Azaindole rock inhibitors for the treatment of medical disorders

Abstract

This invention provides methods of treating selected rho-associated protein kinase (ROCK) mediated disorders comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III to a human patient in need thereof as described further herein.

Description

[0001] AZAINDOLE ROCK INHIBITORS FOR THE TREATMENT OF MEDICAL DISORDERS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application 63 / 667,614, filed July 3, 2024. The entirety of this application is hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides methods of treating selected rho-associated protein kinase (ROCK) mediated disorders comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III to a human patient in need thereof 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 specific disorders mediated by ROCK1 and / or ROCK2 in a human subject in need thereof. SUMMARY OF THE INVENTION Methods of treating specific rho-associated protein kinase (ROCK) mediated disorders are provided comprising administering an effective amount of an azaindole compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof to a human patient in need thereof. In certain aspects the present invention provides a method to treat a ROCK mediated disorder selected from: A) A kidney disease, for example polycystic kidney disease (PKD), diabetic nephropathy, renal fibrosis, glomerulosclerosis, focal segmental glomerulosclerosis, or kidney failure; B) A fibrotic disorder, for example a pulmonary fibrosis, liver fibrosis, renal fibrosis, tubulointerstitial fibrosis, skin fibrosis, or myocardial fibrosis. C) A levodopa-induced dyskinesia (LID). Examples of LID include peak-dose dyskinesia, off- period dyskinesia, and diphasic dyskinesia; D) A traumatic brain injury (TBI), for example a mild TBI, moderate TBI, or severe TBI; E) A bladder dysfunction, for example interstitial cystitis, bladder inflammation, overactive bladder, bladder fibrosis, neurogenic bladder, or lower urinary tract symptoms (LUTS); F) Benign prostatic hyperplasia; G) A diabetic retinopathy, for example proliferative diabetic retinopathy or non-proliferative diabetic retinopathy; H) A sarcoidosis, for example a pulmonary sarcoidosis or neurosarcoidosis; I) Scleroderma; and J) A cancer or tumor. Non-limiting examples of cancer include breast cancer, prostate cancer, melanoma, and a desmoplastic disorder. Specific compounds for use in the present invention for the selected described disorders exhibit advantageous ADME properties (absorption, distribution, metabolism, and / or excretion) and higher potency in enzyme inhibition assays than close analogues (see Example 24 and Example 25). It has also been surprisingly discovered that these compounds also have activity against protein kinase X (PRKX, see Table 2A and Table 2B). In certain aspects the compound for use in the present invention is Compound 1: or a pharmaceutically In certain aspects the compound for use in the present invention is Compound 2: or a pharmaceutically Compound 1 and Compound 2 are highly potent inhibitors of ROCK1, ROCK2, and PRKX (see Table 2A and Table 2B). These two compounds have superior efflux ratios when compared to the eight tested comparator compounds (see Table 3A and Table 3B). These properties are important for the treatment of a ROCK1 or ROCK2 mediated disorder, for example the treatment of a kidney disease. In certain embodiments the compound for use in the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof. In other embodiments the compound for use in the present invention is a compound of Formula II or Formula III or a pharmaceutically acceptable salt thereof. Formula I, Formula II, and Formula III have the following structures: or a pharmaceutically wherein: R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; in certain embodiments R1and R2are hydrogen; in other embodiments R1is hydrogen and R2is methyl; R3is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; in certain embodiments R3is H or CH3; R4and R5are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen; R6is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, C1-C4 alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. 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 aspects the compound of Formula I is of Formula: or a In other aspects the compound of Formula I is of Formula: or a pharmaceutically In certain embodiments the compound of Formula I is selected from: B) F) -J) Non-limiting examples of compounds of Formula I include: Additional non-limiting examples of compounds of Formula I include: In other embodiments, the compound of Formula I is selected from: L) N) ) Additional examples of a compound of Formula I include: ,, In certain embodiments the compound of Formula II is selected from: B) -F) ) In other embodiments, the compound of Formula II is selected from L) Non-limiting examples of compounds of Formula II include: and or a pharmaceutically . Additional non-limiting examples of compounds of Formula II include: ; Additional examples of compounds of Formula II include: In certain embodiments the compound of Formula III is selected from: B) H) Non-limiting examples of compounds of Formula III include: or a pharmaceutically acceptable salt thereof. Select compounds for use in the present invention for treatment of the select disorders described herein have advantageous properties when compared to Fasudil. For example Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5 when tested in head- to-head studies against Fasudil, had superior ROCK1 and ROCK2 inhibiting activity and exhibited a lower efflux ratio (see Example 24 and Example 25). The concentration of Compound 1 required to inhibit half of ROCK2’s activity was more than 50-fold lower than the concentration required for Fasudil (Example 24). Similarly, the concentration of Compound 2, Compound 3, Compound 4, and Compound 5 required to inhibit half of ROCK2’s activity was more than an order of magnitude lower than the concentration required for Fasudil (Example 24). In certain aspects an effective amount of a compound of Formula I, Formula II, or Formula III is administered to a human patient in need thereof to treat a ROCK1 and / or ROCK2 mediated polycystic kidney disease (PKD). 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. In certain embodiments the PKD is ARPKD. In other embodiments the PKD is ADPKD. In certain embodiments an effective amount of Compound 1 is administered to a patient in need thereof to treat a ROCK1 and / or ROCK2 mediated polycystic kidney disease. In other embodiments an effective amount of Compound 2 is administered to a patient in need thereof to treat a ROCK1 and / or ROCK2 mediated polycystic kidney disease. In certain aspects an effective amount of a compound of Formula I, Formula II, or Formula III is administered to a human patient in need thereof to treat a ROCK1 and / or ROCK2 mediated diabetic nephropathy. Diabetic nephropathy is a serious complication of type 1 diabetes and type 2 diabetes and is the leading cause of chronic kidney disease worldwide (Alicic, Radica Z., et al., “Diabetic kidney disease: challenges, progress, and possibilities.” Clinical journal of the American Society of Nephrology 12.12 (2017): 2032-2045). In certain embodiments an effective amount of Compound 1 is administered to a patient in need thereof to treat a ROCK1 and / or ROCK2 diabetic nephropathy. In other embodiments an effective amount of Compound 2 is administered to a patient in need thereof to treat a ROCK1 and / or ROCK2 mediated diabetic nephropathy. In certain embodiments, the selected compound of Formula I, Formula II, or Formula III 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, Formula II, or Formula III, or its pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. For example, in certain embodiments a compound of Formula I, Formula II, or Formula III 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, Formula II, or Formula III 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 method to treat a ROCK1 and / or ROCK2 mediated kidney disease comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof; (b) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a kidney disease that is mediated by ROCK1 and / or ROCK2; (c) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a kidney disease that is mediated by ROCK1 and / or ROCK2; (d) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated kidney disease; (e) A method to treat a ROCK1 and / or ROCK2 mediated bladder dysfunction comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof; (f) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a bladder dysfunction that is mediated by ROCK1 and / or ROCK2; (g) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a bladder dysfunction that is mediated by ROCK1 and / or ROCK2; (h) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated bladder dysfunction; (i) A method to treat a ROCK1 and / or ROCK2 mediated cancer or tumor, for example breast cancer, prostate cancer, melanoma, or a desmoplastic disorder, comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof; (j) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, for example breast cancer, prostate cancer, melanoma, or a desmoplastic disorder, that is mediated by ROCK1 and / or ROCK2; (k) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a cancer, for example breast cancer, prostate cancer, melanoma, or a desmoplastic disorder, that is mediated by ROCK1 and / or ROCK2; (l) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated cancer, for example breast cancer, prostate cancer, melanoma, or a desmoplastic disorder; (m) A method to treat a ROCK1 and / or ROCK2 mediated benign prostatic hyperplasia comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof; (n) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a benign prostatic hyperplasia that is mediated by ROCK1 and / or ROCK2; (o) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a benign prostatic hyperplasia that is mediated by ROCK1 and / or ROCK2; (p) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated benign prostatic hyperplasia; (q) A method to treat a ROCK1 and / or ROCK2 mediated diabetic retinopathy comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof; (r) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a diabetic retinopathy that is mediated by ROCK1 and / or ROCK2; (s) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a diabetic retinopathy that is mediated by ROCK1 and / or ROCK2; (t) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated diabetic retinopathy; (u) A method to treat a ROCK1 and / or ROCK2 mediated disorder comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof, wherein the disorder is selected from levodopa-induced dyskinesia and traumatic brain injury; (v) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by ROCK1 and / or ROCK2, wherein the disorder is selected from levodopa-induced dyskinesia and traumatic brain injury; (w) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a disorder that is mediated by ROCK1 and / or ROCK2, wherein the disorder is selected from levodopa-induced dyskinesia and traumatic brain injury; (x) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated disorder, wherein the disorder is selected from levodopa-induced dyskinesia and traumatic brain injury; (y) A method to treat a ROCK1 and / or ROCK2 mediated disorder comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof, wherein the disorder is selected from sarcoidosis and scleroderma; (z) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by ROCK1 and / or ROCK2, wherein the disorder is selected from sarcoidosis and scleroderma; (aa) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a disorder that is mediated by ROCK1 and / or ROCK2, wherein the disorder is selected from sarcoidosis and scleroderma; (bb) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated disorder, wherein the disorder is selected from sarcoidosis and scleroderma; (cc) A method to treat a ROCK1 and / or ROCK2 mediated fibrosis comprising administering an effective amount of a compound of Formula I, Formula II, or Formula III or pharmaceutically acceptable salt thereof, to a human subject in need thereof; (dd) A compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in the treatment of a fibrosis that is mediated by ROCK1 and / or ROCK2; (ee) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the treatment of a fibrosis that is mediated by ROCK1 and / or ROCK2; (ff) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated fibrosis; (gg) Any of (a)-(ff) above wherein the compound is of Formula I. (hh) Any of (a)-(ff) above wherein the compound is Compound 1. (ii) Any of (a)-(ff) above wherein the compound is Compound 2. (jj) Any of (a)-(ff) above wherein the compound is Compound 10. (kk) Any of (a)-(ff) above wherein the compound is Compound 11. (ll) Any of (a)-(ff) above wherein the compound is Compound 12. (mm) Any of (a)-(ff) above wherein the compound is Compound 13. (nn) Any of (a)-(ff) above wherein the compound is Compound 14. (oo) Any of (a)-(ff) above wherein the compound is of Formula II. (pp) Any of (a)-(ff) above wherein the compound is Compound 3. (qq) Any of (a)-(ff) above wherein the compound is Compound 4. (rr) Any of (a)-(ff) above wherein the compound is Compound 5. (ss) Any of (a)-(ff) above wherein the compound is Compound 7. (tt) Any of (a)-(ff) above wherein the compound is Compound 8. (uu) Any of (a)-(ff) above wherein the compound is Compound 9. (vv) Any of (a)-(ff) above wherein the compound is of Formula III. (ww) Any of (a)-(ff) above wherein the compound is Compound 6. 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, Formula II, or Formula III 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 and prodrugs thereof 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, Formula II, or Formula III, 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-C4 moiety. 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” . Additional non-limiting examples of “haloalkyl” , . Additional non-limiting examples of “haloalkyl” . Additional non-limiting examples of “haloalkyl” . 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, FORMULA II, AND FORMULA III In certain aspects, the present invention provides a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof for use in treating a disorder described herein , r I) wherein all variables are d In certain embodiments, the compound of Formula I is selected from: In certain embodiments, the compound of Formula I is selected from:

[0002] or In certain embodiments, the compound of Formula I is selected from:

[0003] In other embodiments the compound of Formula I is selected from: In other embodiments the compound of Formula I is selected from: In certain embodiments, the compound of Formula I is selected from: Non-limiting examples of compounds of Formula I include: 5 ; In alternative embodiments, the compound of Formula I is selected from: 5 ; Alternative examples of a compound of Formula I include: ,,,; In certain embodiments, the compound of Formula II is selected from:

[0004] In certain embodiments, the compound of Formula II is selected from: 5 Non-limiting examples of compounds of Formula II include: ; or In alternative embodiments, a compound of Formula II is selected from:

[0005] 5 ;

[0006] Additional non-limiting examples of compounds of the present invention include: ; Embodiments of R1In certain embodiments R1is hydrogen. In certain embodiments R1is CH3. In certain embodiments R1is C2H5. In certain embodiments R2is CH2CH2CH3. In certain embodiments R1is iso-C3H7. In certain embodiments R1is F. In certain embodiments R1is Cl. In certain embodiments R1is Br. In certain embodiments R1is CF3. In certain embodiments R1is CH2F. In certain embodiments R1is CH2CF3. Embodiments of R2In certain embodiments R2is hydrogen. In certain embodiments R2is CH3. In certain embodiments R2is C2H5. In certain embodiments R2is CH2CH2CH3. In certain embodiments R2is iso-C3H7. In certain embodiments R2is F. In certain embodiments R2is Cl. In certain embodiments R2is Br. In certain embodiments R2is CF3. In certain embodiments R2is CH2F. In certain embodiments R2is CH2CF3. Embodiments of R3In certain embodiments R3is hydrogen. In certain embodiments R3is CH3. In certain embodiments R3is C2H5. In certain embodiments R3is CH2CH2CH3. In certain embodiments R3is iso-C3H7. In certain embodiments R3is CF3. In certain embodiments R3is CH2F. In certain embodiments R3is CH2CF3. Embodiments of R4In certain embodiments R4is hydrogen. In certain embodiments R4is CH3. In certain embodiments R4is C2H5. In certain embodiments R4is CH2CH2CH3. In certain embodiments R4is iso-C3H7. In certain embodiments R4is F. In certain embodiments R4is Cl. In certain embodiments R4is Br. In certain embodiments R4is CF3. In certain embodiments R4is CH2F. In certain embodiments R4is CH2CF3. Embodiments of R5In certain embodiments R5is hydrogen. In certain embodiments R5is CH3. In certain embodiments R5is C2H5. In certain embodiments R5is CH2CH2CH3. In certain embodiments R5is iso-C3H7. In certain embodiments R5is F. In certain embodiments R5is Cl. In certain embodiments R5is Br. In certain embodiments R5is CF3. In certain embodiments R5is CH2F. In certain embodiments R5is CH2CF3. 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 iso-C3H7. 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. In certain embodiments R6is OH. In certain embodiments R6is OCH3. In certain embodiments R6is OC2H5. In certain embodiments R6is OCH2CH2CH3. In certain embodiments R6is OC3H7-iso. In certain embodiments R6is OCF3. In certain embodiments R6is OCH2CF3. 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 iso-C3H7. In certain embodiments R7is CF3. In certain embodiments R7is CH2F. In certain embodiments R7is CH2CF3. In certain structure: . are typically selected such that they are sufficiently stable to sustain a shelf life of at least two, three, four, or five months under ambient conditions. To accomplish this, each of the variables described herein is selected such that the resulting compound achieves a desired 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 method of treating a ROCK1 or ROCK2 mediated kidney disease comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein: R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. 2. The method of embodiment 1, wherein the kidney disease is polycystic kidney disease. 3. The method of embodiment 1, wherein the kidney disease is diabetic nephropathy. 4. The method of embodiment 1, wherein the kidney disease is glomerulosclerosis. The method of embodiment 1, wherein the kidney disease is focal segmental glomerulosclerosis. The method of embodiment 1, wherein the kidney disease is kidney failure. A method of treating a ROCK1 or ROCK2 mediated bladder dysfunction comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula I, Formula II, or Formula III. The method of embodiment 7, wherein the bladder dysfunction is interstitial cystitis. The method of embodiment 7, wherein the bladder dysfunction is bladder inflammation. The method of embodiment 7, wherein the bladder dysfunction is overactive bladder. The method of embodiment 7, wherein the bladder dysfunction is bladder fibrosis. The method of embodiment 7, wherein the bladder dysfunction is neurogenic bladder. The method of embodiment 7, wherein the bladder dysfunction is a lower urinary tract symptom. A method of treating a ROCK1 or ROCK2 mediated cancer comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula I, Formula II, or Formula III. The method of embodiment 14, wherein the cancer is breast cancer. The method of embodiment 14, wherein the cancer is prostate cancer. The method of embodiment 14, wherein the cancer is melanoma. The method of embodiment 14, wherein the cancer is a desmoplastic disorder. A method of treating a ROCK1 or ROCK2 mediated disorder selected from levodopa-induced dyskinesia and a traumatic brain injury, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula I, Formula II, or Formula III. The method of embodiment 19, wherein the disorder is levodopa-induced dyskinesia. The method of embodiment 19, wherein the disorder is a traumatic brain injury. The method of embodiment 21, wherein the traumatic brain injury is a mild traumatic brain injury. The method of embodiment 21, wherein the traumatic brain injury is a moderate traumatic brain injury. The method of embodiment 21, wherein the traumatic brain injury is a severe traumatic brain injury. A method of treating a ROCK1 or ROCK2 mediated benign prostatic hyperplasia comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula I, Formula II, or Formula III. A method of treating a ROCK1 or ROCK2 mediated diabetic retinopathy comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula I, Formula II, or Formula III. The method of embodiment 26, wherein the diabetic retinopathy is a proliferative diabetic retinopathy. The method of embodiment 26, wherein the diabetic retinopathy is a non-proliferative diabetic retinopathy. A method of treating a ROCK1 or ROCK2 mediated disorder selected from sarcoidosis and scleroderma comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof wherein the compound is of Formula I, Formula II, or Formula III. The method of embodiment 29, wherein the disorder is pulmonary sarcoidosis or neurosarcoidosis. 31. A method of treating a ROCK1 or ROCK2 mediated fibrotic disorder comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula I, Formula II, or Formula III. 32. The method of embodiment 31, wherein the fibrotic disorder is a fibrotic disorder of the lung. 33. The method of embodiment 31, wherein the fibrotic disorder is a fibrotic disorder of the kidney. 34. The method of embodiment 31, wherein the fibrotic disorder is a fibrotic disorder of the skin. 35. The method of embodiment 31, wherein the fibrotic disorder is a fibrotic disorder of the liver. 36. The method of any one of embodiments 1-35, wherein the compound is of Formula: ; or a pharmaceutically 37. The method of any one of embodiments 1-35, wherein the compound is of Formula: B) F) -J) 38. The method of any one of embodiments 1-37, wherein R5is hydrogen. 39. The method of any one of embodiments 1-37, wherein R5is halogen. 40. The method of any one of embodiments 1-37, wherein R5is fluoro. 41. The method of any one of embodiments 1-37, wherein R5is chloro. 42. The method of any one of embodiments 1-37, wherein R5is methyl. 43. The method of any one of embodiments 1-37, wherein R5is ethyl. 44. The method of any one of embodiments 1-35, wherein the compound is of Formula: , or a pharmaceutically 45. The method of any one of embodiments 1-35, wherein the compound is of Formula: B) F) H) -J) 46. The method of embodiment 44 or embodiment 45, wherein R6is hydrogen. 47. The method of embodiment 44 or embodiment 45, wherein R6is OMe. 48. The method of embodiment 44 or embodiment 45, wherein R6is halogen. 49. The method of embodiment 44 or embodiment 45, wherein R6is fluoro. 50. The method of embodiment 44 or embodiment 45, wherein R6is chloro. 51. The method of embodiment 44 or embodiment 45, wherein R6is methyl. 52. The method of embodiment 44 or embodiment 45, wherein R6is ethyl. 53. The method of any one of embodiments 1-35, wherein the compound is of Formula: or a pharmaceutically 54. The method of any one of embodiments 1-35, wherein the compound is of Formula: B)

[0007] ) -H)

[0008] or a pharmaceutically acceptabl 72. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 73. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 74. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 75. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 76. The method of any one is: or a pharmaceutically 77. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 78. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 79. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 80. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 81. The method of any one is: or a pharmaceutically 82. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 83. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 84. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically 85. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically wherein: R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; and R4and R5are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen. 86. The method of embodiment 85, wherein R2is hydrogen. 87. The method of embodiment 85, wherein R2is F. 88. The method of embodiment 85, wherein R2is Cl. 89. The method of embodiment 85, wherein R2is methyl. 90. The method of embodiment 85, wherein R2is C1-C2haloalkyl. 91. The method of any one of embodiments 1-35, wherein the compound is: or a pharmaceutically wherein: R1is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; and R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen. 92. The method of any one of embodiments 85-91, wherein R1is hydrogen. 93. The method of any one of embodiments 85-91, wherein R1is F. 94. The method of any one of embodiments 85-91, wherein R1is Cl. 95. The method of any one of embodiments 85-91, wherein R1is methyl. 96. The method of any one of embodiments 85-91, wherein R1is C1-C2 haloalkyl. 97. The method of any one of embodiments 85-96, wherein R4is hydrogen. The method of any one of embodiments 85-96, wherein R4is halogen. The method of any one of embodiments 85-96, wherein R4is fluoro. . The method of any one of embodiments 85-96, wherein R4is chloro. . The method of any one of embodiments 85-96, wherein R4is C1-C2haloalkyl. . The method of any one of embodiments 85-101, wherein R5is hydrogen. . The method of any one of embodiments 85-101, wherein R5is halogen. . The method of any one of embodiments 85-101, wherein R5is fluoro. . The method of any one of embodiments 85-101, wherein R5is chloro. . The method of any one of embodiments 85-101, wherein R5is C1-C2 haloalkyl. . The method of any one of embodiments 1-106, wherein the disorder is mediated by ROCK1. . The method of any one of embodiments 1-106, wherein the disorder is mediated by ROCK2. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated kidney disease, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated bladder dysfunction, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated cancer, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated disorder selected from levodopa-induced dyskinesia and a traumatic brain injury, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated benign prostatic hyperplasia, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated diabetic retinopathy, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated disorder selected from sarcoidosis and scleroderma, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated fibrotic disorder, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated kidney disease, wherein the compound is of Formula I, Formula II, or Formula III.. Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated bladder dysfunction, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated cancer, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound 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 selected from levodopa-induced dyskinesia and a traumatic brain injury, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated benign prostatic hyperplasia, wherein the compound is of Formula I, Formula II, or Formula III. . Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated diabetic retinopathy, wherein the compound is of Formula I, Formula II, or Formula III. 123. Use of a compound 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 selected from sarcoidosis and scleroderma, wherein the compound is of Formula I, Formula II, or Formula III. 124. Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated fibrotic disorder, wherein the compound is of Formula I, Formula II, or Formula III. 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)). In contrast, 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)). The present invention provides a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt thereof to treat a specific ROCK1 and / or ROCK2 mediated disorder described herein. In certain aspects the disorder is a ROCK1 mediated disorder. In other aspects the disorder is a ROCK2 mediated disorder. In certain embodiments the compound is Compound 1 or Compound 2 or a pharmaceutically acceptable salt thereof. Specific examples of disorders that can be treated with the compounds described herein or their pharmaceutically acceptable salts are described below. 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat PKD. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat diabetic nephropathy. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat diabetic nephropathy. 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat FSGS. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat FSGS. 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat kidney failure. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat an idiopathic pulmonary fibrosis. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat an idiopathic 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat renal fibrosis. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat liver fibrosis. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat skin fibrosis. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat myocardial fibrosis. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat myocardial 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat LID. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat a TBI. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat a 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat benign prostatic hyperplasia. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat benign prostatic hyperplasia. Urinary Bladder Dysfunction (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. In certain embodiments, a compound of the present invention is used to treat neurogenic bladder, interstitial cystitis / bladder pain syndrome, cystitis / bladder inflammation, overactive bladder, bladder fibrosis or 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat a bladder dysfunction. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat a bladder dysfunction. Diabetic Retinopathy 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 Compound 1 or a pharmaceutically acceptable salt thereof is used to treat diabetic retinopathy. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat diabetic retinopathy. In other embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat diabetic macular edema (DME). In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat DME. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat DME. In additional embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat macular degeneration, for example age related macular degeneration, wet macular degeneration, or dry macular degeneration. In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat macular degeneration, for example age related macular degeneration, wet macular degeneration, or dry macular degeneration. In other embodiments, Compound 2 or a pharmaceutically acceptable salt thereof is used to treat macular degeneration, for example age related macular degeneration, wet macular degeneration, or dry macular degeneration. 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat a sarcoidosis. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat a 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat a scleroderma. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat a scleroderma. 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat a cancer. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat a cancer. 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. In certain embodiments Compound 1 or a pharmaceutically acceptable salt thereof is used to treat graft-vs- host disease. In other embodiments Compound 2 or a pharmaceutically acceptable salt thereof is used to treat graft-vs-host disease. 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)). In certain embodiments 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 disease selected from corticobasal degeneration, spinocerebellar ataxia, frontotemporal dementia and CMT2A (Charcot-Marie-Tooth disease type 2A) is provided. 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). IV. PHARMACEUTICAL COMPOSITIONS A compound of Formula I, Formula II, or Formula III or its pharmaceutically acceptable salt thereof, as described herein can be administered as the neat chemical, but is more 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 Formula I, Formula II, or Formula III, 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 described herein. 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. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with levodopa. 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. 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 a disorder described herein. 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 a disorder described herein. 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. Abbreviation Definition DCM Methylene dichloride / Dichloromethane te id

[0009] Example 1: Synthesis of N-(2-fluorobenzyl)-1-methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 1)

[0010] 6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1-3) To a solution of 6-chloro-3-iodopyridin-2-amine (1-1) (9.00 g, 35.4 mmol), 2- oxopropanoic acid (1-2) (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 1-3 (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 (1-4) To a g, was 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 1-4 (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 (1-5) To a 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 1-5 (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 (1-7) To a solution of 1-5 (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 1-6 (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 1-7 (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 (1-8) To a , 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 1-8 (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 1) To a solution of 1-8 (5.9 g, 24.4 mmol) in N,N-dimethylformamide (236 mL) was added (2-fluorophenyl)methanamine 1-9 (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 Compound 1 (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 2: Synthesis of N-(2-fluorobenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 2) 6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-3) To a solution of 6-chloro-3-iodopyridin-2-amine (2-1) (9.00 g, 35.4 mmol), 2- oxopropanoic acid (2-2) (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 (2-4) To a solution of 2-3 (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 (2-4) (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 (2-5) To a 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 (2-5) (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 (2-6) To a (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 (2-6) (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 2) 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 2) 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 3: Synthesis of N-(1-(3-methoxyphenyl)cyclopropyl)-1-methyl-6-(1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 3) To a solution of 3- 16.5 mmol) and Ti(OiPr)4 (5.17 g, 18.2 mmol) in anhydrous tetrahydrofuran (50 mL) was added ethylmagnesium bromide (2 M in THF, 18.2 mL) at -78oC. The yellow solution was stirred for ten minutes at this temperature and then was allowed to warm to room temperature slowly for an hour. To the solution was added boron trifluoride diethyl etherate (1 M in THF, 33 mL), and the reaction mixture was stirred at room temperature for an hour, which was monitored by LCMS. The reaction was quenched with aq. HCl (1 N, 60 mL) and diluted with ethyl acetate (100 mL). The resulting mixture was then basified with aq. sodium hydroxide (10%, 200 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep- HPLC to give compound 3-1 (900 mg, 33% yield) as colorless oil. ESI m / z: 164.1 [M+H]+, retention time 1.525 min, 96% @ 254 nm.1HNMR (500 MHz, DMSOd6) δ 7.18-7.15 (m, 1H), 6.92-6.91 (m, 1H), 6.81-6.79 (m, 1H), 6.70-6.68 (m, 1H), 3.74 (s, 3H), 0.95-0.91 (m, 2H), 0.90- 0.87 (m, 2H) ppm. N-(1-(3-methoxyphenyl)cyclopropyl)-1-methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 3) To a solution of 1-8 (100 mL) were added 1-(3-methoxyphenyl)cyclopropan-1-amine 3-1 (323 mg, 1.98 mmol), HATU (940 mg, 2.5 mmol) and DIPEA (639 mg, 4.95 mmol). The reaction mixture was stirred at room temperature for fifteen minutes. The reaction was then quenched with water (300 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic solution was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified directly by reserved phase flash chromatography (0-100% methanol in aq. ammonium bicarbonate (0.05%)) to give Compound 3 (180 mg, 28% yield) as a light-yellow solid. ESI m / z: 388 [M+H]+. Retention time: 1.78 min, >99.9% @ 214 & 254 nm.1H NMR (400 MHz, DMSOd6) δ 13.1 (s, 1H), 9.25 (s, 1H), 8.34-8.22 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.22-7.19 (m, 2H), 6.82-6.75 (m, 3H), 4.03 (s, 3H), 3.72 (s, 3H), 1.30 (s, 4H) ppm.

[0011] Example 4: Synthesis of N-(1-(2-fluorophenyl)cyclopropyl)-1-methyl-6-(1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 4) Methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate To a acid (4-1) (14 g, 71.214 mmol, 1.0 equiv) and K2CO3(49.21 g, 356.070 mmol, 5.0 equiv) in N,N- dimethylacetamide (150 mL) was added CH3I (21.23 g, 149.549 mmol, 2.1 equiv) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. After completion, the reaction was quenched with water at room temperature. The aqueous layer was extracted with ethyl acetate (2 x 500 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (3:1) to afford methyl 6-chloro-1-methyl-1H-pyrrolo[2,3- b]pyridine-2-carboxylate (4-2) (10.5 g, 65.6%) as a yellow solid. MS (ESI) m / z: 225 [M+H]+. Methyl 1-methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate A (4-2) (10 g, 44.516 mmol, 1.0 equiv), 1H-pyrazol-4-yl-boronic acid (7.47 g, 66.774 mmol, 1.5 equiv), Pd(PPh3)4(5.14 g, 4.452 mmol, 0.1 equiv) and K2CO3(24.61 g, 178.064 mmol, 4.0 equiv) in 1,4- dioxane (90 mL) and H2O (30 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (1:1), to afford methyl 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxylate (4-3) (4.4 g, 38.6%) as a yellow solid. MS (ESI) m / z: 257 [M+H]+. 1-Methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid A carboxylate (4-3) (4.3 g, 16.78 mmol, 1.0 equiv) and LiOH (2.01 g, 83.9 mmol, 5.0 equiv) in tetrahydrofuran (30 mL), methanol (10 mL) and H2O (10 mL) was stirred for two hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate and methanol (5:1), to afford 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (4-4) (3.5 g, 86.1%) as a white solid. MS (ESI) m / z: 243 [M+H]+. N-[1-(2-fluorophenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (Compound 4) (4-4) (3.4 g, 14.036 mmol, 1.0 equiv), DIPEA (9.07 g, 70.180 mmol, 5.0 equiv) and 1-(2- fluorophenyl)cyclopropan-1-amine (3.18 g, 21.054 mmol, 1.5 equiv) in N,N-dimethylformamide (25 mL) was stirred for ten minutes at 0 °C. To the above mixture was added HATU (8.01 g, 21.054 mmol, 1.5 equiv) in portions at 0 °C. The resulting mixture was stirred for an additional two hours at room temperature. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. 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, acetonitrile in water (0.1% FA), 10% to 50% gradient in 40 min; detector, UV 254 nm. This resulted in N-[1-(2-fluorophenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 4) (2.8914 g, 52.7%) as a dark yellow solid. MS (ESI) m / z: 376.30 [M+H]+.1H-NMR (CD3OD) δ: 8.26 (s, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.66 (td, J = 8.0, 1.6 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.32-7.21 (m, 1H), 7.17-6.96 (m, 3H), 4.02 (s, 3H), 1.31 (s, 4H) ppm.

[0012] Example 5: Synthesis of N-(1-(3-methoxyphenyl)cyclopropyl)-6-(5-methyl-1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 5) 1- To a solution and Ti(Oi-Pr)4(5.17 g, 18.2 mmol) in 50 mL of tetrahydrofuran was added ethylmagnesium bromide (2M in THF, 18.2 mL) at -78 °C. The resulting yellow solution was stirred for ten minutes. After the reaction mixture was warmed to room temperature (1 hour), BF3·Et2O (1M in THF, 33 mL) was added to. the reaction mixture, and the mixture was stirred at room temperature for one hour. To the resulting mixture, 1N HCl (60 mL) and ethyl acetate (100 mL) was added, and then NaOH (10% aq, 200 mL) was added. The reaction mixture was extracted with ethyl acetate, concentrated, and purified by prep-HPLC to afford 1-(3-methoxyphenyl) cyclopropan-1-amine (4-2) (900 mg, 33%) as colorless oil. LCMS: LC retention time 1.525 min. MS (ESI) m / z: 164.1 [M+H]+, purity: 98% at 214 nm; 96% at 254 nm.1H NMR (500 MHz, DMSOd6): δ 7.18-7.15 (m, 1H), 6.92-6.91 (m, 1H), 6.81-6.79 (m, 1H), 6.70-6.68 (m, 1H), 3.74 (s, 3H), 0.95-0.91 (m, 2H), 0.90-0.87 (m, 2H) ppm.

[0013] N-(1-(3-methoxyphenyl)cyclopropyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 5) mg, , 6-(5- methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-6) (70 mg, 0.29 mmol), EDCI (84 mg, 0.44 mmol), HOBt (54 mg, 0.44 mmol), DIPEA (187 mg, 1.5 mmol) in N,N- dimethylformamide (2 mL) was stirred at room temperature for twelve hours. LCMS showed the reaction was completed, the mixture was purified by prep-HPLC to give the target product (Compound 5) as a white solid (26 mg, 23%). LCMS: LC retention time 1.643 min. MS (ESI) m / z 388 [M+H]+. Purity: 98% (214 nm).1H NMR (500 MHz, DMSOd6) δ 12.68 (s, 1H), 11.80 (s, 1H), 9.11 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.74 (m, 2H), 3.71 (s, 3H), 2.59 (s, 3H), 1.27(s, 4H) ppm. Example 6: Synthesis of N-(2-chloro-6-(1-hydroxycyclopropyl)benzyl)-6-(5-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 6) o o y o y e y p e y cyc op opa o To a solution of in tetrahydrofuran (20 mL) was added MeMgBr (8.90 mL, 1.0 mol / L), the solution was stirred for ten minutes then cooled to 0 ℃. Then 4-chloroisobenzofuran-1(3H)-one (6-1) (1.00 g, 5.93 mmol) was added, and EtMgBr (3.36 mL, 3.0 mol / L) was added dropwise to the reaction mixture. The solution was stirred at room temperature for one hour under nitrogen. The organic phase was quenched by 10% H2SO4 (7.00 mL), partitioned between water (30.0 mL) and ethyl acetate (30.0 mL x 3), washed with saturated sodium chloride solution (30.0 mL), dried over anhydrous sodium sulfate, and filtered. After filtration, the filtrate was concentrated under the reduced pressure and the crude residue was purified by flash column chromatography to afford 1-(3-chloro-2- (hydroxymethyl)phenyl)cyclopropan-1-ol (6-2) (600 mg, 2.87 mmol, yield: 48.7%) as light oil. LCMS: LC retention time 1.49 min. MS (ESI) m / z: 181.0 [M+H-17]+, 100% at UV 254 nm.1H NMR (500 MHz, DMSO-d6) δ, 7.40-7.38 (m, 1H), 7.35-7.33 (m, 1H), 7.29-7.26 (m, 1H), 5.97 (s, 1H), 4.94-4.93 (m, 1H), 4.90-4.89 (d, J = 5 Hz, 2H), 1.01-0.98 (m, 2H), 0.93-0.91 (m, 2H) ppm.

[0014] 2-(2-Chloro-6-(1-hydroxycyclopropyl)benzyl)isoindoline-1,3-dione (6-3) To a mL) was added isoindoline-1,3- mg, g, 7.55 mmol). The solution was cooled to 0 ℃ and diisopropyl azodicarboxylate (0.763g, 0.00378 mol) was added dropwise under nitrogen. The solution was stirred at room temperature for six hours. The reaction mixture was partitioned between water (10.0 mL) and dichloromethane (10.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, and filtered. After filtration, the solvent was concentrated under the reduced pressure and the crude residue was purified by flash column chromatography to afford 2-(2-chloro- 6-(1-hydroxycyclopropyl)benzyl)isoindoline-1,3-dione (6-3) (700 mg, 76.4%) as a light oil. LCMS: LC retention time 1.80 min. MS (ESI) m / z: 327.9 [M+H]+, purity: 86.9% at UV 254 nm.1H NMR (500 MHz, DMSO) δ, 7.83 (s, 4H), 7.39-7.37 (m, 1H), 7.35-7.33 (m, 1H), 7.30-7.27 (t, J = 15.5 Hz, 1H), 5.85 (s, 1H), 5.21 (s, 2H), 1.08-1.06 (m, 2H), 0.99-0.91 (m, 2H) ppm. 1-(2-(Aminomethyl)-3-chlorophenyl)cyclopropan-1-ol (6-4) To a added hydrazine hydrate (160 mg, 3.20 mmol). The reaction mixture was stirred at 78 ℃ for four hours. The reaction mixture was partitioned between water (10.0 mL) and dichloromethane (10.0 mL x 3), washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, and filtered. After filtration, the solvent was concentrated under the reduced pressure and. the crude residue was purified by reverse phase column chromatography to give 1-(2-(aminomethyl)-3- chlorophenyl) cyclopropan-1-ol (6-4) (350 mg, 78.8%) as a pink solid. LCMS: LC retention time 1.46 min. MS (ESI) m / z: 198.0 [M+H]+,purity: 100% at UV 254 nm. N-(2-chloro-6-(1-hydroxycyclopropyl)benzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 6) (4.00 mL) was added 6-4 (5.71 mg, 0.289 mmol), EDCI (83.1 mg, 0.433 mmol), HOBt (58.6 mg, 0.433 mmol) and DIPEA (112 mg, 0.867 mmol). The reaction mixture was stirred at room temperature for six hours. The reaction mixture was partitioned between water (10.0 mL) and dichloromethane (10.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, and filtered. After filtration, the solvent was concentrated under the reduced pressure and the crude residue was purified by prep-HPLC to give N-(2-chloro- 6-(1-hydroxycyclopropyl)benzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide (Compound 6) (29.0 mg, yield: 23.8%) as a white solid. LCMS: LC retention time 1.93 min. MS (ESI) m / z 422.1 [M+H]+, purity: 98% at UV 254 nm.1H NMR (500 MHz, DMSO) δ 11.86 (s, 1H), 8.40-8.39 (m, 1H), 7.99-7.98 (m, 2H), 7.46-7.33 (m, 4H), 7.07-7.06 (d, J = 2 Hz, 1H), 6.21 (s, 1H), 4.93-4.92 (d, J = 4 Hz, 1H), 2.58 (s, 3H), 1.03-1.01 (m, 2H), 0.98-0.96 (m, 2H). Example 7: Synthesis of N-(1-(3-(1-hydroxycyclopropyl)phenyl)cyclopropyl)-1-methyl-6- (1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 7)

[0015] Tert-B A solution of 1-(3-bromophenyl)cyclopropan-1-amine (5.0 g, 23.58 mmol, 1.0 equiv), di- tert-butyl dicarbonate, and NaHCO3 (0.99 g, 11.79 mmol, 0.5 equiv) in H2O (10 mL) and methanol (40 mL) was stirred for one hour at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5:1) to afford tert-butyl N-[1- (3-bromophenyl)cyclopropyl]carbamate (7-2) (7.1 g, 96.46%) as a light yellow solid. MS (ESI) m / z: 312.2 [M+H]+. Ethyl 3-{1-[(tert-butoxycarbonyl)amino]cyclopropyl}benzoate (7-3) A solution of tert-butyl N-[1-(3-bromophenyl)cyclopropyl]carbamate (7-2) (10.0 g, 32.03 mmol, 1.0 equiv) and Pd(dppf)Cl2 (2.34 g, 3.20 mmol, 0.1 equiv) in ethanol (20 mL) was stirred for 4 hours at 100 °C under carbon monoxide atmosphere. 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 residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (6:1) to afford ethyl 3-{1-[(tert- butoxycarbonyl)amino]cyclopropyl}benzoate (7-3) (8.7 g, 88.95%) as a colorless oil. MS (ESI) m / z: 306.2 [M+H]+. Tert-Butyl N-{1-[3-(1-hydroxycyclopropyl)phenyl]cyclopropyl}carbamate (7-4) To a stirred cyclopropyl}benzoate (7- 3) (1.0 g, 3.28 mmol, 1.0 equiv) and Ti(Oi-Pr)4 (1.40 g, 4.91 mmol, 1.5 equiv) in tetrahydrofuran (50 mL) was added ethylmagnesium bromide (2.62 g, 19.65 mmol, 6.0 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for one and half hours at room temperature under nitrogen atmosphere. After completion, the reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution (3 x 15 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (9:1) to afford tert-butyl N-{1-[3-(1- hydroxycyclopropyl)phenyl]cyclopropyl}carbamate (7-4) (467 mg, 49.28%) as a yellow oil. MS (ESI) m / z: 290.3 [M+H]+. 1-(3-(1-Aminocyclopropyl)phenyl)cyclopropan-1-ol (7-5) A solution cyclopropyl}carbamate (7-4) (476 mg, 1.65 mmol, 1.0 equiv) and TFA (2.44 mL, 32.90 mmol, 20 equiv) in dichloromethane (4 mL) was stirred for 30 minutes at 0 °C. The reaction was monitored by LCMS. The resulting mixture was neutralized with NaHCO3powder at 0oC and successively concentrated under reduced pressure after filtration. The crude product (7-5) was used in the next step directly without further purification. MS (ESI) m / z: 190.2 [M+H]+. N-(1-(3-(1-hydroxycyclopropyl)phenyl)cyclopropyl)-1-methyl-6-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 7) acid (1-8) (200 mg, 0.826 mmol, 1.0 equiv), 1-[3-(1-aminocyclopropyl)phenyl]cyclopropan-1-ol (7-5) (234 mg, 1.24 mmol, 1.5 equiv), Et3N (230 μL, 1.65 mmol, 2.0 equiv) and HATU (471 mg, 1.24 mmol, 1.5 equiv) in N,N-dimethylformamide (6 mL) was stirred for two hours at room temperature. The reaction was monitored by LCMS. After completion, the reaction was quenched with water, neutralized to pH 7 with HCl (1 M. aq.) at 0oC. The resulting mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with water (2 x 30 mL), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30 * 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeOH-Preparative; Flow rate: 60 mL / min; Gradient: 40% B to 56% B in 10 min, 56% B; Wave Length: 220 / 254 nm; RT1 (min): 10.48; Number Of Runs: 0) to afford N-{1-[3-(1-hydroxycyclopropyl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 7) (24 mg, purity 97.7%, yield 9.73%) as a white solid. MS (ESI) m / z: 414.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) ^^ ^^^^^ (s, 1H), 9.23 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.23-7.16 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.01 (s, 3H), 1.33-1.22 (m, 4H), 1.09-1.04 (m, 2H), 0.92-0.86 (m, 2H) ppm. Example 8: Synthesis of N-{1-[2-(fluoromethyl)phenyl]cyclopropyl}-1-methyl-6-(1H- pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 8) N-[1-(2-bromophenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (8-1) acid (1-8) (1.0 g, 4.13 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was treated with 1-(2- bromophenyl)cyclopropan-1-amine (0.96 g, 4.54 mmol, 1.1 equiv), HOBt (558 mg, 4.13 mmol, 1.0 equiv), EDCI (791 mg, 4.13 mmol, 1.0 equiv) and DIPEA (2.16 mL, 12.38 mmol, 3.0 equiv) for two hours at room temperature. The reaction was monitored by LCMS. After completion, the reaction was quenched with water (10 mL) then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous Na2SO4, and filtered. 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, acetonitrile in water (0.1% FA), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in N-[1-(2-bromophenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (8-1) (1.14 g, 63.29%) as a light yellow powder. MS (ESI) m / z: 436.20 [M+H]+. N-[1-(2-ethenylphenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (8-2) A solution of N-[1-(2-bromophenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (8-1) (1.59 g, 3.66 mmol, 1.0 equiv), ethenyltrifluoroborate potassium (976 mg, 7.29 mmol, 2.0 equiv), Cs2CO3 (3.57 g, 10.94 mmol, 3.0 equiv) and Pd(dppf)Cl2·CH2Cl2(594 mg, 0.73 mmol, 0.2 equiv) in tetrahydrofuran (36 mL) and H2O (3.6 mL) was stirred for six hours at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. After completion, the reaction was quenched with water (100 mL) then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford N-[1-(2- ethenylphenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxamide (8-2) (480 mg, 34.35%) as a yellow solid. MS (ESI) m / z: 384.45 [M+H]+. N-[1-(2-formylphenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (8-3) 4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (8-2) (450 mg, 1.17 mmol, 1.0 equiv), OsO4 (30.5 mg, 0.12 mmol, 0.1 equiv) and NaIO4(753 mg, 3.52 mmol, 3.0 equiv) in tetrahydrofuran (2 mL) and H2O (2 mL) was stirred for 40 minutes at 0 °C. The resulting mixture was successively stirred for an additional two hours at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated Na2S2O3 (aq.) (3 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 20 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford N-[1- (2-formylphenyl)cyclopropyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (8-3) (160 mg, 35.37%) as an orange solid. MS (ESI) m / z: 386.40 [M+H]+. N-{1-[2-(hydroxymethyl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b] pyridine-2-carboxamide (8-4) A pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (8-3) (160 mg, 0.42 mmol, 1.0 equiv) and NaBH4(63 mg, 1.66 mmol, 4.0 equiv) in methanol (2 mL) was stirred for three hours at room temperature. The reaction was monitored by LCMS. After completion, the reaction was quenched by the addition of water (1 mL) at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (10:1) to afford N-{1-[2-(hydroxymethyl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b] pyridine-2-carboxamide (8-4) (116 mg, 72.12%) as a light yellow solid. MS (ESI) m / z: 388.15 [M+H]+. N-{1-[2-(fluoromethyl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 8) A pyrazol-4- yl)pyrrolo[2,3-b] pyridine-2-carboxamide (8-4) (110 mg, 0.28 mmol, 1.0 equiv) and DAST (187 µL, 1.42 mmol, 5.0 equiv) in dichloromethane (5 mL) was stirred for 30 minutes at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for an additional one hour at room temperature. The reaction was monitored by LCMS. After completion, the reaction was quenched by the addition of water (3 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 20 mL), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate 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, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 10 min, 50% B; Wave Length: 254 / 220 nm; RT1 (min): 10.78; Number Of Runs: 0) to afford N-{1-[2-(fluoromethyl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 8) (1.7 mg, purity 98.6%, yield 1.52%) as a white solid. MS (ESI) m / z: 390.20 [M+H]+.1H NMR (400 MHz, MeOH-d4) ^^ ^^^^ (s, 1H), 8.19 (s, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.82-7.78 (m, 1H), 7.46-7.41 (m, 2H), 7.38-7.29 (m, 2H), 6.91 (s, 1H), ^^^^ (d, J = 47.6 Hz, 2H), ^^^^ (s, 3H), 1.38-1.32 (m, 2H), 1.29-1.23 (m, 2H) ppm. Example 9: Synthesis of N-{1-[3-(2-fluoropropan-2-yl)phenyl]cyclopropyl}-1-methyl-6-(1H- pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 9) Tert-Butyl N-{1-[3-(2-hydroxypropan-2-yl)phenyl]cyclopropyl}carbamate (9-1) A (7-3) (2 g, 6.549 mmol, 1.0 equiv) and MeMgBr (1.51 mL, 13.098 mmol, 2.0 equiv) in tetrahydrofuran (10 mL) was stirred for four hours at 0 °C under nitrogen atmosphere. Desired product could be detected by LCMS. After completion, the reaction was quenched by the addition 20 mL of saturated NH4Cl (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous Na2SO4, and filtered. 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, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 60% gradient in 30 minutes; detector, UV 220 nm. This resulted in tert-butyl N-{1-[3-(2- hydroxypropan-2-yl)phenyl]cyclopropyl}carbamate (9-1) (1.6 g, 83.84%) as a white solid. MS (ESI) m / z: 292.2 [M+H]+. 2-[3-(1-Aminocyclopropyl)phenyl]propan-2-ol (9-2) A solution of tert-butyl N-{1-[3-(2-hydroxypropan-2-yl)phenyl]cyclopropyl}carbamate (9-1) (1.5 g, 5.15 mmol, 1.0 equiv) and ZnBr2(11.60 g, 51.50 mmol, 10 equiv) in 1,2- dichloroethane (20 mL) was stirred for one and half hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford 2-[3-(1-aminocyclopropyl)phenyl]propan-2-ol (9-2) (330 mg, 33.52%) as a light grey solid. MS (ESI) m / z: 192.1 [M+H]+. N-{1-[3-(2-hydroxypropan-2-yl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (9-3) acid (1-8) (300 mg, 1.24 mmol, 1.0 equiv) and 2-[3-(1-aminocyclopropyl)phenyl]propan-2-ol (9-2) (355 mg, 1.86 mmol, 1.5 equiv) in N,N-dimethylformamide (0.5 mL) was stirred for 3 minutes at 0 °C. To the above mixture was added HATU (942 mg, 2.48 mmol, 2.0 equiv) in portions at 0 °C. The resulting mixture was stirred for an additional one hour at room temperature. The reaction was monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 20% to 70% gradient in 30 minutes; detector, UV 220 nm. This resulted in N-{1-[3- (2-hydroxypropan-2-yl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3- b]pyridine-2-carboxamide (9-3) (46 mg, 8.94%) as a light yellow solid. MS (ESI) m / z: 416.2 [M+H]+. N-{1-[3-(2-fluoropropan-2-yl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 9) 6-(1H- pyrazol-4-yl)pyrrolo [2,3-b]pyridine-2-carboxamide (9-3) (46 mg, 0.11 mmol, 1.0 equiv) and DAST (29 µL, 0.22 mmol, 2.0 equiv) in dichloromethane (0.5 mL) was stirred for 2 minutes at -78 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated NaHCO3 (aq.) (1.0 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 * 150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 36% B to 55% B in 9 minutes, 55% B; Wave Length: 254 / 220 nm; RT1 (min): 9.53; Number Of Runs: 0) to afford N-{1-[3-(2-fluoropropan-2-yl)phenyl]cyclopropyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 9) (23.2 mg, 46.73%) as a white solid. MS (ESI) m / z: 418.25 [M+H]+.1H NMR (400 MHz, MeOH-d4) ^ ^ ^^^^-^^^^ (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.30-7.26 (m, 1H), 7.24-7.20 (m, 2H), 7.07 (s, 1H), 4.07 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H), 1.40-1.32 (m, 4H) ppm. Example 10: Synthesis of N-{[2-(fluoromethyl)phenyl]methyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 10)

[0016] N-{[2-(hydroxymethyl)phenyl]methyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine- 2-carboxamide (10-1) (1-8) (150 mg, 0.619 mmol, 1.0 equiv), [2-(aminomethyl)phenyl]methanol (127 mg, 0.928 mmol, 1.5 equiv) in N,N-dimethylformamide (4 mL) was treated with DIPEA (400 mg, 3.095 mmol, 5.0 equiv) for 10 minutes at 0oC under nitrogen atmosphere followed by the addition of HATU (471 mg, 1.238 mmol, 2.0 equiv) in portions at 0oC. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. After completion, the reaction was quenched with water (15 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride solution (20 mL) and dried over anhydrous Na2SO4and filtered. 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, acetonitrile in water (0.1% TFA), 3% to 50% gradient in 30 minutes; detector, UV 254 nm, 220 nm. This resulted in N-{[2- (hydroxymethyl)phenyl]methyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (10-1) (110.0 mg, 49.1%) as a white solid. MS (ESI) m / z: 362.1 [M+H]+. N-{[2-(fluoromethyl)phenyl]methyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 10) 4-yl)pyrrolo[2,3-b]pyridine- 2-carboxamide (10-1) (210 mg, 0.581 mmol, 1.0 equiv) in dichloromethane (14 mL) was added DAST (280.9 mg, 1.743 mmol, 3.0 equiv) dropwise at -78oC under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. After completion, the reaction was quenched with NaHCO3 (aq. sat.) at room temperature. The precipitated solids were collected by filtration and washed with H2O (2 x 30 mL).The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30 * 150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: Acetonitrile; Flow rate: 50 mL / min; Gradient: 4% B to 15% B in 8 minutes, 15% B; Wave Length: 254 / 220 nm; RT1 (min): 7.17; Number Of Runs: 0) to afford N-{[2-(fluoromethyl)phenyl]methyl}-1-methyl-6-(1H- pyrazol-4-yl)pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 10) (40.7 mg, 18.5%) as a white solid. MS (ESI) m / z: 364.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 13.04 (s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.14 (s, (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.47- 7.37 (m, 3H), 7.36-7.28 (m, 1H), 7.16 (s, 1H), 5.64 (d, J = 47.6 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 4.05 (s, 3H) ppm. Example 11: Synthesis of N-[(2-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)-2H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 11) Methyl 6-[3-(trifluoromethyl)-2H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (11-2) A solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (11-1) (1.2 g, 5.697 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-2H- pyrazole (2.24 g, 8.546 mmol, 1.5 equiv), K2CO3 (1.57 g, 11.394 mmol, 2.0 equiv), XPhos Pd G3 (482.2 mg, 0.570 mmol, 0.1 equiv) and XPhos (271.6 mg, 0.570 mmol, 0.1 equiv) in dioxane (75 mL) and H2O (15 mL) was stirred for four hours at 100oC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 100 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (5:1) to afford methyl 6-[3- (trifluoromethyl)-2H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (11-2) (1.1 g, 62.2%) as a yellow solid. MS (ESI) m / z: 311.1 [M+H]+. 6-[3-(Trifluoromethyl)-2H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (11-3) A - - b]pyridine- 2-carboxylate (11-2) (1.2 g, 3.548 mmol, 1.0 equiv) and LiOH·H2O (811.5 mg, 19.340 mmol, 5.0 equiv) in tetrahydrofuran (27 mL), methanol (9 mL), and H2O (9 mL) was stirred for three hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL) and acidified to pH 5 with HCl (aq.). The precipitated solids were collected by filtration and washed with diethyl ether (3 x 50 mL). This resulted in 6-[3-(trifluoromethyl)-2H-pyrazol-4-yl]-1H- pyrrolo[2,3-b]pyridine-2-carboxylic acid (11-3) (720.0 mg, crude) as a white solid. MS (ESI) m / z: 297.2 [M+H]+N-[(2-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)-2H-pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 11) A solution of 6-[3-(trifluoromethyl)-2H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2- carboxylic acid (11-3) (300 mg, 1.013 mmol, 1.0 equiv), HOBt (205.2 mg, 1.519 mmol, 1.5 equiv), DIEA (529.2 µL, 3.039 mmol, 3.0 equiv) and 1-(2-fluorophenyl)methanamine (190.1 mg, 1.519 mmol, 1.5 equiv) in N,N-dimethylformamide (10 mL) was stirred for three hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 100 mL), dried over anhydrous Na2SO4and filtered. After filtration, the filtrate was concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30 * 150 mm, 5 µm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 30% B to 48 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.73) to afford N-[(2-fluorophenyl)methyl]-6-[3-(trifluoromethyl)-2H-pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 11) (58.0 mg, 14.0%) as a white solid. MS (ESI) m / z: 403.95 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 13.77 (s, 1H), 12.03(s, 1H), 8.99 (t, J = 5.8 Hz, 1H), 8.49–8.34 (m, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.51–7.28 (m, 3H), 7.28–7.10 (m, 3H), 4.57 (d, J = 5.7 Hz, 2H) ppm.19F NMR (282 MHz, DMSO-d6) d -58.32 (s), -118.83 (s) ppm. Example 12: Synthesis of N-{[2-(difluoromethyl)phenyl]methyl}-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 12) 8) (325.0 mg, 1.342 mmol, 1.0 equiv), 1-[2-(difluoromethyl)phenyl]methanamine (253.03 mg, 1.610 mmol, 1.2 equiv), EDCI (385.79 mg, 2.013 mmol, 1.5 equiv), HOBt (271.94 mg, 2.013 mmol, 1.5 equiv) and DIPEA (701.10 µL, 4.026 mmol, 3.0 equiv) in N,N-dimethylformamide (10 mL) was stirred for three hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (70 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 100 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The crude product (300.0 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30 * 150 mm, 5 µm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / minute; Gradient: isocratic 28% B to 48% B in 10 minutes; Wave Length: 254 nm / 220 nm; RT1(min): 11.4) to afford N-{[2- (difluoromethyl)phenyl]methyl}-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (Compound 12) (59.7 mg, 11.4%) as a white solid. MS (ESI) m / z: 382.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.13 (t, J = 6.0 Hz, 1H), 8.27 (s, 2H), 8.06 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.58–7.48 (m, 3H), 7.47–7.40 (m, 1H), 7.37 (t, J = 54.8 Hz, 1H), 7.18 (s, 1H), 4.65 (d, J = 5.9 Hz, 2H), 4.06 (s, 3H) ppm.19F NMR (376 MHz, DMSO- d6) δ -74.88 (s), - 111.20 (s) ppm. Example 13: Synthesis of 1-Methyl-6-(1H-pyrazol-4-yl)-N-{[3- (trifluoromethyl)phenyl]methyl}pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 13) (400 mg, 1.651 mmol, 1.0 equiv), EDCI (475 mg, 2.477 mmol, 1.5 equiv) , HOBt (335 mg, 2.477 mmol, 1.5 equiv) in N,N-dimethylformamide (16 mL) was treated with DIPEA (320 mg, 2.477 mmol, 1.5 equiv) for 3 minutes at room temperature under nitrogen atmosphere followed by the addition of 1-[3-(trifluoromethyl)phenyl]methanamine (434 mg, 2.477 mmol, 1.5 equiv) dropwise at room temperature. The resulting mixture was stirred for two hours at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution (3 x 20 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The crude product (250 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 * 150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.1%NH3·H2O), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / minute; Gradient: 32% B to 50% B in 10 minutes; Wave Length: 254 nm / 220 nm; RT1 (min): 1) to afford 1-methyl-6-(1H-pyrazol-4-yl)-N-{[3- (trifluoromethyl)phenyl]methyl}pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 13) (63.4 mg, 9.49%) as a white solid, MS (ESI) m / z: 400.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.20 (t, J = 6.1 Hz, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.73–7.56 (m, 4H), 7.53 (d, J = 8.2 Hz, 1H), 7.16 (s, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.06 (s, 3H) ppm.19F NMR (282 MHZ, DMSO-d6) δ -61.03 (s) ppm. Example 14: Synthesis of 1-Methyl-6-(1H-pyrazol-4-yl)-N-{[2- (trifluoromethyl)phenyl]methyl}pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 14) (1-8) (414 mg, 1.71 mmol, 1.0 equiv), HATU (651 mg, 1.71 mmol, 1.0 equiv) and DIPEA (897 µL, 5.14 mmol, 3.0 equiv) in N,N-dimethylformamide (5 mL) was stirred for 10 minutes at room temperature followed by the addition of 1-[2-(trifluoromethyl)phenyl]methanamine (300 mg, 1.71 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for an additional two hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4,and filtered. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 * 150 mm, 5 µm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.1% NH3·H2O), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / minute; Gradient: 23% B to 36% B in 10 minutes; Wave Length: 254 nm / 220 nm; RT1(min): 3) to afford 1-methyl-6-(1H-pyrazol-4-yl)-N-{[2-(trifluoromethyl)phenyl]methyl}pyrrolo[2,3- b]pyridine-2-carboxamide (59.2 mg, 8.60%) (Compound 14) as a white solid. MS (ESI) m / z: 400.20 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ: 8.33-8.11 (m, 2H), 8.00 (d, J = 10.8 Hz, 1H), 7.80-7.70 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.42 (m, 2H), 7.09 (s, 1H), 4.80 (s, 2H), 4.12 (s, 3H) ppm.19F NMR (376 MHz, Methanol-d4) δ -61.57 (s) ppm.

[0017] Example 15: Synthesis of N-(2,6-dimethoxybenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 1, see generally WO 2011 / 050245) (4 mL) was added (2,6-dimethoxyphenyl)methanamine (48.3 mg, 0.289 mmol), N-(3- (dimethylamino)propyl) propionamide dihydrochloride (83.1 mg, 0.433 mmol), 1- hydroxybenzotriazole (58.6 mg, 0.433 mmol) and N,N-diisopropylethylamine (112 mg, 0.867 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between water (10.0 mL) and dichloromethane (10.0 mL three times). The organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by prep- HPLC to give N-(2,6-dimethoxybenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Comparator 1) (30.0 mg, 26%) as a white solid. LCMS: LC retention time 1.55 min. MS (ESI) m / z: 391.9 [M+H]+, purity: 98.85 % at 214 nm.1H NMR (500 MHz, DMSO) δ 12.63 (s, 1H), 11.08 (s, 1H), 8.02-8.00 (m, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 9 Hz, 1H), 7.32-7.28 (m, 1H), 7.06 (s, 1H), 6.72 (d, J = 8 Hz, 2H), 4.48 (s, 2H), 3.83 (s, 6H), 2.88(s, 3H) ppm.

[0018] Example 16: Synthesis of N-(2-fluoro-6-methoxybenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 2, see generally WO 2011 / 050245) mL), (2- fluoro-6-methoxyphenyl)methanamine (53.8 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 18 hours. Then water (6 mL) was added to the reaction mixture. And the reaction mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL), then dried with sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified with prep-HPLC to give N-(2-fluoro-6- methoxybenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 2) (28.8 mg, 26.4% ) as a white solid. LCMS: ESI (M+H)+379.9, retention time 1.56 min, purity 98.7 % at 254 nm.1H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 11.81 (s, 1H), 8.39 (t, J =5.0 Hz, 1H), 8.16–7.89 (m, 2H), 7.45–7.23 (m, 2H), 7.08 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.84 (t, J = 8.5 Hz, 1H), 4.51 (d, J = 5.0 Hz, 2H), 3.86 (s, 3H), 2.59 (s, 3H).

[0019] Example 17: Synthesis of N-(2-chloro-6-(oxetan-3-yloxy)benzyl)-6-(5-methyl-1H-pyrazol-4- yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 3, see generally WO 2011 / 050245) 2- To a solution of (10 mL) was added NaH (0.62g, 0.0258 mol). The reaction mixture was stirred at room temperature for 1 hour. Then 2-chloro-6-fluorobenzonitrile (17-1) (2 g, 0.0129 mol) was added to the reaction. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was extracted with dichloromethane (50 mL x 3) and washed with water (50 mL), the organic layers were concentrated and purified by flash column chromatography (ethyl acetate in petroleum ether 0-10%) to afford 2-chloro-6-(oxetan-3-yloxy) benzonitrile (17-2) (1.2 g, 44%). LCMS: LC retention time 1.58 min. MS (ESI) m / z 209.9 [M+H]+. (2-Chloro-6-(oxetan-3-yloxy)phenyl)methanamine (17-3) The reaction mixture of 2-chloro-6-(oxetan-3-yloxy)benzonitrile (17-2) (1.2 g, 5.7 mmol), NH3·H2O (2 mL) and Raney Ni (0.03 g, 0.57 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 16 hours under H2. The reaction mixture was filtered and concentrated in vacuo, then purified by flash column chromatography (ethyl acetate in petroleum ether 0-60%) to afford (2-chloro-6-(oxetan-3-yloxy)phenyl)methanamine (17-3) (0.28 g, 23%). LCMS: LC retention time 1.33 min. MS (ESI) m / z: 213.9 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 7.19- 7.16 (m, 1H), 7.05 (d, J = 8 Hz, 1H), 6.59 (d, J = 8 Hz, 1H), 5.33-5.29 (m, 1H), 4.94-4.91(m, 2H), 4.59-4.57 (m, 2H), 3.83 (s, 2H) ppm. N-(2-chloro-6-(oxetan-3-yloxy)benzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Comparator 3) To a (0.07 g, 0.33 mmol) in N,N-dimethylformamide (2 mL) was added 2-6 (0.07 g, 0.29 mmol), 1- hydroxybenzotriazole (0.058 g, 0.435 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.435 mmol) and N,N-diisopropylethylamine (0.012 g, 0.87 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was extracted with dichloromethane (20 mL x 3) and washed with water (20 mL). The organic layers were combined, concentrated and then purified by prep-HPLC to afford N-(2-chloro-6-(oxetan-3-yloxy)benzyl)-6- (5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 3) (0.0258 g, 18%) as a white solid. LCMS: LC retention time 1.54 min. MS (ESI) m / z: 437.8 [M+H]+, purity:100% (254 nm)1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.97 (d, J=6Hz, 1H), 7.39(d, J = 8 Hz, 1H), 7.30-7.28 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 6.68 (d, J = 8 Hz, 1H), 5.36-5.34 (m, 1H), 4.90-4.88(m 2H), 4.69 (s, 2H), 4.60-4.57(m, 2H), 2.58 (s, 3H). Example 18: Synthesis of 6-(5-Methyl-1H-pyrazol-4-yl)-N-(2-(oxetan-3-yloxy)benzyl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 4, see generally WO 2011 / 050245) The reaction mixture of 2-chloro-6-(oxetan-3-yloxy)benzonitrile (18-1) (1.2 g, 5.7 mmol), NH3·H2O (2 mL) and Raney Ni (0.03 g, 0.57 mmol) in tetrahydrofuran (50mL) was stirred at room temperature for 16 hours under H2. The reaction mixture was filtered and concentrated in vacuo, then purified by flash chromatography (ethyl acetate in petroleum ether 0-60%) to afford (2-(oxetan-3-yloxy)phenyl)methanamine (18-2) (0.18 g, 15%). LCMS:LC retention time 0.55 min. MS (ESI) m / z: 180.1 [M+H]+, purity: 100% (254 nm)1H NMR (500 MHz, DMSO-d6) δ 7.37(d, J = 6.5 Hz, 1H), 7.14 (m, 1H), 6.94 (m, 1H), 6.54 (d, J =8 Hz, 1H), 5.28-5.26 (m, 1H), 4.94-4.91(m, 2H), 4.57-4.54(m, 2H), 3.72(s, 2H). 6-(5-Methyl-1H-pyrazol-4-yl)-N-(2-(oxetan-3-yloxy)benzyl)-1H-pyrrolo[2,3-b]pyridine-2- carboxamide (Comparator 4) To a 0.33 mmol) in N,N-dimethylformamide (2 mL) was added 6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxylic acid (2-6) (0.07g, 0.29 mmol), 1-hydroxybenzotriazole (0.058 g, 0.435 mmol), 1-ethyl-3-(3 -dimethylaminopropyl)carbodiimide hydrochloride (0.067g, 0.435 mmol) and N,N-diisopropyl ethylamine (0.012g, 0.87 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was extracted with dichloromethane (20 mL x 3) and washed with water (20 mL), concentrated and purified by prep-HPLC to afford 6-(5-methyl-1H- pyrazol-4-yl)-N-(2-(oxetan-3-yloxy)benzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 4) (38.7 mg, 31.5%) as a white solid. LCMS: LC retention time 1.52 min. MS (ESI) m / z: 403.9 [M+H]+,purity:100% (254 nm).1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.78 (s, 1H), 8.03 (d, J = 8 Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 7.29 (d, J = 1.2Hz, 1H), 7.14 (d, J = 1.2Hz, 1H), 6.96 (s, 1H), 6.63 (d, J = 7.6 Hz, 1H), 5.35-5.34 (m, 1H), 4.95 (m, 2H), 4.62-4.59 (m, 2H), 4.55 (d, J = 6 Hz, 2H), 2.60 (s, 3H).

[0020] Example 19: Synthesis of N-(4-cyano-5-ethoxy-2-fluorobenzyl)-6-(5-methyl-1H-pyrazol-4- yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 5, see generally WO 2011 / 050245) A mixture of 4-bromo-2,5-difluorobenzonitrile (19-1) (4.36 g, 20 mmol), K2CO3(8.3 g, 60 mmol), EtOH (9.4 g, 200 mmol) in N,N-dimethylformamide (70 mL) was stirred at 80oC for 16 hours. LCMS showed the reaction was completed; the mixture was filtered and concentrated. The mixture was extracted with ethyl acetate (100 mL x 3) and washed with water (120 mL). The organic layers were combined, dried on Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified to give 19-2 as a yellow solid (3.9 g, 80%). LCMS: LC retention time 1.861 min. MS (ESI) m / z: 244[M+H]+. Purity: 80% (214 nm). Methyl 4-cyano-5-ethoxy-2-fluorobenzoate(19-3) A mixture of 4-bromo-2-ethoxy-5-fluorobenzonitrile (19-2) (1 g, 4.1 mmol), Pd(OAc)2 (50 mg, catalyst), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, catalyst), Et3N (4.1 g, 41 mmol) in methanol (20 mL) was stirred at 80oC for 48 hours under carbon monoxide gas. LCMS showed the reaction was completed, then the mixture was concentrated and diluted with H2O (60 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and washed with water (60 mL), followed by drying on Na2SO4, and filtered. The filtrate was concentrated; the residue was purified by SGC to give 19-3 as a yellow solid (0.73 g, 80%). LCMS: LC retention time 1.761 min. MS (ESI) m / z: 224 [M+H]+. Purity: 100% (214 nm). 2-Ethoxy-5-fluoro-4-(hydroxymethyl)benzonitrile (19-4) To a mixture of methyl 4-cyano-5-ethoxy-2-fluorobenzoate (19-3) (730 mg, 3.3 mmol) in methanol (20 mL) was added NaBH4 (371 mg, 9.9 mmol) at 0oC. After addition, the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was completed, the mixture was concentrated the residue was purified by SGC to give 19-4 as a yellow solid (0.60 g, 94%). LCMS: LC retention time 1.58 min. MS (ESI) m / z: 196 [M+H]+. Purity: 95% (214 nm). 2-Ethoxy-5-fluoro-4-(hydroxymethyl)benzonitrile (19-5) To a 4) (600 mg, 3.1 mmol), isoindoline-1,3-dione (456 mg, 3.1 mmol), PPh3 (975 mg, 3.72 mmol) in tetrahydrofuran (20 mL) was added DIAD (750 mg, 3.72 mmol) at 0oC under argon atmosphere. After addition, the mixture was stirred at room temperature for 12 hours. LCMS showed the reaction was completed; the mixture was diluted with ethyl acetate (80 mL) and washed with water (50 mL). The organic layers were combined, dried on Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by SGC to give 19-5 as a yellow solid (0.8 g, 80%). LCMS: LC retention time 1.842 min. MS (ESI) m / z: 325 [M+H]+. Purity: 75% (214 nm). 4-(Aminomethyl)-2-ethoxy-5-fluorobenzonitrile (19-6) A - (19-5) (0.8 g, 2.46 mmol), N2H4.H2O (200 mg, 5 mmol) in ethanol (12 mL) was stirred at 70oC for 3 hours. LCMS showed the reaction was completed, the mixture was concentrated, and the residue was purified by prep-HPLC to give 19-6 as a white solid (300 mg, 63%). LCMS: LC retention time 1.04 min. MS (ESI) m / z: 195 [M+H]+. Purity: 95% (214 nm). N-(4-cyano-5-ethoxy-2-fluorobenzyl)-6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Comparator 5) A 0.29 mmol), 6-(5-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-6) (70 mg, 0.29 mmol), EDCI (84 mg, 0.44 mmol), HOBt (54 mg, 0.44 mmol), DIPEA (187 mg, 1.5 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 12 hours. LCMS showed the reaction was completed; the reaction was extracted with dichloromethane (20mL x 3) and washed with water (20mL), concentrated, and purified by prep-HPLC to give Comparator 5 as a white solid (33 mg, 27%). LCMS: LC retention time 1.523 min. MS (ESI) m / z: 419 [M+H]+. Purity: 100% (214 nm).1H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.90 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 4.58 (d, J = 5.5 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 2.59 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H) ppm. Example 20: Synthesis of N-(3-methoxybenzyl)-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (Comparator 6, see WO 2011 / 050245) 6-chloro-N-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (20-1) mmol, 1 equiv) in N,N-dimethylformamide (9 mL) was treated with HATU (2.90 g, 7.630 mmol, 1.5 equiv) for half an hour at room temperature followed by the addition of 1-(3- methoxyphenyl)methanamine (1.05 g, 7.630 mmol, 1.5 equiv) and triethylamine (1.03 g, 10.174 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (0-10%) to give the crude product. The crude was purified by trituration with H2O (10 mL) to afford 6-chloro-N-[(3-methoxyphenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (20-1) (420 mg, 26.15%) as a yellow solid. LC-MS (ESI, m / z): 316 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.12 (t, J = 6.0 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.94–6.89 (m, 2H), 6.83 (dd, J = 9.0, 2.4 Hz, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.74 (s, 3H).

[0021] N-(3-methoxybenzyl)-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 6) b]pyridine-2-carboxamide (20-1) (400 mg, 1.267 mmol, 1 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (737.42 mg, 3.801 mmol, 3 equiv) in N,N-dimethylformamide / H2O (4 mL / 0.8 mL) were added Pd(PPh3)4(146.39 mg, 0.127 mmol, 0.1 equiv) and K2CO3(350.15 mg, 2.534 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (0-10%) to give the crude product. The crude was purified by trituration with methanol (10 mL) to afford N- [(3-methoxyphenyl)methyl]-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Comparator 6) (186.2 mg, 42.14%) as a white solid which was contaminated with about 2% methanol residue. LC-MS (ESI, m / z): 348 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 11.94 (s, 1H), 8.92 (t, J = 6.0 Hz, , 8.06 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.95–6.89 (m, 2H), 6.85–6.79 (m, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3.74 (s, 3H).

[0022] Example 21: Synthesis of N-(3,4-difluorobenzyl)-6-(1H-pyrazol-4-yl)-1H-indole-3- carboxamide (Comparator 7, see WO 2011 / 050245) 6-bromo-N-(3,4-difluorobenzyl)-1H-indole-3-carboxamide (21-1) A solution of 6-bromo-1H-indole-3-carboxylic acid (1 g, 4.166 mmol, 1 equiv) in N,N- dimethylformamide (9 mL) was treated with HATU (2.38 g, 6.249 mmol, 1.5 equiv) for 30 minutes at room temperature followed by the addition of 1-(3,4-difluorophenyl)methanamine (0.89 g, 6.249 mmol, 1.5 equiv) and triethylamine (1.26 g, 12.498 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for 1 hour at room temperature. The reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (0-10%) to give crude product. The crude was further purified by trituration with H2O (10 mL) to afford 6-bromo-N- [(3,4-difluorophenyl)methyl]-1H-indole-3-carboxamide (400 mg, 26.29%) as a yellow solid. LC-MS (ESI, m / z): 365, 367 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.11–8.06 (m, 2H), 7.64 (s, 1H), 7.50–7.31 (m, 2H), 7.24 (dd, J = 8.6, 1.8 Hz, 1H), 7.22–7.15 (m, 1H), 4.45 (d, J = 6.0 Hz, 2H). N-(3,4-difluorobenzyl)-6-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide (Comparator 7) - 3- carboxamide (370 mg, 1.013 mmol, 1 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (589.81 mg, 3.039 mmol, 3 equiv) in N,N-dimethylformamide / H2O (4 mL / 0.8 mL) was added Pd(PPh3)4 (117.08 mg, 0.101 mmol, 0.1 equiv) and K2CO3 (280.06 mg, 2.026 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (0-10%) to give crude product. The crude was further purified by trituration with methanol (10 mL) to afford N-[(3,4- difluorophenyl)methyl]-6-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide (236.4 mg, 65.42%) as a white solid. LC-MS (ESI, m / z): 353 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 11.52 (d, J = 3.0 Hz, 1H), 8.48 (t, J = 6.1 Hz, 1H), 8.23–7.85 (m, 4H), 7.60 (d, J = 1.5 Hz, 1H), 7.46–7.33 (m, 3H), 7.26–7.13 (m, 1H), 4.46 (d, J = 6.0 Hz, 2H).

[0023] Example 22: Synthesis of 6-(1H-pyrazol-4-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3- b]pyridine-3-carboxamide (Comparator 8, see WO 2011 / 050245) 6-chloro-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (22-1) A solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (1 g, 5.087 mmol, 1 equiv) in N,N-dimethylformamide (10 mL) was treated with HATU (2.90 g, 7.630 mmol, 1.5 equiv) for 30 minutes at room temperature followed by the addition of 4-pyridinemethaneamine (0.83 g, 7.630 mmol, 1.5 equiv) and triethylamine (1.03 g, 10.174 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for one hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (0-10%) to give crude product. The crude was purified by trituration with water (15 mL) to afford 6-chloro-N-(pyridin-4-ylmethyl)- 1H-pyrrolo[2,3-b]pyridine-3-carboxamide (22-1) (430 mg, 29.48%) as a yellow solid. LC-MS (ESI, m / z): 287 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.75 (t, J = 6.1 Hz, 1H), 8.54–8.49 (m, 2H), 8.46 (d, J = 8.2 Hz, 1H), 8.25 (s, 1H), 7.33 (d, J = 5.0 Hz, 2H), 7.26 (d, J = 8.2 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H). 6-(1H-pyrazol-4-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Comparator 8) 3- carboxamide (400 mg, 1.395 mmol, 1 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (812.11 mg, 4.185 mmol, 3 equiv) in N,N-dimethylformamide / H2O (4 mL / 0.8 mL) were added K2CO3 (385.62 mg, 2.790 mmol, 2 equiv) and Pd(PPh3)4 (161.22 mg, 0.140 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (10%-30%) to give crude product. The crude was further purified by trituration with acetonitrile (10 mL) to afford 6-(1H-pyrazol-4-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (220.0 mg, 49.54%) as a white solid. LC-MS (ESI, m / z): 319 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 12.06 (d, J = 2.9 Hz, 1H), 8.65 (t, J = 6.0 Hz, 1H), 8.56–8.47 (m, 2H), 8.47–8.00 (m, 4H), 7.54 (d, J = 8.3 Hz, 1H), 7.40–7.27 (m, 2H), 4.51 (d, J = 5.9 Hz, 2H).

[0024] Example 23: Exemplary Compounds of the Present Invention Table 1A Cmpd # Structure Cmpd # Structure Table 1B Comparators: Cmpd # Structure Example 24: 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%. An IC50value less than 50.8 pM or higher than 1 μM is estimated based on the best curve fitting available. The resulting data for the tested compounds is shown in Table 2A and Table 2B below. The data for Compound 1 and Compound 2 in Table 2B is the geometric mean of the IC50 data from multiple enzyme inhibition experiments. Each experiment was run in the same lab with this procedure. Table 2A – IC50 Values of Representative Compounds of the Present Invention Compound ROCK1 ROCK2 ) Compound ROCK1 ROCK2 ) Table 2B – IC50 Values of Representative Compounds of the Present Invention Compound ROCK1 ROCK2 PRKX PKA ) Compound ROCK1 ROCK2 PRKX PKA ) Example 25: MDCK-MDR1 Efflux Assay Experimental Procedure 1: MDCK-MDR1 cells grown in tissue culture flasks were trypsinized, suspended in medium, and the suspensions were applied to wells of a Millipore 96 well plate. The cells were allowed to grow and differentiate for five days, feeding at 2-day intervals. For Apical to Basolateral (A→B) permeability, the test article was added to the apical (A) side and amount of permeation was determined on the basolateral (B) side; for Basolateral to Apical (B→A) permeability, the test article was added to the B side and the amount of permeation was determined on the A side. The A-side buffer contained 100 µM lucifer yellow dye, in Transport Buffer (1.98 g / L glucose in 10 mM HEPES, 1x Hank’s Balanced Salt Solution) pH 7.4, and the B-side buffer was Transport Buffer at pH 7.4. MDCK-MDR1 cells were incubated with test articles in these buffers for 2 hours, and at the end of the assay, donor and receiver side solution samples were collected, quenched by 100 % methanol containing an internal standard and centrifuged at 5000 rpm for 10 minutes at 4 ºC. Following centrifugation, the supernatant for donor and receiver side samples were analyzed by LC-MS / MS. Data Analysis: Data was expressed as permeability (Papp): Papp = (dQ / dt) / (C0A) where dQ / dt is rate of permeation, C0 is initial concentration of test article, and A is the area of monolayer. In bidirectional permeability studies, the Efflux Ratio (Re) was calculated: Re = [Papp(B→A)] / [Papp(A→B)] Re> 2 indicates a potential substrate for P-gp efflux transporters. Detailed data are shown in Table 3A. Table 3A – Efflux Ratios of Representative Compounds Compound Efflux Ratio MDCK-MDR1 Experimental Procedure 2: 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% CO2for one hour before cell seeding. Afterwards, MDCKII-MDR1 cells were diluted to 1.56х106cells / 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 3B. Table 3B – Efflux Ratios of Representative Compounds Compound Efflux Ratio MDCK-MDR1 Example 26: hERG Kd Compounds were dissolved in DMSO to a stock concentration of 10 mM and tested in 10- dose IC50 mode, in triplicate, with a 3-fold serial dilution starting at 100 µM. Control compound E-4031 was tested in 10-dose IC50mode with 3-fold serial dilution starting at 1 µM. The assay is based on the competition of fluorescently labeled Tracer binding to the membrane preparation containing 1X Predictor™ hERG Membrane with 1 nM Predictor™ hERG Tracer Red in a buffer with the composition of 25 mM Hepes, pH 7.5, 15 mM KCl, 1 mM MgCl2, 0.05% PF-127, and 1% DMSO. Compounds in DMSO were added into the membrane mixture by using sonication, the tracer was added and gently mixed in the dark. The fluorescence was measured after 4 hours incubation at room temperature. The measurement parameters are as follows: Ex = 531 nm FP and Em = 595 nm P and S. Curve fits were performed by GraphPad Prism software when the activities at the highest concentration of compounds were less than 65%. The background was established by the average FP signal in the presence of 10 µM E-4031. The data is provided in Table 4 below. Table 4 – hERG Activity Compound hERG Kd (nM) Compound 1 >100,000 Example 27 : Mouse, Human and Rat Liver Microsomes The master solution was prepared according to Table 5 and using the correct species’ microsomes. Table 5 – Preparation of master solution Stock Reagent Volume Final Concentration L 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): 0.693∗ (volume of incubation (µL) ^^^^ ^^^^^^^^^^ CLint= t1 / 2 amount of proteins (mg) ) below. Table 6 – Mouse, Rat, and Human Live Microsome Data Compound Mouse Liver Rat Liver Human Liver Microsomes Microsomes Microsomes Compound Mouse Liver Rat Liver Human Liver Microsomes Microsomes Microsomes 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 Table 7 – Kinetic Solubility of Representative Compounds Compound Kinetic Solubility PBS pH 7.4 (µM) Example The following method evaluated the pharmacokinetics of repeat-dosing of compound at 20 mg / kg via oral administration in B6SJLF1 / J mice over 24 hours. Table 8 – Animal Specifications Species: Mouse Weight Range: 20-25 g Source: The Jackson Laboratory T Atmti mnii l wtr rti lt nd hr l filtrd or y- ed by the manufacturer for concentrations of specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The bedding was analyzed by the manufacturer for acceptable levels of heavy metals, aflatoxins, bacteria, yeasts, molds, and organophosphates prior to certification. No contaminants were known to be present in the feed, water, or bedding at levels that might have interfered with achieving the objectives of the study. Table 10 – Study Design No. of Route of Dose Volume Conc. Group Sex Test Article 1 1 1 1 3 3 7 12 M PO 100 10 10 Compound 3 8 12 F PO 10 10 1 Compound 3 Route Dose Volume Conc. Grou of Vehicle Test Article 1 1 1 1 3 3 3 3 o t be drawn into a syringe. The dose volume was doubled to compensate for the lowered concentration. Full dosing was completed in two parts with an approximate 1–2-minute rest between. e s a m n s ra ons: Groups 2, 3, 4, 6, and 8: Test article was dissolved in a minimal amount of DMSO (Groups 2, 4, 6, 8: 40-50 µL, Group 3: 100 µL), 0.5% methylcellulose was added to final volume, then solution was sonicated for 2 minutes. Group 7: Test article was dissolved in 100 µL DMSO, saline was added to final volume, then solution was sonicated for 2 minutes. IV administrations: Group 1 and 5: Test article was dissolved in NMP (N-methylpyrrolidone) corresponding to a final concentration of 5% NMP, Solutol HS-15 was added corresponding to a final concentration of 5% Solutol HS-15, PEG-400 was added corresponding to a final concentration of 30% PEG-400, then solution was diluted to final volume with saline. Dose Administration Groups 1, 5: The test article was administered as a single dose via slow bolus intravenous administration into a lateral tail vein, with a 27G needle. Groups 2, 4, 6, 7, 8: The test article was administered as a single dose directly to the stomach by oral gavage. Group 3: The test article was administered as a single dose in two parts with an approximate 1–2-minute rest between due to volume administered. Sampling Blood and cerebrospinal fluid (CSF) samples were collected as shown in Table 12. Table 12 – Sample Collection Sample timepoints (h) Group Sample Collected Animal # en , . ma was spun and separated within 30 minutes of collection and stored frozen at -20 °C until shipment. Prior to the terminal blood collection, CSF was collected. The animal was fully anesthetized with a cocktail of ketamine / xylazine, and CSF was collected by gaining access to the cisterna magna by cutting through the skin at the back of the neck and skull, separation of the muscles at the back of the neck and insertion of a pulled beveled glass microneedle. The glass microneedle was attached via polyethylene tubing to a syringe positioned in a foot pedal actuated syringe pump. The syringe provided a controlled vacuum for removal of CSF. Approximately 5- 12 µL of CSF was collected from the anesthetized mouse prior to cardiac stick for the plasma sample. The resulting data is shown in Tables 13, 14, 15, 16 and 17 below. Table 13 – Mouse Pharmacokinetics Summary for Compound 1 Tmax T1 / 2 Tlast Cm AUC0-t / D G# R t S ax AUC0-t AUC0-∞ (h* / L) ) Tmax T1 / 2 Tlast Cmax AUC0- AUC0-t / D G# Route Sex t AUC0-∞ (h) (h) (h) (ng / mL) (h*ng / mL) (h*ng / mL) (h*ng / mL) ) Ratio to 10 mg / kg Dose Level G# R t S Cmax AUC0-t AUC0-∞ ) Table 15 – Mouse armaco netcs Summary or Compound 3 A G# Route Sex T T T C x AUC0-t A UC0-t / D max 1 / 2 last ma UC0-∞ * * Vd (h*ng / mL) ) Table 16 – Mouse Pharmacokinetics Summary for Compound 3 Continued Ratio to 10 mg / kg Dose Level G# Route Sex Cmax AUC0-t AUC0-∞ ) Example 30: Seve The following method evaluated the pharmacokinetics of repeat-dosing of Compound 1 at 20 mg / kg via oral administration in B6SJLF1 / J mice over 7 days. Parameters evaluated included mortality, cage-side observations, physical examinations, and body weights over a 7-day period. Blood and cerebrospinal fluid (CSF) samples were collected at identified timepoints and plasma and CSF samples were submitted to KCAS Bioanalytical Service for analysis. Table 17 – Animal Specifications Species: Mouse 24 hours prior to the first dose. During that time, animals were identified by an indelible marker according to Xyzagen’s procedure that was recorded and used throughout the study. Before the start of the in-life phase, each animal was physically examined and weighed prior to test article administration. Table 18 – Husbandry Information Feed: Envigo Rodent #2016 Diet (Pellets) Automatic municipal water, particulate and charcoal filtered or Water: water bottles (as needed) y- zed y p y , , ated hydrocarbons, and organophosphates. The bedding was analyzed by the manufacturer for acceptable levels of heavy metals, aflatoxins, bacteria, yeasts, molds, and organophosphates prior to certification. No contaminants were known to be present in the feed, water, or bedding at levels that might have interfered with achieving the objectives of the study. Table 19 – Study Design Route Vol. Conc. No. of Dosing Dose e 1 1 Dose Formulations and Administration On day of dosing, Compound 1 was dissolved in a minimum of DMSO (50 μL per 3.0 mg of Compound 1), then mixed with vehicle, 0.5% (w / v) methyl cellulose in water. The resulting formulation was vortexed and sonicated for 3-5 minutes to ensure homogeneity. The daily formulations were also vortexed throughout the day’s dosing procedure. Table 20 – Formulations Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Drug Soln. Required of es were based on the most recently recorded body weight. Sampling Blood and CSF samples were collected as outlined below in the following tables. Table 21 – Animals Sampled for Each Time Point Sample Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day7 5 5 Table 22 – Sample Timepoints – Groups 2 and 3 Day Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 t- e Day Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 t- e re- dose timepoints 100-150 µl, then the maximal volume by cardiac stick was collected for the final timepoint post-dose. Blood was collected in K2EDTA tubes and kept on wet ice until processing. The blood was be spun and plasma separated within 30 minutes of collection. Prior to the terminal blood collection for groups 1 and 2 (animals 31-35), CSF was collected. The animal was fully anesthetized with a cocktail of ketamine / xylazine, and CSF was collected by gaining access to the cisterna magna by cutting through the skin at the back of the neck and skull, separation of the muscles at the back of the neck and insertion of a pulled beveled glass microneedle. The glass microneedle was attached via polyethylene tubing to a syringe positioned in a foot pedal actuated syringe pump. The syringe provided a controlled vacuum for removal of CSF. Approximately 5-12 µL of CSF was collected from the anesthetized mouse prior to cardiac stick for the plasma sample. Plasma and CSF samples were stored at -20 °C. In the study of 20 mg / kg, PO, QD no animals died or had adverse events. There was no accumulation and average CSF levels were 183 ng / ml and 105 ng / ml one hour after dosing at day 1 and day 7, respectively. Plasma dosing was found to be below the detection limit in 24 hours. Example 31: 24 Hour Rat Pharmacokinetic Summary Following similar techniques to those described in Example 30 a pharmacokinetic (PK) study was conducted on 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 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. The solutions were prepared at a concentration of 1.5 mg / mL for intravenous administration and 1 mg / mL for oral administration. Blood samples were taken at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours. The resulting data is provided in the following tables. Table 23 – Rat Pharmacokinetics Summary for Compound 1 TmaxT1 / 2AUC0-t / D G# Route Sex TlastCmaxAUC0-tAUC0-∞* * Vss (h*ng / mL) ) T0maxT1 / 2T AUC-t / D G# R t SlastCmaxAUC0-tAUC0-∞V h* L) ) Table 25 – Rat Pharmacokinetics Summary for Compound 3 Tmax T1 / 2 Tlast Cmax AUC AUC- AUC0-t / D G# Route Sex 0-t 0 ∞ (h) (h) (h) (ng / mL) (h*ng / mL) (h*ng / mL) Vss (h*ng / mL) k) y p T AUC0-t max / D G# Route Sex T1 / 2TlastCmaxAUC0-tAUC0-∞(h) (h) (h) (n / mL) (h*n / mL) (h*n / mL) Vss (h*ng / mL) ) Table 27 – Rat Pharmacokinetics Summary for Compound 10 G# Route Sex T1 / 2 Cmax AUC0-∞ (h) (n / mL) (h*n / mL) Vss 9 Table 28 – Rat Pharmacokinetics Summary for Comparator 6 TmaxT1 / 2TlastCmaxAUC0-tAUC0-∞AUC0-t / D * L) ) G# Route Sex T T T st Cmax A AUC0-t / D max 1 / 2 la UC0-t AUC0-∞ (h) (h) (h) (ng / mL) (h*ng / mL) (h*ng / mL) Vss (h*ng / mL) / (m / k ) T AUC0-t m / D G# Route SexaxT1 / 2TlastCmaxAUC0-tAUC0-∞(h) (h) (h) (ng / mL) (h*ng / mL) (h*ng / mL) Vss (h*ng / mL) ) Table 30 – Rat Pharmacokinetics Summary for Comparator 8 T T T C AUC AUC - AUC0-t max 1 / 2 last max 0 / D G# Route Sex -t 0 ∞ * * Vss (h*ng / mL) ) 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 method of treating a ROCK1 or ROCK2 mediated kidney disease comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

2. The method of claim 1, wherein the kidney disease is polycystic kidney disease.

3. The method of claim 1, wherein the kidney disease is diabetic nephropathy.

4. The method of claim 1, wherein the kidney disease is glomerulosclerosis.

5. The method of claim 1, wherein the kidney disease is focal segmental glomerulosclerosis.

6. The method of claim 1, wherein the kidney disease is kidney failure.

7. A method of treating a ROCK1 or ROCK2 mediated bladder dysfunction comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

8. The method of claim 7, wherein the bladder dysfunction is interstitial cystitis.

9. The method of claim 7, wherein the bladder dysfunction is bladder inflammation.

10. The method of claim 7, wherein the bladder dysfunction is overactive bladder.

11. The method of claim 7, wherein the bladder dysfunction is bladder fibrosis.

12. The method of claim 7, wherein the bladder dysfunction is neurogenic bladder.

13. The method of claim 7, wherein the bladder dysfunction is a lower urinary tract symptom.

14. A method of treating a ROCK1 or ROCK2 mediated cancer comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen; R6is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, C1-C4 alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

15. The method of claim 14, wherein the cancer is breast cancer.

16. The method of claim 14, wherein the cancer is prostate cancer.

17. The method of claim 14, wherein the cancer is melanoma.

18. The method of claim 14, wherein the cancer is a desmoplastic disorder.

19. A method of treating a ROCK1 or ROCK2 mediated disorder selected from levodopa-induced dyskinesia and a traumatic brain injury, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen; R6is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, C1-C4 alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

20. The method of claim 19, wherein the disorder is levodopa-induced dyskinesia.

21. The method of claim 19, wherein the disorder is a traumatic brain injury.

22. The method of claim 21, wherein the traumatic brain injury is a mild traumatic brain injury.

23. The method of claim 21, wherein the traumatic brain injury is a moderate traumatic brain injury.

24. The method of claim 21, wherein the traumatic brain injury is a severe traumatic brain injury.

25. A method of treating a ROCK1 or ROCK2 mediated benign prostatic hyperplasia comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen; R3is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, C1-C4 alkyl-OR7, and OR7; andR7is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl.

26. A method of treating a ROCK1 or ROCK2 mediated diabetic retinopathy comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

27. The method of claim 26, wherein the diabetic retinopathy is a proliferative diabetic retinopathy.

28. The method of claim 26, wherein the diabetic retinopathy is a non-proliferative diabetic retinopathy.

29. A method of treating a ROCK1 or ROCK2 mediated disorder selected from sarcoidosis and scleroderma comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

30. The method of claim 29, wherein the disorder is pulmonary sarcoidosis or neurosarcoidosis.

31. A method of treating a ROCK1 or ROCK2 mediated fibrotic disorder comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a human subject in need thereof, wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, C1-C4 alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl.

32. The method of claim 31, wherein the fibrotic disorder is a fibrotic disorder of the lung.

33. The method of claim 31, wherein the fibrotic disorder is a fibrotic disorder of the kidney.

34. The method of claim 31, wherein the fibrotic disorder is a fibrotic disorder of the skin.

35. The method of claim 31, wherein the fibrotic disorder is a fibrotic disorder of the liver.

36. The method of any one of claims 1-35, wherein the compound is of Formula: ; or a pharmaceutically37. The method of any one is of Formula: B) F)38. The method of any one of claims 1-37, wherein R5is hydrogen.

39. The method of any one of claims 1-37, wherein R5is halogen.

40. The method of any one of claims 1-37, wherein R5is fluoro.

41. The method of any one of claims 1-37, wherein R5is chloro.

42. The method of any one of claims 1-37, wherein R5is methyl.

43. The method of any one of claims 1-37, wherein R5is ethyl.

44. The method of any one of claims 1-35, wherein the compound is of Formula: , or a pharmaceutically45. The method of any one is of Formula: B) F)46. The method of claim 44 or claim 45, wherein R6is hydrogen.

47. The method of claim 44 or claim 45, wherein R6is OMe.

48. The method of claim 44 or claim 45, wherein R6is halogen.

49. The method of claim 44 or claim 45, wherein R6is fluoro.

50. The method of claim 44 or claim 45, wherein R6is chloro.

51. The method of claim 44 or claim 45, wherein R6is methyl.

52. The method of claim 44 or claim 45, wherein R6is ethyl.

53. The method of any one of claims 1-35, wherein the compound is of Formula: or a pharmaceutically54. The method of any one of Formula: H)55. The method of claim 53 or claim 54, wherein R7is methyl.

56. The method of claim 53 or claim 54, wherein R7is hydrogen.

57. The method of any one of claims 1-56, wherein R1is hydrogen.

58. The method of any one of claims 1-56, wherein R1is halogen.

59. The method of any one of claims 1-56, wherein R1is methyl.

60. The method of any one of claims 1-59, wherein R2is hydrogen.

61. The method of any one of claims 1-59, wherein R2is halogen.

62. The method of any one of claims 1-59, wherein R2is methyl.

63. The method of any one of claims 1-59, wherein R2is C1-C2haloalkyl.

64. The method of any one of claims 1-63, wherein R3is hydrogen.

65. The method of any one of claims 1-63, wherein R3is methyl.

66. The method of any one of claims 1-65, wherein R4is hydrogen.

67. The method of any one of claims 1-65, wherein R4is halogen.

68. The method of any one of claims 1-65, wherein R4is fluoro.

69. The method of any one of claims 1-65, wherein R4is chloro.

70. The method of any one of claims 1-65, wherein R4is C1-C2haloalkyl.

71. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically72. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically73. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically74. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically75. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically76. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically77. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically78. The method of any one is: or a pharmaceutically79. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically80. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically81. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically82. The method of any one of claims 1-35, wherein the compound is:or a pharmaceutically acceptable salt thereof.

83. The method of any one of claims 1-35, wherein the compound is: or a pharmaceutically84. The method of any one is: or a pharmaceutically85. The method of any one of claims 1-35, wherein the compound is: or a pharmaceuticallywherein: R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; and R4and R5are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, and halogen.

86. The method of claim 85, wherein R2is hydrogen.

87. The method of claim 85, wherein R2is F.

88. The method of claim 85, wherein R2is Cl.

89. The method of claim 85, wherein R2is methyl.

90. The method of claim 85, wherein R2is C1-C2 haloalkyl.

91. The method of any one of claims 1-35, wherein the compound is: or a pharmaceuticallywherein: R1is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; and R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen.

92. The method of any one of claims 85-91, wherein R1is hydrogen.

93. The method of any one of claims 85-91, wherein R1is F.

94. The method of any one of claims 85-91, wherein R1is Cl.

95. The method of any one of claims 85-91, wherein R1is methyl.

96. The method of any one of claims 85-91, wherein R1is C1-C2 haloalkyl.

97. The method of any one of claims 85-96, wherein R4is hydrogen.

98. The method of any one of claims 85-96, wherein R4is halogen.

99. The method of any one of claims 85-96, wherein R4is fluoro.

100. The method of any one of claims 85-96, wherein R4is chloro.

101. The method of any one of claims 85-96, wherein R4is C1-C2haloalkyl.

102. The method of any one of claims 85-101, wherein R5is hydrogen.

103. The method of any one of claims 85-101, wherein R5is halogen.

104. The method of any one of claims 85-101, wherein R5is fluoro.

105. The method of any one of claims 85-101, wherein R5is chloro.

106. The method of any one of claims 85-101, wherein R5is C1-C2 haloalkyl.

107. The method of any one of claims 1-106, wherein the disorder is mediated by ROCK1.

108. The method of any one of claims 1-106, wherein the disorder is mediated by ROCK2.

109. Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated kidney disease, bladder dysfunction, cancer, levodopa-induced dyskinesia, traumatic brain injury, benign prostatichyperplasia, diabetic retinopathy, sarcoidosis, scleroderma, or fibrotic disorder wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

110. Use of a compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated kidney disease, bladder dysfunction, cancer, levodopa-induced dyskinesia,traumatic brain injury, benign prostatic hyperplasia, diabetic retinopathy, sarcoidosis, scleroderma, or fibrotic disorder wherein the compound is of Formula: wherein:R1and R2are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R3is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; R4and R5are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; R6is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, halogen, C1-C4alkyl-OR7, and OR7; and R7is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

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