New rock inhibitors

Abstract

This invention provides rho-associated protein kinase (ROCK) inhibiting compounds for therapeutic applications as described further herein.

Description

[0001] NEW ROCK INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application 63 / 667,625, filed July 3, 2024, and U.S. Provisional Application 63 / 682,249 filed August 12, 2024. The entirety of these applications are hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides rho-associated protein kinase (ROCK) inhibiting compounds for therapeutic applications as described further herein. BACKGROUND ROCK (Rho-associated protein kinase) is a kinase belonging to the AGC (cAMP- dependent protein kinase (PKA) / protein kinase G (PKG) / protein kinase C (PKC)) family of serine- threonine kinases and is activated by the GTP-bound form of RhoA. Two isoforms of mammalian Rho kinase, ROCK1 and ROCK2, have been described. They are approximately 160-kDa in weight proteins consisting of 1354 and 1388 amino acids, respectively, and contain an N- terminally located kinase domain, followed by a coiled-coil region containing the Rho-binding domain (RBD), a Pleckstrin homology domain (PH), and a cysteine-rich region at the C-terminus. The RBD binds exclusively to GTP-bound active RhoA and RhoC. The two ROCK isoforms share approximately 60% overall amino acid identity and approximately 90% identity within the N- terminal kinase domain. The carboxyl-terminal region comprises two cysteine-rich zinc finger- like motif domains and a split pleckstrin homology domain, which plays a role in the stabilization of the membrane binding of ROCK. (See, S. Hartmann, A. J. Ridley, and S. Lutz. “The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease” Frontiers in Pharmacology, November 2015, Vol. 6, Art. 276; J. C. Koch, L. Tatenhorst, A.-E. Roser, K.-A. Saal, L. Tönges, P. Lingor. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation” Pharmacology & Therapeutics 189 (2018) 1–21; Y. Feng, P. V. LoGrasso, O. Defert, and R. Li. “Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential” J. Med. Chem.2016, 59, 2269−2300). In its native form, ROCK is enzymatically inactive. This is caused by an auto-inhibition of the ROCK kinase domain by the carboxyl-terminal region of ROCK. The best-characterized upstream activators of ROCK are Rho-GTPase proteins RhoA and RhoC. In the activated GTP- bound state, they interact with the Rho-binding domain of ROCK and induce conformational changes that disrupt the autoinhibitory function of the carboxyl-terminal region. (J. C. Koch, L. Tatenhorst, A.-E. Roser, K.-A. Saal, L. Tönges, P. Lingor. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation” Pharmacology & Therapeutics 189 (2018) 1–21). There are a large number of downstream targets that are phosphorylated by ROCK. Activation of ROCK leads to the phosphorylation of several central regulator proteins resulting in diverse cellular responses like autophagy, cell survival and apoptosis, vesicle dynamics, cytoskeleton regulation, cell growth and regeneration, as well as cell shape and motility. In response to activators of Rho, which stimulate Rho-guanine nucleotide exchange factor (GEF) and lead to the formation of active GTP-bound Rho, ROCKs mediate a broad range of cellular responses that involve the actin cytoskeleton. For example, they control assembly of the actin cytoskeleton and cell contractility by phosphorylating a variety of proteins, such as myosin light chain (MLC) phosphatase, LIM-kinases, adducin and Ezrin / Radixin / Moesin (ERM) proteins. ROCK2 can alter the sensitivity of smooth muscle cell contraction to Ca2+, since MLCK is Ca2+sensitive. ROCKs are important regulators of cellular growth, migration, metabolism and apoptosis, through control of the actin cytoskeletal assembly and cell contraction. ROCK1 expression tends to be more ubiquitous (ROCK1 messenger RNA and protein are highly expressed in the lung, liver, spleen, kidney, and testis), while ROCK2 is most highly expressed in cardiac and brain tissues. ROCKs regulate cell polarity and migration, predominantly through enhancing actomyosin contraction and focal adhesions. Increased ROCK activity is observed in tumor metastasis and overexpression of constitutively activated ROCK promotes tumor invasion. (Y. Rikitake et al. “ROCKs as therapeutic targets in cardiovascular diseases” Expert. Rev. Cardiovasc. Ther., 2005 May; 3(3): 441–451. doi:10.1586 / 14779072.3.3.441; A. V. Schofield and O. Bernard, “Rho-associated coiled-coil kinase (ROCK) signaling and disease” Crit. Rev. Biochem. Mol. Biol. 2013 Jul-Aug; 48(4): 301-16). Pharmacologic inhibitors of ROCKs, such as Y-27632, Fasudil (HA1077) and hydroxyfasudil, which target their ATP-dependent kinase domains, can inhibit both ROCK1 and ROCK2. ROCK inhibitors have been investigated for the treatment of a variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration and osteoporosis. To date, three ROCK inhibitors are approved for clinical use: Fasudil for the treatment of cerebral vasospasm, Ripasudil for the treatment of glaucoma and Belumosudil for the treatment of graft versus host disease. Fasudil (an isoquinoline derivative) was shown to effectively inhibit ROCK and other kinases like PKA, PKG, PKC, and MLCK (J. C. Koch et al. “Compassionate use of the ROCK inhibitor Fasudil in three patients with amyotrophic lateral sclerosis” Front. Neurol. March 2020, Volume 11, Article 173). Fasudil has been the subject of multiple clinical trials for the treatment of amyotrophic lateral sclerosis (ALS) (Wolff, Andreas W., et al. “SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.” CNS drugs 38.4 (2024): 291-302; Lingor, Paul, et al. “ROCK-ALS: protocol for a randomized, placebo-controlled, double-blind phase IIa trial of safety, tolerability and efficacy of the rho kinase (ROCK) inhibitor fasudil in amyotrophic lateral sclerosis.” Frontiers in neurology 10 (2019): 293). Several synthetic ROCK inhibitors identified by researchers at Scripps Research Institute based on indole, 5-azaindole, and 7-azaindole heterocyclic systems have been described in literature (S. Chowdhury et al. “Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)” Bioorg. Med. Chem. Lett.21 (2011) 7107–7112; E. H. Sessions et al. “Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (Part-II)” Bioorg. Med. Chem. Lett. 21 (2011) 7113–7118.) Synthesis and inhibitory activity of some benzothiazole derivatives against ROCK have also been previously disclosed (Y. Yin et al. “Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors” Bioorg. Med. Chem. Lett. 19 (2009) 6686–6690.). Additional ROCK inhibitors are described in WO 2011 / 050245 which was filed by researchers at Scripps Research Institute. The ROCK inhibitory activity of these indole, azaindole and benzothiazole compounds varies significantly depending on substituents attached to the heterocyclic ring. Avicenna Biosciences, Inc. describes ROCK inhibitors and their uses in WO 2024 / 145569. Additional patent applications describing ROCK inhibitors and their uses include WO 2024 / 110851, WO 2024 / 023276, WO 2023 / 209692, WO 2023 / 139379, WO 2023 / 110700, WO 2022 / 020381, WO 2022 / 150676, WO 2022 / 042712, WO 2022 / 012409, WO 2021 / 214200, WO 2021 / 095945, WO 2020 / 177292, WO 2020 / 094111, WO 2019 / 000683, WO 2019 / 000682, WO 2018 / 130178, WO 2018 / 108156, WO 2014 / 177699, WO 2013 / 112722, WO 2011 / 050245, WO 2010 / 065907, WO 2010 / 065907, WO 2010 / 032875, WO 2009 / 155209, WO 2007 / 026920, and WO 2006 / 088088. Despite these efforts, there remains a need for new ROCK inhibiting compounds to treat disorders mediated by ROCK1 and / or ROCK2 in a subject in need thereof for example a human. SUMMARY OF THE INVENTION Compounds of the present invention and their pharmaceutically acceptable salts, uses, and manufacture are provided that inhibit a rho-associated protein kinase (ROCK). These compounds exhibit advantageous ADME properties (absorption, distribution, metabolism, and / or excretion). For example, when administered to Sprague-Dawley rats (Example 71) all twelve of the tested ROCK inhibitors of the present invention had bioavailability values (%F) of greater than 20% (see Table 10). It has also been surprisingly discovered that these compounds also have activity against protein kinase X (PRKX, see Example 67, Table 2). Both ROCK and PRKX activity drive neurodegeneration in amyotrophic lateral sclerosis (ALS). Therefore by inhibiting both enzymes certain compounds of the present invention are expected to exert advantageous therapeutic efficacy against this disease in humans. An effective amount of a compound of the present invention provided herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable composition can be used to treat a disorder that is mediated by ROCK1 and / or ROCK2. In some embodiments, a method to treat a subject with a disorder mediated by ROCK1 and / or ROCK2 is provided that includes administering an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, to the subject, typically a human, optionally in a pharmaceutically acceptable composition. In certain embodiments the disorder is mediated by ROCK1. In additional embodiments the disorder is mediated by ROCK2. In other embodiments the disorder is mediated by PRKX. In certain embodiments, the disorder is mediated by ROCK1 and PRKX. In certain aspects a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII is provided: or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; in certain embodiments R1and R2are each hydrogen; in certain embodiments R2is CH3; in other embodiments R1is hydrogen and R2is methyl; R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; in certain embodiments R3is H or CH3; R4is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C(O)NR12R13, and halogen; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R6is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R8is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, and OR7; R7is independently selected at each instance from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; in certain embodiments R7is CH3; in certain embodiments R7is CHF2; R9is C1-C6alkyl, C1-C6haloalkyl, or a heterocycle; in certain embodiments R9is CH3; in certain embodiments R9is cyclopropyl; R12and R13are independently selected at each instance from the group consisting of hydrogen and C1-C6alkyl; m is 0 or 1; and A is CH or N. 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 a compound of the present invention is used to treat a ROCK1 or ROCK2 mediated disorder in the central nervous system (CNS). In other aspects a compound of the present invention is used to treat a peripheral disorder that is mediated by ROCK1 or ROCK2. In certain aspects the compound of Formula I is of Formula: or a pharmaceutically acceptable salt thereof. In other aspects the compound of Formula I is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula II is of Formula:

[0002] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula III is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula IV is of Formula:

[0003] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula V is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VI is of Formula:

[0004] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VII is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VIIII is of Formula:

[0005] or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the present invention has sufficient properties to penetrate the blood brain barrier. Achieving blood brain barrier penetration is difficult. The blood brain period is a specially adapted layer of endothelial cells which guard the central nervous system (CNS) against pathogens, toxins, and xenobiotic compounds. The cells of the blood brain barrier form junctions between them which restrict passive diffusion. Even if a compound can diffuse through the cell membrane into the cytosol of the endothelial cells themselves the compound faces an array of transporter proteins ready to pump it back out into the blood stream. To reach the CNS, a compound must diffuse through the cell membrane, avoid being pumped out by transport proteins, and then diffuse across the cell membrane into the CNS. Adequate levels of blood brain barrier penetration are important for the treatment of neurodegenerative disorders. For example, blood brain barrier penetration is required to treat amyotrophic lateral sclerosis because this disease primarily affects nerve cells in the brain. In other embodiments a compound of the present invention is used to treat stroke, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, or levodopa-induced dyskinesia (LID). In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, for example, a human, optionally in a pharmaceutically acceptable composition. For example, in certain embodiments, an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a human to treat a neurodegenerative disorder, for example amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), or Parkinson’s disease (PD). In other embodiments, an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a human to treat a kidney disorder, for example diabetic nephropathy, or polycystic kidney disease. In certain embodiments, an effective amount of a compound of the present invention is used to treat ALS. For example, in certain embodiments, an effective amount of a compound of the present invention is used to treat bulbar, respiratory, flail arm, classical, pyramidal, or flail leg ALS. In certain embodiments, an effective amount of a compound of the present invention is used to treat Parkinson’s disease. For example, in certain embodiments, an effective amount of a compound of the present invention is used to treat motor-cognitive, cognitive dominant or motor dominant Parkinson’s disease. In certain embodiments, a compound of the present invention is used to treat levodopa-induced dyskinesia (LID). For example, in certain embodiments, a compound of the present invention is used to treat peak-dose dyskinesia, wearing-off / off-period dyskinesia, or diphasic dyskinesia of LID. In other embodiments, an effective amount of a compound of the present invention is used to treat a disorder selected from cerebral vasospasm, pulmonary hypertension, acute lung injury exfoliation syndrome, ocular hypertension, glaucoma (for example exfoliative glaucoma), levodopa-induced dyskinesia, Huntington's disease, traumatic brain injuries, polycystic kidney disease, renal fibrosis, renal failure, diabetic nephropathy (kidney disease), benign prostatic hyperplasia, urinary bladder dysfunction, motor neuron disease, diabetic retinopathy, sarcoidosis, scleroderma, focal segmental glomerulosclerosis, or cancers. Alternatively, an effective amount of a compound of the present invention can be used to treat an edema (for example pulmonary edema), inflammatory bowel disease, or inflammation. In certain embodiments, the selected compound of the present invention 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 the present invention or a pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. For example, in certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof has one or more deuterium substitutions at a site of metabolism. In other embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof has one or more deuterium substitutions next to the site of metabolism. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A compound of the present invention as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A method to treat a ROCK1 and / or ROCK2 mediated disorder, such as a neurodegenerative disorder, including for example ALS or Parkinson’s disease, comprising administering an effective amount of a compound of the present invention or pharmaceutically acceptable salt thereof, to a subject in need thereof; (c) The method of (b) wherein the ROCK1 and / or ROCK2 mediated disorder is a kidney disease, including for example diabetic nephropathy or polycystic kidney disease; (d) The method of (b) wherein the ROCK1 and / or ROCK2 mediated disorder is levodopa-induced dyskinesia; (e) The method of (b) wherein the ROCK1 and / or ROCK2 mediated disorder is a fibrotic disorder, including for example a fibrotic disorder of the lung, kidney, liver or skin; (f) A compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by ROCK1 and / or ROCK2, for example a neurodegenerative disorder, including for example ALS or Parkinson’s disease; (g) The compound of (f) wherein the ROCK1 and / or ROCK2 mediated disorder is a kidney disease, including for example diabetic nephropathy or polycystic kidney disease; (h) The compound of (f) wherein the ROCK1 and / or ROCK2 mediated disorder is levodopa-induced dyskinesia; (i) The compound of (f) wherein the ROCK1 and / or ROCK2 mediated disorder is a fibrotic disorder, including for example a fibrotic disorder of the lung, kidney, liver or skin; (j) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a subject in need thereof, typically a human, with a ROCK1 and / or ROCK2 mediated disorder, for example a neurodegenerative disorder, including for example ALS or Parkinson’s disease; (k) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a ROCK1 and / or ROCK2 mediated disorder, for example a neurodegenerative disorder, including for example ALS or Parkinson’s disease; (l) The use of (j) or (k) wherein the ROCK1 and / or ROCK2 mediated disorder is a kidney disease, including for example diabetic nephropathy or polycystic kidney disease; (m) The use of (j) or (k) wherein the ROCK1 and / or ROCK2 mediated disorder is levodopa-induced dyskinesia; (n) The use of (j) or (k) wherein the ROCK1 and / or ROCK2 mediated disorder is a fibrotic disorder, including for example a fibrotic disorder of the lung, kidney, liver or skin; (o) A pharmaceutical composition comprising an effective subject-treating amount of a compound of the present invention, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. The present invention includes a compound 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 the present invention, 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, CHD CH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3etc.). 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, C1-C4, C1-C5, or C1-C6alkyl and where the alkyl is cyclic, it may be, for example a C3-C6moiety. 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-C4alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms or a cyclic alkyl group having 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-C6alkyl, C1-C5alkyl, 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. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. 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-C6cycloalkyl, C3-C5cycloalkyl, C3-C4cycloalkyl, C4-C6cycloalkyl, or C5-C6cycloalkyl. In certain embodiments “cycloalkyl” has three carbons. In certain embodiments “cycloalkyl” has four carbons. In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons. Non-limiting examples of “alkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. “Halo” and “Halogen” refers independently to fluorine, chlorine, bromine or iodine. “Haloalkyl” is a straight, branched or cyclic alkyl group 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-C6haloalkyl, C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl, or C1-C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” is perhaloalkyl. Non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: , , , Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include , The term “cyano” denotes a -C≡N group. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group. In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. For example, is an “aryl” group. However, is a “heterocycle” group. In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring. For example, is an “aryl” group. However, is a “cycloalkyl” group. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro- 1H-1λ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole-2(3H)- onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl, and dihydrothiazolyl. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused / condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. For example, is a “heterocycle” group. However, is an “aryl” group. The term “heteroaryl” denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3- triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl]; unsaturated 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl. The term “bicycle” refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Bicyclic ring systems also include spiro-fused bicyclic ring systems. Non-limiting examples of bicycle groups include: 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 THE PRESENT INVENTION In certain aspects, the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII or a pharmaceutically acceptable salt thereof:

[0006] or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; in certain embodiments R1and R2are each hydrogen; in certain embodiments R2is CH3; R3is selected from the group consisting of hydrogen, C1-C4alkyl, and C1-C6haloalkyl; in certain embodiments R3is H or CH3; R4is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C(O)NR12R13, and halogen; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R6is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R8is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, and OR7; R7is independently selected at each instance from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; R9is C1-C6alkyl or C1-C6haloalkyl; R12and R13are independently selected at each instance from the group consisting of hydrogen and C1-C6alkyl; m is 0 or 1; and A is CH or N. Formula I In certain embodiments the compound of Formula I is selected from:

[0007] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula I is selected from: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula I is of Formula: or a parmaceu ca y accepa e sa ereo. In certain aspects the compound of Formula I is of Formula:

[0008] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula I is selected from:

[0009] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula I is selected from:

[0010] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is selected from:

[0011] or a pharmaceutically acceptable salt thereof. Non-limiting examples of the compound of Formula I include:

[0012] or a pharmaceutically acceptable salt thereof. Additional non-limiting examples of the compound of Formula I include: or a pharmaceutically acceptable salt thereof. Formula II In certain embodiments the compound of Formula II is selected from:

[0013] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula II is selected from: or a parmaceu ca y accepa e sa ereo.

[0014] In certain aspects the compound of Formula II is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula II is of Formula:

[0015] or or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula II is selected from:

[0016] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula II is selected from:

[0017] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is selected from: and ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is selected from: and ; or a pharmaceutically acceptable salt thereof. Non-limiting examples of the compound of Formula II include:

[0018] or a pharmaceutically acceptable salt thereof. Formula III In certain embodiments the compound of Formula III is selected from:

[0019] and ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula III is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula III is of Formula:

[0020] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula III is selected from:

[0021] o r a parmaceutca y accepta e sat tereo. In certain embodiments the compound of Formula III is selected from: and ; or a pharmaceutically acceptable salt thereof. Non-limiting examples of the compound of Formula III include: or a pharmaceutically acceptable salt thereof.

[0022] Formula IV In certain embodiments the compound of Formula IV is selected from:

[0023] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula IV is selected from or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula IV is of Formula: or ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula IV is of Formula:

[0024] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula IV is selected from:

[0025] and ; or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula IV is selected from:

[0026] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula IV is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula IV is selected from or a pharmaceutically acceptable salt thereof. Non-limiting examples of the compound of Formula IV include:

[0027] o a pa aceu ca y accepa e sa eeo. Formula V In certain embodiments the compound of Formula V is selected from: and or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula V is of Formula:

[0028] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula V is of Formula:

[0029] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula V is selected from:

[0030] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula V is selected from:

[0031] or a pharmaceutically acceptable salt thereof. Non-limiting examples of the compound of Formula V include: or a pharmaceutically acceptable salt thereof. Additional non-limiting examples of the compound of the present invention include:

[0032] or a pharmaceutically acceptable salt thereof. Formula VI In certain embodiments the compound of Formula VI is selected from:

[0033] and or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VI is of Formula:

[0034] or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VI is of Formula:

[0035] or or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula VI is selected from:

[0036] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula VI is selected from:

[0037] and or a pharmaceutically acceptable salt thereof. Formula VII In certain embodiments the compound of Formula VII is selected from:

[0038] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VII is of Formula: or ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VII is of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula VII is selected from:

[0039] and ; or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula VII is selected from:

[0040] and ; or a pharmaceutically acceptable salt thereof. Non-limiting examples of the compound of Formula VII include: and ; or a pharmaceutically acceptable salt thereof. Formula VIII In certain embodiments the compound of Formula VIII is selected from:

[0041] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VIII is of Formula: or ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of Formula VIII is of Formula: or ; or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula VIII is selected from: ; or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula VIII is selected from:

[0042] or a pharmaceutically acceptable salt thereof. Additional Formulas of the Present Invention In certain aspects, the present invention provides a compound of Formula:

[0043] or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; in certain embodiments R1and R2are each hydrogen; in certain embodiments R2is CH3; R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; in certain embodiments R3is H or CH3; R4is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C(O)NR12R13, and halogen; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R6is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R8is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, and OR7; R7is independently selected at each instance from the group consisting of hydrogen, C1- C6alkyl, and C1-C6haloalkyl; R9is C1-C6alkyl, C1-C6haloalkyl or a heterocycle; R10is independently selected from the group consisting of cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R11is C1-C2alkyl or C1-C6haloalkyl; R12and R13are independently selected at each instance from the group consisting of hydrogen and C1-C6alkyl; m is 0 or 1; A is CH or N; Cycle A is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms, a 4-, 5-, or 6- membered heterocycle, a C4-C6cycloalkyl or a bicycle; each of which is optionally substituted with one R6and one R8; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; Cycle B is a 5- or 6-membered heteroaryl with 2 or 3 heteroatoms, a 4-, 5-, or 6-membered heterocycle, a C4-C6cycloalkyl, or a bicycle; each of which is optionally substituted with one R6and one R8; Cycle C is a 5- or 6-membered heteroaryl optionally substituted with one R1and one R2; in certain embodiments Cycle C is ; in certain embodiments Cycle C is ; in certain embodiments Cycle C is ; in certain embodiments Cycle C is ; in certain embodiments Cycle C is ; in certain embodiments Cycle C is ; in certain embodiments Cycle C is . Cycle D is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms, a 4-, 5-, or 6- membered heterocycle, a C4-C6cycloalkyl or a bicycle; each of which is substituted with one R10group and optionally substituted with one R8; Cycle F is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms, a 4-, or 5-membered heterocycle, a C4-C6cycloalkyl or a bicycle; each of which is optionally substituted with one R6and one R8; and Cycle G is a 5- or 6-membered heteroaryl with 2 or 3 heteroatoms, a 4-, 5-, or 6-membered heterocycle with 2 or 3 heteroatoms, or a C4-C5cycloalkyl; each of which is optionally substituted with one R6and one R8. In certain aspects the compound of the present invention is of Formula: or ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0044] or a p harmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0045] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0046] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0047] In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0048] or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0049] or a pharmaceutically acceptable salt thereof. In other aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0050] or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof.

[0051] In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0052] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a parmaceutca y acceptabe sat tereo.

[0053] In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0054] ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or ; or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a ph armaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0055] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In other aspects the compound of the present invention is of Formula: or ; or a pharmaceutically acceptable salt thereof. In other aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a parmaceutca y accepta e sat tereo. In certain aspects the compound of the present invention is of Formula:

[0056] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0057] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0058] or a p armaceu ca y accepa e sa ereo. Non-limiting examples of the compound of the present invention include: or a pharmaceutically acceptable salt thereof. Other non-limiting examples of the compound of the present invention include: or a pa aceu ca y accepa e sa eeo. Additional non-limiting examples of the compound of the present invention include:

[0059] or a parmaceu ca y accepa e sa ereo; wherein: X2is N or CH; Y2is N or CH; W2is N or CH; W3is O or NH; A2is H, F, or CH3; A3is H or CH3. In certain aspects, the present invention provides a compound of Formula:

[0060] or a pharmaceutically acceptable salt thereof; wherein: A is N or CH; R1and R2are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; in certain embodiments R1and R2are each hydrogen; in certain embodiments R2is CH3; R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; in certain embodiments R3is H or CH3; R6is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R8is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, and OR7; R7is independently selected at each instance from the group consisting of hydrogen, C1- C6alkyl, and C1-C6haloalkyl; R9is C1-C6alkyl, C1-C6haloalkyl or a heterocycle; R12and R13are independently selected at each instance from the group consisting of hydrogen and C1-C6alkyl; Cycle A is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms, a 4-, 5-, or 6- membered heterocycle, a C4-C6cycloalkyl or a bicycle; each of which is optionally substituted with one R6and one R8; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; in certain embodiments Cycle A is ; X is bond, CH2, or O; p is 0 or 1; R14is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or OR15; R15is hydrogen, C1-C6alkyl, C1-C6haloalkyl, aryl or heteroaryl; wherein aryl and heteroaryl are optionally substituted with one R6and one R8; Y is CH2, O or NR12; and Cycle E is selected from the group consisting of , , , , and ; wherein indicates the attachment point to the carbonyl, for example, when0 Cycle E is , is . In certain embodiments, the present invention provides a compound of Formula: . In certain aspects the compound of the present invention is of Formula:

[0061] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0062] or a pharm aceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula:

[0063] or a parmaceutca y acceptabe sat tereo. In certain aspects the compound of the present invention is of Formula:

[0064] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is of Formula: or or a pharmaceutically acceptable salt thereof. Additional non-limiting examples of the compound of the present invention include:

[0065] or a pharmaceutically acceptable salt thereof; wherein: X is CH2, O, or N-Pr. In alternative embodiments, the compound is selected from: or a pharmaceutically acceptable salt thereof; Non-limiting examples of the compound of the present invention include: and ; or a pharmaceutically acceptable salt thereof. Embodiments of R1In certain embodiments R1is hydrogen. In certain embodiments R1is C1-C6alkyl. In certain embodiments R1is CH3. In certain embodiments R1is C2H5. In certain embodiments R1is 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 C1-C6haloalkyl. In certain embodiments R1is CF3. In certain embodiments R1is CHF2. In certain embodiments R1is CH2F. In certain embodiments R1is CH2CF3. Embodiments of R2In certain embodiments R2is hydrogen. In certain embodiments R2is C1-C6alkyl. 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 C1-C6haloalkyl. In certain embodiments R2is CF3. In certain embodiments R2is CHF2. In certain embodiments R2is CH2F. In certain embodiments R2is CH2CF3. Embodiments of R3In certain embodiments R3is hydrogen. In certain embodiments R3is C1-C6alkyl. 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 C1-C6haloalkyl. In certain embodiments R3is CF3. In certain embodiments R3is CHF2. In certain embodiments R3is CH2F. In certain embodiments R3is CH2CF3. In alternative embodiments R3is . In alternative embodiments R3is . In alternative embodiments R3is . In alternative embodiments R3is C2-C6alkyl substituted with heterocycle, OR7, N(CH3)R7, or N(H)R7. Embodiments of R4In certain embodiments R4is hydrogen. In certain embodiments R4is C1-C6alkyl. 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 I. In certain embodiments R4is C1-C6haloalkyl. In certain embodiments R4is CF3. In certain embodiments R4is CHF2. In certain embodiments R4is CH2F. In certain embodiments R4is CH2CF3. In certain embodiments R4is cyano. In certain embodiments R4is C(O)NR12R13. In certain embodiments R4is C(O)NH2. Embodiments of R5In certain embodiments R5is hydrogen. In certain embodiments R5is C1-C6alkyl. 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 I. In certain embodiments R5is C1-C6haloalkyl. In certain embodiments R5is CF3. In certain embodiments R5is CHF2. In certain embodiments R5is CH2F. In certain embodiments R5is CH2CF3. Embodiments of R6In certain embodiments R6is hydrogen. In certain embodiments R6is C1-C6alkyl. 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 I. In certain embodiments R6is C1-C6haloalkyl In certain embodiments R6is CF3. In certain embodiments R6is CHF2. In certain embodiments R6is CH2F. In certain embodiments R6is CH2CF3. In certain embodiments R6is OR7. 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 OCHF2. In certain embodiments R6is OCH2CF3. In certain embodiments R6is cyano. In certain embodiments R6is C(O)NR12R13. In certain embodiments R6is C(O)NH2. Embodiments of R7In certain embodiments R7is hydrogen. In certain embodiments R7is C1-C6alkyl. 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 cyclopentyl. In certain embodiments R7is C1-C6haloalkyl. In certain embodiments R7is CF3. In certain embodiments R7is CH2F. In certain embodiments R7is CH2CF3. Embodiments of R8In certain embodiments R8is hydrogen. In certain embodiments R8is C1-C6alkyl. In certain embodiments R8is CH3. In certain embodiments R8is C2H5. In certain embodiments R8is CH2CH2CH3. In certain embodiments R8is iso-C3H7. In certain embodiments R8is F. In certain embodiments R8is Cl. In certain embodiments R8is Br. In certain embodiments R8is I. In certain embodiments R8is C1-C6haloalkyl. In certain embodiments R8is CF3. In certain embodiments R8is CHF2. In certain embodiments R8is CH2F. In certain embodiments R8is CH2CF3. In certain embodiments R8is OR7. In certain embodiments R8is OH. In certain embodiments R8is OCH3. In certain embodiments R8is OC2H5. In certain embodiments R8is OCH2CH2CH3. In certain embodiments R8is OC3H7-iso. In certain embodiments R8is OCF3. In certain embodiments R8is OCHF2. In certain embodiments R8is OCH2CF3. Embodiments of R9In certain embodiments R9is C1-C6alkyl. In certain embodiments R9is CH3. In certain embodiments R9is C2H5. In certain embodiments R9is CH2CH2CH3. In certain embodiments R9is iso-C3H7. In certain embodiments R9is . In certain embodiments R9is C1-C6haloalkyl. In certain embodiments R9is CF3. In certain embodiments R9is CH2F. In certain embodiments R9is CH2CF3. In certain embodiments R9is a heterocycle. In certain embodiments R9is . Embodiments of R10In certain embodiments R10is C1-C6alkyl. In certain embodiments R10is CH3. In certain embodiments R10is C2H5. In certain embodiments R10is CH2CH2CH3. In certain embodiments R10is iso-C3H7. In certain embodiments R10is F. In certain embodiments R10is Cl. In certain embodiments R10is Br. In certain embodiments R10is I. In certain embodiments R10is C1-C6haloalkyl. In certain embodiments R10is CF3. In certain embodiments R10is CHF2. In certain embodiments R10is CH2F. In certain embodiments R10is CH2CF3. In certain embodiments R10is OR7. In certain embodiments R10is OH. In certain embodiments R10is OCH3. In certain embodiments R10is OC2H5. In certain embodiments R10is OCH2CH2CH3. In certain embodiments R10is OC3H7-iso. In certain embodiments R10is OCF3. In certain embodiments R10is OCHF2. In certain embodiments R10is OCH2CF3. In certain embodiments R10is cyano. In certain embodiments R10is C(O)NR12R13. In certain embodiments R10is C(O)NH2. Embodiments of R11In certain embodiments R11is C1-C2alkyl. In certain embodiments R11is CH3. In certain embodiments R11is C2H5. In certain embodiments R11is C1-C6haloalkyl. In certain embodiments R11is CF3. In certain embodiments R11is CHF2. In certain embodiments R11is CH2F. In certain embodiments R11is CH2CF3. Embodiments of R12In certain embodiments R12is hydrogen. In certain embodiments R12is C1-C6alkyl. In certain embodiments R12is CH3. In certain embodiments R12is C2H5. In certain embodiments R12is CH2CH2CH3. In certain embodiments R12is iso-C3H7. Embodiments of R13In certain embodiments R13is hydrogen. In certain embodiments R13is C1-C6alkyl. In certain embodiments R13is CH3. In certain embodiments R13is C2H5. In certain embodiments R13is CH2CH2CH3. In certain embodiments R13is iso-C3H7. Embodiments of R14In certain embodiments R14is hydrogen. In certain embodiments R14is C1-C6alkyl. In certain embodiments R14is CH3. In certain embodiments R14is C2H5. In certain embodiments R14is CH2CH2CH3. In certain embodiments R14is iso-C3H7. In certain embodiments R14is . In certain embodiments R14is C1-C6haloalkyl. In certain embodiments R14is CF3. In certain embodiments R14is CHF2. In certain embodiments R14is CH2F. In certain embodiments R14is CH2CF3In certain embodiments R14is OR15. In certain embodiments R14is OMe. In certain embodiments R14is O-iPr. In certain embodiments R14is . Embodiments of R15In certain embodiments R15is hydrogen. In certain embodiments R15is C1-C6alkyl. In certain embodiments R15is CH3. In certain embodiments R15is C2H5. In certain embodiments R15is CH2CH2CH3. In certain embodiments R15is iso-C3H7. In certain embodiments R15is C1-C6haloalkyl. In certain embodiments R15is CF3. In certain embodiments R15is CHF2. In certain embodiments R15is CH2F. In certain embodiments R15is CH2CF3In certain embodiments R15is an aryl optionally substituted with one R6and one R8. In certain embodiments R15is . In certain embodiments R15is . In certain embodiments R15is . In certain embodiments R15is a heteroaryl optionally substituted with one R6and one R8. In certain embodiments R15is . In certain embodiments R15is . In certain embodiments R15is . Embodiments of A In certain embodiments A is CH. In certain embodiments A is N. Embodiments of X In certain embodiments X is bond. In certain embodiments X is CH2. In certain embodiments X is O. Embodiments of m In certain embodiments m is 0. In certain embodiments m is 1. Embodiments of p In certain embodiments p is 0. In certain embodiments p is 1. Embodiments of Y In certain embodiments Y is CH2. In certain embodiments Y is O. In certain embodiments Y is NR12. In certain embodiments Y is N-iPr. Embodiments of Cycle A In certain embodiments Cycle A is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms optionally substituted with one R6and one R8. In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is a 4-, 5-, or 6-membered heterocycle optionally substituted with one R6and one R8. In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is a C4-C6cycloalkyl optionally substituted with one R6and one R8. In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is a bicycle optionally substituted with one R6and one R8. In certain embodiments Cycle A is . In certain embodiments Cycle A is . In certain embodiments Cycle A is . Embodiments of Cycle B In certain embodiments Cycle B is a 5- or 6-membered heteroaryl with 2 or 3 heteroatoms optionally substituted with one R6and one R8. In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is a 4-, 5-, or 6-membered heterocycle optionally substituted with one R6and one R8. In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is a C4-C6cycloalkyl optionally substituted with one R6and one R8. In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is a bicycle optionally substituted with one R6and one R8. In certain embodiments Cycle B is . In certain embodiments Cycle B is . In certain embodiments Cycle B is . Embodiments of Cycle C In certain embodiments Cycle C is a 5-membered heteroaryl optionally substituted with one R1and one R2; In certain embodiments Cycle C is a 6-membered heteroaryl optionally substituted with one R1and one R2; In certain embodiments Cycle C is . In certain embodiments Cycle C is . In certain embodiments Cycle C is . In certain embodiments Cycle C is . In certain embodiments Cycle C is . In certain embodiments Cycle C is . In certain embodiments Cycle C is . Embodiments of Cycle D In certain embodiments Cycle D is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms substituted with one R10group and optionally substituted with one R8. In certain embodiments Cycle D is a 4-, 5-, or 6-membered heterocycle substituted with one R10group and optionally substituted with one R8. In certain embodiments Cycle D is a C4-C6cycloalkyl substituted with one R10group and optionally substituted with one R8. In certain embodiments Cycle D is a bicycle substituted with one R10group and optionally substituted with one R8. Embodiments of Cycle E In the following embodiments, indicates the attachment point to the carbonyl, and indicates the attachment point to the phenyl moiety; for example, when Cycle E is , is . In certain embodiments Cycle E is . In certain embodiments Cycle E is . In certain embodiments Cycle E is . In certain embodiments Cycle E is . In certain embodiments Cycle E is . Embodiments of Cycle F In certain embodiments Cycle F is a 5- or 6-membered heteroaryl with 1, 2 or 3 heteroatoms optionally substituted with one R6and one R8. In certain embodiments Cycle F is a 4-, or 5-membered heterocycle optionally substituted with one R6and one R8. In certain embodiments Cycle F is a C4-C6cycloalkyl optionally substituted with one R6and one R8. In certain embodiments Cycle F is a bicycle optionally substituted with one R6and one R8. Embodiments of Cycle G In certain embodiments Cycle G is a 5- or 6-membered heteroaryl with 2 or 3 heteroatoms optionally substituted with one R6and one R8. In certain embodiments Cycle G is a 4-, 5-, or 6-membered heterocycle with 2 or 3 heteroatoms optionally substituted with one R6and one R8. In certain embodiments Cycle G is a C4-C5cycloalkyl optionally substituted with one R6and one R8. In certain embodiments, is of structure:

[0066] or .In certain embodiments, is of structure:or . In certain embodiments, is of structure: or . In certain embodiments, is of structure: or . The structure of the compounds of the present invention 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. One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions. Illustrative Embodiments 1. A compound of Formula:

[0067] or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; R4is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C(O)NR12R13, and halogen; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R6is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R8is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, and OR7; R7is independently selected at each instance from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; R9is C1-C6alkyl, C1-C6haloalkyl, or a heterocycle; R12and R13are independently selected at each instance from the group consisting of hydrogen and C1-C6alkyl; m is 0 or 1; and A is CH or N. 2. The compound of embodiment 1, wherein the compound is of Formula: ; or a pharmaceutically acceptable salt thereof. 3. The compound of embodiment 2, wherein the compound is of Formula: or or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1, wherein the compound is of Formula: (II); or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 5, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 7. The compound of embodiment 5, wherein the compound is of Formula:

[0068] or a pharmaceutically acceptable salt thereof. 8. The compound of embodiment 1, wherein the compound is of Formula: ; or a pharmaceutically acc eptabe sat t ereo . 9. The compound of embodiment 8, wherein the compound is of Formula:

[0069] or a pharmaceutically acceptable salt thereof. 10. The compound of embodiment 8, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 11. The compound of embodiment 1, wherein the compound is of Formula: ); or a pharmaceutically acceptable salt thereof. 12. The compound of embodiment 11, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 13. The compound of embodiment 11, wherein the compound is of Formula: or a p armaceut ca y acceptabe sat t ereo . 14. The compound of embodiment 1, wherein the compound is of Formula: (V); or a pharmaceutically acceptable salt thereof. 15. The compound of embodiment 14, wherein the compound is of Formula: or or a pharmaceutically acceptable salt thereof. 16. The compound of embodiment 14, wherein the compound is of Formula:

[0070] or a pharmaceutically acceptable salt thereof. 17. The compound of embodiment 1, wherein the compound is of Formula: ; or a pharmaceutically acceptable sa t t ereo . 18. The compound of embodiment 17, wherein the compound is of Formula:

[0071] or or a pharmaceutically acceptable salt thereof. 19. The compound of embodiment 17, wherein the compound is of Formula:

[0072] or a pharmaceutically acceptable salt thereof. 20. The compound of any one of embodiments 1-19, wherein R6is hydrogen. 21. The compound of any one of embodiments 1-19, wherein R6is halogen. 22. The compound of any one of embodiments 1-19, wherein R6is -F. 23. The compound of any one of embodiments 1-19, wherein R6is -Cl. 24. The compound of any one of embodiments 1-19, wherein R6is -Br. 25. The compound of any one of embodiments 1-19, wherein R6is -I. 26. The compound of any one of embodiments 1-19, wherein R6is C1-C6alkyl. 27. The compound of any one of embodiments 1-19, wherein R6is methyl. 28. The compound of any one of embodiments 1-19, wherein R6is C1-C6haloalkyl. 29. The compound of any one of embodiments 1-19, wherein R6is -CHF2. 30. The compound of any one of embodiments 1-19, wherein R6is -CF3. 31. The compound of any one of embodiments 1-19, wherein R6is cyano. 32. The compound of any one of embodiments 1-19, wherein R6is C(O)NR12R13. 33. The compound of any one of embodiments 1-19, wherein R6is C(O)NH2. 34. The compound of any one of embodiments 1-19, wherein R6is OR7. 35. The compound of embodiment 34, wherein R7is hydrogen. 36. The compound of embodiment 34, wherein R7is C1-C6alkyl. 37. The compound of embodiment 34, wherein R7is methyl. 38. The compound of embodiment 34, wherein R7is C1-C6haloalkyl. 39. The compound of embodiment 34, wherein R7is -CHF2. 40. The compound of any one of embodiments 1-39, wherein R8is hydrogen. 41. The compound of any one of embodiments 1-39, wherein R8is halogen. 42. The compound of any one of embodiments 1-39, wherein R8is -F. 43. The compound of any one of embodiments 1-39, wherein R8is -Cl. 44. The compound of any one of embodiments 1-39, wherein R8is -Br. 45. The compound of any one of embodiments 1-39, wherein R8is -I. 46. The compound of any one of embodiments 1-39, wherein R8is C1-C6alkyl. 47. The compound of any one of embodiments 1-39, wherein R8is methyl. 48. The compound of any one of embodiments 1-39, wherein R8is C1-C6haloalkyl. 49. The compound of any one of embodiments 1-39, wherein R8is -CHF2. 50. The compound of any one of embodiments 1-39, wherein R8is -CF3. 51. The compound of any one of embodiments 1-39, wherein R8is OR7. 52. The compound of embodiment 51, wherein R7is hydrogen. 53. The compound of embodiment 51, wherein R7is C1-C6alkyl. 54. The compound of embodiment 51, wherein R7is methyl. 55. The compound of embodiment 51, wherein R7is C1-C6haloalkyl. 56. The compound of embodiment 51, wherein R7is -CHF2. 57. The compound of embodiment 1, wherein the compound is of Formula: , or a pharmaceutically ac ceptabe sat t ereo . 58. The compound of embodiment 57, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 59. The compound of embodiment 57, wherein the compound is of Formula: or ; or a pharmaceutically acceptable salt thereof. 60. The compound of embodiment 1, wherein the compound is of Formula: , or a pharmaceutically acceptable salt thereof. 61. The compound of embodiment 60, wherein the compound is of Formula: or ; or a pharmaceutically acceptable salt thereof. 62. The compound of embodiment 60, wherein the compound is of Formula: or a p harmaceutically acceptable salt thereof. 63. The compound of any one of embodiments 57-62, wherein R4is hydrogen. 64. The compound of any one of embodiments 57-62, wherein R4is halogen. 65. The compound of any one of embodiments 57-62, wherein R4is -F. 66. The compound of any one of embodiments 57-62, wherein R4is -Cl. 67. The compound of any one of embodiments 57-62, wherein R4is -Br. 68. The compound of any one of embodiments 57-62, wherein R4is -I. 69. The compound of any one of embodiments 57-62, wherein R4is C1-C6alkyl. 70. The compound of any one of embodiments 57-62, wherein R4is methyl. 71. The compound of any one of embodiments 57-62, wherein R4is C1-C6haloalkyl. 72. The compound of any one of embodiments 57-62, wherein R4is -CHF2. 73. The compound of any one of embodiments 57-62, wherein R4is -CF3. 74. The compound of any one of embodiments 57-62, wherein R4is cyano. 75. The compound of any one of embodiments 57-62, wherein R4is C(O)NR12R13. 76. The compound of any one of embodiments 57-62, wherein R4is C(O)NH2. 77. The compound of any one of embodiments 57-76, wherein R5is hydrogen. 78. The compound of any one of embodiments 57-76, wherein R5is halogen. 79. The compound of any one of embodiments 57-76, wherein R5is -F. 80. The compound of any one of embodiments 57-76, wherein R5is -Cl. 81. The compound of any one of embodiments 57-76, wherein R5is -Br. 82. The compound of any one of embodiments 57-76, wherein R5is -I. 83. The compound of any one of embodiments 57-76, wherein R5is C1-C6alkyl. 84. The compound of any one of embodiments 57-76, wherein R5is methyl. 85. The compound of any one of embodiments 57-76, wherein R5is C1-C6haloalkyl. 86. The compound of any one of embodiments 57-76, wherein R5is -CHF2. 87. The compound of any one of embodiments 57-76, wherein R5is -CF3. 88. The compound of any one of embodiments 57-87, wherein R9is C1-C6alkyl. 89. The compound of any one of embodiments 57-87, wherein R9is methyl. 90. The compound of any one of embodiments 57-87, wherein R9is cyclopropyl. 91. The compound of any one of embodiments 57-87, wherein R9is C1-C6haloalkyl. 92. The compound of any one of embodiments 57-87, wherein R9is a heterocycle. 93. The compound of any one of embodiments 57-87, wherein R9is . 1 94. The compound of any one of embodiments 1-93, wherein R is hydrogen. 95. The compound of any one of embodiments 1-93, wherein R1is halogen. 96. The compound of any one of embodiments 1-93, wherein R1is C1-C6alkyl. 97. The compound of any one of embodiments 1-93, wherein R1is methyl. 98. The compound of any one of embodiments 1-93, wherein R1is C1-C6haloalkyl. 99. The compound of any one of embodiments 1-98, wherein R2is hydrogen. 100. The compound of any one of embodiments 1-98, wherein R2is halogen. 101. The compound of any one of embodiments 1-98, wherein R2is C1-C6alkyl. 102. The compound of any one of embodiments 1-98, wherein R2is methyl. 103. The compound of any one of embodiments 1-98, wherein R2is C1-C6haloalkyl. 104. The compound of any one of embodiments 1-103, wherein R3is hydrogen. 105. The compound of any one of embodiments 1-103, wherein R3is C1-C6alkyl. 106. The compound of any one of embodiments 1-103, wherein R3is methyl. 107. The compound of any one of embodiments 1-103, wherein R3is C1-C6haloalkyl. 108. A compound selected from: and or a pharmaceutically acceptable salt thereof. 109. A compound selected from: and or a pharmaceutically acceptable salt thereof. 110. A pharmaceutical composition comprising a compound of any one of embodiments 1-109 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 111. The pharmaceutical composition of embodiment 110, wherein the pharmaceutical composition is suitable for oral administration. 112. The pharmaceutical composition of embodiment 110, wherein the pharmaceutical composition is suitable for parenteral administration. 113. The pharmaceutical composition of embodiment 110, wherein the pharmaceutical composition is suitable for intravenous administration. 114. A method of treating a ROCK1 or ROCK2 mediated disorder comprising administering an effective amount of a compound of any one of embodiments 1-109 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a subject in need thereof. 115. The method of embodiment 114, wherein the subject is a human. 116. The method of embodiment 114 or 115, wherein the disorder is a neurodegenerative disorder. 117. The method of embodiment 116, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis. 118. The method of embodiment 116, wherein the neurodegenerative disorder is Parkinson’s disease. 119. The method of embodiment 116, wherein the neurodegenerative disorder is Huntington’s disease. 120. The method of embodiment 116, wherein the neurodegenerative disorder is Alzheimer’s disease. 121. The method of embodiment 114 or 115, wherein the disorder is a kidney disease. 122. The method of embodiment 121, wherein the kidney disease is diabetic nephropathy. 123. The method of embodiment 121, wherein the kidney disease is polycystic kidney disease. 124. The method of embodiment 121, wherein the kidney disease is focal segmental glomerulosclerosis. 125. The method of embodiment 114 or 115, wherein the disorder is Levodopa-induced dyskinesia. 126. The method of embodiment 114 or 115, wherein the disorder is a bladder dysfunction. 127. The method of embodiment 126, wherein the bladder dysfunction is interstitial cystitis. 128. The method of embodiment 126, wherein the bladder dysfunction is bladder inflammation. 129. The method of embodiment 126, wherein the bladder dysfunction is overactive bladder. 130. The method of embodiment 126, wherein the bladder dysfunction is bladder fibrosis. 131. The method of embodiment 126, wherein the bladder dysfunction is neurogenic bladder. 132. The method of embodiment 126, wherein the bladder dysfunction is a lower urinary tract symptom. 133. The method of embodiment 114 or 115, wherein the disorder is a cancer. 134. The method of embodiment 133, wherein the cancer is breast cancer. 135. The method of embodiment 133, wherein the cancer is prostate cancer. 136. The method of embodiment 133, wherein the cancer is melanoma. 137. The method of embodiment 133, wherein the cancer is a desmoplastic disorder. 138. The method of embodiment 114 or 115, wherein the disorder is a traumatic brain injury. 139. The method of embodiment 114 or 115, wherein the disorder is diabetic retinopathy. 140. The method of embodiment 114 or 115, wherein the disorder is idiopathic pulmonary fibrosis. 141. The method of embodiment 114 or 115, wherein the disorder is pulmonary sarcoidosis. 142. The method of embodiment 114 or 115, wherein the disorder is neurosarcoidosis. 143. The method of embodiment 114 or 115, wherein the disorder is scleroderma. 144. The method of embodiment 114 or 115, wherein the disorder is a fibrotic disorder. 145. The method of embodiment 144, wherein the disorder is a fibrotic disorder of the lung. 146. The method of embodiment 144, wherein the disorder is a fibrotic disorder of the kidney. 147. The method of embodiment 144, wherein the disorder is a fibrotic disorder of the liver. 148. The method of embodiment 144, wherein the disorder is a fibrotic disorder of the skin. 149. The method of any one of embodiments 114-148, wherein the disorder is mediated by ROCK1. 150. The method of any one of embodiments 114-148, wherein the disorder is mediated by ROCK2. 151. Use of a compound of any one of embodiments 1-109 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated disorder. 152. Use of a compound of any one of embodiments 1-109 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated disorder. III. METHODS OF TREATMENT Rho-associated coiled-coil kinase (ROCK) isoforms 1 and 2 are downstream targets of GTP-bound and activated Rho GTPase proteins that phosphorylate a number of substrates involved in myosin-actin-cytoskeletal architecture, actin-filament dynamics, neurofilament, and actin-binding proteins. ROCK1 is expressed in a variety of human tissues including the heart, pancreas, lung, liver, skeletal muscle, and kidney, but is not substantially expressed in the brain (Fujisawa, K. et al. Identification of the rho-binding domain of p160ROCK, a rho-associated coiled-coil containing protein kinase. J Biol Chem.271:23022-8(1996)). ROCK2 is preferentially expressed in the brain and skeletal muscle (Nakagawa, O. et al. ROCK-I and ROCK-II, two isoforms of rho-associated coiled-coil forming protein serine / threonine kinase in mice. FEBS Lett. 395:189-93(1996)). Increased activity of ROCK2 is implicated in defects on dendritic spine structure and function in several model systems (Swanger, S.A. et al. ROCK1 and ROCK2 inhibition alters dendritic spine morphology in hippocampal neurons. Cell Logist. 5:e1133266(2015); Sellers, K.J. et al. Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimer’s Dement. 14:306-17(2018); Henderson et al. Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against beta-amyloid. Sci Signal. 12:eaaw9318(2019)). Indeed, ROCK2 is implicated in a number of neurodegenerative and neurological disorders including Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), spinal cord injury, stroke, and neuroinflammation (Weber, A.J. et al. Perspectives on ROCK2 as a Therapeutic Target for Alzheimer’s Disease. Front in Cell Neurosci. 15:636017(2021)). ROCK2 is shown to regulate several complex neuronal processes associated with neurodegenerative disorders. For example, AAV.shRNA-mediated downregulation of ROCK2 rescued dopaminergic neurons in the substantia nigra (SN) and preserves motor behavior in a 6- hydroxydopamine (6-OHDA)-induced Parkinson mouse model (Saal, K. et al. Neurobiol Dis. 73:150-62(2015)). ROCK inhibition can be used to modulate these neuronal processes. For example, in a study in mice ROCK inhibition led to decreased midbrain alpha-synuclein pathology and improved motor and cognitive function in a mouse model expressing human mutant alpha- synuclein (aSynA53T) (Tatenhorst et al. Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease. Acta Neuropathol Commun.4:39(2016)). ROCK proteins are present in many types of nerve cells in the CNS. Excess activity of ROCK proteins in the CNS leads to oxidative stress, uncontrolled inflammation, immune abnormality, energy metabolism disorders, neuronal cell loss, reactive gliosis, and / or impaired synaptic transmission, thus promoting the development of neurodegenerative diseases. ROCK protein overexpression has been detected in the lesions of Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), revealing that ROCK proteins are involved in the pathology of these diseases and might be important initiators of pathogenesis. Inhibition of ROCK proteins has been shown to cause several biological events, such as increased neurite outgrowth, axonal regeneration, and activation of prosurvival protein kinase B (AKT). (Q. Wang et al. “Advantages of Rho-associated kinases and their inhibitor Fasudil for the treatment of neurodegenerative diseases”, Neural Regen. Res.2022, 17(12):2623-2631.) Because of ROCK’s role in neuronal processes, its over activity or increased concentration is associated with various neurological defects. For example, increased levels of ROCK2 protein are observed in progressive stages of AD (Herskowitz et al.2013). While increased ROCK activity is observed in SOD1G93AALS mutant model mice (Gunther, R. et al. Rho Kinase Inhibition with Fasudil in the SOD1G93AMouse Model of Amyotrophic Lateral Sclerosis – Symptomatic Treatment Potential After Disease Onset. Front Pharmacol.8:17(2017)). Thus, a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in an effective amount to treat a neurological disease. Non-limiting examples of neurological diseases include amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Huntington's Disease (HD), Alzheimer’s disease (AD), and neurological deficiencies caused by spinal cord injuries. Based on the above-described roles of ROCK1 and ROCK2 in central nervous system disorders, methods and uses to treat subjects such as humans afflicted with such disorders are provided herein. In certain embodiments a method of treating a subject with a ROCK1 and / or ROCK2 mediated disorder is provided comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject. Non-limiting examples of disorders mediated by ROCK1 and / or ROCK2 are provided below. In certain aspects the compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a ROCK1 mediated disorder. In certain aspects the compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a ROCK2 mediated disorder. Specific examples of disorders that can be treated with the compounds described herein or their pharmaceutically acceptable salts are described below. Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disease that affects an estimated million individuals (Hardiman, O. et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 3(17071):1-19(2017)), with different risk levels geographically. ALS is characterized by degeneration of upper motor neurons and lower motor neurons that contribute to both motor and non-motor symptoms. Several subtypes of ALS have been identified including bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat ALS. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat bulbar, respiratory, flail arm, classical, pyramidal, or flail leg ALS. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with ALS or a secondary condition associated with ALS. Parkinson disease (PD) Parkinson disease (PD) is the second-most common neurodegenerative disorder following Alzheimer disease, with an estimated 2 to 3 cases per 100,000 individuals worldwide (Parkinson’s Foundation. Statistics. 2022). PD is characterized by several dysregulated mechanisms and pathways which contribute to neuronal loss in the substantia nigra (SN), including alpha-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation (Poewe, W. et al. Parkinson disease. Nat Rev Dis Primers. 3(17013):1- 21(2017)). Intracellular alpha-synuclein aggregates are a hallmark of PD, as well as SN neuronal loss and striatal dopamine deficiency. Subjects are diagnosed with PD based on the presence of bradykinesia and other motor defects, as well as non-motor symptoms. Several subtypes of PD have been identified including motor-cognitive, cognitive dominant and motor dominant PD. There is presently no cure for PD and treatments focus on slowing the progression and / or decreasing the symptoms of PD. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat PD. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat motor-cognitive, cognitive dominant or motor dominant PD. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with PD or a secondary condition associated with PD. Alzheimer disease (AD) Alzheimer disease (AD) is the most common cause of dementia affecting over 40 million people in 2016 (GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18(1):88-106(2019)) and is expected to increase to 150 million by 2050 worldwide. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 7(2):e105-e125(2022)). AD is a neurodegenerative disorder characterized by extracellular plaques comprising amyloid beta and intracellular neurofibrillary tangles comprising tau leading to neuronal loss (Knopman, D.S. et al. Alzheimer disease. Nat Rev Dis Primers. 7(33):1-21(2021)). Subjects with AD present with cognitive impairment and dementia. Symptoms of cognitive impairment include loss in short-term memory, expressive speech, visuospatial processing, and executive functioning. AD risk factors include rare, dominantly inherited mutations in APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) causing autosomal dominant forms of AD. Much more common is the development of sporadic late-onset AD which is influenced by more common but incompletely penetrant genetic polymorphisms in genes such as APOE. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat AD. AD treatments can be beneficial at several stages in the progression of the disease. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a subject with no cognitive impairment but high levels of amyloid beta and / or tau biomarkers, subjective cognitive decline in the absence of impaired cognitive testing scoring, mild cognitive impairment, clinically confirmed AD, or autosomal dominant AD. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with AD or a secondary condition associated with AD. Spinal cord injury Spinal cord injuries can trigger complex and varied neurological effects including axon degeneration and mild to severe loss of cognitive function. In certain embodiments a compound described herein is used to treat a spinal cord injury. For example, a compound of the present invention or a pharmaceutically acceptable salt thereof may be used to promote axon regeneration and functional recovery in a subject who has had a spinal cord injury. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a spinal cord injury or a secondary condition associated with a spinal cord injury. Stroke Stroke is a neurological disorder that occurs when one or more blood vessels that supply blood to the brain are blocked or rupture. The depletion of blood in the brain causes damage to the brain tissue in the area where the blood vessel previously delivered blood. There are two common categories of stroke: ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when the brain tissue is ischemic due to a decrease in the supply of blood caused by a blockage. Hemorrhagic stroke instead occurs due to hemorrhage when a blood vessel ruptures. Ischemic stroke is the most common form of stroke. When an ischemic stroke occurs, cells cannot obtain sufficient oxygen and nutrients due to the interruption of blood flow. In certain embodiments a compound described herein is used to treat a stroke. Non-limiting examples of strokes include ischemic stroke, acute ischemic stroke, thrombosis, embolism, transient ischemic attack, leukoplakia, and infarction. In other embodiments a compound herein is used to prevent a stroke or provide neuroprotection, for example acute neuroprotection. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human who has had a stroke or a secondary condition associated with a stroke. Other Neurodegenerative Disorders In addition to ROCKs important role in the regulation of several complex neuronal processes research has identified ROCK as a regulator of reactive oxygen species (ROS). This biological function allows ROCK inhibition to modulate additional neurodegenerative disorders (Kang H. et al. Chemical Screening Identifies ROCK as a Target for Recovering Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome. Aging Cell 16:541-50(2017) and Sheng W. et al. Reactive Oxygen Species from Human Astrocytes Induce Functional Impairment and Oxidative Damage. Neurochem. Res.38:2148-59(2013)). Non-limiting examples of neurodegenerative diseases including ataxia, Huntington's disease, motor neuron disease, multiple system atrophy, Creutzfeldt-Jakob disease, dementia, non- dementia cognitive impairment, and progressive supranuclear palsy. Non-limiting examples of dementia include senile dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumors, and dementia caused by chronic subdural hematoma. Additional non- limiting examples of neurodegenerative diseases including corticobasal degeneration, spinocerebellar ataxia, frontotemporal dementia and CMT2A (Charcot-Marie-Tooth disease type 2A). In certain embodiments the neurodegenerative disease is corticobasal degeneration. In certain embodiments the neurodegenerative disease is spinocerebellar ataxia. In certain embodiments the neurodegenerative disease is frontotemporal dementia. In certain embodiments the neurodegenerative disease is CMT2A (Charcot-Marie-Tooth disease type 2A). In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof is used to reduce inflammation. For example, a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a subject in need thereof to reduce inflammation in the brain. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a neurodegenerative disorder such as one of those listed above or a secondary condition associated with the neurodegenerative disorder. ROCK has recently emerged as a novel therapeutic target for neurodegenerative disorders (J. C. Koch, L. Tatenhorst, A.-E. Roser, K.-A. Saal, L. Tönges, P. Lingor. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation” Pharmacology & Therapeutics 189 (2018) 1–21). While ROCK1 is expressed preferentially in peripheral tissue, ROCK2 is highly expressed in the central nervous system (CNS). Axonal growth inhibitory molecules (e.g., Nogo, MAG, OMgp, ephrins, semaphorins) bind to specific extracellular receptors and signal via ROCK to trigger axonal degeneration, growth cone collapse, and impaired axonal regeneration. In non-neuronal structures, regulation of the actin cytoskeleton plasticity by ROCK also mediates vasoconstriction and vascular remodeling. Levels of ROCK increase with age and tissue of ALS patients shows increased levels of ROCK2 as well as its downstream targets LIMK1 and cofilin. Increased ROCK activity results in higher levels of phosphorylated adducin as well as activation of phosphatase and tensin homolog (PTEN) and decreased Akt activity. PTEN activation by ROCK exerts negative effects on cell growth, proliferation and metabolism. Inhibition of ROCK counteracts neuronal apoptosis and axonal degeneration and on the other hand fosters axonal regeneration and modulates microglia activation. (J. C. Koch et al. “Compassionate use of the ROCK inhibitor Fasudil in three patients with amyotrophic lateral sclerosis” Front. Neurol. March 2020, Volume 11, Article 173, doi: 10.3389 / fneur.2020.00173). Pain Disorders Pain is a subjective sensation reflecting a tissue damage and exhibits various forms. Pain is classified into somatic pain and psychogenic pain, and somatic pain is further classified into nociceptive pain and neuropathic pain. Nociceptive pain is caused by external stimulation or visceral pathology. Nociceptive pain is mainly acute, which disappears following cure of underlying disease, and plays a role as a biological signal generated by a disorder. Neuropathic pain is chronic pain caused by dysfunction of the peripheral or central nervous system and includes pain from various sources including pain due to diabetes, nerve compression and spinal cord injury. Psychogenic pain is chronic pain, which is due to mental disorder rather than physical disorder and cannot be explained by organic disorder, and includes chronic headache, abdominal pain of unknown cause and the like. Chronic pain can impart large distress to patients and thus, is an important target of treatment. Non-limiting examples of chronic pain include chronic pain associated with arthritis, diabetes, cancer and the like which requires pain treatment in addition to treatment of underlying disease. ROCK inhibitors have been shown to exert an analgesic effect on pain. In certain embodiments a compound described herein is used to treat a pain disorder. In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof may be used to treat somatic pain. For example, a compound of the present invention or a pharmaceutically acceptable salt thereof may be used to treat nociceptive pain or neuropathic pain. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat nociceptive pain. Non-limiting examples of nociceptive pain include acute pain arising from an underlying disease. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat neuropathic pain. Non-limiting examples of neuropathic pain include chronic pain caused by diabetes, nerve compression, or a spinal cord injury. In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof. is used to treat pain arising from arthritis, for example, osteoarthritis or rheumatoid arthritis. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a pain disorder such as one of those listed above or a secondary condition associated with the pain disorder. Cardiovascular Diseases Studies have demonstrated that the Rho / ROCK pathway is increased in hypertensive patients. For example, increased ROCK-dependent smooth muscle contraction is observed in the aorta in the early stage of atherosclerosis. During atherosclerosis lesion formation, ROCK activity, is increased in certain areas and cell types including endothelium, periadventitial adipocytes and macrophage foam cells, supporting a role of ROCK in the ERM phosphorylation-mediated macrophage infiltration and foam cell formation. ROCK has a role in cardiac ischemia / reperfusion injuries, where blood flow is restricted or cut off and then is reintroduced into the area. A deleterious role of RhoA / ROCK signaling in ischemia / reperfusion injury has been demonstrated in several in vivo models including mouse, rat and swine. (M. Surma et al. “Rho kinase as a therapeutic target in cardiovascular disease” Future Cardiol. 2011 September; 7(5): 657–671. doi:10.2217 / fca.11.51). In certain embodiments a compound described herein is used to treat a cardiovascular disorder. Non-limiting examples of cardiovascular disorders include coronary heart disease, stroke, peripheral arterial disease, and aortic disease. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with a cardiovascular disorder such as one of those listed above or a secondary condition associated with the cardiovascular disorder. Ocular Disorders The ability of ROCK proteins to mediate smooth muscle contractions in the eye has made ROCK a target for the treatment of ocular disorders. ROCK mediates calcium sensitization and smooth muscle contraction. The Ca2+-sensitizing effect of smooth muscle constricting agents has been ascribed to ROCK-mediated phosphorylation of MYPT-I, the regulatory subunit of myosin light chain phosphatase (MLCP). MYPT-1 is used by the body to inhibit the activity of MLCP. By inhibiting MLCP ROCK activated phosphorylation of MYPT-1 results in enhanced phosphorylation of the myosin light chain and smooth muscle contraction (WO 2005 / 003101 and WO 2005 / 034866). Glaucoma is an ophthalmic disease that leads to irreversible visual impairment. Glaucoma is characterized by a progressive optic neuropathy caused in part by deleterious effects resulting from increased intraocular pressure. In healthy individuals, intraocular pressures ranges from 12 to 20 mm Hg, averaging approximately 16 mm Hg. However, in individuals suffering from primary open angle glaucoma, intraocular pressures generally rise above 22 to 30 mm Hg. In angle closure or acute glaucoma intraocular pressure can reach as high as 70 mm Hg leading to blindness within only a few days. The loss of vision can also result from statistically normal intraocular pressures in individuals with unusually pressure-sensitive eyes; a condition known as normotensive glaucoma (See, e.g., P. L. Kaufman and T. W. Mittag, “Medical Therapy Of Glaucoma” Ch.9, Sec. II (pp.9.7-9.30) In P. L. Kaufman and T. W. Mittag (eds.): Glaucoma (Vol. 7 of S. M. Podos and M. Yanoff (eds): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994); A. C. Guyton, Textbook of Medical Physiology (W. B. Saunders Co., Sixth Ed.), pp. 386-89 (1981)). Open-angle glaucoma constitutes the majority of all primary glaucomas and is characterized by abnormally high resistance to fluid (aqueous humor) drainage from the eye. In the glaucomatous eye, the rate of aqueous humor production remains constant, while it is the increased resistance to outflow that is responsible for the elevated intraocular pressure. ROCK has also been implicated in the pathogeneses of vitreoretinal diseases caused by age and diabetic pathology. ROCK is involved in the ischemia response, angiogenesis, inflammation and membrane contraction, all key drivers of vitreoretinal diseases like age-related macular degeneration, diabetic retinopathy and proliferative vitreoretinopathies. (https: / / pmc.ncbi.nlm.nih.gov / articles / PMC5449758 / ). Diabetic retinopathy is a serious sight- threatening complication of diabetes. Diabetes damages small blood vessels throughout the body, including the retina. Diabetic retinopathy occurs when these tiny blood vessels leak blood and other fluids. This causes the retinal tissue to swell, resulting in cloudy or blurred vision. Diabetic retinopathy is classified into two types: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy (“Diabetic retinopathy” American Optometric Association). ROCK proteins have been studied in diabetic retinopathy (Wong, T., Cheung, C., Larsen, M. et al. “Diabetic retinopathy.” Nat Rev Dis Primers 2, 16012 (2016); Durham, Jennifer T., et al. “Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics.” American Journal of Physiology-Cell Physiology 307.9 (2014): C878-C892; Arita, Ryoichi, et al. “Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage.” Diabetes 58.1 (2009): 215-226; Nakagawa, Takahiko, et al. “Abnormal angiogenesis in diabetic nephropathy.” Diabetes 58.7 (2009): 1471; Singh, Kirti, and Arshi Singh. “Rho-kinase inhibitors in ocular diseases: a translational research journey.” Journal of current glaucoma practice 17.1 (2023): 44). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat diabetic retinopathy. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat non-proliferative diabetic retinopathy. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat proliferative diabetic retinopathy. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with diabetic retinopathy or a secondary condition associated with diabetic retinopathy. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat an ocular disorder. Non-limiting examples of ocular disorders include glaucoma (for example open angle glaucoma, angle closure glaucoma, acute glaucoma, and normotensive glaucoma) or intraocular pressure. In other aspects the disorder is diabetic macular edema (DME). In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat an ocular disorder. Non-limiting examples of ocular disorders include glaucoma (for example open angle glaucoma, angle closure glaucoma, acute glaucoma, and normotensive glaucoma) or intraocular pressure. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a human with glaucoma or a secondary condition associated with glaucoma. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat glaucoma. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat open angle glaucoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat angle closure glaucoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat acute glaucoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat normotensive glaucoma. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a human with diabetic macular edema (DME) or a secondary condition associated with diabetic macular edema (DME). For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat diabetic macular edema (DME). In additional embodiments, the disorder is a macular degeneration, for example age related macular degeneration, wet macular degeneration, or dry macular degeneration. In certain embodiments the disorder is age related macular degeneration. In certain embodiments the disorder is wet macular degeneration. In certain embodiments the disorder is dry macular degeneration. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with an ocular disorder such as one of those listed above or a secondary condition associated with the ocular disorder. Huntington's Disease (HD) Huntington's disease (HD) is a progressive brain disorder caused by a defective gene. This disease causes changes in the central area of the brain, which affect movement, mood and thinking skills. In Western populations HD has a prevalence of 10.6–13.7 individuals per 100 000 (McColgan, Peter, and Sarah J. Tabrizi. “Huntington's disease: a clinical review.” European journal of neurology 25.1 (2018): 24-34). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat HD. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat Adult-onset Huntington's disease, or juvenile Huntington's disease. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with HD or a secondary condition associated with HD. Motor Neuron Diseases (MND) Motor neuron disease (MND) is an adult-onset neurodegenerative disorder characterized by loss of upper motor neurons and lower motor neurons (Bäumer, Dirk, Kevin Talbot, and Martin R. Turner. “Advances in motor neurone disease.” Journal of the Royal Society of Medicine 107.1 (2014): 14-21.). Nonlimiting examples of motor neuron disease include amyotrophic lateral sclerosis, primary lateral sclerosis, progressive bulbar palsy, pseudobulbar palsy, progressive muscular atrophy, spinal muscular atrophy, and Kennedy’s disease. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat motor neuron disease. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat amyotrophic lateral sclerosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat primary lateral sclerosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with motor neuron disease or a secondary condition associated with motor neuron disease. Polycystic Kidney Disease (PKD) Polycystic kidney disease (PKD) is a genetic disease that causes the growth of fluid-filled cysts in the kidneys. Autosomal recessive polycystic kidney disease (ARPKD) and Autosomal dominant polycystic kidney disease (ADPKD) are the two kinds of PKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common type of PKD and one of the most common genetic kidney diseases. About 9 out of every 10 people with PKD have ADPKD. It is characterized by relentless development of kidney cysts, hypertension, and eventually end-stage renal disease (ESRD). Clinical symptoms typically do not arise until adulthood. (Chebib, Fouad T., and Vicente E. Torres. “Autosomal dominant polycystic kidney disease: core curriculum 2016.” American Journal of Kidney Diseases 67.5 (2016): 792-810). In contrast to ADPKD, autosomal recessive polycystic kidney disease (ARPKD) is typically an infantile disease (Bergmann, Carsten. “ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies.” Pediatric Nephrology 30.1 (2015): 15- 30). It is a rare genetic disorder that can cause palpable kidneys, enlarged liver, respiratory failure, hypertension, or urinary tract infections (Zerres, K., et al. “Autosomal recessive polycystic kidney disease.” Journal of molecular medicine 76 (1998): 303-309.). ROCK proteins have been studied in polycystic kidney disease (PKD) (Ma, Shenghong, and Kun-Liang Guan. “Polycystic kidney disease: a Hippo connection.” Genes & Development 32.11-12 (2018): 737-739; Cai, Jing, et al. “A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease.” Genes & development 32.11-12 (2018): 781-793). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat polycystic kidney disease (PKD). For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with PKD or a secondary condition associated with PKD. In certain embodiments 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. 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. Kidney Failure Kidney failure (renal failure) means one or both of the kidneys no longer function well on their own. Kidney failure is also called end-stage renal disease (ESRD). Kidney failure is sometimes temporary and develops quickly (referred to as acute kidney injury (AKI)). Other times it’s a chronic (long-term) condition that slowly gets worse (chronic kidney disease (CKD)). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat kidney failure, end-stage renal disease (ESRD). For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat kidney failure caused by acute kidney injury (AKI) or kidney failure caused by chronic kidney disease (CKD). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with kidney failure or a secondary condition associated with kidney failure. Fibrotic disorders Non-limiting examples of fibrotic disorders include pulmonary fibrosis, renal fibrosis, liver fibrosis, heart fibrosis, and skin fibrosis (Antar SA, et. al. “Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation” Int J Mol Sci. 24.4 (2023): 4004). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a fibrotic disorder. Pulmonary fibrosis (fibrosis of the lungs) is lung disease that occurs when lung tissue becomes damaged and develops scars. A subtype of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) which is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation (Meltzer, Eric B., and Paul W. Noble. “Idiopathic pulmonary fibrosis.” Orphanet journal of rare diseases 3 (2008): 1-15). ROCK proteins have been studied in pulmonary fibrosis (Knipe, Rachel S., et al. “The Rho kinase isoforms ROCK1 and ROCK2 each contribute to the development of experimental pulmonary fibrosis.” American journal of respiratory cell and molecular biology 58.4 (2018): 471-481; Knipe, Rachel S., Andrew M. Tager, and James K. Liao. “The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacological reviews 67.1 (2015): 103-117; Li, Qingfang, et al. “Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarization through phosphorylation of STAT3.” Clinical and Translational Medicine 12.10 (2022): e1036; Wu, Xinhui, et al. “Rho-kinase 1 / 2 inhibition prevents transforming growth factor-β-induced effects on pulmonary remodeling and repair.” Frontiers in pharmacology 11 (2021): 609509). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat pulmonary fibrosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat idiopathic pulmonary fibrosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with pulmonary fibrosis or a secondary condition associated with pulmonary fibrosis. Renal fibrosis, characterized by tubulointerstitial fibrosis and glomerulosclerosis, is the final manifestation of chronic kidney disease. Renal fibrosis is characterized by an excessive accumulation and deposition of extracellular matrix components (Cho, Min Hyun. “Renal fibrosis.” Korean journal of pediatrics 53.7 (2010): 735). Rho-associated protein kinase (ROCK) inhibitor fasudil has been studied for use in treating renal interstitial fibrosis (Baba, Itsuko, et al. “Inhibitory effects of fasudil on renal interstitial fibrosis induced by unilateral ureteral obstruction.” Molecular Medicine Reports 12.6 (2015): 8010-8020). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat renal fibrosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat tubulointerstitial fibrosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat glomerulosclerosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with renal fibrosis or a secondary condition associated with renal fibrosis. Liver fibrosis is the excessive formation of scar tissue in the liver. It is a wound-healing response generated as a result of chronic liver injury and has the potential to progress into cirrhosis, and if not prevented, it may lead to liver cancer and liver failure (Aydın, M. Merve, and Kamil Can Akçalı. “Liver fibrosis” The Turkish Journal of Gastroenterology 29.1 (2018): 14). Studies have shown that ROCK proteins play a role in liver fibrosis (Xie, Y., et al. “Fasudil alleviates hepatic fibrosis in type 1 diabetic rats: involvement of the inflammation and RhoA / ROCK pathway.” European Review for Medical & Pharmacological Sciences 22.17 (2018); Murata, Toru, et al. “Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells.” Journal of hepatology 35.4 (2001): 474- 481; Zanin-Zhorov, Alexandra, et al. “Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism.” Communications biology 6.1 (2023): 1176; Tada, Seiya, et al. “A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.” Journal of hepatology 34.4 (2001): 529- 536). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with liver fibrosis or a secondary condition associated with liver fibrosis. Skin fibrosis is characterized by an excessive buildup of collagen and other connective tissues in the skin (Wang K, et al. “Extracellular matrix stiffness-The central cue for skin fibrosis” Front Mol Biosci. 8.10 (2023): 1132353). The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with skin fibrosis or a secondary condition associated with skin fibrosis. Heart fibrosis or myocardial fibrosis occurs when excessive extracellular matrix proteins are deposited in cardiac tissue (Frangogiannis NG. “Cardiac fibrosis” Cardiovasc Res. 25.117 (2021): 1450-1488). The association of ROCK protein and cardiovascular fibrosis has been explored (Yu B, et al. “Targeting Rho-associated coiled-coil forming protein kinase (ROCK) in cardiovascular fibrosis and stiffening” Expert Opin Ther Targets.24.1 (2020): 47-62) The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject with myocardial fibrosis or a secondary condition associated with heart fibrosis. Levodopa-induced dyskinesia (LID) Levodopa is a used in the treatment of Parkinson's disease (PD), but its long-term use is complicated by motor fluctuations and dyskinesia. Different types of movement disorders are seen in levodopa-induced dyskinesia (LID) including chorea, ballism, dystonia, myoclonus, or combination of any of these movements. These dyskinesias are seen in the neck, facial muscles, jaw, tongue, hip, shoulder, trunk, and limb or may appear as involuntary flexion of toes (Pandey, Sanjay, and Prachaya Srivanitchapoom. “Levodopa-induced dyskinesia: clinical features, pathophysiology, and medical management.” Annals of Indian Academy of Neurology 20.3 (2017): 190-198). There have been studies on the involvement of ROCK in the pathophysiology of LID (Lopez‐Lopez, Andrea, et al. “Rho kinase inhibitor fasudil reduces L‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease.” British Journal of Pharmacology 177.24 (2020): 5622-5641; Lopez-Lopez, Andrea, et al. “Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia.” Antioxidants 12.7 (2023): 1454). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat LID. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat peak-dose dyskinesia, wearing-off / off-period dyskinesia, or diphasic dyskinesia of LID. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with LID or a secondary condition associated with LID. Traumatic Brain Injury (TBI) Traumatic brain injuries (TBIs) can affect people of all ages and are a major cause of death and disability, with an incidence of ∼10 million people worldwide (Blennow, Kaj, et al. “Traumatic brain injuries.” Nature reviews Disease primers 2.1 (2016): 1-19.). Traumatic brain injuries (TBIs) are clinically grouped by severity: mild, moderate and severe. Mild TBI (the least severe form) is synonymous with concussion and is typically caused by blunt non-penetrating head trauma. ROCK proteins have been studied in traumatic brain injuries (Fujita, Yuki, and Toshihide Yamashita. “Axon growth inhibition by RhoA / ROCK in the central nervous system.” Frontiers in neuroscience 8 (2014): 338; Lerouet, Dominique, Catherine Marchand‐Leroux, and Valérie C. Besson. “Neuropharmacology in traumatic brain injury: from preclinical to clinical neuroprotection?” Fundamental & clinical pharmacology 35.3 (2021): 524-538; Brabeck, Christine, et al. “Lesional expression of RhoA and RhoB following traumatic brain injury in humans.” Journal of neurotrauma 21.6 (2004): 697-706; Mulherkar, Shalaka, et al. “RhoA-ROCK inhibition reverses synaptic remodeling and motor and cognitive deficits caused by traumatic brain injury.” Scientific reports 7.1 (2017): 10689; Feng, Shi-jun, and Jian-guo Han. “Treatment of traumatic brain injury in rats by RhoA gene silencing combined with umbilical cord mesenchymal stem cell transplantation.” Chinese Journal of Tissue Engineering Research 17.1 (2013): 23.). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat TBI. For example, in certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat mild TBI, moderate TBI or severe TBI. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with TBI or a secondary condition associated with TBI. Benign Prostatic Hyperplasia (BPH) Benign prostatic hyperplasia (BPH) results in a benign enlargement of the prostate gland due to unregulated hyperplastic growth of the epithelial andfibromuscular tissues of the transition zone (TZ) and periurethral area. (Devlin, Conor M., Matthew S. Simms, and Norman J. Maitland. “Benign prostatic hyperplasia–what do we know?” BJU international 127.4 (2021): 389-399.) Benign prostatic hyperplasia (BPH) is a major cause of lower urinary tract symptoms (LUTS) including nocturia, urinary frequency, urgency, decreased urine flow rates, incomplete bladder emptying, and hesitancy (Laborde, Eric E., and Kevin T. McVary. “Medical management of lower urinary tract symptoms.” Reviews in urology 11. Suppl 1 (2009): S19.). ROCK proteins have been studied in benign prostatic hyperplasia (Shan, Shidong, et al. “Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-β-catenin signaling axis and static & dynamic dual roles.” Molecular Medicine 29.1 (2023): 139; Takahashi, Ryosuke, et al. “RhoA / Rho kinase‐ mediated Ca2+sensitization in the contraction of human prostate.” Neurourology and urodynamics 26.4 (2007): 547-551; Morelli, Annamaria, et al. “BXL‐628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA / Rho kinase signaling in rat and human bladder.” The Prostate 67.3 (2007): 234-247; La Vignera, S., et al. “Endocrine control of benign prostatic hyperplasia.” Andrology 4.3 (2016): 404- 411). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat benign prostatic hyperplasia. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat lower urinary tract symptoms associated with benign prostatic hyperplasia. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with benign prostatic hyperplasia or a secondary condition associated with benign prostatic hyperplasia. Urinary Bladder Dysfunction (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. Sarcoidosis Sarcoidosis is a multi-system disease characterized by the formation of granulomas in various organs. Sarcoidosis most commonly affects the lungs and lymph nodes, but it can affect any organ including the eyes, skin, heart and nervous system (Sève, Pascal, et al. "Sarcoidosis: a clinical overview from symptoms to diagnosis." Cells 10.4 (2021): 766). ROCK proteins have been studied in sarcoidosis (Pehlivan, Yavuz, et al. “Investigation of the association between Rho / Rho-kinase gene polymorphisms and systemic sclerosis.” Rheumatology international 36 (2016): 421-427; Yuan, Ying, et al. “The role of the RhoA / ROCK signaling pathway in mechanical strain-induced scleral myofibroblast differentiation.” Investigative ophthalmology & visual science 59.8 (2018): 3619-3629; Li, Bo, et al. “Esophageal dysfunction in systemic sclerosis: an update.” Rheumatology and Therapy (2021): 1-15; Bei, Yihua, et al. “RhoA / Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis.” Experimental lung research 42.1 (2016): 44-55). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat pulmonary sarcoidosis. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat neurosarcoidosis. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with sarcoidosis or a secondary condition associated with sarcoidosis. Scleroderma Scleroderma is a rare, chronic autoimmune disease that affects skin and internal organs. Scleroderma results from the immune system and often causes inflammation and tissues changes leading to skin tightening and thickening. It can affect joints, muscles, heart, lungs, kidneys, blood vessels or intestines. (“Scleroderma” American College of Rheumatology, https: / / rheumatology.org / patients / scleroderma). ROCK proteins have been studied in scleroderma (Thompson‐Torgerson, Caitlin S., et al. “RhoA and Rho kinase activity is increased in scleroderma microvascular smooth muscle cells.” (2007): A1372-A1372). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat scleroderma. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with scleroderma or a secondary condition associated with scleroderma. Cancer There has been early, basic research on the role of ROCK in cancer (Ridley, A. J. “RhoA, RhoB and RhoC have different roles in cancer cell migration.” Journal of microscopy 251.3 (2013): 242-249; Barcelo, Jaume, Remi Samain, and Victoria Sanz-Moreno. “Preclinical to clinical utility of ROCK inhibitors in cancer.” Trends in Cancer 9.3 (2023): 250-263; Chin, Venessa T., et al. “Rho-associated kinase signaling and the cancer microenvironment: novel biological implications and therapeutic opportunities.” Expert reviews in molecular medicine 17 (2015): e17). For example, in certain advanced stage breast cancer models, ROCK has been shown to be overexpressed or of higher activity (Guerra, Fabiana Sélos, et al. “ROCK inhibition with Fasudil induces beta-catenin nuclear translocation and inhibits cell migration of MDA-MB 231 human breast cancer cells.” Scientific reports 7.1 (2017): 13723). Likewise, an amplification of ROCK1 and ROCK2 expression was observed in selected pancreatic cancer models. (Kim, Seohyun, et al. “Rho-kinase as a target for cancer therapy and its immunotherapeutic potential.” International journal of molecular sciences 22.23 (2021): 12916). Additional studies on ROCK protein in pancreatic cancer include the papers by Whatcott, Clifford J., et al. “Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer.” PloS one 12.8 (2017): e0183871; Mu, Ganggang, et al. “Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12 / 13–RhoA–ROCK signaling pathway.” Experimental & Molecular Medicine 50.5 (2018): 1-14; Vennin, Claire, et al. “Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy.” Small GTPases 11.1 (2020): 45-52; Vennin, Claire, et al. “Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.” Science translational medicine 9.384 (2017): eaai8504; and Zhu, Shuai, et al. “ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca2+ / RhoA pathway.” Cell death & disease 8.5 (2017): e2806-e2806. ROCK proteins have also been researched in melanoma models (Chang, Fei, et al. “ROCK inhibitor enhances the growth and migration of BRAF‐mutant skin melanoma cells.” Cancer science 109.11 (2018): 3428-3437; Teiti, Iotefa, et al. “In vivo effects in melanoma of ROCK inhibition-induced FasL overexpression.” Frontiers in oncology 5 (2015): 156; and Kaczorowski, Maciej, et al. “ROCK1 and ROCK2 are down-regulated in aggressive and advanced skin melanomas–a clinicopathological perspective.” Anticancer Research 40.4 (2020): 1931-1942). Initial studies on the role of ROCK proteins in prostate cancer have also been reported (Chen, Weihua, et al. “The role of the RhoA / Rho kinase pathway in anti-angiogenesis and its potential value in prostate cancer.” Oncology letters 8.5 (2014): 1907-1911; Steurer, Stefan, et al. “Up regulation of Rho-associated coiled-coil containing kinase1 (ROCK1) is associated with genetic instability and poor prognosis in prostate cancer.” Aging (Albany NY) 11.18 (2019): 7859; Liu, Kang, et al. “Genetic variants in RhoA and ROCK1 genes are associated with the development, progression and prognosis of prostate cancer.” Oncotarget 8.12 (2017): 19298). In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat pancreatic cancer. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat breast cancer. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat prostate cancer. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat melanoma. In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat desmoplastic syndromes associated with cancer. The present invention includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with cancer or a secondary condition associated with cancer. Non-limiting examples of cancer include pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer. Non-limiting examples of cancer include carcinomas, Kaposi’s sarcoma, melanoma, mesothelioma, soft tissue sarcoma, pancreatic cancer, lung cancer, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, and other), lymphoma (Hodgkin's and non- Hodgkin’s), multiple myeloma, adrenocortical carcinoma, cerebellar astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, Burkitt's lymphoma, carcinoid tumor, central nervous system lymphoma, cervical cancer, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, germ cell tumor, glioma,, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, retinoblastoma, islet cell carcinoma ( endocrine pancreas), laryngeal cancer, lip and oral cavity cancer, liver cancer, medulloblastoma, Merkel cell carcinoma, squamous neck cancer with occult mycosis fungoides, myelodysplastic syndromes, myelogenous leukemia, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma, soft tissue sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, Waldenström’s macroglobulinemia, and Wilms' tumor. Protein Kinase X (PRKX) PRKX, human protein kinase X, is an X chromosome encoded cAMP-dependent serine / threonine kinase. The cAMP-dependent protein kinases (cAPKs) play a key role in many signal transduction processes, mediating the majority of the known effects of cAMP in the eukaryotic cell. These multisubstrate enzymes regulate the activity of proteins involved in signal transduction, energy metabolism, cell proliferation, or differentiation by phosphorylation of Ser or Thr residues, which alters the biological properties of the target proteins. The human protein kinase PRKX is related to the catalytic subunit of cAMP-dependent protein kinases but is distinct from the isoforms Cα, Cβ, and Cγ. PRKX has 53.2% identity to the human Cα subunit of cAPK (PKA- Cα) in the catalytic core region. This degree of homology is much lower than the similarity of the two human isoforms Cα and Cβ (90.5% identity). PRKX mRNA is present in a variety of tissues, with the highest levels of expression in fetal and adult brain, kidney, and lung. (B. Zimmermann et al. “PRKX Is a Novel Catalytic Subunit of the cAMP-dependent Protein Kinase Regulated by the Regulatory Subunit Type I” Journal of Biological Chemistry, Vol. 274, No. 9, Issue of February 26, pp. 5370-5378, 1999.) In contrast to the ubiquitously expressed Cα subunit, PRKX is mainly active during embryonic organ development and cellular differentiation in hematopoietic lineages. It was found to be crucial for macrophage and granulocyte maturation. PRKX was shown to be involved in renal development, regulating epithelial cell migration, ureteric bud branching, and induction of glomeruli formation (M. Diskar et al. “Regulation of cAMP-dependent protein kinases: the human protein kinase X (PrKX) reveals the role of the catalytic subunit αH – αI loop” Journal of Biological Chemistry, Vol.285, No.46, pp.35910 –35918, November 12, 2010). The role of PRKX in disease pathology is not well understood. However, a recent study identified the dysregulation of PRKX expression as a possible molecular cause for Mayer– Rokitansky–Küster–Hauser (MRKH) syndrome (P. Pontecorvi et al. “Altered Expression of Candidate Genes in Mayer–Rokitansky–Küster–Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X” Biology, 2021, 10, 450.). PRKX has also been indicated in the pathology of amyotrophic lateral sclerosis (ALS) (Oliverira G. et al., Early Gene Expression Changes in Skeletal Muscle from SOD1(G93A) Amyotrophic Lateral Sclerosis Animal Model). In certain embodiments a method of treating a subject with a PRKX mediated disorder is provided comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome PRKX has been implicated in the development of Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome (P. Pontecorvi et al. “Altered Expression of Candidate Genes in Mayer– Rokitansky–Küster–Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X” Biology, 2021, 10, 450.). Thus, in certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat MRKH syndrome. The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome or a secondary condition associated with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. Graft-vs-Host Disease ROCK is associated as a driver in the pathogenesis of corticosteroid-refectory acute graft- vs-host disease, and ROCK1 / 2 inhibition has been shown to reduce immune activation in both the innate and adaptive immune systems. In animal models and clinical trials of acute graft-vs-host disease (aGVHD), ROCK inhibitors have demonstrated the ability to reduce alloimmune activation at a variety of cellular and molecular levels (https: / / www.nature.com / articles / s41467- 024-44703-7). The present invention thus includes the use of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a subject such as a human with graft-vs-host disease or a secondary condition associated with graft-vs-host disease. IV. PHARMACEUTICAL COMPOSITIONS A compound of the present invention 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 the present invention, or a pharmaceutically acceptable salt thereof can be used in an effective amount, either alone or in combination with a second therapeutic agent, to treat a subject such as a human with a ROCK1 and / or ROCK2 mediated disorder. The term “second therapeutic agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In certain embodiments, the compound of the present invention and the second therapeutic agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter. In another embodiment, the compound of the present invention and the second therapeutic agent are administered to a subject in need thereof and they do not have overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic efficacy of the other. Non-limiting examples of second therapeutic agents include riluzole, edaravone, sodium phenyl butyrate, taurursodiol, levodopa, selegiline, rasagiline, safinamide, pramipexole, rotigotine, apomorphine, tolcapone, entacapone, trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, amantadine, and istradefylline. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with tiluzole, edaravone, or taurusodiol to treat ALS. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with levodopa, selegiline, rasagiline, safinamide, pramipexole, rotigotine, apomorphine, tolcapone, entacapone, trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, amantadine, and istradefylline to treat PD. In other embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with levodopa and carbidopa to treat PD. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with amantadine, donepezil, clozapine, quetiapine, olanzapine, and apomorphine, tetrabenazine, clonazepam, propranolol, branched-chain amino acids (BCAAs), ginkgo biloba, zonisamide, levetiracetam, melatonin, omega-3 fatty acids, piracetam, resveratrol, vitamin B6, or vitamin E to treat Levodopa-induced dyskinesia. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with dapagliflozin, finerenone, canagliflozin, angiotensin receptor blockers (ARBs), bexagliflozin, empagliflozin, ertugliflozin, ramipril, quinapril, or lisinopril to treat diabetic nephropathy. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with tolvaptan, dapagliflozin, finerenone, canagliflozin, angiotensin receptor blockers (ARBs), bexagliflozin, empagliflozin, ertugliflozin, ramipril, quinapril, or lisinopril to treat polycystic kidney disease. In certain aspects a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with another ROCK inhibitor. Non-limiting examples of ROCK inhibitors include fasudil, netarsudil, and ripasudil. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with fasudil to treat ALS, PD, Levodopa-induced dyskinesia, diabetic nephropathy, or polycystic kidney disease. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination or alternation with netarsudil or ripasudil to treat an ocular disorder. VI. GENERAL SYNTHESIS The compounds described herein can be prepared by methods known by those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the schemes below. The abbreviations used in the synthetic procedures have the following definitions. Abbreviation Definition Example 1: Synthesis of (3S)-3-(2-Fluorophenyl)-4-[6-(3-methyl-2H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carbonyl]morpholine (Compound 1) Methyl 6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1-2) A solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (500.0 mg, 2.374 mmol, 1.0 equiv), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazole (740.9 mg, 3.561 mmol, 1.5 equiv) K2CO3(656.2 mg, 4.748 mmol, 2.0 equiv), XPhos (113.2 mg, 0.237 mmol, 0.1 equiv) and XPhos Pd G3 (200.9 mg, 0.237 mmol, 0.1 equiv) in dioxane (20 mL) and H2O (4 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford methyl 6-(3-methyl-2H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (237 mg, 39.0%) as a yellow solid. MS (ESI) m / z: 257.25 [M+H]+. 6-(3-Methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1-3) A solution of methyl 6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (227.0 mg, 0.886 mmol, 1.0 equiv) and LiOH·H2O (185.8 mg, 4.430 mmol, 5.0 equiv) in THF (3 mL), MeOH (1 mL) and H2O (1 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The mixture was acidified to pH 5-6 with HCl (2 M aq.). The resulting mixture was concentrated under reduced pressure to afford 6-(3-methyl-2H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxylic acid (563 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. MS (ESI) m / z: 243.05 [M+H]+. (3S)-3-(2-Fluorophenyl)-4-[6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (Compound 1) A solution of 6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (76.0 mg, 0.314 mmol, 1.0 equiv), DIEA (273.2 µL, 1.570 mmol, 5.0 equiv) and (3S)-3-(2- fluorophenyl)morpholine (56.8 mg, 0.314 mmol, 1.0 equiv) in dimethylformamide (3 mL) was stirred for 10 minutes at 0 °C. To the above mixture was added HATU (238.6 mg, 0.628 mmol, 2.0 equiv). The resulting mixture was stirred for an additional 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19 * 250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 46% B in 10 min, 46% B; Wave Length: 254 / 220 nm; RT1(min): 9.69; to afford (3S)-3-(2-fluorophenyl)-4-[6-(3- methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl]morpholine (36.1 mg, 28.4%) as a white solid. MS (ESI) m / z: 406.25 [M+H]+ 1 H NMR (400 MHz, Methanol-d4) δ 7.99 (d, J = 8.3 Hz, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.43 – 7.33 (m, 2H), 7.23 (td, J = 7.6, 1.3 Hz, 1H), 7.13 (ddd, J = 11.1, 8.2, 1.2 Hz, 1H), 6.74 (s, 1H), 5.92 (s, 1H), 4.44 (d, J = 12.2 Hz, 1H), 4.36 (d, J = 11.3 Hz, 1H), 4.09 – 3.94 (m, 2H), 3.75 – 3.57 (m, 2H), 2.64 (s, 3H) ppm. Example 2: Synthesis of (3S)-3-(2-Fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carbonyl]morpholine (Compound 2) Methyl 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2-1) A solu on o me y -c oro- -pyrroo[ , - ]pyr ne- -car oxya e ( g, . mmol, 1.0 equiv), K2CO3(3.94 g, 28.488 mmol, 2.0 equiv), XPhos Pd G3 (1.21 g, 1.424 mmol, 0.1 equiv), XPhos (679.0 mg, 1.424 mmol, 0.1 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (4.15 g, 21.366 mmol, 1.5 equiv) in 1,4-dioxane (108 mL) and H2O (22 mL) was stirred overnight at 100oC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (300 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2.6 g, 75.3%) as a yellow solid. MS (ESI) m / z: 243.0 [M+H]+. 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-2) A solution of methyl 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2.6 g, 10.733 mmol, 1.0 equiv) and LiOH (1.3 g, 53.665 mmol, 5.0 equiv) in THF (24 mL), MeOH (8 mL) and H2O (8 mL) was stirred for 2 hours at room temperature. The reaction was monitored by LCMS. After completion, the mixture was acidified to pH 5 with HCl (aq. 1 M) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / MeOH (1:1) to afford 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.8 g, 73.4%) as a yellow solid. MS (ESI) m / z: 229.0 [M+H]+. (3S)-3-(2-Fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (Compound 2) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (188.9 mg, 0.828 mmol, 1.0 equiv), (3S)-3-(2-fluorophenyl)morpholine (150.0 mg, 0.828 mmol, 1.0 equiv), DIEA (432.5 uL, 2.484 mmol, 3.0 equiv), HOBT (111.9 mg, 0.828 mmol, 1.0 equiv) and EDCI (158.7 mg, 0.828 mmol, 1.0 equiv) in dimethylformamide (5 mL) was stirred overnight at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water. The mixture was acidified to pH 5 with HCl (2 M aq.). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19 * 250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 23% B to 43% B in 10 min, 43% B; Wave Length: 254 / 220 nm; RT1(min): 10.58; to afford (3S)-3-(2-fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carbonyl]morpholine (98.8 mg, 30.5%) as a white solid. MS (ESI) m / z: 392.00 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.72 (td, J = 8.0, 0.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 – 7.31 (m, 1H), 7.23 (td, J = 7.6, 1.2 Hz, 1H), 7.20 – 7.10 (m, 1H), 6.74 (s, 1H), 5.91 (s, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.36 (d, J = 10.8 Hz, 1H), 4.08 – 3.93 (m, 2H), 3.76 – 3.59 (m, 2H) ppm. Example 3: Synthesis of (3R)-3-(2-fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carbonyl]morpholine (Compound 3)

[0073] 2-Amino-2-(2-fluorophenyl)ethanol (3-1) To a stirred solution of LiBH4 (2 M in THF, 29.6 mL, 59.12 mmol, 2.0 equiv.) in THF was added chlorotrimethylsilane (10.6 mL, 83.95 mmol, 2.8 equiv) over 2 minutes at room temperature under nitrogen atmosphere. The white suspension was cooled to 0 °C and amino (2-fluorophenyl) acetic acid (5.00 g, 29.56 mmol, 1.0 equiv) was added portion-wise over 5 min. The ice bath was removed and the compact off-white suspension was stirred at room temperature for 20 h. Desired product could be detected by LCMS. The mixture was cooled again to 0 °C and treated carefully with methanol (15 mL). The mixture was stirred at room temperature for 30 min, filtered and the cake was washed with MeOH. The filtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-amino-2-(2- fluorophenyl)ethanol (2.65 g, 57.8%) as a brown solid. MS (ESI) m / z: 156.20 [M+H]+. 2-Chloro-N-[1-(2-fluorophenyl)-2-hydroxyethyl]acetamide (3-2) A solution of 2-amino-2-(2-fluorophenyl)ethanol (2.5 g, 16.11 mmol, 1.0 equiv) and Et3N (4.89 g, 48.33 mmol, 3.0 equiv) in THF (20 mL) was stirred at 0 °C. To the above mixture was added chloroacetyl chloride (2.18 g, 19.33 mmol, 1.2 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional one hour at 0 °C. Desired product could be detected by LCMS. After completion, the reaction was quenched by saturated NH4Cl (aq.) The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-chloro-N-[1-(2-fluorophenyl)-2- hydroxyethyl]acetamide (3.4 g, 91.1%) as a white solid. MS (ESI) m / z: 232.45 [M+H]+. (5R)-5-(2-fluorophenyl)morpholin-3-one (3-3) A solution of 2-chloro-N-[1-(2-fluorophenyl)-2-hydroxyethyl]acetamide (2.5 g, 10.79 mmol, 1.0 equiv) in THF (150 mL) was stirred at room temperature under nitrogen atmosphere. To the above mixture was added NaH (0.52 g, 12.95 mmol, 1.2 equiv, 60% in mineral oil) at room temperature. The resulting mixture was stirred for additional one hour at room temperature. Desired product could be detected by LCMS. After completion, the reaction was quenched by HCl (1 M, aq.), The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford rac-5-(2-fluorophenyl)morpholin-3-one (1.7 g, 80.7%) as a light yellow solid. The racemic product was separated by Prep-SFC with the following conditions (Column: NB_CHIRALPAK AD-H, 3 * 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH--HPLC; Flow rate: 70 mL / min; Gradient: isocratic 55% B; Column Temperature (℃): 35; Back Pressure(bar): 100; Wave Length: 262 / 204 nm; RT1 (min): 3.52; RT2 (min): 7.72 (target peak); Sample Solvent: MeOH: DCM=1: 1--HPLC; injection volume: 4 mL; to afford (5R)-5-(2- fluorophenyl)morpholin-3-one (603 mg) as a light yellow solid. MS (ESI) m / z: 196.20 [M+H]+. (3R)-3-(2-fluorophenyl)morpholine (3-4) A solution of (5R)-5-(2-fluorophenyl)morpholin-3-one (300 mg, 1.54 mmol, 1.0 equiv) and BH3- THF (4.0 mL, 4.0 mmol, 2.6 equiv) in THF (4.0 mL) was stirred for one hour at room temperature under nitrogen atmosphere. Then, the resulting mixture was stirred overnight at 80 °C. After completion, the reaction was quenched with water at room temperature and neutralized to pH 7 with NaOH (2 M). The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (3R)-3-(2-fluorophenyl)morpholine (130 mg, 46.7%) as a yellow oil. MS (ESI) m / z: 182.20 [M+H]+. (3R)-3-(2-fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (Compound 3) A sol ution of (3R)-3-(2-fluorophenyl)morpholine (120 mg, 0.66 mmol, 1.0 equiv), 6-(1H-pyrazol- 4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (151 mg, 0.66 mmol, 1.0 equiv), EDCI (127 mg, 0.66 mmol, 1.0 equiv), HOBT (89 mg, 0.66 mmol, 1.0 equiv) and DIEA (346 µL, 1.99 mmol, 3.0 equiv) in DMF (2.0 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. After completion, the mixture was acidified to pH 6 with HCl (2 M). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19 * 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.1% NH3·H2O), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 24% B to 41% B in 8 min, 41% B; Wave Length: 254 / 220 nm; RT1 (min): 8.32; to afford (3R)-3-(2-fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (36.5 mg, 13.9%) as a white solid. MS (ESI) m / z: 392.20 [M+H]+.1H NMR (400 MHz, MeOH-d4) δ: 8.19 (s, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.25 - 7.19 (m, 1H), 7.16 - 7.08 (m, 1H), 6.73 (s, 1H), 5.90 (d, J = 3.6 Hz, 1H), 4.43 (d, J = 12 Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.05 - 3.90 (m, 2H), 3.73 - 3.58 (m, 2H) ppm.19F NMR (376 MHz, MeOH-d4) δ -116.98 (s) ppm. Example 4: Synthesis of (3S)-3-(2-fluorophenyl)-4-[1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carbonyl]morpholine (Compound 4) 6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (4-3) To a solution of 6-chloro-3-iodopyridin-2-amine (4-1) (9.00 g, 35.4 mmol), 2-oxopropanoic acid (4-2) (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 4-3 (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 (4-4) To a solution of 4-3 (5.70 g, 35.4 mmol) in ethanol (170 mL) was added 98% sulfuric acid (14.5 g, 145 mmol) at 0oC, and the reaction mixture was stirred at 80oC for eighteen hours, which was monitored by LCMS. The resulting mixture was neutralized with sat. aq. sodium bicarbonate to pH 7-8 and then concentrated to remove ethanol. The residual aqueous mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 2) to give 4-4 (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 (4-5) To a suspension of 4-4 (1.03 g, 4.60 mmol) and potassium carbonate (2.54 g, 18.4 mmol) in N,N-dimethylacetamide (DMA, 21.0 mL) was added iodomethane (1.96 g, 13.8 mmol). The reaction mixture was stirred at room temperature for 72 hours, which was monitored by LCMS. The resulting mixture was poured into water (63 mL). The precipitate was filtered to collect, washed with water (5 mL × 2) and dried. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 2) to give 4-5 (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 (4-7) To a solution of 4-5 (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 4-6 (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 4-7 (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 (4-8) To a solution of compound 4-7 (400 mg, 1.48 mmol) in water (2.6 mL), tetrahydrofuran (THF, 7.8 mL) and methanol (2.6 mL) was added lithium hydroxide monohydrate (0.311 g, 7.41 mmol). The reaction mixture was stirred at 20oC for three hours and the reaction progress was monitored by LCMS. The reaction mixture was concentrated in vacuo and diluted with water (2 mL). The aqueous mixture was acidified with conc. aq. hydrochloride to pH 1 and then filtered. The filter-cake was dried in vacuo to give 4-8 (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. (3S)-3-(2-fluorophenyl)-4-[1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (Compound 4) To a stirred solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (111.0 mg, 0.458 mmol, 1.0 equiv) in DMF (3 mL) was added (3S)-3-(2-fluorophenyl)morpholine (99.6 mg, 0.550 mmol, 1.2 equiv), DIEA (399.1 µL, 2.290 mmol, 5.0 equiv) and HATU (348.5 mg, 0.916 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. After completion, the resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate 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: MeOH--HPLC; Flow rate: 60 mL / min; Gradient: 48% B to 62% B in 9 min, 62% B; Wave Length: 254 / 220 nm; RT1 (min): 11.13; to afford (3S)-3-(2-fluorophenyl)-4-[1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine- 2-carbonyl]morpholine (57.8 mg, 31.1%) as a white solid. MS (ESI) m / z: 406.25 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.81 (td, J = 8.0, 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41 – 7.34 (m, 1H), 7.25 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (ddd, J = 10.8, 8.8, 0.8 Hz, 1H), 6.66 (s, 1H), 5.87 (s, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.21 – 4.12 (m, 1H), 4.08 (dd, J = 12.0, 4.0 Hz, 1H), 3.99 (dd, J = 11.2, 2.8 Hz, 1H), 3.89 (s, 3H), 3.71 (td, J = 12.0, 2.8 Hz, 1H), 3.53 – 3.43 (m, 1H) ppm. Example 5: Synthesis of 4-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (Compound 5) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (165.8 mg, 0.726 mmol, 1.0 equiv), (2R)-2-(2-fluorophenyl)pyrrolidine (120.0 mg, 0.726 mmol, 1.0 equiv), DIEA (379.6 µL, 2.178 mmol, 3.0 equiv), HOBT (98.2 mg, 0.726 mmol, 1.0 equiv) and EDCI (139.2 mg, 0.726 mmol, 1.0 equiv) in DMF (4 mL) was stirred overnight at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate 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+ 0.1% NH3·H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 42% B in 9 min, 42% B; Wave Length: 254 / 220 nm; RT1 (min): 12.67; to afford 4-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]- 1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (98.8 mg, 36.2%) as a white solid. MS (ESI) m / z: 376.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.18 (s, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.34 – 7.09 (m, 4H), 7.04 (s, 1H), 5.44 (s, 1H), 4.24 – 3.74 (m, 2H), 2.46 – 2.29 (m, 1H), 2.07 – 1.91 (m, 2H), 1.83 – 1.69 (m, 1H) ppm. Example 6: Synthesis of N-cyclopropyl-N-[(2-fluorophenyl)methyl]-6-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 6) N-[(2-fluorophenyl)methyl]cyclopropanamine (6-1) A solution of 2-flu oro-benzaldehyde (1.0 mL, 9.491 mmol, 1.0 equiv) and cyclopropanamine (789 µL, 11.39 mmol, 1.2 equiv) in MeOH (8 mL) was stirred for 30 minutes at 0 °C. To the above mixture was added NaBH3CN (1193 mg, 18.98 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for an additional 2 hours at room temperature. Desired product could be detected by LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-[(2-fluorophenyl)methyl]cyclopropanamine (870 mg, 55.5%) as a colorless oil. MS (ESI) m / z: 166.35 [M+H]+. N-cyclopropyl-N-[(2-fluorophenyl)methyl]-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 6) A solution of N-[(2-fluorophenyl)methyl]cyclopropanamine (200 mg, 1.21 mmol, 1.0 equiv), 6- (1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (276 mg, 1.21 mmol, 1.0 equiv), EDCI (232 mg, 1.21 mmol, 1.0 equiv), HOBT (164 mg, 1.21 mmol, 1.0 equiv) and DIEA (469 mg, 3.63 mmol, 3.0 equiv) in DMF (2 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. After completion, the reaction was quenched with water and acidified to pH 5 with HCl (1 M aq.). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 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: MeCN; Flow rate: 50 mL / min; Gradient: 32% B to 49% B in 8 min, 49% B; Wave Length: 254 / 220 nm; RT1 (min): 8.17; to afford N-cyclopropyl-N-[(2-fluorophenyl)methyl]-6-(1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (35.2 mg, 7.6%) as a white solid. MS (ESI) m / z: 376.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 13.03 (s, 1H), 11.93 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.25 - 7.17 (m, 2H), 7.05 (d, J = 4.0 Hz, 1H), 4.79 (s, 2H), 3.13 - 3.01 (m, 1H), 0.82 - 0.75 (m, 2H), 0.72 - 0.65 (m, 2H) ppm.19F NMR (376 MHz, DMSO-d6) δ: -120.30 (s) ppm.

[0074] Example 7: Synthesis of N-[(2-fluorophenyl)methyl]-N-methyl-6-(1H-pyrazol-4-yl)- 1H- pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 7) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (200 mg, 0.876 mmol, 1.0 equiv), EDCI (168.0 mg, 0.876 mmol, 1.0 equiv), HOBT (118.4 mg, 0.876 mmol, 1.0 equiv), DIEA (457.0 µL, 2.628 mmol, 3.0 equiv) and [(2-fluorophenyl)methyl](methyl)amine (182.9 mg, 1.314 mmol, 1.5 equiv) in DMF (4 mL) was stirred overnight at room temperature. The reaction was monitored by LCMS. After completion, the mixture was neutralized to pH 7 with HCl (aq.1 M) and concentrated under reduced pressure. The residue 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: MeCN; Flow rate: 60 mL / min; Gradient: 22% B to 38% B in 10 min, 38% B; Wave Length: 220 / 254 nm; RT1 (min): 12.73) to afford N-[(2-fluorophenyl)methyl]-N-methyl-6-(1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2- carboxamide (50.3 mg, 16.2%) as a white solid. MS (ESI) m / z: 350.25 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 13.01 (s, 1H), 12.00 (s, 1H), 8.47 - 8.04 (m, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.28 - 7.18 (m, 2H), 6.81 (s, 1H), 4.83 (s, 2H), 3.20 (s, 3H) ppm. Example 8: Synthesis of N-[(2-fluorophenyl)methyl]-N-(oxetan-3-yl)-6-(1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 8)

[0075] N-[(2-fluorophenyl)methyl]oxetan-3-amine (8-1) A solution of 2-fluoro-benzaldehyde (1.0 mL, 9.49 mmol, 1.0 equiv) and oxetan-3-amine (832.5 mg, 11.39 mmol, 1.2 equiv) in MeOH (1.0 mL) was stirred for 30 minutes at 0 °C. To the above mixture was added NaBH3CN (1192.9 mg, 18.98 mmol, 2.0 equiv) in portions at 0 °C. The resulting mixture was stirred for additional one hour at room temperature. Desired product could be detected by LCMS. After completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford N-[(2-fluorophenyl)methyl]oxetan-3-amine (876.0 mg, 50.9%) as a colorless oil. MS (ESI) m / z: 182.1 [M+H]+. N-[(2-fluorophenyl)methyl]-N-(oxetan-3-yl)-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 8) To a stirred solution of N-[(2-fluorophenyl)methyl]oxetan-3-amine (95.0 mg, 0.526 mmol, 1.0 equiv) in DMF (2.0 mL) was added 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (120.0 mg, 0.53 mmol, 1.0 equiv), EDCI (100.8 mg, 0.53 mmol, 1.0 equiv), HOBT (71.1 mg, 0.53 mmol, 1.0 equiv) and DIEA (275 µL, 1.58 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for additional 2 hours at room temperature. The mixture was acidified to pH 5 with 1 M HCl (aq.) and extracted with EtOAc (3 x 5.0 mL). The combined organic layers were washed with brine (3 x 5.0 mL) and dried over anhydrous Na2SO4. 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: MeCN; Flow rate: 60 mL / min; Gradient: 15% B to 33% B in 9 min, 33% B; Wave Length: 254 / 220 nm; RT1 (min): 12.38; to afford N-[(2-fluorophenyl)methyl]-N-(oxetan-3-yl)-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carboxamide (19.10 mg, 9.2%) as a white solid. MS (ESI) m / z: 392.20 [M+H]+.1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 8.20 (s, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.11 - 7.22 (m, 2H), 6.60 (s, 1H), 5.39 (s, 1H), 5.17 (s, 2H), 4.84 (t, J = 7.3 Hz, 2H), 4.76 (t, J = 7.0 Hz, 2H) ppm. Example 9: Synthesis of 4-(2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1- methylpyrrolo[2,3-b]pyridin-6-yl-1H-pyrazole (Compound 9) A solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (300 mg, 1.24 mmol, 1.0 equiv), EDCI (356 mg, 1.86 mmol, 1.5 equiv), HOBt (251 mg, 1.86 mmol, 1.5 equiv), DIEA (647 µL, 3.71 mmol, 3.0 equiv) and (2R)-2-(2-fluorophenyl)pyrrolidine (225 mg, 1.36 mmol, 1.1 equiv) in DMF (8 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 30 mL), dried over anhydrous Na2SO4. 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: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 40% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 11.45) to afford 4-(2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1- methylpyrrolo[2,3-b]pyridin-6-yl-1H-pyrazole (55.3 mg, 11.2%) as a white solid. MS (ESI) m / z: 390.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 12.83 (s,1H), 8.31 - 8.14 (m, 2H), 8.04 - 7.76 (m, 1H), 7.53 - 7.09 (m, 4H), 6.99 (s, 1H), 5.53 - 5.33 (m, 1H), 4.07 - 3.75 (m, 4H), 3.63 (s, 1H), 2.46 - 2.34 (m, 1H), 2.01 -1.69 (m, 4H) ppm.19F NMR (376 MHz, DMSO-d6) δ -118.66 (s), - 119.35 (s) ppm. Example 10: Synthesis of 2-[(2R)-1-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]pyrrolidin-2-yl]pyridine (Compound 10) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (250.0 mg, 1.095 mmol, 1.0 equiv), 2-[(2R)-pyrrolidin-2-yl]pyridine (194.8 mg, 1.314 mmol, 1.2 equiv), EDCI (252.0 mg, 1.314 mmol, 1.2 equiv), HOBt (177.6 mg, 1.314 mmol, 1.2 equiv) and DIEA (583.4 μL, 3.285 mmol, 3.0 equiv) in DMF (4 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19 * 250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.1% NH3·H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 33% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.87) to afford 2-[(2R)-1-[6-(1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carbonyl]pyrrolidin-2-yl]pyridine (66.0 mg, 16.8%) as a white solid.MS (ESI) m / z: 359.05 [M+H]+. Retention time: 1.29 min, 99.4% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 11.81 (s, 1H), 8.53 – 8.47 (m, 1H), 8.18 (s, 2H), 8.04 (d, J = 8.3 Hz, 1H), 7.90 – 7.65 (m, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 6.2 Hz, 1H), 7.03 (s, 1H), 5.29 (s, 1H), 4.16 – 3.78 (m, 2H), 2.34 (s, 1H), 2.10 – 1.72 (m, 3H) ppm. Example 11: Synthesis of 4-(2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl-3-methyl-1H-pyrazole (Compound 11) A solution of 6-(3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (250.0 mg, 1.032 mmol, 1.0 equiv), (2R)-2-(2-fluorophenyl)pyrrolidine (204.6 mg, 1.238 mmol, 1.2 equiv), EDCI (237.4 mg, 1.238 mmol, 1.2 equiv), HOBt (167.3 mg, 1.238 mmol, 1.2 equiv) and DIEA (539.3 µL, 3.096 mmol, 3.0 equiv) in DMF (5 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1). 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: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 46% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 2) to afford 4-(2-[(2R)-2- (2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl-3-methyl-1H-pyrazole (99.0 mg, 24.6%) as a white solid. MS (ESI) m / z: 390.05[M+H]+. Retention time: 1.50 min, 99.8% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 12.85 – 12.54 (m, 1H), 11.79 (s, 1H), 8.25 – 7.77 (m, 2H), 7.55 – 6.95 (m, 6H), 5.45 (s, 1H), 4.29 – 3.75 (m, 2H), 2.70 – 2.52 (m, 3H), 2.46 – 2.33 (m, 1H), 2.10 – 1.68 (m, 3H) ppm.19F NMR (376 MHz, DMSO-d6) δ -118.18 (s), -119.18 (s) ppm. Example 12: Synthesis of N-[(1R)-1-(2-fluorophenyl)ethyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 12) A solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (474 mg, 1.957 mmol, 1.0 equiv); HOBt (397 mg, 2.936 mmol, 1.5 equiv); DIEA (759 mg, 5.871 mmol, 3.0 equiv) and (1R)-1-(2-fluorophenyl)ethanamine (300 mg, 2.153 mmol, 1.1 equiv) in DMF (20 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 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: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 43% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.7) to afford N-[(1R)-1-(2-fluorophenyl)ethyl]- 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxamide (60.0 mg, 8.4%) as a white solid. MS (ESI) m / z: 364.25 [M+H]+. Retention time: 1.80 min, 99.5% @ 254 nm.1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.59 – 7.46 (m, 2H), 7.36 – 7.24 (m, 2H), 7.24 – 7.12 (m, 2H), 5.51 – 5.33 (m, 1H), 4.00 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H) ppm.19F NMR (282 MHz, DMSO-d6) δ -119.90 (s) ppm.

[0076] Example 13: Synthesis of N-[(1R)-1-(3-chlorophenyl)ethyl]-1-methyl-6-(1H-pyrazol-4- yl)pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 13) A solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (300 mg, 1.238 mmol, 1.0 equiv), HOBt (251 mg, 1.857 mmol, 1.5 equiv), DIEA (240 mg, 1.857 mmol, 1.5 equiv), and (1R)-1-(3-chlorophenyl)ethanamine (212 mg, 1.362 mmol, 1.1 equiv) in DMF (12 mL) was stirred for 2 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 EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford an off-white solid. The crude product (250 mg) 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+0.1% NH3·H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 52% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.05) to afford N-[(1R)-1-(3-chlorophenyl)ethyl]-1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2- carboxamide (57.0 mg, 12.1%) as a white solid. MS (ESI) m / z: 380.2 [M+H]+. Retention time: 1.76 min, 99.7% @ 254 nm.1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.43 – 7.36 (m, 2H), 7.35 – 7.26 (m, 1H), 7.24 (s, 1H), 5.27 – 5.10 (m, 1H), 4.01 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H) ppm.

[0077] Example 14: Synthesis of 4-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-imidazole (Compound 14) Methyl 6-[3-(oxan-2-yl)imidazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (14-1) A s olution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.1 g, 5.22 mmol, 1.0 equiv), 1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (1.74 g, 6.27 mmol, 1.2 equiv), XPhos Pd G3 (0.44 g, 0.52 mmol, 0.1 equiv), XPhos (0.25 g, 0.52 mmol, 0.1 equiv) and K2CO3(1.44 g, 10.45 mmol, 2.0 equiv) in dioxane (10 mL) and H2O (2 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered the filter cake was washed with EtOAc (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 6-[3-(oxan-2-yl)imidazol-4-yl]-1H- pyrrolo[2,3-b]pyridine-2-carboxylate (1.22 g, 71.6%) as a brown yellow solid. 6-[3-(oxan-2-yl)imidazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (14-2) A solution of methyl 6-[3-(oxan-2-yl)imidazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.22 g, 3.74 mmol, 1.0 equiv) and lithium hydroxide hydrate (784 mg, 18.69 mmol, 5.0 equiv) in MeOH (200 µL), H2O (2 mL) and THF (6 mL) was stirred for one hour at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with HCl (1 M). The resulting mixture was filtered the filter cake was washed with EtOAc (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. 5-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1- (oxan-2-yl) imidazole (14-3) A solution of 6-[3-(oxan-2-yl)imidazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (550 mg, 1.76 mmol, 1.0 equiv), DIEA (920 µL, 5.28 mmol, 3.0 equiv), HATU (1004 mg, 2.64 mmol, 1.5 equiv) and (2R)-2-(2-fluorophenyl)pyrrolidine (349 mg, 2.11 mmol, 1.2 equiv) in DMF (3 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was quenched with water (10 mL). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 5- {2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1-(oxan-2- yl) imidazole (424 mg, 52.4%) as a brown oil. 4-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H- imidazole (Compound 14) A solution of 5-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6- yl}-1-(oxan-2-yl)imidazole (400 mg, 0.87 mmol, 1.0 equiv) and HCl (4 M) in 1,4-dioxane (0.53 mL) was stirred for 30 minutes at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with saturated Na2CO3(aq.). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. 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 (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 65% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 10.85), 4-{2-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-imidazole (53.6 mg, 16.3%) was afforded as a white solid. Compound was noted to contain approx. 0.7 mol% TFA by19F NMR. MS (ESI) m / z: 376.55 [M+H]+. Retention time: 1.39 min, 99.7% @ 254 nm.1H NMR (400 MHz, Methanol-d4) δ: 8.15 - 7.49 (m, 4H), 7.40 - 7.03 (m, 5H), 5.81 - 5,53 (m, 1H), 4.26 -3.88 (m, 2H), 2.50 - 2.37 (m, 1H), 2.18 - 1.85 (m, 3H) ppm.19F NMR (376 MHz, Methanol-d4) δ: -79.69 (s), -119.88 (s), -120.59 (s), -121.39 (s) ppm.

[0078] Example 15: Synthesis of 4-(2-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl-1H-pyrazole (Compound 15) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (240.0 mg, 1.052 mmol, 1.0 equiv), (2R)-2-(3-methoxyphenyl)pyrrolidine hydrochloride (269.7 mg, 1.262 mmol, 1.2 equiv), EDCI (241.9 mg, 1.262 mmol, 1.2 equiv), HOBt (170.5 mg, 1.262 mmol, 1.2 equiv) and DIEA (732 µL, 4.208 mmol, 4.0 equiv) in DMF (4 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20:1). 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: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 41% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 1) to afford 4- (2-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl-1H- pyrazole (68.0 mg, 16.7%) as a white solid. MS (ESI) m / z: 388.05 [M+H]+. Retention time: 1.78 min, 98.9% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 11.85 (s, 1H), 8.30 (s, 1H), 8.17 – 7.79 (m, 2H), 7.54 – 7.34 (m, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.02 (s, 1H), 6.92 – 6.72 (m, 3H), 5.54 - 5.23 (m, 1H), 4.26 – 3.78 (m, 2H), 2.44 – 2.24 (m, 1H), 2.06 – 1.84 (m, 2H), 1.85 – 1.63 (m, 1H) ppm. Example 16: Synthesis of 4-{3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (Compound 16) Methyl-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (16-1) A solution of methyl-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.26 g, 5.982 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.74 g, 8.973 mmol, 1.5 equiv), K2CO3(1.65 g, 11.964 mmol, 2.0 equiv), XPhos (285.2 mg, 0.598 mmol, 0.1 equiv) and XPhos Pd G3 (16.8 mg, 0.020 mmol, 0.1 equiv) in dioxane (45 mL) and H2O (9 mL) was stirred for 4 hours at 100oC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford methyl-6-(1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (700.0 mg, 48.3%) as a white solid. MS (ESI) m / z: 243.1 [M+H]+. 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (16-2) A solution of methyl 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500 mg, 2.064 mmol, 1.0 equiv) and LiOH·H2O (1.73 g, 41.280 mmol, 20 equiv) in THF (12 mL), MeOH (4 mL) and H2O (4 mL) was stirred for 3 hours at 80oC. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The mixture was acidified to pH 3 with HCl (aq.). The precipitated solids were collected by filtration and washed with diethyl ether (3 x 50 mL). This resulted in 6-(1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (400.0 mg, crude) as a white solid. MS (ESI) m / z: 229.1 [M+H]+. 4-{3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H- pyrazole (Compound 16) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (300.0 mg, 1.315 mmol, 1.0 equiv), (2R)-2-(2-fluorophenyl)pyrrolidine (260.6 mg, 1.578 mmol, 1.2 equiv), EDCI (378.0 mg, 1.972 mmol, 1.5 equiv), HOBt (266.4 mg, 1.972 mmol, 1.5 equiv) and DIEA (686.9 uL, 3.945 mmol, 3.0 equiv) in DMF (10 mL) was stirred overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (260.0 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), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 36% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 2) to afford 4-{3-[(2R)-2-(2- fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (70.7 mg, 14.0%) as a white solid. MS (ESI) m / z: 376.00 [M+H]+. Retention time: 4.02 min, 98.0% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ: 13.00 (s, 1H), 12.16 (s, 1H), 8.47 – 7.90 (m, 4H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 - 7.10 (m, 4H), 5.49 (s, 1H), 4.25 – 3.80 (m, 2H), 2.45 – 2.28 (m, 1H), 2.10 – 1.65 (m, 3H) ppm.19F NMR (376 MHz, DMSO-d6) δ: -119.30 (s) ppm. Example 17: Synthesis of 1-Methyl-6-(1H-pyrazol-4-yl)-N-(pyridin-2-ylmethyl)pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 17) A solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (300.0 mg, 1.238 mmol, 1.0 equiv), 2-pyridinemethaneamine (200.9 mg, 1.857 mmol, 1.5 equiv), EDCI (288.4 mg, 1.857 mmol, 1.5 equiv), HOBt (251.0 mg, 1.857 mmol, 1.5 equiv) and DIEA (647.1 µL, 3.714 mmol, 3.0 equiv) in DMF (10 mL) was stirred for 3 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (290.0 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: ACN; Flow rate: 60 mL / min; Gradient: isocratic 2% B to 18% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 11.63). The salt 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+0.1% NH3·H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 21% B to 36% B in 9 min; Wave Length: 254 nm / 220 nm; RT1 (min): 7.53 / 8.83) to afford 1-methyl-6-(1H-pyrazol-4-yl)-N-(pyridin-2-ylmethyl)pyrrolo[2,3- b]pyridine-2-carboxamide (54.0 mg, 12.9%) as a white solid. MS (ESI) m / z: 333.00 [M+H]+. Retention time: 1.13 min, 98.9% at 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.16 (t, J = 6.1 Hz, 1H), 8.59 – 8.48 (m, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.28 (dd, J = 7.5, 4.9 Hz, 1H), 7.20 (s, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.07 (s, 3H) ppm. Example 18: Synthesis of 1-Methyl-6-(1H-pyrazol-4-yl)-N-[(1R)-1-[3- (trifluoromethyl)phenyl]ethyl]pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 18) A solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (175 mg, 0.722 mmol, 1.0 equiv), EDCI (167 mg, 0.866 mmol, 1.2 equiv), HOBt (146 mg, 1.083 mmol, 1.5 equiv) in DMF (7 mL) was treated with DIEA (140 mg, 1.083 mmol, 1.5 equiv) for 5 minutes at room temperature under nitrogen atmosphere followed by the addition of (1R)-1-[3- (trifluoromethyl)phenyl]ethanamine (150 mg, 0.794 mmol, 1.1 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 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 EtOAc (3 x 50 mL). The combined organic layers were washed with HCl (pH = 5, 40 mL) and brine (3 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford a white solid. The crude product (200 mg) 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+0.05% NH3·H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 54.5% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.92) to afford 1-methyl-6-(1H-pyrazol-4-yl)-N-[(1R)-1-[3- (trifluoromethyl)phenyl]ethyl]pyrrolo[2,3-b]pyridine-2-carboxamide (57.0 mg, 19.0%) as a white solid. MS (ESI) m / z: 414.2 [M+H]+. Retention time: 1.84 min, 99.7% at 254 nm.1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.00 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.82 – 7.69 (m, 2H), 7.64 – 7.55 (m, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 5.35 – 5.20 (m, 1H), 4.00 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H) ppm.19F NMR (282 MHz, DMSO-d6) δ -60.92 (s) ppm. Example 19: Synthesis of (3S)-3-(3-chlorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carbonyl]morpholine (Compound 19) (2S)-2-amino-2-(3-chlorophenyl)ethanol (19-1) To a stirred solution of LiBH4 (2 M in THF, 2.9 mL, 25.9 mmol, 2.0 equiv) was added chlorotrimethylsilane (4.7 mL, 36.72 mmol, 2.84 equiv) dropwise over 2 minutes under nitrogen atmosphere. The mixture was allowed to cool down to 0 °C. To the above mixture was added (S)- amino(3-chlorophenyl)acetic acid (2.4 g, 12.93 mmol, 1.0 equiv) in portions over 1 minute at 0 °C. The resulting mixture was stirred for additional 20 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched with MeOH at 0 °C. The resulting mixture was stirred for 30 minutes at room temperature. The resulting mixture was washed with 2 x 30 mL of MeOH. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (2S)-2-amino- 2-(3-chlorophenyl)ethanol (2.07 g, 93.3%) as a white solid. 2-Chloro-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]acetamide (19-2) To a stirred solution of (2S)-2-amino-2-(3-chlorophenyl)ethanol (1.8 g, 10.49 mmol, 1.0 equiv) and Et3N (4.37 mL, 31.46 mmol, 3.0 equiv) in THF (45 mL) was added chloroacetyl chloride (1.42 g, 12.59 mmol, 1.2 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional one hour at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-chloro-N-[(1S)-1-(3- chlorophenyl)-2-hydroxyethyl]acetamide (1.34 g, 51.5%) as a brown yellow oil. (5S)-5-(3-chlorophenyl)morpholin-3-one (19-3) A solution of 2-chloro-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]acetamide (1.3 g, 5.24 mmol, 1.0 equiv) and sodium hydride (251 mg, 10.48 mmol, 2.0 equiv) in THF (10 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (5S)-5-(3- chlorophenyl)morpholin-3-one (435 mg, 39.2%) as a yellow solid. (3S)-3-(3-chlorophenyl)morpholine (19-4) A solution of (5S)-5-(3-chlorophenyl)morpholin-3-one (415 mg, 1.96 mmol, 1.0 equiv) and BH3- THF (4.90 mL, 4.90 mmol, 2.5 equiv) in THF (4.9 mL) was stirred for one hour at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to remove THF. The resulting mixture was extracted with CH2Cl2(2 x 30 mL). The combined organic layers were washed with water (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 30% gradient in 20 min; detector, UV 254 nm. This resulted in (3S)-3-(3- chlorophenyl)morpholine (202 mg, 52.1%) as a colorless solid.

[0079] (3S)-3-(3-chlorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (Compound 19) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (210.13 mg, 0.921 mmol, 1.0 equiv), HATU (350.11 mg, 0.921 mmol, 1.0 equiv), DIEA (481.16 µL, 2.763 mmol, 3 equiv) in DMF (4.5 mL) was stirred for 10 minutes at room temperature followed by the addition of (3S)-3-(3-chlorophenyl)morpholine (182 mg, 0.921 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for additional 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4. 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: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 41% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 3) to afford (3S)-3-(3-chlorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carbonyl]morpholine (64.5 mg, 16.9%) as a white solid. MS (ESI) m / z: 407.95 [M+H]+. Retention time: 1.44 min, 98.3% @ 254 nm.1H NMR (400 MHz, Methanol-d4) δ: 8.19 (s, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.49 – 7.43 (m, 2H), 7.40 – 7.30 (m, 2H), 6.74 (s, 1H), 5.71(s, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.30 (d, J = 13.6 Hz, 1H), 4.00 – 3.91 (m, 2H), 3.71 (td, J = 11.6, 2.8 Hz, 1H), 3.48 – 3.37 (m, 1H) ppm.

[0080] Example 20: Synthesis of N-[(1R)-1-[2-(difluoromethyl)phenyl]ethyl]-1-methyl-6-(1H- pyrazol-4-yl) pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 20) 1-[2-(Difluoromethyl)phenyl]ethanone (20-1) A solution of 1-bromo-2-(difluoromethyl)benzene (2 g, 9.661 mmol, 1.0 equiv), Pd(PPh3)2Cl2(1.36 g, 1.938 mmol, 0.2 equiv) and tributyl(1-ethoxyethenyl)stannane (3.92 mL, 11.593 mmol, 1.2 equiv) in dioxane (40 mL) was stirred overnight at 100oC under nitrogen atmosphere. The reaction was monitored by LCMS and TLC. The reaction was quenched with KF (aq.) at 0oC and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with 1 mol / L HCl(aq.) (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-[2-(difluoromethyl)phenyl]ethanone (1.3 g, 79.0%) as a colorless oil. MS (ESI) m / z: 171.2 [M+H]+. (R)-N-[(1R)-1-[2-(difluoromethyl)phenyl]ethyl]-2-methylpropane-2-sulfinamide (20-2) A solution of 1-[2-(difluoromethyl)phenyl]ethanone (1.0 g, 5.877 mmol, 1.0 equiv), Ti(OEt)4(2.68 g, 11.754 mmol, 2.0 equiv), Na2SO4(4.17 g, 29.385 mmol, 5.0 equiv) and (R)-2-methylpropane- 2-sulfinamide (925.9 mg, 7.640 mmol, 1.3 equiv) in THF (25 mL) was stirred for 3 hours at 80oC. The reaction was monitored by LCMS. Then to the above mixture was added NaBH4 (444.6 mg, 11.754 mmol, 2.0 equiv) in portions over 5 minutes at -48oC, the resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at 0oC. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (R)-N-[(1R)-1-[2- (difluoromethyl)phenyl]ethyl]-2-methylpropane-2-sulfinamide (650.0 mg, 40.1%) as a colorless oil. MS (ESI) m / z: 276.1 [M+H]+(1R)-1-[2-(difluoromethyl)phenyl]ethanamine (20-3) A solution of (R)-N-[(1R)-1-[2-(difluoromethyl)phenyl]ethyl]-2-methylpropane-2-sulfinamide (620.0 mg, 2.252 mmol, 1.0 equiv) in dioxane (5 mL) was treated with hydrogen chloride (5 mL, 20.000 mmol, 8.88 equiv) for 2 minutes at 0oC. The resulting mixture was stirred for 30 minutes at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in (1R)-1-[2- (difluoromethyl)phenyl]ethanamine (450.0 mg, crude) as a white solid. MS (ESI) m / z: 172.2 [M+H]+. N-[(1R)-1-[2-(difluoromethyl)phenyl]ethyl]-1-methyl-6-(1H-pyrazol-4-yl) pyrrolo[2,3- b]pyridine-2-carboxamide (Compound 20) A solution of (1R)-1-[2-(difluoromethyl)phenyl]ethanamine (450.0 mg, 2.629 mmol, 1.0 equiv), 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (636.7 mg, 2.629 mmol, 1.0 equiv), EDCI (755.8 mg, 3.944 mmol, 1.5 equiv), HOBt (532.8 mg, 3.944 mmol, 1.5 equiv) and DIEA (1.36 g, 10.516 mmol, 4.0 equiv) in DMF (20 mL) was stirred for 3 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford crude product (300 mg). 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: MeOH--HPLC; Flow rate: 60 mL / min ; Gradient: isocratic 51% B to 71% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 10.47) to afford N-[(1R)-1-[2-(difluoromethyl)phenyl]ethyl]-1-methyl-6-(1H-pyrazol-4-yl) pyrrolo[2,3- b]pyridine-2-carboxamide (55.0 mg, 5.2%) as a white solid. MS (ESI) m / z: 396.00 [M+H]+. Retention time: 1.73 min, 99.0% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.09 (d, J = 7.5 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.56 – 7.50 (m, 1H), 7.47 (s, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.25 (s, 1H), 5.41 (p, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H) ppm.19F NMR (376 MHz, DMSO- d6) δ -104.19 (d, J = 297.4 Hz), -116.15 (d, J = 297.4 Hz) ppm. Example 21: Synthesis of 1-Methyl-6-(1H-pyrazol-4-yl)-N-[(1R)-1-[2- (trifluoromethyl)phenyl]ethyl]pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 21) A solution of 1-methyl-6-(1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (260.0 mg, 1.073 mmol, 1.0 equiv), (1R)-1-[2-(trifluoromethyl)phenyl]ethanamine (243.6 mg, 1.288 mmol, 1.2 equiv), HATU (612.2 mg, 1.609 mmol, 1.5 equiv) and DIEA (561 µL, 3.219 mmol, 3.0 equiv) in DMF (4 mL) was stirred for 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20:1), then 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+ 0.1% NH3·H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 39% B to 52% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.72) to afford 1-methyl-6-(1H-pyrazol-4-yl)-N-[(1R)-1-[2- (trifluoromethyl)phenyl]ethyl]pyrrolo[2,3-b]pyridine-2-carboxamide (105.5 mg, 23.8%) as a white solid. MS (ESI) m / z: 414.00 [M+H]+. Retention time: 1.70 min, 99.6% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.06 (d, J = 7.3 Hz, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.1 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.28 (s, 1H), 5.48 (p, J = 7.0 Hz, 1H), 3.97 (s, 3H), 1.49 (d, J = 6.9 Hz, 3H) ppm.19F NMR (376 MHz, DMSO-d6) δ -57.31 (s) ppm. Example 22: Synthesis of (3S)-3-(3-methoxyphenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-2-carbonyl]morpholine (Compound 22) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (236 mg, 1.03 mmol, 1.0 equiv), HATU (393 mg, 1.03 mmol, 1.0 equiv), DIEA (540 µL, 3.10 mmol, 3.0 equiv) in DMF (5 mL) was stirred for 10 minutes at room temperature followed by the addition of (3S)- 3-(3-methoxyphenyl)morpholine (200 mg, 1.03 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for additional 2 hours at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4. 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: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 35% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 3) to afford (3S)-3-(3-methoxyphenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- 2-carbonyl]morpholine (56.5 mg, 13.4%) as a white solid. MS (ESI) m / z: 404.10 [M+H]+. Retention time: 1.28 min, 99.4% @ 254 nm.1H NMR (400 MHz, Methanol-d4) δ: 8.18 (s, 2H), 7.96 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.4 Hz , 1H), 7.33 -7.28 (m, 1H), 7.11 - 7.03 (m, 2H), 6.89 - 6.85 (m, 1H), 6.72 (s, 1H), 5.67 (s, 1H), 4.52 (d, J = 12.4 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 4.00 - 3.90 (m, 2H), 3.78 (s, 3H), 3.72 - 3.63 (m, 1H), 3.49 - 339 (m, 1H) ppm.

[0081] Example 23: Synthesis of 4-(2-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]- 1H-pyrrolo[2,3-b]pyridin-6-yl-1H-pyrazole (Compound 23) 4- chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (23-1) A soluti on of 1-bromo-3-(difluoromethoxy)benzene (10.00 g, 44.840 mmol, 1.0 equiv) and 4- chloro-N-methoxy-N-methylbutanamide (7.43 g, 44.840 mmol, 1.0 equiv) in toluene (100 mL) was stirred at -78 °C under nitrogen atmosphere. To the above mixture was added n-BuLi (35.87 mL, 89.680 mmol, 2.0 equiv) (2.5M in n-hexane) dropwise over 20 minutes at -78 °C. The resulting mixture was stirred for 1.5 hours at -78 °C and 0.5 hour at room temperature. Desired product could be detected by TLC. The reaction was quenched with sat. NH4Cl (aq.) (100 mL). The resulting mixture was separated. The aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 4-chloro-1-[3- (difluoromethoxy)phenyl]butan-1-one (1.57 g, 14.1%) as a yellow liquid.1H NMR (400 MHz, Methanol-d4) δ 7.88 (dt, J = 7.7, 1.3 Hz, 1H), 7.72 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.3, 2.5 Hz, 1H), 6.91 (t, J = 73.6 Hz, 1H), 3.68 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 7.0 Hz, 2H), 2.17 (p, J = 6.8 Hz, 2H) ppm. (R)-N-[(1R)-4-chloro-1-[3-(difluoromethoxy)phenyl]butyl]-2-methylpropane-2-sulfinamide (23-2) Step 1: A solution of 4-chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (1.00 g, 4.022 mmol, 1.0 equiv), (R)-2-methylpropane-2-sulfinamide (633.7 mg, 5.229 mmol, 1.3 equiv) and tetraethoxytitanium (1.83 g, 8.044 mmol, 2.0 equiv) in THF (10 mL) was stirred for 3 hours at 70 °C. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. MS (ESI) m / z: 352 [M+H]+. Step 2: To the above reaction mixture was added NaBH4 (215.04 mg, 5.684 mmol, 1.4 equiv) at - 48 °C. The resulting mixture was stirred for one hour at -48°C. Desired product could be detected by LCMS. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1). The residue was purified by reversed-phase flash chromatography with the following conditions: (column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3·H2O), 5% to 45% gradient in 50 min; detector, UV 254 nm.) to afford (R)-N-[(1R)-4-chloro-1-[3- (difluoromethoxy)phenyl]butyl]-2-methylpropane-2-sulfinamide (200 mg, 14.1% in two steps) as a yellow oil. MS (ESI, m / z): 354 [M+H]+. (2R)-2-[3-(difluoromethoxy)phenyl]-1-[(R)-2-methylpropane-2-sulfinyl]pyrrolidine (23-3) A solution of (R)-N-[(1R)-4-chloro-1-[3-(difluoromethoxy)phenyl]butyl]-2-methylpropane-2- sulfinamide (1.7 g, 4.804 mmol, 1.0 equiv) and NaH (384.3 mg, 9.608 mmol, 2.0 equiv, 60%) in THF (10 mL) was stirred for one hour at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.5 g) 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+ 0.05% NH3·H2O), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 30% B to 60% B in 30 min; Wave Length: 254 nm / 220 nm; RT1(min): 26.0; RT2(min): 27.0) to afford (2R)-2-[3- (difluoromethoxy)phenyl]-1-[(R)-2-methylpropane-2-sulfinyl]pyrrolidine (1.08 g, 70.8%) as a pink oil. MS (ESI, m / z): 318 [M+H]+. (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine (23-4) A solution of (2R)-2-[3-(difluoromethoxy)phenyl]-1-[(R)-2-methylpropane-2-sulfinyl]pyrrolidine (520 mg, 1.638 mmol, 1.0 equiv) in HCl (gas) in 1,4-dioxane (5 mL) was stirred for 30 minutes at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to afford (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine (570 mg, crude) as a pink oil. The crude product was used in the next step directly without further purification. MS (ESI, m / z): 213 [M+H]+. 4-(2-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3- b]pyridin-6-yl-1H-pyrazole (Compound 23) A solution of (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine (523.2 mg, 1.472 mmol, 1.2 equiv, 60%), 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (280.0 mg, 1.227 mmol, 1.0 equiv), EDCI (282.2 mg, 1.472 mmol, 1.2 equiv), HOBt (198.9 mg, 1.472 mmol, 1.2 equiv) and DIEA (854.9 µL, 4.908 mmol, 4.0 equiv) in DMF (10 mL) was stirred for one hour at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (15:1). 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: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 45% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 1) to afford 4- (2-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl- 1H-pyrazole (72.9 mg, 14.0%) as a white solid. MS (ESI) m / z: 424.05[M+H]+. Retention time: 1.64 min, 98.6% @ 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 11.86 (s, 1H), 8.42 – 7.93 (m, 3H), 7.50 (d, J = 8.3 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 73.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.11 – 6.99 (m, 3H), 5.25 (s, 1H), 4.31 – 3.75 (m, 2H), 2.45 – 2.30 (m, 1H), 2.09 – 1.83 (m, 2H), 1.84 – 1.65 (m, 1H) ppm.19F NMR (376 MHz, DMSO-d6) δ -81.71 (s), - 81.94 (s) ppm. Example 24: Synthesis of 4-{3-[(2R)-2-(3-chlorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (Compound 24) 1-{6-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2,2-trifluoroethanone (24-1) To a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine (30.0 g, 196.618 mmol, 1.0 equiv) in DMF (500 mL) was added trifluoroacetic anhydride (32.8 mL, 235.942 mmol, 1.2 equiv) dropwise at 0 oC. Then the resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. After completion, the reaction was quenched with saturated NaHCO3(aq.) at 0oC. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. And the resulting mixture was diluted with EtOAc (100 mL). The precipitated solids were collected by filtration and washed with cold EtOAc (4 x 40 mL). This resulted in 1-{6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2,2-trifluoroethanone (23.0 g, 47.0%) as an off-white solid.MS (ESI) m / z: 247.00 [M-H]-. 2,2,2-Trifluoro-1-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethenone (24-2) A solution of 1-{6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2,2-trifluoroethanone (10.0 g, 40.227 mmol, 1.0 equiv), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23.4 g, 120.681 mmol, 3.0 equiv), Pd(PPh3)4(4.7 g, 4.024 mmol, 0.10 equiv) and K2CO3(11.1 g, 80.454 mmol, 2.0 equiv) in DMF (120 mL) and H2O (30 mL) was stirred at 90oC for 30 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (1.0 L). The resulting mixture was extracted with EtOAc (3 x 900 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2,2,2-trifluoro-1-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanone (8.5 g, 75.4%) as a light yellow solid. MS (ESI) m / z: 281.05 [M+H]+. 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (24-3) A solution of 2,2,2-trifluoro-1-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanone (4.5 g, 16.059 mmol, 1.0 equiv) in NaOH (6 M, in water, 45 mL) was stirred at 100oC for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The mixture was acidified to pH 3 with HCl (aq.). The resulting mixture was filtered, the filter cake was washed with water (3 x 15 mL). The filtrate was concentrated under reduced pressure. This resulted in 6-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-3-carboxylic acid (4.1 g, crude) as a light yellow solid. The reaction was repeated to produce one more batch. MS (ESI) m / z: 229.10 [M+H]+. 4-{3-[(2R)-2-(3-chlorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H- pyrazole (Compound 24) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (500.0 mg, 2.191 mmol, 1.0 equiv), (2R)-2-(3-chlorophenyl)pyrrolidine (477.6 mg, 2.629 mmol, 1.2 equiv), (3- [[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (630.0 mg, 3.286 mmol, 1.5 equiv), 1H-1,2,3-benzotriazol-1-ol (444.08 mg, 3.286 mmol, 1.5 equiv) and DIEA (1.14 mL, 6.573 mmol, 3.0 equiv) in DMF (20 mL) was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with water at 0oC. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 48% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 10.37) to afford 4-{3- [(2R)-2-(3-chlorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (151.7 mg, 17.6%,) as an off-white solid. MS (ESI) m / z: 392.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 12.13 (s, 1H), 8.85 – 7.70 (m, 4H), 7.51 (d, J = 8.0 Hz, 1H), 7.42 – 6.99 (m, 4H), 5.24 (s, 1H), 4.11 (s, 1H), 3.90 (s, 1H), 2.34 (dq, J = 14.6, 7.1 Hz, 1H), 2.20 – 1.54 (m, 3H) ppm. Example 25: Synthesis of 4-{3-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (Compound 25) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (500.0 mg, 2.191 mmol, 1.0 equiv), (2R)-2-(3-methoxyphenyl)pyrrolidine hydrochloride (561.8 mg, 2.629 mmol, 1.2 equiv), (3-[[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (630.0 mg, 3.286 mmol, 1.5 equiv), HOBT (444.0 mg, 3.286 mmol, 1.5 equiv) and DIEA (1.53 mL, 8.764 mmol, 4.0 equiv) in DMF (20 mL) was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with water at 0oC. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 38 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.809) to afford 4-{3- [(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (170.8 mg, 20.1%) as an off-white solid. MS (ESI) m / z: 388.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 12.31 – 11.56 (m, 1H), 8.30 (s, 2H), 8.04 (s, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 6.95 – 6.64 (m, 3H), 5.69 – 5.12 (m, 1H), 4.09 (s, 1H), 3.87 (s, 1H), 3.73 (s, 3H), 2.41 – 2.21 (m, 1H), 2.06 – 1.53 (m, 3H) ppm. Example 26: Synthesis of 4-{3-[(2R)-2-(3,4-difluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (Compound 26) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (500.0 mg, 2.191 mmol, 1.0 equiv), (3-[[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (630.0 mg, 3.286 mmol, 1.5 equiv), HOBT (444.0 mg, 3.286 mmol, 1.5 equiv) in DMF (20 mL) was treated with N, N-diisopropylethylamine (1.14 mL, 6.573 mmol, 3.0 equiv) at room temperature for 5 minutes followed by the addition of (2R)-2-(3,4-difluorophenyl)pyrrolidine (602.0 mg, 3.286 mmol, 1.5 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with water at 0oC. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (94:6) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 m; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 35% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 15.08) to afford 4-{3-[(2R)-2-(3,4-difluorophenyl)pyrrolidine-1- carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (134.7 mg, 15.6%) as an off-white solid. MS (ESI) m / z: 394.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 12.13 (s, 1H), 8.53 – 7.78 (m, 4H), 7.50 (d, J = 8.3 Hz, 1H), 7.35 (q, J = 8.7 Hz, 2H), 7.13 (s, 1H), 5.25 (s, 1H), 4.46 – 3.64 (m, 2H), 2.32 (dq, J = 14.7, 7.3 Hz, 1H), 2.11 – 1.56 (m, 3H) ppm.19F NMR (376 MHz, DMSO-d6) δ -139.3 (s), -142.4 (s) ppm. Example 27: Synthesis of 4-{3-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]- 1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (Compound 27) 4-Chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (27-1) sou on o -romo--( uorome oxy)enzene ( . g, . mmo, . equv) and 4- chloro-N-methoxy-N-methylbutanamide (7.4 g, 44.840 mmol, 1.0 equiv) in toluene (100 mL) was cooled down to -78oC under nitrogen atmosphere. To the above mixture was added n-BuLi (35.8 mL, 89.680 mmol, 2.0 equiv, 2.5 M in n-hexane) dropwise at -78oC. The resulting mixture was stirred for 1.5 hours at -78oC and 0.5 hour at room temperature. Desired product could be detected by TLC and LCMS. The reaction was quenched with sat. NH4Cl (aq.). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 4-chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (1.56 g, 13.9%) as a yellow liquid. 1H NMR (400 MHz, Chloroform-d) δ 7.83 (dt, J = 7.7, 1.4 Hz, 1H), 7.72 (t, J = 2.1 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.2, 2.5 Hz, 1H), 6.77 – 6.35 (m, 1H), 3.68 (t, J = 6.2 Hz, 2H), 3.18 (t, J = 6.9 Hz, 2H), 2.24 (p, J = 6.6 Hz, 2H) ppm. (S)-N-{4-chloro-1-[3-(difluoromethoxy)phenyl]butylidene}-2-methylpropane-2-sulfinamide (27-2) A solution of 4-chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (1.5 g, 6.033 mmol, 1 equiv), (S)-2-methylpropane-2-sulfinamide (1.1 g, 9.050 mmol, 1.5 equiv) and Ti(OEt)4(2.8 g, 12.066 mmol, 2.0 equiv) in THF (60 mL) was stirred at 65oC overnight. The reaction was monitored 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 PE / EA (2 : 1) to afford (S)-N-{4-chloro-1-[3- (difluoromethoxy)phenyl]butylidene}-2-methylpropane-2-sulfinamide (1.18 g, 55.5%) as a yellow oil. MS (ESI) m / z: 351.95 [M+H]+. (2R)-2-[3-(difluoromethoxy)phenyl]-1-[(S)-2-methylpropane-2-sulfinyl]pyrrolidine (27-3) A solution of (S)-N-{4-chloro-1-[3-(difluoromethoxy)phenyl]butylidene}-2-methylpropane-2- sulfinamide (1.1 g, 3.126 mmol, 1.0 equiv) in THF (16 mL) was treated with lithium triethylborohydride (1.0 M in tetrahydrofuran) (4.7 mL, 4.689 mmol, 1.5 equiv) at -78oC for 2 hours under nitrogen atmosphere. Then the resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4Cl (aq.) at 0oC. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford (2R)-2-[3- (difluoromethoxy)phenyl]-1-[(S)-2-methylpropane-2-sulfinyl]pyrrolidine (650.0 mg, 65.5%) as a colorless oil. MS (ESI) m / z: 318.10 [M+H]+. (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine hydrochloride (27-4) A solution of (2R)-2-[3-(difluoromethoxy)phenyl]-1-[(S)-2-methylpropane-2-sulfinyl]pyrrolidine (620.0 mg, 1.953 mmol, 1.0 equiv) in 1,4-dioxane (8.0 mL) was treated with HCl (in 1,4-dioxane, 4.0 M, 2.0 mL) at 0oC for 5 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine hydrochloride (535.0 mg, crude) as a light yellow oil. MS (ESI) m / z: 214.15 [M+H]+.

[0082] 4-{3-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3- b]pyridin-6-yl}-1H-pyrazole (Compound 27) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (581.2 mg, 2.548 mmol, 1.2 equiv), (3-[[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (610.3 mg, 3.185 mmol, 1.5 equiv), HOBT (430.2 mg, 3.185 mmol, 1.5 equiv) in DMF (15.0 mL) was treated with DIEA (1.5 mL, 8.492 mmol, 4.0 equiv) at room temperature for 5 minutes followed by the addition of (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine hydrochloride (530.0 mg, 2.123 mmol, 1.0 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 180 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 42 % B in 17 min; Wave Length: 254 nm / 220 nm; RT1(min): 10.114) to afford 4-{3-[(2R)-2-[3- (difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1H-pyrazole (132.5 mg, 14.7%) as an off-white solid. MS (ESI) m / z: 424.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 12.13 (s, 1H), 8.53 – 7.78 (m, 4H), 7.50 (d, J = 8.2 Hz, 1H), 7.46 – 7.04 (m, 4H), 7.01 (d, J = 7.9 Hz, 1H), 5.30 (s, 1H), 4.42 – 3.64 (m, 2H), 2.35 (dq, J = 15.5, 8.5, 8.1 Hz, 1H), 2.09 – 1.57 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ 81.9 (m) ppm. Example 28: Synthesis of 4-(3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl-3-methyl-2H-pyrazole (Compound 28) (2R)-1-(6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2-(2-fluorophenyl)pyrrolidine (28- 1) A mixture of 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (500 mg, 2.543 mmol, 1 equiv), (R)-2-(2-fluorophenyl)pyrrolidine hydrochloride (766.815 mg, 3.815 mmol, 1.5 equiv), (([3-(dimethylamino)propyl]iminomethylidene)(ethyl)amine (592.27 mg, 3.815 mmol, 1.5 equiv), DIEA (1314.89 mg, 10.172 mmol, 4 equiv) and HOBT (515.51 mg, 3.815 mmol, 1.5 equiv) in DMF (10 mL) was stirred at room temperature for 2 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford (2R)-1-(6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2-(2- fluorophenyl)pyrrolidine (420 mg, 48.0% yield) as a yellow solid. MS (ESI) m / z: 343.95 [M+H]+. 4-(3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl-3- methyl-2H-pyrazole (Compound 28) A mixture of (2R)-1-(6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2-(2- fluorophenyl)pyrrolidine (400 mg, 1.164 mmol, 1 equiv), 5-methyl-4-(tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (726.27 mg, 3.492 mmol, 3 equiv), K2CO3(321.60 mg, 2.328 mmol, 2 equiv) and Pd(PPh3)4(134.45 mg, 0.116 mmol, 0.1 equiv) in DMF (8 mL) and H2O (2 mL) was stirred at 100°C for 12 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 45% gradient in 5 min; detector, UV 254 nm. This resulted in 4-(3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl-3-methyl-2H-pyrazole (215.8 mg, 47.6% yield) as a white solid. MS (ESI) m / z: 390.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 12.66 (s, 1H), 12.10 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.01 (s, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.33 – 7.02 (m, 4H), 5.48 (s, 1H), 4.01 (d, J = 77.6 Hz, 2H), 2.58 (s, 3H), 2.44 – 2.30 (m, 1H), 1.96 (t, J = 6.0 Hz, 2H), 1.76 (s, 1H) ppm.19F NMR (376 MHz, DMSO-d6) d -118.3 (s), -119.3 (s) ppm. Example 29: Synthesis of 3-(3-Methoxyphenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]morpholine (Compound 29) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (800.0 mg, 3.506 mmol, 1.0 equiv), DIEA (1.83 mL, 10.518 mmol, 3 equiv) in DMF (15 mL) was treated with HATU (2.00 g, 5.259 mmol, 1.5 equiv) at room temperature for 5 minutes followed by the addition of (3S)-3-(3-methoxyphenyl)morpholine (812.9 mg, 4.207 mmol, 1.2 equiv) dropwise at room temperature. The reaction was monitored by LCMS. The reaction was quenched with water after stirring overnight at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 3 % to 100% gradient in 35 min; detector, UV 254 nm, 200 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 34% B in 17 min; Wave Length: 254 nm / 220 nm; RT1(min): 13.252) to afford 3-(3- methoxyphenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]morpholine (145.4 mg, 10.2%) as an off-white solid. MS (ESI) m / z: 404.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 12.10 (s, 1H), 8.41 – 7.99 (m, 3H), 7.71 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.86 (dd, J = 8.1, 1.9 Hz, 1H), 5.53 (s, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.21 – 4.05 (m, 1H), 3.98 – 3.79 (m, 2H), 3.73 (s, 3H), 3.65 – 3.50 (m, 1H), 3.27 (s, 1H) ppm. Example 30: Synthesis of 3-(2-Fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]morpholine (Compound 30) A solution of 6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (800.0 mg, 3.506 mmol, 1.0 equiv), DIEA (1.8 mL, 10.518 mmol, 3.0 equiv) in DMF (15 mL) was treated with HATU (2.00 g, 5.260 mmol, 1.5 equiv) at room temperature for 5 minutes followed by the addition of (3S)-3-(2-fluorophenyl)morpholine (762.2 mg, 4.207 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. After completion, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol / L NH4HCO3), 3% to 100% gradient in 30 min; detector, UV 254 nm, 200 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 35% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.302) to afford 3-(2-fluorophenyl)-4-[6-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-3-carbonyl]morpholine (115.6 mg, 8.4% yield) as an off-white solid. MS (ESI) m / z: 392.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 12.13 (s, 1H), 8.29 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.79 (s, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.36 (q, J = 7.5 Hz, 1H), 7.30 – 7.13 (q, J = 11.3, 9.2 Hz, 2H), 5.74 (s, 1H), 4.36 – 4.19 (m, 1H), 4.18 – 4.04 (m, 1H), 4.03 – 3.83 (m, 2H), 3.74 – 3.48 (m, 2H) ppm.19F NMR (376 MHz, DMSO-d6) δ -116.0 (s) ppm. Example 31: Synthesis of 6-(1H-Pyrazol-4-yl)-2-[(2R)-2-(pyridin-2-yl)pyrrolidine-1- carbonyl]-1H-indole (Compound 31) 6-Bromo-2-[(2R)-2-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1H-indole (31-1) To a stirred solution of 6-bromo-1H-indole-2-carboxylic acid (600 mg, 2.499 mmol, 1 equiv) and 2-[(2R)-pyrrolidin-2-yl]pyridine (444.52 mg, 2.999 mmol, 1.2 equiv) in DMF (1 mL) were added HOBT (506.60 mg, 3.748 mmol, 1.5 equiv) and (([3- (dimethylamino)propyl]iminomethylidene)(ethyl)amine (582.03 mg, 3.748 mmol, 1.5 equiv) and DIEA (1292.17 mg, 9.996 mmol, 4 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 6-bromo-2- [(2R)-2-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1H-indole (800 mg, 86.5%) as a white solid. MS (ESI) m / z: 370.10 [M+H]+. 6-(1H-Pyrazol-4-yl)-2-[(2R)-2-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1H-indole (Compound To a stirred solution of 6-bromo-2-[(2R)-2-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1H-indole (400 mg, 1.080 mmol, 1 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (628.89 mg, 3.240 mmol, 3 equiv) in DMF (6.4 mL) were added K2CO3(298.62 mg, 2.160 mmol, 2 equiv) and Pd(PPh3)4 (124.84 mg, 0.108 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 3 hours under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 40% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 6-(1H-pyrazol-4-yl)-2-[(2R)-2-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1H-indole with 0.2 eq formic acid (250 mg, 57.4% yield) as a white solid. MS (ESI) m / z: 358.15 [M+H]+. LCMS was conducted on a Shimadzu LCMS-2020 system with PDA: SPD-M40 and MS: LCMS- 2020 detectors using HALO--C18, 30 * 2.1 mm, Mobile phase A: Water / 0.1%FA, Mobile Phase B: Acetonitrile / 0.1%FA, Flow rate: 1.50 mL / min, Gradient: 5%B-70%B-100%B-1.0-3.0 min; tR: 0.854 min.1H NMR (400 MHz, DMSO-d6) δ 12.83 (br, 1H), 11.60 – 11.19 (m, 1H), 8.65 – 8.45 (m, 1H), 8.21 (s, 0.2H), 8.07 – 7.91 (m, 2H), 7.80 – 7.67 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.59 – 7.48 (m, 1H), 7.42 – 7.19 (m, 3H), 7.12 – 6.12 (m, 1H), 5.68 – 5.15 (m, 1H), 4.28 – 3.75 (m, 2H), 2.42 – 2.25 (m, 1H), 2.13 – 1.82 (m, 3H) ppm.

[0083] Example 32: Synthesis of 2-[(2R)-1-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-2- carbonyl]pyrrolidin-2-yl]pyridine (Compound 32) 2-[(2R)-1-{6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl}pyrrolidin-2-yl]pyridine (32-1) A solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (500.0 mg, 2.543 mmol, 1.0 equiv), 2-[(2R)-pyrrolidin-2-yl]pyridine hydrochloride (563.6 mg, 3.052 mmol, 1.2 equiv), (3- {[(ethylimino)methylidene]amino}propyl)dimethylamine hydrochloride (731.3 mg, 3.815 mmol, 1.5 equiv), HOBT (515.5 mg, 3.815 mmol, 1.5 equiv) and DIEA (1314.9 mg, 10.172 mmol, 4.0 equiv) in DMF (8 mL) was stirred at room temperature for 1h under nitrogen atmosphere. The resulting mixture was diluted with water (120 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2- [(2R)-1-{6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl}pyrrolidin-2-yl]pyridine (830 mg, 99.9% yield) as a white solid. MS (ESI) m / z: 327.15 [M+H]+. 2-[(2R)-1-[6-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-2-carbonyl]pyrrolidin-2- yl]pyridine (Compound 32) A solution of 2-[(2R)-1-{6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl}pyrrolidin-2-yl]pyridine (400.0 mg, 1.224 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (712.6 mg, 3.672 mmol, 3.0 equiv), Pd(dppf)Cl2CH2Cl2(99.96 mg, 0.122 mmol, 0.1 equiv) and K2CO3(338.3 mg, 2.448 mmol, 2.0 equiv) in 1,4-dioxane (5 mL) and H2O (1 mL) was stirred at 100°C for 1h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (360 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 27% B in 16 min; Wave Length: 254nm / 220nm; RT1(min): 11.53) to afford 2-[(2R)-1-[6-(1H- pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-2-carbonyl]pyrrolidin-2-yl]pyridine (156.5 mg, 35.7% yield) as a white solid. MS (ESI) m / z: 359.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 11.90 – 11.80 (m, 1H), 8.91 (s, 1H), 8.71 – 8.45 (m, 1H), 8.30 – 8.20 (m, 1H), 8.10 – 7.90 (m, 1H), 7.82 – 7.66 (m, 1H), 7.55 – 7.40 (m, 1H), 7.35 – 6.30 (m, 3H), 5.67 – 5.24 (m, 1H), 4.26 – 3.73 (m, 2H), 2.40 – 2.30 (m, 1H), 2.09 – 1.99 (m, 2H), 1.96 – 1.88 (m, 1H) ppm. Example 33: Synthesis of (S)-3-[3-(2-fluorophenyl)morpholine-4-carbonyl]-6-(1H-pyrazol-4- yl)-1H-indole (Compound 33)

[0084] To a stirred solution of 6-bromo-1H-indole-3-carboxylic acid (1.2 g, 4.999 mmol, 1 equiv) in THF (75 mL) were added NaOH (15.00 mL, 15.000 mmol, 3.00 equiv) and (Boc)2O (1.20 g, 5.499 mmol, 1.1 equiv) dropwise at 0°C. The resulting mixture was stirred at 30°C for 1 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (50:1) to afford 6-bromo-1-(tert- butoxycarbonyl)indole-3-carboxylic acid (590 mg, 34.7% yield) as a white solid. MS (ESI) m / z: 339.80 [M+H]+. tert-Butyl (S)-6-bromo-3-[3-(2-fluorophenyl)morpholine-4-carbonyl]indole-1-carboxylate (33-2) A solution of 6-bromo-1-(tert-butoxycarbonyl)indole-3-carboxylic acid (563.17 mg, 1.656 mmol, 1.2 equiv), (3S)-3-(2-fluorophenyl)morpholine (250 mg, 1.380 mmol, 1.00 equiv), EDCI (321.27 mg, 2.070 mmol, 1.5 equiv), HOBT (279.63 mg, 2.070 mmol, 1.5 equiv) and DIEA (961.25 uL, 5.520 mmol, 4 equiv) in DMF (0.5 mL) was stirred at room temperature for 15 h. The resulting mixture was filtered. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 60% B to 80% B in 15 min; Wave Length: 254nm / 220nm to afford tert-butyl (S)-6-bromo-3-[3-(2-fluorophenyl)morpholine-4- carbonyl]indole-1-carboxylate (615 mg, 88.6% yield) as a white solid. MS (ESI) m / z: 502.95 [M+H]+, 504.85 [M+2+H]+. (S)-3-[3-(2-fluorophenyl)morpholine-4-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (Compound 33) A solution of tert-butyl (S)-6-bromo-3-[3-(2-fluorophenyl)morpholine-4-carbonyl]indole-1- carboxylate (485 mg, 0.964 mmol, 1 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (560.88 mg, 2.892 mmol, 3 equiv), Pd(PPh3)4(111.34 mg, 0.096 mmol, 0.1 equiv) and K2CO3(266.32 mg, 1.928 mmol, 2 equiv) in DMF (8 mL) and H2O (2 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford 3-[3-(2- fluorophenyl)morpholine-4-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (270 mg, crude) as a white solid. The residue was purified by trituration with EtOAc (10 mL) and PE (5 mL). This resulted in (S)-3-[3-(2-fluorophenyl)morpholine-4-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (183.1 mg, 48.7% yield) as a white solid. MS (ESI) m / z: 391.05 [M+H]+. LCMS was conducted on a Shimadzu LCMS-2020 system with PDA: SPD-M40 and MS: LCMS-2020 detectors using Poroshell HPH- C18-1.9, 30 * 3.0 mm, Mobile phase A: Water / 5mM NH4HCO3, Mobile Phase B: Acetonitrile, Flow rate: 1.50 mL / min, Gradient: 10% B – 70% B 95% B in 1.2 – 3.0 min; tR: 3.74 min.1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.58 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.72 – 7.54 (m, 4H), 7.41 – 7.31 (m, 2H), 7.27 – 7.16 (m, 2H), 5.74 (s, 1H), 4.25 (d, J = 12.0 Hz, 1H), 4.09 – 4.00 (m, 1H), 3.97 – 3.85 (m, 2H), 3.64 – 3.50 (m, 2H) ppm.19F NMR (400 MHz, DMSO-d6) ppm: - 115.9 (s) ppm. Example 34: Synthesis of 3-[(2R)-2-(2-Fluorophenyl)pyrrolidine-1-carbonyl]-6-(1H-pyrazol- 4-yl)-1H-indole (Compound 34) 6-Bromo-3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-indole (34-1) A solution of (2R)-2-(2-fluorophenyl)pyrrolidine hydrochloride (603.0 mg, 2.990 mmol, 1.0 equiv), 6-bromo-1H-indole-3-carboxylic acid (861.3 mg, 3.588 mmol, 1.2 equiv), (3- [[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (859.7 mg, 4.485 mmol, 1.5 equiv), HOBT (606.0 mg, 4.485 mmol, 1.5 equiv) and DIEA (2.1 mL, 11.960 mmol, 4.0 equiv) in DMF (15 mL) was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 6-bromo-3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-indole (140.0 mg, 12.0%) as a light yellow solid. The reaction was repeated to produce one more batch. MS (ESI) m / z: 388.85 [M+H]+. 3-[(2R)-2-(2-Fluorophenyl)pyrrolidine-1-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (Compound 34) A solution of 6-bromo-3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-1H-indole (180.0 mg, 0.465 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (117.2 mg, 0.605 mmol, 1.3 equiv), K2CO3(128.5 mg, 0.930 mmol, 2.0 equiv), Pd(PPh3)4(53.7 mg, 0.047 mmol, 0.1 equiv) and DMF (1.5 mL) in H2O (6.0 mL) was stirred at 90oC overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (120 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 26% B in 2 min, 26% to 45% B in 15 min; Wave Length: 254nm / 220 nm; RT1(min): 10.90 min to afford 3-[(2R)-2-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-(1H- pyrazol-4-yl)-1H-indole (79.7 mg, 45.8%) as a light yellow solid. MS (ESI) m / z: 375.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 11.60 (s, 1H), 8.38 – 7.76 (m, 4H), 7.57 (s, 1H), 7.48 – 6.94 (m, 5H), 5.48 (s, 1H), 4.06 (s, 1H), 3.90 (s, 1H), 2.45 – 2.27 (m, 1H), 1.94 (s, 2H), 1.76 (s, 1H) ppm.19F NMR (376 MHz, DMSO-d6) δ -119.3 (s) ppm. Example 35: Synthesis of 3-[(2R)-2-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-6-(1H- pyrazol-4-yl)-1H-indole (Compound 35) 6-Bromo-3-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H-indole (35-1) A solution of (2R)-2-(3-methoxyphenyl)pyrrolidine hydrochloride (600.0 mg, 2.808 mmol, 1.0 equiv), 6-bromo-1H-indole-3-carboxylic acid (808.8 mg, 3.370 mmol, 1.2 equiv), (3- [[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (807.3 mg, 4.212 mmol, 1.5 equiv), HOBT (569.1 mg, 4.212 mmol, 1.5 equiv) and DIEA (1.5 g, 11.232 mmol, 4.0 equiv) in DMF (15 mL) was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 6-bromo-3-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H-indole (360.0 mg, 32.1%) as a light yellow solid. MS (ESI) m / z: 400.90 [M+H]+. 3-[(2R)-2-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (Compound 35) A solution of 6-bromo-3-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-1H-indole (330.0 mg, 0.826 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (481.1 mg, 2.478 mmol, 3.0 equiv), K2CO3(228.4 mg, 1.652 mmol, 2.0 equiv), Pd(PPh3)4(95.5 mg, 0.083 mmol, 0.1 equiv) and H2O (1.5 mL) in DMF (6 mL) was stirred at 90oC overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (150 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 um; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 50% B in 10 min; Wave Length: 254 nm / 220 nm ; RT1(min): 9.77) to afford 3-[(2R)-2-(3-methoxyphenyl)pyrrolidine-1-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (118.1 mg, 36.9%) as an off-white solid. MS (ESI) m / z: 387.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 11.55 (s, 1H), 8.31 (s, 1H), 8.02 (s, 3H), 7.56 (s, 1H), 7.47 – 7.12 (m, 2H), 7.11 – 6.55 (m, 3H), 5.30 (s, 1H), 4.35 – 3.59 (m, 5H), 2.32 (s, 1H), 2.05 – 1.60 (m, 3H) ppm. Example 36: Synthesis of (3S)-3-(3-Methoxyphenyl)-4-[6-(3-methyl-2H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine-2-carbonyl]morpholine (Compound 36)

[0085] (3S)-4-{6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl}-3-(3-methoxyphenyl)morpholine (36-1) A mixture of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (500.51 mg, 2.546 mmol, 1.2 equiv), (3S)-3-(3-methoxyphenyl)morpholine (410 mg, 2.122 mmol, 1.00 equiv), ({[3- (dimethylamino)propyl]imino}methylidene)(ethyl)amine (494.06 mg, 3.183 mmol, 1.5 equiv), HOBT (430.03 mg, 3.183 mmol, 1.5 equiv) and DIEA (1.10 g, 8.488 mmol, 4 equiv) in DMF (10 mL) was stirred at room temperature for 2 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (3S)-4-{6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl}-3-(3- methoxyphenyl)morpholine (650 mg, 82.4% yield) as an off-white solid. MS (ESI) m / z: 372.00 [M+H]+. (3S)-3-(3-Methoxyphenyl)-4-[6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (Compound 36) A mixture of (3S)-4-{6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl}-3-(3- methoxyphenyl)morpholine (500 mg, 1.345 mmol, 1 equiv), 3-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2H-pyrazole (839.40 mg, 4.035 mmol, 3 equiv), K2CO3(371.70 mg, 2.690 mmol, 2 equiv) and Pd(PPh3)4(155.40 mg, 0.135 mmol, 0.1 equiv) in DMF (8 mL) and H2O (2 mL) was stirred at 100°C for 3 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 45% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3S)-3-(3- methoxyphenyl)-4-[6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2- carbonyl]morpholine (185.3 mg) as a white solid. MS (ESI) m / z: 418.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 10.75 (s, 1H), 8.05 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.38 – 7.28 (m, 2H), 7.16 – 7.07 (m, 2H), 6.87 (dd, J = 8.3, 2.5 Hz, 1H), 6.63 (s, 1H), 5.79 (s, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 13.3 Hz, 1H), 3.97 (dt, J = 11.3, 3.2 Hz, 2H), 3.80 (s, 3H), 3.72 (td, J = 11.7, 2.8 Hz, 1H), 3.50 (s, 1H), 2.67 (s, 3H) ppm. Example 37: Synthesis of 4-{2-[(2R)-2-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-1H- pyrrolo[2,3-b]pyridin-6-yl}-3-methyl-2H-pyrazole (Compound 37) (2R)-1-{6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl}-2-(3-methoxyphenyl)pyrrolidine (37-1) A mixture of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (551.93 mg, 2.808 mmol, 1.2 equiv), (2R)-2-(3-methoxyphenyl)pyrrolidine hydrochloride (500 mg, 2.340 mmol, 1.00 equiv), ({[3-(dimethylamino)propyl]imino}methylidene)(ethyl)amine (544.82 mg, 3.510 mmol, 1.5 equiv), HOBT (474.22 mg, 3.510 mmol, 1.5 equiv) and DIEA (1.21 g, 9.360 mmol, 4 equiv) in DMF (10 mL) was stirred at room temperature for 2 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (2R)-1-{6-chloro-1H-pyrrolo[2,3-b]pyridine- 2-carbonyl}-2-(3-methoxyphenyl)pyrrolidine (660 mg, 79.3% yield) as a light yellow oil. MS (ESI) m / z: 356.00 [M+H]+. 4-{2-[(2R)-2-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-3- h l 2H l C d 37 A mixture of (2R)-1-{6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl}-2-(3- methoxyphenyl)pyrrolidine (500 mg, 1.405 mmol, 1 equiv), 3-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2H-pyrazole (877.14 mg, 4.215 mmol, 3 equiv), K2CO3(388.41 mg, 2.810 mmol, 2 equiv) and Pd(PPh3)4(162.38 mg, 0.141 mmol, 0.1 equiv) in DMF (8 mL) and H2O (2 mL) was stirred at 100°C for 3 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Phenyl OBD Column, 30*150mm 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 45% B in 17 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.235) to afford 4-{2-[(2R)-2-(3- methoxyphenyl)pyrrolidine-1-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-3-methyl-2H-pyrazole (273.0 mg, 48.4% yield) as a white solid. MS (ESI) m / z: 402.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 12.72 (s, 1H), 11.80 (s, 1H), 8.00 – 7.90 (m, 2H), 7.47 – 7.13 (m, 2H), 7.10 – 6.15 (m, 4H), 5.69 – 5.13 (m, 1H), 4.23 – 3.77 (m, 2H), 3.74 (s, 3H), 2.60 (s, 3H), 2.34 (dd, J = 12.4, 6.5 Hz, 1H), 2.05 – 1.84 (m, 2H), 1.76 (dd, J = 11.7, 5.4 Hz, 1H) ppm. Example 38: Synthesis of N-[(1R)-1-(2-Fluorophenyl)ethyl]-6-(3-methyl-2H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 38) N-[(1R)-1-(2-Fluorophenyl)ethyl]-6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- 2-carboxamide (38-1) A mixture of 6-chloro-N-[(1R)-1-(2-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2- carboxamide (500 mg, 1.574 mmol, 1 equiv), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2H-pyrazole (982.23 mg, 4.722 mmol, 3 equiv), K2CO3(434.95 mg, 3.148 mmol, 2 equiv) and Pd(PPh3)4(181.84 mg, 0.157 mmol, 0.1 equiv) in DMF (8 mL) and H2O (2 mL) was stirred at 100°C for 3 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), then dried over anhydrous Na2SO4. 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, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 23% B to 40% B in 16 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.72) to afford N-[(1R)-1-(2-fluorophenyl)ethyl]-6-(3- methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (113.5 mg, 19.9% yield) as a white solid. MS (ESI) m / z: 317.95 [M+H]+. N-[(1R)-1-(2-Fluorophenyl)ethyl]-6-(3-methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 38) A mixture of 6-chloro-N-[(1R)-1-(2-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2- carboxamide (500 mg, 1.574 mmol, 1 equiv), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2H-pyrazole (982.23 mg, 4.722 mmol, 3 equiv), K2CO3(434.95 mg, 3.148 mmol, 2 equiv) and Pd(PPh3)4(181.84 mg, 0.157 mmol, 0.1 equiv) in DMF (8 mL) and H2O (2 mL) was stirred at 100°C for 3 hours under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), then dried over anhydrous Na2SO4. 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, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 23% B to 40% B in 16 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.72) to afford N-[(1R)-1-(2-fluorophenyl)ethyl]-6-(3- methyl-2H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (113.5 mg, 19.9% yield) as a white solid. MS (ESI) m / z: 364.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 12.74 (s, 1H), 11.87 (s, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.10 – 7.89 (m, 2H), 7.51 (td, J = 7.9, 2.0 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.36 – 7.26 (m, 1H), 7.24 – 7.13 (m, 3H), 5.43 (p, J = 7.2 Hz, 1H), 2.62 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H) ppm.19F NMR (356 MHz, DMSO-d6) d -119.7 (s) ppm. Example 39: Synthesis of 3-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-6- (1H-pyrazol-4-yl)-1H-indole (Compound 39) 4-Chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (39-1) A solution of 1-bromo-3-(difluoromethoxy)benzene (20.0 g, 89.679 mmol, 1.0 equiv) and 4- chloro-N-methoxy-N-methylbutanamide (14.8 g, 89.679 mmol, 1.0 equiv) in toluene (200 mL) was cooled down to -78oC under nitrogen atmosphere. To the above mixture was added n-BuLi (71.7 mL, 179.358 mmol, 2.0 equiv) (2.5M in n-hexane) dropwise at -78oC. The resulting mixture was stirred for 1.5 hours at -78oC and 0.5 hour at room temperature. Desired product could be detected by TLC and LCMS. The reaction was quenched with sat. NH4Cl (aq.) (300 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 4-chloro-1-[3- (difluoromethoxy)phenyl]butan-1-one (2.0 g, 9.0%) as a yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 7.83 (dt, J = 7.7, 1.4 Hz, 1H), 7.72 (t, J = 2.1 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.2, 2.5 Hz, 1H), 6.77 – 6.35 (m, 1H), 3.68 (t, J = 6.2 Hz, 2H), 3.18 (t, J = 6.9 Hz, 2H), 2.24 (p, J = 6.6 Hz, 2H) ppm. (S)-N-{4-Chloro-1-[3-(difluoromethoxy)phenyl]butylidene}-2-methylpropane-2-sulfinamide (39-2) A solution of 4-chloro-1-[3-(difluoromethoxy)phenyl]butan-1-one (2.0 g, 8.043 mmol, 1.0 equiv), (S)-2-methylpropane-2-sulfinamide (1.5 g, 12.064 mmol, 1.5 equiv) and Ti(OEt)4(3.7 g, 16.086 mmol, 2.0 equiv) in THF (80 mL) was stirred at 65oC overnight. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 50 mL). And the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford (S)-N-{4-chloro-1-[3- (difluoromethoxy)phenyl]butylidene}-2-methylpropane-2-sulfinamide (1.3 g, 45.9%) as a yellow oil. MS (ESI) m / z: 351.95 [M+H]+. (2R)-2-[3-(Difluoromethoxy)phenyl]-1-[(S)-2-methylpropane-2-sulfinyl]pyrrolidine (39-3) A solution of (S)-N-{4-chloro-1-[3-(difluoromethoxy)phenyl]butylidene}-2-methylpropane-2- sulfinamide (1.3 g, 3.695 mmol, 1.0 equiv) in THF (18 mL) was treated with lithium triethylborohydride (1.0 M in tetrahydrofuran) (5.6 mL, 5.542 mmol, 1.5 equiv) at -78oC for 2 hours under nitrogen atmosphere. Then the resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4Cl (aq.) at 0oC. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford (2R)-2-[3- (difluoromethoxy)phenyl]-1-[(S)-2-methylpropane-2-sulfinyl]pyrrolidine (700.0 mg, 59.6%) as a colorless oil. MS (ESI) m / z: 318.10 [M+H]+. (2R)-2-[3-(Difluoromethoxy)phenyl]pyrrolidine hydrochloride (39-4) A solution of (2R)-2-[3-(difluoromethoxy)phenyl]-1-[(S)-2-methylpropane-2-sulfinyl]pyrrolidine (700.0 mg, 2.205 mmol, 1.0 equiv) in 1,4-dioxane (8.0 mL) was treated with HCl (4.0 M, in 1,4- dioxane, 2.0 mL) at 0oC for 5 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine hydrochloride (780.0 mg, crude) as a light yellow oil. MS (ESI) m / z: 214.15 [M+H]+. tert-Butyl 6-bromo-3-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]indole-1- carboxylate (39-5) A solution of 6-bromo-1-(tert-butoxycarbonyl)indole-3-carboxylic acid (809.3 mg, 2.379 mmol, 1.1 equiv), (3-{[(ethylimino)methylidene]amino}propyl)dimethylamine hydrochloride (621.9 mg, 3.244 mmol, 1.5 equiv), HOBT (438.4 mg, 3.244 mmol, 1.5 equiv) in DMF (10 mL) was treated with DIEA (1.5 mL, 8.652 mmol, 4.0 equiv) at room temperature for 10 minutes followed by the addition of (2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine hydrochloride (540.0 mg, 2.163 mmol, 1.0 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford tert-butyl 6-bromo-3-[(2R)-2-[3- (difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]indole-1-carboxylate (650.0 mg, 56.1%) as a light yellow solid. The reaction was repeated to produce one more batch. MS (ESI) m / z: 536.85 [M+H]+. 3-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-6-(1H-pyrazol-4-yl)-1H- indole (Compound 39) A solution of tert-butyl 6-bromo-3-[(2R)-2-[3-(difluoromethoxy)phenyl]pyrrolidine-1- carbonyl]indole-1-carboxylate (400.0 mg, 0.747 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (434.9 mg, 2.241 mmol, 3.0 equiv), Pd(PPh3)4(86.3 mg, 0.075 mmol, 0.1 equiv) and K2CO3(206.5 mg, 1.494 mmol, 2.0 equiv) in DMF (6.0 mL) and H2O (1.5 mL) was stirred at 90oC for 4 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (94:6) to afford the crude product. The residue was then purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 3 % to 70 % gradient in 45 min; detector, UV 254 nm, 200 nm. This resulted in 3-[(2R)-2-[3- (difluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-6-(1H-pyrazol-4-yl)-1H-indole (143.9 mg, 45.5%) as an off-white solid. MS (ESI) m / z: 423.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.60 (s, 1H), 8.37 – 7.72 (m, 4H), 7.58 (s, 1H), 7.48 – 7.30 (m, 2H), 7.23 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H),...

Claims

CLAIMS We claim:

1. A compound of Formula:or a pharmaceutically acceptable salt thereof; wherein:R1and R2are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; R4is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C(O)NR12R13, and halogen; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and halogen; R6is selected from the group consisting of hydrogen, cyano, C1-C6alkyl, C1-C6haloalkyl, halogen, OR7, and C(O)NR12R13; R8is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, and OR7; R7is independently selected at each instance from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl; R9is C1-C6alkyl, C1-C6haloalkyl, or a heterocycle; R12and R13are independently selected at each instance from the group consisting of hydrogen and C1-C6alkyl; m is 0 or 1; and A is CH or N.

2. The compound of claim 1, wherein the compound is of Formula: (I); or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

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

6. The compound of claim 5, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, wherein the compound is of Formula: or or a pharmaceutically acceptable salt thereof.

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

9. The compound of claim 8, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is of Formula: ); or a pharmaceutically acceptabe sa e eo .

12. The compound of claim 11, wherein the compound is of Formula:or ; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 11, wherein the compound is of Formula: oror a pharmaceutically acceptable salt thereof.

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

15. The compound of claim 14, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

16. The compound of claim 14, wherein the compound is of Formula:or a parmaceutca y acceptabe sat tereo.

17. The compound of claim 1, wherein the compound is of Formula:(VI); or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the compound is of Formula:or or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17, wherein the compound is of Formula:or or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-19, wherein R6is hydrogen.

21. The compound of any one of claims 1-19, wherein R6is halogen.

22. The compound of any one of claims 1-19, wherein R6is -F.

23. The compound of any one of claims 1-19, wherein R6is -Cl.

24. The compound of any one of claims 1-19, wherein R6is -Br.

25. The compound of any one of claims 1-19, wherein R6is -I.

26. The compound of any one of claims 1-19, wherein R6is C1-C6alkyl.

27. The compound of any one of claims 1-19, wherein R6is methyl.

28. The compound of any one of claims 1-19, wherein R6is C1-C6haloalkyl.

29. The compound of any one of claims 1-19, wherein R6is -CHF2.

30. The compound of any one of claims 1-19, wherein R6is -CF3.

31. The compound of any one of claims 1-19, wherein R6is cyano.

32. The compound of any one of claims 1-19, wherein R6is C(O)NR12R13.

33. The compound of any one of claims 1-19, wherein R6is C(O)NH2.

34. The compound of any one of claims 1-19, wherein R6is OR7.

35. The compound of claim 34, wherein R7is hydrogen.

36. The compound of claim 34, wherein R7is C1-C6alkyl.

37. The compound of claim 34, wherein R7is methyl.

38. The compound of claim 34, wherein R7is C1-C6haloalkyl.

39. The compound of claim 34, wherein R7is -CHF2.

40. The compound of any one of claims 1-39, wherein R8is hydrogen.

41. The compound of any one of claims 1-39, wherein R8is halogen.

42. The compound of any one of claims 1-39, wherein R8is -F.

43. The compound of any one of claims 1-39, wherein R8is -Cl.

44. The compound of any one of claims 1-39, wherein R8is -Br.

45. The compound of any one of claims 1-39, wherein R8is -I.

46. The compound of any one of claims 1-39, wherein R8is C1-C6alkyl.

47. The compound of any one of claims 1-39, wherein R8is methyl.

48. The compound of any one of claims 1-39, wherein R8is C1-C6haloalkyl.

49. The compound of any one of claims 1-39, wherein R8is -CHF2.

50. The compound of any one of claims 1-39, wherein R8is -CF3.

51. The compound of any one of claims 1-39, wherein R8is OR7.

52. The compound of claim 51, wherein R7is hydrogen.

53. The compound of claim 51, wherein R7is C1-C6alkyl.

54. The compound of claim 51, wherein R7is methyl.

55. The compound of claim 51, wherein R7is C1-C6haloalkyl.

56. The compound of claim 51, wherein R7is -CHF2.

57. The compound of claim 1, wherein the compound is of Formula:(VII), or a pharmaceutically acceptable salt thereof.

58. The compound of claim 57, wherein the compound is of Formula: or ; or a pharmaceutically acceptable salt thereof.

59. The compound of claim 57, wherein the compound is of Formula: ora pharmaceutically acceptable salt thereof.

60. The compound of claim 1, wherein the compound is of Formula: (VIII), or a pharmaceutically acceptable salt thereof.

61. The compound of claim 60, wherein the compound is of Formula: or apharmaceutically acceptable salt thereof.

62. The compound of claim 60, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

63. The compound of any one of claims 57-62, wherein R4is hydrogen.

64. The compound of any one of claims 57-62, wherein R4is halogen.

65. The compound of any one of claims 57-62, wherein R4is -F.

66. The compound of any one of claims 57-62, wherein R4is -Cl.

67. The compound of any one of claims 57-62, wherein R4is -Br.

68. The compound of any one of claims 57-62, wherein R4is -I.

69. The compound of any one of claims 57-62, wherein R4is C1-C6alkyl.

70. The compound of any one of claims 57-62, wherein R4is methyl.

71. The compound of any one of claims 57-62, wherein R4is C1-C6haloalkyl.

72. The compound of any one of claims 57-62, wherein R4is -CHF2.

73. The compound of any one of claims 57-62, wherein R4is -CF3.

74. The compound of any one of claims 57-62, wherein R4is cyano.

75. The compound of any one of claims 57-62, wherein R4is C(O)NR12R13.

76. The compound of any one of claims 57-62, wherein R4is C(O)NH2.

77. The compound of any one of claims 57-76, wherein R5is hydrogen.

78. The compound of any one of claims 57-76, wherein R5is halogen.

79. The compound of any one of claims 57-76, wherein R5is -F.

80. The compound of any one of claims 57-76, wherein R5is -Cl.

81. The compound of any one of claims 57-76, wherein R5is -Br.

82. The compound of any one of claims 57-76, wherein R5is -I.

83. The compound of any one of claims 57-76, wherein R5is C1-C6alkyl.

84. The compound of any one of claims 57-76, wherein R5is methyl.

85. The compound of any one of claims 57-76, wherein R5is C1-C6haloalkyl.

86. The compound of any one of claims 57-76, wherein R5is -CHF2.

87. The compound of any one of claims 57-76, wherein R5is -CF3.

88. The compound of any one of claims 57-87, wherein R9is C1-C6alkyl.

89. The compound of any one of claims 57-87, wherein R9is methyl.

90. The compound of any one of claims 57-87, wherein R9is cyclopropyl.

91. The compound of any one of claims 57-87, wherein R9is C1-C6haloalkyl.

92. The compound of any one of claims 57-87, wherein R9is a heterocycle.

93. The compound of any one of claims 57-87, wherein R9is .

94. The compound of any one of claims 1-93, wherein R1is hydrogen.

95. The compound of any one of claims 1-93, wherein R1is halogen.

96. The compound of any one of claims 1-93, wherein R1is C1-C6alkyl.

97. The compound of any one of claims 1-93, wherein R1is methyl.

98. The compound of any one of claims 1-93, wherein R1is C1-C6haloalkyl.

99. The compound of any one of claims 1-98, wherein R2is hydrogen.

100. The compound of any one of claims 1-98, wherein R2is halogen.

101. The compound of any one of claims 1-98, wherein R2is C1-C6alkyl.

102. The compound of any one of claims 1-98, wherein R2is methyl.

103. The compound of any one of claims 1-98, wherein R2is C1-C6haloalkyl.

104. The compound of any one of claims 1-103, wherein R3is hydrogen.

105. The compound of any one of claims 1-103, wherein R3is C1-C6alkyl.

106. The compound of any one of claims 1-103, wherein R3is methyl.

107. The compound of any one of claims 1-103, wherein R3is C1-C6haloalkyl.

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

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

110. A pharmaceutical composition comprising a compound of any one of claims 1-109 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

111. The pharmaceutical composition of claim 110, wherein the pharmaceutical composition is suitable for oral administration.

112. The pharmaceutical composition of claim 110, wherein the pharmaceutical composition is suitable for parenteral administration.

113. The pharmaceutical composition of claim 110, wherein the pharmaceutical composition is suitable for intravenous administration.

114. A method of treating a ROCK1 or ROCK2 mediated disorder comprising administering an effective amount of a compound of any one of claims 1-109 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a subject in need thereof.

115. The method of claim 114, wherein the subject is a human.

116. The method of claim 114 or 115, wherein the disorder is a neurodegenerative disorder.

117. The method of claim 116, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis.

118. The method of claim 116, wherein the neurodegenerative disorder is Parkinson’s disease.

119. The method of claim 116, wherein the neurodegenerative disorder is Huntington’s disease.

120. The method of claim 116, wherein the neurodegenerative disorder is Alzheimer’s disease.

121. The method of claim 114 or 115, wherein the disorder is a kidney disease.

122. The method of claim 121, wherein the kidney disease is diabetic nephropathy.

123. The method of claim 121, wherein the kidney disease is polycystic kidney disease.

124. The method of claim 121, wherein the kidney disease is focal segmental glomerulosclerosis.

125. The method of claim 114 or 115, wherein the disorder is Levodopa-induced dyskinesia.

126. The method of claim 114 or 115, wherein the disorder is a bladder dysfunction.

127. The method of claim 126, wherein the bladder dysfunction is interstitial cystitis.

128. The method of claim 126, wherein the bladder dysfunction is bladder inflammation.

129. The method of claim 126, wherein the bladder dysfunction is overactive bladder.

130. The method of claim 126, wherein the bladder dysfunction is bladder fibrosis.

131. The method of claim 126, wherein the bladder dysfunction is neurogenic bladder.

132. The method of claim 126, wherein the bladder dysfunction is a lower urinary tract symptom.

133. The method of claim 114 or 115, wherein the disorder is a cancer.

134. The method of claim 133, wherein the cancer is breast cancer.

135. The method of claim 133, wherein the cancer is prostate cancer.

136. The method of claim 133, wherein the cancer is melanoma.

137. The method of claim 133, wherein the cancer is a desmoplastic disorder.

138. The method of claim 114 or 115, wherein the disorder is a traumatic brain injury.

139. The method of claim 114 or 115, wherein the disorder is diabetic retinopathy.

140. The method of claim 114 or 115, wherein the disorder is idiopathic pulmonary fibrosis.

141. The method of claim 114 or 115, wherein the disorder is pulmonary sarcoidosis.

142. The method of claim 114 or 115, wherein the disorder is neurosarcoidosis.

143. The method of claim 114 or 115, wherein the disorder is scleroderma.

144. The method of claim 114 or 115, wherein the disorder is a fibrotic disorder.

145. The method of claim 144, wherein the disorder is a fibrotic disorder of the lung.

146. The method of claim 144, wherein the disorder is a fibrotic disorder of the kidney.

147. The method of claim 144, wherein the disorder is a fibrotic disorder of the liver.

148. The method of claim 144, wherein the disorder is a fibrotic disorder of the skin.

149. The method of any one of claims 114-148, wherein the disorder is mediated by ROCK1.

150. The method of any one of claims 114-148, wherein the disorder is mediated by ROCK2.

151. Use of a compound of any one of claims 1-109 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to treat a ROCK1 or ROCK2 mediated disorder.

152. Use of a compound of any one of claims 1-109 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament to treat a ROCK1 or ROCK2 mediated disorder.

Images