pharmaceutically acceptable salt thereof.

49. A compound selected from:or a pharmaceutically acceptable salt thereof.

50. A compound selected from:andor a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising a compound of any one of claims 1-50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

52. The pharmaceutical composition of claim 51, wherein the pharmaceutical composition is suitable for oral administration.

53. The pharmaceutical composition of claim 51, wherein the pharmaceutical composition is suitable for parenteral administration.

54. The pharmaceutical composition of claim 51, wherein the pharmaceutical composition is suitable for intravenous administration.

55. A method of treating a ROCK1 or ROCK2 mediated disorder comprising administering an effective amount of a compound of any one of claims 1-50 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a subject in need thereof.

56. The method of claim 55, wherein the subject is a human.

57. The method of claim 55 or 56, wherein the disorder is a neurodegenerative disorder.

58. The method of claim 57, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis.

59. The method of claim 57, wherein the neurodegenerative disorder is Parkinson’s disease.

60. The method of claim 57, wherein the neurodegenerative disorder is Huntington’s disease.

61. The method of claim 57, wherein the neurodegenerative disorder is Alzheimer’s disease.

62. The method of claim 55 or 56, wherein the disorder is a kidney disease.

63. The method of claim 62, wherein the kidney disease is diabetic nephropathy.

64. The method of claim 62, wherein the kidney disease is polycystic kidney disease.

65. The method of claim 62, wherein the kidney disease is focal segmental glomerulosclerosis.

66. The method of claim 55 or 56, wherein the disorder is Levodopa-induced dyskinesia.

67. The method of claim 55 or 56, wherein the disorder is a bladder dysfunction.

68. The method of claim 67, wherein the bladder dysfunction is interstitial cystitis.

69. The method of claim 67, wherein the bladder dysfunction is bladder inflammation.

70. The method of claim 67, wherein the bladder dysfunction is overactive bladder.

71. The method of claim 67, wherein the bladder dysfunction is bladder fibrosis.

72. The method of claim 67, wherein the bladder dysfunction is neurogenic bladder.

73. The method of claim 67, wherein the bladder dysfunction is a lower urinary tract symptom.

74. The method of claim 55 or 56, wherein the disorder is a cancer.

75. The method of claim 74, wherein the cancer is breast cancer.

76. The method of claim 74, wherein the cancer is prostate cancer.

77. The method of claim 74, wherein the cancer is melanoma.

78. The method of claim 74, wherein the cancer is a desmoplastic disorder.

79. The method of claim 55 or 56, wherein the disorder is a traumatic brain injury.

80. The method of claim 55 or 56, wherein the disorder is diabetic retinopathy.

81. The method of claim 55 or 56, wherein the disorder is idiopathic pulmonary fibrosis.

82. The method of claim 55 or 56, wherein the disorder is a pulmonary sarcoidosis.

83. The method of claim 55 or 56, wherein the disorder is a neurosarcoidosis.

84. The method of claim 55 or 56, wherein the disorder is scleroderma.

85. The method of claim 55 or 56, wherein the disorder is a fibrotic disorder.

86. The method of claim 85, wherein the disorder is a fibrotic disorder of the lung.

87. The method of claim 85, wherein the disorder is a fibrotic disorder of the kidney.

88. The method of claim 85, wherein the disorder is a fibrotic disorder of the liver.

89. The method of claim 85, wherein the disorder is a fibrotic disorder of the skin.

90. The method of any one of claims 55-89, wherein the disorder is mediated by ROCK1.

91. The method of any one of claims 55-89, wherein the disorder is mediated by ROCK2.

92. Use of a compound of any one of claims 1-50 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated disorder.

93. Use of a compound of any one of claims 1-50 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated disorder.

Images