Patent Publication Number: US-2021163421-A1

Title: Inhibitors of rho associated coiled-coil containing protein kinase

Description:
FIELD OF THE INVENTION 
     The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of inhibiting ROCK1 and/or ROCK2 that are useful for the treatment of disease. 
     BACKGROUND OF THE INVENTION 
     Rho Associated Coiled-Coil Containing Protein Kinases (ROCK) are members of the serine/threonine kinase family. Two isoforms, ROCK 1 and ROCK 2, have been identified. Both isoforms are activated by GTP-bound forms of Rho GTPase and when activated phosphorylate a variety of downstream substrates. ROCKs play important roles in numerous cellular processes including smooth muscle cell contraction, cell proliferation, adhesion and migration. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including, for example, asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, pulmonary hypertension, neuronal degeneration, and osteoporosis. 
     ROCK is a key intracellular regulator of cytoskeletal dynamics and cell motility. ROCK regulates a number of downstream targets of RhoA through phosphorylation, including, for example, myosin light chain, the myosin light chain phosphatase binding subunit and LIM-kinase 2. These substrates regulate actin filament organization and contractility. In smooth muscle cells, ROCK mediates calcium sensitization and smooth muscle contraction. Inhibition of Rho-kinase blocks 5-HT and phenylephrine agonist induced muscle contraction. When introduced into non-smooth muscle cells, ROCK induces stress fiber formation and is required for the cellular transformation mediated by RhoA. ROCK participates in a variety of cellular processes, including but not limited to cell adhesion, cell motility and migration, growth control, cell contraction, and cytokinesis. ROCK is also involved in Na/H exchange transport system activation, stress fiber formation, adducin activation, and physiological processes such as vasoconstriction, bronchial smooth muscle constriction, vascular smooth muscle and endothelial cell proliferation, platelet aggregation, and others. 
     Inhibition of ROCK activity in animal models has demonstrated a number of benefits of ROCK inhibition for the treatment of human diseases. These include models of cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, central nervous system disorders such as neuronal degeneration and spinal cord injury, and in neoplasias. Inhibition of ROCK activity has been shown to inhibit tumor cell growth and metastasis, angiogenesis, arterial thrombotic disorders such as platelet aggregation and leukocyte aggregation, asthma, regulation of intraocular pressure, and bone resorption. The inhibition of ROCK activity in patients has benefits for controlling cerebral vasospasms and ischemia following subarachnoid hemorrhage, reduction of intraocular pressure, increase in ocular aqueous outflow by relaxation of trabecular meshwork tissue, improving blood flow to the optic nerve, and protection of healthy ganglion cells. 
     A substantial body of in vivo data has been generated focusing on the activity of ROCK in the CNS. Abnormal activation of the ROCK pathway has been documented in many disorders of the central nervous system. For example, axon growth and synaptic plasticity are dependent on the structural regulation of the actin cytoskeleton. The Rho-ROCK cascade has a central role in synaptic plasticity, both in dendrite morphogenesis and stability as well as in growth cone motility and collapse. In addition, multiple axon growth inhibitory molecules converge on RhoA/ROCK in neurons making this an attractive pathway for intervention in CNS disorders. 
     Nogo-receptors (NgR) (along with other complex members, including LINGO-1) and their ligands are perhaps the most well characterized and potent inhibitors of neurite outgrowth. Some of the earliest events downstream of receptor activation by the myelin-associated inhibitors are the upregulation of RhoA and ROCKs. These events lead to increased contractility and have strong inhibitory effects on axonal growth in mature neurons. Thus, the possibility of inhibiting this signal cascade provides a very promising therapeutic strategy in Spinal Cord and Optical Nerve injuries. Neurodegenerative conditions such as Huntington&#39;s and Alzheimer&#39;s (AD) disease are also being investigated as responsive to inhibition of the NgR signaling. Not only do NgR family members associate with APP processing but also subcellular localization of NgR and Nogo is altered in AD brain. 
     Alzheimer&#39;s disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder, which involves a gradual decline of many cognitive functions including memory impairment (Selkoe, 2001). Synaptic loss is generally observed in AD pathology and is the hallmark of synaptic dysfunction in AD (Tanzi and Bertram, 2005). Oligomerized β-amyloid peptides have been implicated in the loss of synaptic plasticity and neural network dysfunction. Synaptic plasticity is dependent on the structural regulation of the actin cytoskeleton in dendritic spines. Rho-ROCK cascade has a central role in synaptic plasticity, both in dendrite morphogenesis and stability as well as in growth cone motility and collapse (Govek et al., 2005; Linseman and Loucks, 2008). Several studies have demonstrated that ROCK kinases can induce generation of toxic β-amyloid peptide and furthermore, inhibition of ROCKs, can inhibit toxic peptide processing. In a feed-forward mechanism, β-amyloid increases the Rho GTPase activity, which via ROCK activation inhibits neurite outgrowth and synapse formation (Petratos et al., 2008). Thus, ROCK inhibitors may hold the potential for preventing synaptic and neuronal degradation as well as for promoting regenerative processes in AD. A recent study by Herskowitz et al. showed that ROCK knockdown decreased αβ levels. These effects demonstrate that highly ROCK selective inhibitors are needed to provide an effective treatment of Alzheimer&#39;s disease (AD). A model compound SR3677 was tested in a rodent model of AD, in an effort to demonstrate the use of ROCK inhibition for AD, by altering BACE-1 distribution and amyloid precursor protein (APP) trafficking to lysosomes. After a direct i.p. injection into hippocampus due to its poor oral PK properties (5% F and &lt;1 hr half-life) and lack of brain penetration, SR3677 had the promising effect of lowering sAPPP. 
     Huntington&#39;s disease (HD) is a devastating, untreatable, dominantly inherited neurodegenerative disease characterized by psychiatric disturbance, motor impairment, and dementia. Misfolding and aggregation of the Htt protein, a product of the huntingtin gene, causes the HD pathology (Shao and Diamond, 2007). Very few mechanism-based therapeutic leads for treatment of HD have been developed. While scientific investigations are still ongoing, multiple lines of evidence suggest that ROCK inhibition may constitute an effective treatment for HD. In mouse models of HD, ROCK inhibition significantly reduced soluble Htt levels, reversed aggregate formation, neurite retraction and was protective against neuronal cell death (Deyts et al., 2009; Li et al., 2009). Similar results were obtained in  Drosophila  studies, where inhibition of ROCK controlled Htt aggregation (Shao et al., 2008a; Shao et al., 2008b). The ROCK signaling pathway is a promising therapeutic target for HD. 
     ROCK signaling has also been implicated in Parkinson&#39;s disease and amyotrophic lateral sclerosis (ALD). See, e.g., Tonges, L. et al. (2012). “Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson&#39;s disease.” Brain. 135(11):3355-70. 
     ROCKs phosphorylate multiple downstream substrates, including myosin-light-chain (MLC, at threonine 18 and serine 19) and myosin light-chain phosphatase (MYPT1, at threonine 853), to drive the polymerization of globular G-actin into filamentous F-actin and assemble actomyosin contractile machinery. It has been recognized that this pathway is may contribute to the pathogenesis of several CNS disorders such as spinal cord injuries, stroke, and AD. In the adult CNS, injured axons regenerate poorly due to the presence of myelin-associated axonal growth inhibitors. Myelin-associated inhibitors such as myelin-associated glycoprotein (MAG), Nogo, oligodendrocyte-myelin glycoprotein (OMgp) and repulsive guidance molecule (RGM) limit axonal regeneration in the injured brain and spinal cord. A common mechanism for various myelin-associated inhibitors is that they all activate Rho and its downstream effector kinase ROCKs to inhibit neurite outgrowth. 
     Blockade of Rho/ROCK pathway by small molecule is a desirable strategy in central nervous system (CNS) disorders. However, the blood-brain barrier (BBB) while serving a critical role in brain homeostasis, also significantly impedes the penetration of most small molecule inhibitors. With growing interest in developing selective and potent inhibitors for the treatment of CNS diseases, there is an urgent need for inhibitors of ROCK 1 and/or ROCK 2, in particular those that cross the blood-brain barrier. 
     SUMMARY OF THE INVENTION 
     In one aspect, the present invention provides compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       R 2  is selected from the group consisting of aryl, heteroaryl, aralkyl, and heterocyclyl, each of which may be unsubstituted or optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—;   alternatively, R 1  and R 2  taken together form a monocyclic group or a bicyclic group, wherein the monocyclic group has 4 to 7 ring atoms, including up to 2 ring heteroatoms, and the bicyclic group has 8 to 10 ring atoms, including up to 3 ring heteroatoms, and wherein the monocyclic group and bicyclic group are unsubstituted or are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, aryl and heteroaryl;   R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-;   R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   R 5  is selected from H, lower alkyl and C 3 -C 6  cycloalkyl;   a is 0 or 1;   b is 0 to 2;   and   each R and R′ is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl, or alternatively, R and R′ taken together form a 5 to 6 membered heterocyclic ring.   

     The present invention includes pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier. 
     The present invention includes compositions comprising a substantially pure compound of the invention and a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, and a pharmaceutically acceptable carrier. 
     In one aspect, the invention provides a method of inhibiting a ROCK in a mammal comprising administering an effective amount of one or more compounds of Formula I. The invention provides a method of treating a patient suffering from a disease comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound of Formula I. In certain such embodiments, the compound of Formula I inhibits ROCK1 and/or ROCK2. In certain such embodiments, the compound of Formula I selectively inhibits ROCK1 and/or ROCK2. Non-limiting diseases and conditions treated according to the instant invention include central nervous system disorders such as neuronal degeneration and spinal cord injury, cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, arterial thrombotic disorders such as platelet aggregation and leukocyte aggregation, asthma, regulation of intraocular pressure, and bone resorption. In neoplasias, inhibition of Rho-kinase inhibits tumor cell growth and metastasis, and angiogenesis. 
     The invention provides a method of treating a central nervous system disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Central nervous system disorders include, without limitation, neuronal degeneration or spinal cord injury, as well as Huntington&#39;s disease, Parkinson&#39;s disease, Alzheimer&#39;s disease, Amyotrophic lateral sclerosis (ALS), or multiple sclerosis. 
     The invention provides a method of treating an autoimmune disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Autoimmune disorders include, without limitation, rheumatoid arthritis, (multiple sclerosis), systemic lupus erythematosus (SLE; lupus), psoriasis, Crohn&#39;s disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD). 
     The invention provides a method of treating a cardiovascular disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Cardiovascular disorders include, without limitation, hypertension, atherosclerosis, angina, arterial obstruction, peripheral arterial disease, peripheral circulatory disorder, cerebral cavernous malformation, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, acute respiratory distress syndrome (ARDS) or erectile dysfunction. 
     The invention provides a method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Inflammation includes, without limitation, asthma, cardiovascular inflammation, renal inflammation or arteriosclerosis. 
     The invention provides a method of treating an arterial thrombotic disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Non-limiting examples of arterial thrombotic disorders are platelet aggregation, or leukocyte aggregation. 
     The invention provides a method of treating a fibrotic disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Non-limiting examples of fibrotic disorders are pulmonary fibrosis including cystic and idiopathic pulmonary fibrosis, radiation induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, old myocardial infraction, arterial stiffness, atherosclerosis, restenosis, arthrofibrosis, Crohn&#39;s disease, myelofibrosis, Peyronie&#39;s diseases, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal cavity fibrosis, schleroderma/systemic sclerosis, mediastinal fibrosis, Keloids and hypertrophic scars, glial scaring, or renal fibrosis. 
     The invention provides a method of maintaining epithelial stability comprising administering to the subject a therapeutically effective amount of a compound of Formula I. 
     The invention provides a method of treating glaucoma or regulating intraocular pressure in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Non-limiting examples of glaucoma include primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, neovascular glaucoma, congenital glaucoma, normal tension glaucoma, or secondary glaucoma. 
     The invention provides a method of treating a neoplastic disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. Neoplastic diseases include, without limitation, a lymphoma, carcinoma, leukemia, sarcoma, or blastoma, such as squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, or head and neck cancer. 
     The invention also provides a method of treating metabolic syndrome, insulin resistance, hyperinsulinemia, type 2 diabetes, or glucose intolerance in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. 
     Further, the invention provides a method of treating osteoporosis or promoting bone formation a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I. 
     The invention provides a method of treating an ocular disorder having an angiogenic component comprising administering to the subject a therapeutically effective amount of a compound of Formula I and an angiogenesis inhibitor. Non-limiting examples of such ocular disorders include age related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic macular edema (DME), iris neovascularization, uveitis, neovascular glaucoma, or retinitis of prematurity (ROP). 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1 . Representative Z′-Lyte assay results. The ROCK inhibitors of the present invention show as low as single digit nanomolar potencies towards both isoforms of ROCK. 
         FIG. 2 . Compounds of the present invention inhibit both ROCK isoforms in cells. HCT116 cells with either a ROCK1 or ROCK2 knockout (ROCK1KO and ROCK2KO, respectively) were treated with the inhibitor for 90 min and pMypt (T853) levels were visualized by western blotting. The ROCK inhibitor efficiently blocked ROCK target MYPT1 phosphorylation at 110 nM. 
         FIG. 3 . Human oligodendrocyte/neuron progenitor cells were cultured in vitro with or without ROCK inhibitor (Example 2 compound) for 2 &amp; 14 days. Nestin and MAP2 proteins were visualized by staining with commercial antibodies to identify different stages of neuronal cell differentiation. The ROCK inhibitor significantly facilitated mature neuronal cell marker MAP2 expression while improved neurite outgrowth, as evidenced by strong increase in MAP2 signal in cells differentiated in the presence of the ROCK inhibitor. 
         FIG. 4 . Under co-cultured condition of rat oligodendrocytes with rat dorsal root ganglia (DRG) explants, treatment with the ROCK inhibitor (Example 2 compound) changed cytoskeletal organization, producing many shorter ordered myelin segments, which were identified by neurofilament staining. At the same time, the ROCK inhibitor also facilitated axonal support of oligodendrocyte, which was demonstrated by the alignment of oligodendrocyte (stained for MBP) along with the direction of axonal (stained for neurofilament) extension. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     ROCK Inhibitors 
     Compounds according to the present invention include those having the formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       R 2  is selected from the group consisting of aryl, heteroaryl, aralkyl, and heterocyclyl, each of which may be unsubstituted or optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—;   alternatively, R 1  and R 2  taken together form a monocyclic group or a bicyclic group, wherein the monocyclic group has 4 to 7 ring atoms, including up to 2 ring heteroatoms, and the bicyclic group has 8 to 10 ring atoms, including up to 3 ring heteroatoms, and wherein the monocyclic group and bicyclic group are unsubstituted or are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, aryl and heteroaryl;   R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-;   R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   R 5  is selected from H, lower alkyl and C 3 -C 6  cycloalkyl;   a is 0 or 1;   b is 0 to 2;   and   each R and R′ is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl, or alternatively, R and R′ taken together form a 5 to 6 membered heterocyclic ring.   

     Compounds according to the present invention include those having the formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       R 2  is selected from the group consisting of aryl, heteroaryl, aralkyl, and heterocyclyl, each of which may be unsubstituted or optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—;   alternatively, R 1  and R 2  taken together form a monocyclic group or a bicyclic group, wherein the monocyclic group has 4 to 7 ring atoms, including up to 2 ring heteroatoms, and the bicyclic group has 8 to 10 ring atoms, including up to 3 ring heteroatoms, and wherein the monocyclic group and bicyclic group are unsubstituted or are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, aryl and heteroaryl;   R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-;   R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   b is 0 to 2; and   each R and R′ is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl, or alternatively, R and R′ taken together form a 5 to 6 membered heterocyclic ring.   

     In a certain embodiments of the present invention, there is provided a compound of the formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       R 2  is selected from the group consisting of aryl, heteroaryl, aralkyl, and heterocyclyl, each of which may be unsubstituted or optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—;   alternatively, R 1  and R 2  taken together form a monocyclic group or a bicyclic group, wherein the monocyclic group has 4 to 7 ring atoms, including up to 2 ring heteroatoms, and the bicyclic group has 8 to 10 ring atoms, including up to 3 ring heteroatoms, and wherein the monocyclic group and bicyclic group are unsubstituted or are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, aryl and heteroaryl;   R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-; and   each R and R′ is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl, or alternatively, R and R′ taken together form a 5 to 6 membered heterocyclic ring.   

     In a certain embodiments of the present invention, there is provided a compound of the formula IV: 
     
       
         
         
             
             
         
       
     
     wherein:
     ring A is a 5- or 6-membered aromatic ring which optionally contains up to 3 ring heteroatoms;   R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-;   R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   b is 0 to 2;   R 6  is selected from the group consisting of H, halo, lower alkyl, substituted lower alkyl, lower alkoxy, amino, hydroxyl, and carboxyl;   R 7  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, and RCONR′—;   each R and R′ is independently selected from H, lower alkyl, and C3-C6 cycloalkyl, or alternatively, R and R′ taken together form a 5 to 6 membered heterocyclic ring; and m is 1 to 3.   

     In a certain embodiments of the present invention, there is provided a compound of the formula V: 
     
       
         
         
             
             
         
       
     
     wherein:
     ring B is a 5- or 6-membered aromatic ring which optionally contains up to 3 ring heteroatoms;   R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-;   R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   b is 0 to 2;   R 8  is selected from the group consisting of H, halo, lower alkyl, substituted lower alkyl, lower alkoxy, amino, hydroxyl and carboxyl;   R 9  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy and carboxyl, RR′N—, RR′NCO—, RCONH—, and RCONR′—;   each R and R′ is independently selected from H, lower alkyl, and C3-C6 cycloalkyl, or alternatively, R and R′ taken together form a 5 to 6 membered heterocyclic ring; and m is 1 to 3.   

     In a certain embodiments of the present invention, there is provided a compound of the formula VI: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       R 3  is selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C 2-4  alkyl)-;   R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   b is 0 to 2;   each R 21  is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—; and   n is 0 to 3.   

     In a certain embodiments of the present invention, there is provided a compound of the formula VII: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       R 4  is selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RR′N—(C 2-4  alkyl)-, and RR′N—(C 2-4  alkyl)-O—;   b is 0 to 2;   each R 21  is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—; and   n is 0 to 3.   

     In a certain embodiments of the present invention, there is provided a compound of the formula VIII: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       each R 21  is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, C 1 -C 3  perfluoro alkyl, C 1 -C 3  perfluoro alkoxy, carboxyl, RR′N—, RR′NCO—, RCONH—, RCONR′—, RO 2 C—, aryl-O— and heteroaryl-O—; and   n is 0 to 3.   

     In a certain embodiments of the present invention, there is provided a compound of the formula IX: 
     
       
         
         
             
             
         
       
     
     wherein:
     R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, C 3 -C 6  cycloalkyl, substituted C 3 -C 6  cycloalkyl, R 10 R 11 N(CR 12 R 13 ) c —, R 10 O(CR 12 R 13 ) c —, W(CR 12 R 13 ) d — and R 10 R 11 N—C(═O)—(CR 12 R 13 ) c —;
       each R 10  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 11  is independently selected from H, lower alkyl, and C 3 -C 6  cycloalkyl;   each R 12  is independently selected from H and lower alkyl;   each R 13  is independently selected from H and lower alkyl;   additionally or alternatively, an R 12  and an R 13  attached to the same carbon atom may be taken together to form a C 3 -C 6  cycloalkyl group;   W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms;   c is 2 to 4;   d is 1 to 4;   
       each R 22  is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, lower alkoxy, amino, C 1 -C 3  perfluoro alkyl, and C 1 -C 3  perfluoro alkoxy; and   n is 0 to 3.   

     In preferred embodiments for the Formulas I to IX, R 1  is selected to be lower alkyl. More preferably, R 1  is C 1  to C 3  alkyl, and still more preferably, R 1  is methyl or ethyl. 
     The term “alkyl” refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 8 or fewer carbon atoms in its backbone (e.g., C1-C8 for straight chain, C3-C8 for branched chain), and more preferably 6 or fewer. Likewise, preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 3 to 6 carbons in the ring structure. 
     Unless the number of carbons is otherwise specified, “lower alkyl” as used herein means an alkyl group, as defined above, but having from one to four carbons, and more preferably from one to three carbon atoms. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl. Lower alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl. 
     The term “cycloalkyl” refers to saturated, carbocyclic groups having from 3 to 6 carbons in the ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
     The term “substituted alkyl” refers to an alkyl group as defined above, and having one to three substituents. The substituents are selected from the group consisting of halo, hydroxy, lower alkoxy, amino, lower alkyl amino, nitro, cyano, perfluoro lower alkyl, perfluoro lower alkoxy and carboxyl. 
     “Substituted lower alkyl” refers to a lower alkyl group as defined above, and having one to three substituents. The substituents are selected from the group consisting of halo, hydroxy, lower alkoxy, amino, nitro, cyano, perfluoro lower alkyl, perfluoro lower alkoxy and carboxyl. 
     “Substituted cycloalkyl,” such as “substituted C 3 -C 6  cycloalkyl” refers to a cycloalkyl group as defined above, and having one to three substituents. The substituents are selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, nitro, cyano, perfluoro lower alkyl, perfluoro lower alkoxy and carboxyl. 
     As used herein, the term “halogen” or “halo” designates —F, —Cl, —Br or —I, and preferably F, Cl or Br. 
     The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group, as defined above, that is attached through an oxygen atom. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “lower alkoxy” refers to an alkoxy substituent in which a lower alkyl is bonded through an oxygen atom, wherein the “lower alkyl” portion is as defined above. 
     The terms “amine” and “amino” refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula: 
     
       
         
         
             
             
         
       
     
     wherein R and R′ are each independently selected from H and lower alkyl. 
     The term “aryl” as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaryl” groups. The aromatic ring can be substituted at one or more ring positions with such substituents as described above. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic. 
     The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. Preferably, the alkyl group is a lower alkyl, as described above. 
     The term “heterocycle” of “heterocyclyl” refer to non-aromatic heterocycles having from 4 to 7 ring atoms and including from 1 to 3 ring heteroatoms. 
     The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. Most preferred are nitrogen and oxygen. 
     As used herein, the definition of each expression, e.g. alkyl, m, n, R 1 , R 2 , etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. 
     It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. 
     As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. 
     The phrase “protecting group” as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). 
     Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including c is- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention. The invention also contemplates the substitution of isotopes of the atoms for the compounds, for example deuterium for hydrogen, etc. 
     In one aspect, the present invention provides compounds of Formulas I-IX that are inhibitors of ROCK. ROCK is found in two forms, ROCK 1 (ROCKβ; p160-ROCK) and ROCK 2 (ROCKα). In some embodiments, the compound of Formulas I-IX selectively inhibits ROCK1. In some embodiments, the compound of Formulas I-IX selectively inhibits ROCK2. In some embodiments, the compound of Formulas I-IX is non-selective with respect to inhibition of ROCK1 and ROCK2. In the context of this invention, selective means the inhibitor demonstrates an IC 50  that is at least 2-fold, at least 5-fold, at least 10-fold, or at least 25-fold lower for one kinase as compared to the IC 50  for the other kinase. 
     Methods of determining kinase inhibition are known in the art. For example, kinase activity of an enzyme and the inhibitory capacity of a test compound can be determined by measuring enzyme specific phosphorylation of a substrate. Commercial assays and kits are available and can be employed. For example, kinase inhibition can be determined using an IMAP® assay (Molecular Devices). This assay method involves the use of a fluorescently tagged peptide substrate. Phosphorylation of the tagged peptide by a kinase of interest promotes binding of the peptide to a trivalent metal-based nanoparticle via the specific, high affinity interaction between the phospho-group and the trivalent metal. Proximity to the nanoparticle results in increased fluorescence polarization. Inhibition of the kinase by a kinase inhibitor prevents phosphorylation of the substrate and thereby limits binding of the fluorescently-tagged substrate to the nanoparticle. Such an assay can be compatible with a microwell assay format, allowing simultaneous determination of IC 50  of multiple compounds. 
     Methods of Treating Disease 
     In one aspect of the present invention there is provided a method of treating a patient suffering from a disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention. The phrase “therapeutically-effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment. 
     CNS Disorders 
     Compounds of Formulas I-IX demonstrate effective blood brain barrier (BBB) penetration, and distribution to tissues of the central nervous system. Thus, the compounds of the invention are useful for treatment of central nervous system disorders, as well as disorders, such as certain ocular disorders, that benefit from the ability to cross the BBB. Such disorders may involve neuronal degeneration or physical injury to neural tissue, including without limitation, Huntington&#39;s disease, Parkinson&#39;s Disease, Alzheimer&#39;s, Amyotrophic lateral sclerosis (ALS), Batten disease, dementia, spinal muscular atrophy, motor neurone diseases, spinocerebellar ataxia, acute or chronic pain, dementia, neuronal degeneration, spinal cord injury, cerebral vasospasm or multiple sclerosis. 
     Cardiovascular and Other Diseases 
     Compounds of the invention that inhibit ROCK and/or ROCK mediated phosphorylation are useful for treatment of patients suffering from cardiovascular and non-cardiovascular diseases involving Rho-kinase function, such as hypertension, pulmonary hypertension, atherosclerosis, restenosis, coronary heart disease, cardiac hypertrophy, ocular hypertension, retinopathy, ischemic diseases, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, peripheral circulatory disorder, peripheral artery occlusive disease, glaucoma, (e.g., regulating intraocular pressure), fibroid lung, fibroid liver, fibroid kidney, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, central nervous system disorders such as neuronal degeneration and spinal cord injury. Further, ROCK inhibiters of the invention can be used to treat arterial thrombotic disorders such as platelet aggregation and leukocyte aggregation, and bone resorption. 
     In an embodiment of the invention, compounds are used to treat cerebral cavernous malformation (CCM). CCMs are vascular lesions consisting of clusters of leaky, dilated capillaries and are associated with central nervous system (CNS) disorders, including seizures and stroke. The loss of vascular integrity is thought to involve activation of RhoA and activation of ROCK, leading to changes in cytoskeletal stability and increased vascular permeability. The compounds of the invention inhibit ROCK activation and restore vascular endothelialfunction. 
     Glaucoma 
     In an embodiment of the invention, a compound of Formulas I-IX is used to treat glaucoma. The two most common, primary open-angle glaucoma and acute angle-closure glaucoma, are characterized by high ocular pressure. Pigmentary glaucoma and congenital glaucoma also are characterized by reduced fluid outflow and high intraocular pressure (IOP). Normal tension glaucoma is thought to be due to another mechanism, in particular poor blood flow to the optic nerve. Secondary glaucoma can result from injury, infection, inflammation, tumor or cataracts, and is also associated with prolonged use of steroids, systemic hypertension, diabetic retinopathy, and central retinal vein occlusion. Glaucomas having a neovascular component can benefit from administration of an angiogenesis inhibitor in addition to a ROCK inhibitor. 
     Inflammation 
     The invention provides a method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formulas I-IX. Inflammation includes, without limitation, asthma, cardiovascular inflammation, renal inflammation, atherosclerosis and arteriosclerosis, and sepsis. Other inflammatory conditions that can be treated by methods of the invention include fibrotic conditions (including, e.g., idiopathic pulmonary fibrosis, NASH, scleroderma, systemic sclerosis, and cirrhosis). 
     Autoimmune Disorders 
     The invention provides a method of treating an autoimmune disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formulas I-IX. Autoimmune disorders include, without limitation, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE; lupus), psoriasis, Crohn&#39;s disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD), Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison&#39;s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal &amp; neuronal neuropathies, Balo disease, Behcet&#39;s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn&#39;s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic&#39;s disease (neuromyelitis optica), Discoid lupus, Dressler&#39;s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture&#39;s syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener&#39;s Granulomatosis), Graves&#39; disease, Guillain-Barre syndrome, Hashimoto&#39;s encephalitis, Hashimoto&#39;s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere&#39;s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren&#39;s ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic&#39;s), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with  Streptococcus ), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis,  Pernicious anemia , POEMS syndrome,  Polyarteritis nodosa , Type I, II, &amp; III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynaud&#39;s phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter&#39;s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren&#39;s syndrome, Sperm &amp; testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac&#39;s syndrome, Sympathetic ophthalmia, Takayasu&#39;s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, and Vitiligo. 
     According to the invention, targeting Th17 (IL-17-secreting) cells by ROCK inhibition provides a method for treating Th17 cell-mediated diseases, including but not limited to autoimmune disorders such as RA, MS, SLE, Psoriasis, and Crohn&#39;s disease, and GVHD in humans. In an embodiment of the invention, the ROCK inhibitor is a compound of Formula I. 
     The development and function of Tregs depend on activation of specific signaling transduction pathways. TGF-β and TL-2 activate expression of Foxp3 and STAT5 transcription factors that both play an essential role in the control of Treg suppressive function. On the other hand, pro-inflammatory cytokines inhibit Foxp3 expression via up-regulation of STAT3 phosphorylation. According to the invention, pharmacological inhibition of ROCK2 may regulate Treg function. 
     Neoplastic Disease 
     ROCK inhibitors of the invention inhibit tumor cell growth and metastasis, and angiogenesis, and are useful for treating neoplastic diseases. Neoplastic diseases include any malignant growth or tumor caused by abnormal or uncontrolled cell division, and may spread to other parts of the body through the lymphatic system or the blood stream. Neoplastic disease includes, without limitation, lymphoma (a neoplasm of lymph tissue that is usually malignant), carcinoma (any malignant tumor derived from epithelial tissue), leukemia (malignant neoplasm of blood-forming tissues; characterized by abnormal proliferation of leukocytes), sarcoma (a usually malignant tumor arising from connective tissue (bone or muscle etc.), and blastoma (malignancy in precursor cells). Nonlimiting examples include squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, and various types of head and neck cancer. 
     Weight Gain/Loss 
     According to the invention, ROCK inhibitors are used to effect weight loss and/or limit weight gain. ROCK inhibitors promote weight loss in normal subjects, and limit weight gain in subjects prone to obesity. 
     Insulin Resistance 
     In an embodiment of the invention, a ROCK inhibitor is used to reduce or prevent insulin resistance or restore insulin sensitivity. Accordingly, in one embodiment, the compounds of the invention are used to promote or restore insulin-dependent glucose uptake. In another embodiment of the invention, a ROCK-inhibitors of the invention is used to promote or restore glucose tolerance. In another embodiment of the invention, a ROCK inhibitor of the invention is used to treat metabolic syndrome. In another embodiment, ROCK inhibitors of the invention is used to reduce or prevent hyperinsulinemia. In an embodiment of the invention, a ROCK inhibitor is used to treat diabetes (particularly type 2 diabetes). ROCK inhibitors of the invention may also be used to promote or restore insulin-mediated relaxation of vascular smooth muscle cells (VSMCs). 
     Angiogenesis 
     The invention provides methods and compounds for treating diseases and disorders with an angiogenic component. According to the invention, in certain embodiments, such diseases and disorders are treated by administering to a subject an effective amount of a ROCK inhibitor. According to the invention, such diseases and disorders can also be treated by administering an effective amount of a rho kinase inhibitor and an effective amount of an angiogenesis inhibitor. According to the invention, ocular diseases and disorders having an angiogenic component are treated in this manner. In one embodiment, the invention provides a method of treating age related macular degeneration (AMD), which occurs in “dry” and “wet” forms. The “wet” form of AMD causes vision loss due to abnormal blood vessel growth (neovascularization). Bleeding, leaking, and scarring from these retinal blood vessels eventually causes irreversible damage to the photoreceptors. The dry form results from atrophy of the retinal pigment epithelial layer, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. In another embodiment, the invention provides a method of treating choroidal neovascularization (CNV). Choroidal neovascularization is a process in which new blood vessels grow in the choroid, through the Bruch membrane and invade the subretinal space, and is a symptom of, among other causes, age-related macular degeneration, myopia and ocular trauma. In another embodiment, the invention provides a method of treating diabetic macular edema (DME). In another embodiment, the invention provides a method of treating macular edema that is secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). In other embodiments, the diseases to be treated include, without limitation, retinal neovascularization, infectious and non-infectious, corneal neovascularization infectious and non-infectious, iris neovascularization, uveitis, neovascular glaucoma, and retinitis of prematurity (ROP). The method of treatment can be prophylactic, such as to stave off corneal neovascularization after corneal transplant, or to modulate the wound healing process in trabeculectomy surgery. These diseases and disorders may be characterized as having an angiogenic component. According to the invention, such disorders are treated by administering a ROCK inhibitor, and an angiogenesis inhibitor. 
     Accordingly, in one such embodiment, the disease or disorder is AMD, and a subject in need of treatment for AMD is administered an amount of a ROCK inhibitor effective to treat AMD. In another embodiment, the subject is administered a ROCK inhibitor and an angiogenesis inhibitor in amounts effective to treat AMD. In some embodiments, the angiogenesis inhibitor is a VEGFR2 antagonist. In certain such embodiments, the VEGFR2 antagonist binds to VEGF. In other such embodiments, the VEGFR2 antagonist binds to VEGFR2. Such VEGFR2-binding inhibitors include agents that bind to the extracellular domain of VEGFR2, including but not limited to antibodies and VEGFR2-binding fragments thereof, and agents that interact with the intracellular domain of VEGFR2 and block activation of VEGFR2-dependent signal transduction. VEGFR2 antagonists further include agents that interact with other cellular components to block VEGFR2-dependent signal transduction. In other embodiments of the invention, other ocular diseases and disorders having an angiogenic component, such as are indicated above, are similarly treated. 
     According to the invention, a ROCK inhibitor and an angiogenesis inhibitor are administered to a subject in amounts effective amount to treat or preventing a pathologic condition characterized by excessive angiogenesis. Such conditions, involving for example, vascularization and/or inflammation, include atherosclerosis, rheumatoid arthritis (RA), hemangiomas, angiofibromas, and psoriasis. Other non-limiting examples of angiogenic disease are retinopathy of prematurity (retrolental fibroplastic), corneal graft rejection, corneal neovascularization related to complications of refractive surgery, corneal neovascularization related to contact lens complications, corneal neovascularization related to pterygium and recurrent pterygium, corneal ulcer disease, and non-specific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chron&#39;s disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograph rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognition defects induced by neuronal inflammation, Osler-Weber syndrome, restenosis, and fungal, parasitic and viral infections, including cytomegaloviral infections. 
     The invention provides pan-ROCK inhibitors (i.e., compounds that inhibit ROCK1 and ROCK2). One study observed that ROCK2 is frequently over expressed in hepatocellular cancer compared to non-timorous livers while ROCK1 expression is unaltered. Other cancers that may benefit from treatment with a ROCK2 selective inhibitor include, but are not limited to, colon and bladder cancer. In contrast, ROCK1 expression levels have been observed to be higher in mammary tumors. Any cancer may be tested to determine whether there is overexpression of ROCK1 and/or ROCK2 and treated accordingly. In certain circumstances, ROCK 1 and ROCK2 isoforms show similarity in regulating certain downstream targets and neither isoform seems to be predominant. In such cases, a pan-ROCK inhibitor may be preferred. 
     Combinations with Other Agents 
     Compounds of the invention can be advantageously administered with second agents to patients in need thereof. When ROCK inhibitor is administered with a second agent, the ROCK inhibitor and the second agent can be administered sequentially or concomitantly. Sequentially means that one agent is administered for a time followed by administration of the other agent, which may be followed by administration of the first agent. When agents are administered sequentially, the level of one agent may not be maintained at a therapeutically effective level when the second agent is administered, and vice versa. Concomitantly means that the first and second agents are administered according to a schedule that maintains both agents at a substantially therapeutically effective level, even though the agents are not administered simultaneously. Each agent can be administered in single or multiple doses, and the doses can be administered on any schedule, including, without limitation, twice daily, daily, weekly, every two weeks, and monthly. 
     The invention also includes adjunctive administration. Adjunctive administration means that a second agent is administered to a patient in addition to a first agent that is already being administered to treat a disease or disease symptom. In some embodiments, adjunctive administration involves administering a second agent to a patient in which administration of the first agent did not sufficiently treat a disease or disease symptom. In other embodiments, adjunctive administration involves administration of the second agent to a patient whose disease has been effectively treated by administration of the first agent, with the expectation that the adjunctive treatment improves the outcome of the treatment. In some embodiments, the effect of administering the first and second agents is synergistic. In some embodiments, administration of the first and second agents prevents or lengthens the time until relapse, compared to administration of either of the agents alone. In some embodiments, administration of the first and second agents allows for reduced dosage and/or frequency of administration of the first and second agent. 
     Anti-inflammatories and immunosuppressants that can be administered in combination with the compounds of the present invention include steroid drugs such as glucocorticoids (e.g., dexamethasone), FK506 (tacrolimus), ciclosporin, fingolimod, interferon, such as IFNβ or IFNγ, a tumor necrosis factor-alpha (TNF-α) binding protein such as infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira), mycophenolic acid, MMF, Methotrexate, NSAID, Statins, Sirolimus/temsirolimus/everolimus, abatacept (Orencia), anakinra (Kineret), certolizumab (Cimzia), golimumab (Simponi), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), daclizumab (Zinbryta), muromonab (Orthoclone OKT3), Jakafi (Ruxolitinib), Xeljanz (Tofacitnib), and Otezla (Apremilast). 
     In an embodiment of the invention, a rho-kinase inhibitor of the invention and an anti-neoplastic agent are administered to a subject in need thereof. In another embodiment, a rho-kinase inhibitor of the invention and an angiogenesis inhibitor are administered to a subject in need thereof. In another embodiment, a rho-kinase inhibitor of the invention and an anti-inflammatory agent are administered to a subject in need thereof. In yet another embodiment, a ROCK inhibitor of the invention and an immunosuppressant are administered. The second agent can be, without limitation, a small molecule, an antibody or antigen binding fragment thereof, or radiation. 
     Antineoplastic agents include, without limitation, cytotoxic chemotherapeutic agents, targeted small molecules and biological molecules, and radiation. Compounds and agents that can be administered for oncological treatment, in addition to a rho kinase inhibitor of the invention, include the following: irinotecan, etoposide, camptothecin, 5-fluorouracil, hydroxyurea, tamoxifen, paclitaxel, capcitabine, carboplatin, cisplatin, bleomycin, dactomycin, gemcitabine, doxorubicin, danorubicin, cyclophosphamide, and radiotherapy, which can be external (e.g., external beam radiation therapy (EBRT)) or internal (e.g., brachytherapy (BT)). 
     Targeted small molecules and biological molecules include, without limitation, inhibitors of components of signal transduction pathways, such as modulators of tyrosine kinases and inhibitors of receptor tyrosine kinases, and agents that bind to tumor-specfic antigens. Examples include inhibitors of epidermal growth factor receptor (EGFR), including gefitinib, erlotinib, and cetuximab, inhibitors of HER2 (e.g., trastuzumab, trastuzumab emtansine (trastuzumab-DM1; T-DM1) and pertuzumab), anti-VEGF antibodies and fragments (e.g., bevacizumab), antibodies that inhibit CD20 (e.g., rituximab, ibritumomab), anti-VEGFR antibodies (e.g., ramucirumab (IMC-1121B), IMC-1C11, and CDP791), anti-PDGFR antibodies, and imatinib. Small molecule kinase inhibitors can be specific for a particular tyrosine kinase or be inhibitors of two or more kinases. For example, the compound N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c] pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine (also known as XL647, EXEL-7647 and KD-019) is an in vitro inhibitor of several receptor tyrosine kinases (RTKs), including EGFR, EphB4, KDR (VEGFR), Flt4 (VEGFR3) and ErbB2, and is also an inhibitor of the SRC kinase, which is involved in pathways that result in nonresponsiveness of tumors to certain TKIs. In an embodiment of the invention, treatment of a subject in need comprises administration of a ROCK inhibitor of Formulas I-IX and administration of KD-019. 
     Dasatinib (BMS-354825; Bristol-Myers Squibb, New York) is another orally bioavailable, ATP-site competitive Src inhibitor. Dasatanib also targets Bcr-Abl (FDA-approved for use in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)) as well as c-Kit, PDGFR, c-FMS, EphA2, and Src family kinases. Two other oral tyrosine kinase inhibitor of Src and Bcr-Abl are bosutinib (SKI-606) and saracatinib (AZD0530). 
     According to the invention, angiogenesis inhibitors can be administered to a subject in conjunction with compounds of the invention. Angiogenesis inhibitors include any substance that inhibits the growth of new blood vessels. For example, angiogenesis inhibitors include antagonists of VEGF, P1GF, and VEGF receptors, including the antibodies disclosed herein. A VEGF antagonist reduces or blocks a function in a cell that is associated with VEGF. A VEGF antagonist may act on VEGF, by binding to VEGF and blocking binding to its receptors and/or may act on another cellular component involved in VEGF-mediated signal transduction. Similarly, a VEGFR2 antagonist is an agent that reduces or blocks VEGFR2-mediated signal transduction by binding to VEGFR2 and blocking ligand binding or interaction with a VEGFR2 substrate, or acts on another cellular component to reduce or block VEGFR2-mediated signal transduction. Thus, angiogenesis inhibitors include anti-VEGFR2 antibodies, and antagonists of, without limitation, VEGF, VEGFR1, VEGFR2, PDGF, PDGFR-β, neuropilin-1 (NRP1), and complement. 
     Angiogenesis inhibitors include intracellular agents that block signal transduction mediated by, for example, VEGF, PDGF, ligands of VEGF or PDGF receptors, or complement. Intracellular agents that inhibit angiogenesis inhibitors include the following, without limitation. Sunitinib (Sutent; SU11248) is a panspecific small-molecule inhibitor of VEGFR1-VEGFR3, PDGFRα and PDGFRβ, stem cell factor receptor (cKIT), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R). Axitinib (AG013736; Inlyta) is another small molecule tyrosine kinase inhibitor that inhibits VEGFR-1-VEGFR-3, PDGFR, and cKIT. Cediranib (AZD2171) is an inhibitor of VEGFR-1-VEGFR-3, PDGFRO, and cKIT. Sorafenib (Nexavar) is another small molecular inhibitor of several tyrosine protein kinases, including VEGFR, PDGFR, and Raf kinases. Pazopanib (Votrient; (GW786034) inhibits VEGFR-1, -2 and -3, cKIT and PDGFR. Foretinib (GSK1363089; XL880) inhibits VEGFR2 and MET. CP-547632 is as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases. E-3810 ((6-(7-((1-aminocyclopropyl) methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide) inhibits VEGFR-1, -2, and -3 and FGFR-1 and -2 kinases in the nanomolar range. Brivanib (BMS-582664) is a VEGFR-2 inhibitor that also inhibits FGF receptor signaling. CT-322 (Adnectin) is a small protein based on a human fibronectin domain and binds to and inhibits activation of VEGFR2. Vandetanib (Caprelas; Zactima; ZD6474) is an inhibitor of VEGFR2, EGFR, and RET tyrosine kinases. X-82 (Xcovery) is a small molecule indolinone inhibitor of signaling through the growth factor receptors VEGFR and PDGFR 
     Pharmaceutical Compositions 
     In one aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of Formulas I-IX, formulated together with one or more pharmaceutically excipients. As described below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. 
     The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio. 
     The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer&#39;s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. 
     As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term “pharmaceutically-acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (see, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). 
     The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. 
     In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et al., supra). 
     Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. 
     Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. 
     Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. 
     In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention. 
     Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. 
     Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. 
     In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable excipients including a pharmaceutically-acceptable carrier, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. 
     A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. 
     The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. 
     Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 
     Besides diluents, the oral compositions can also include additional excipients such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. 
     Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. 
     Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. 
     Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. 
     Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. 
     The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. 
     Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. 
     Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. 
     Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. 
     Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. 
     Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. 
     These compositions may also contain additional excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. 
     In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. 
     Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. 
     When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. 
     Routes of Administration and Dose 
     The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. 
     The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. 
     The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient&#39;s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. 
     These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. 
     Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. 
     Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. 
     The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. 
     A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. 
     In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day. 
     In certain embodiments, a dose of a compound or a composition is administered to a subject every day, every other day, every couple of days, every third day, once a week, twice a week, three times a week, or once every two weeks. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments, a dose(s) of a compound or a composition is administered for 2 days, 3 days, 5 days, 7 days, 14 days, or 21 days. In certain embodiments, a dose of a compound or a composition is administered for 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or more. 
     The above-described administration schedules are provided for illustrative purposes only and should not be considered limiting. A person of ordinary skill in the art will readily understand that all doses are within the scope of the invention. 
     The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. 
     The compounds for use in the methods of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutic effects of the first administered one is not entirely disappeared when the subsequent is administered. 
     The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. 
     Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as “Applied Animal Nutrition”, W.H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding” O and B books, Corvallis, Ore., U.S.A., 1977). 
     Microemulsification technology may be employed to improve bioavailability of lipophilic (water insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, S. K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991) and REV 5901 (Sheen, P. C., et al., J Pharm Sci 80(7), 712-714, 1991). Among other things, microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation. 
     Controlled Release 
     The release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers. Release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine. An enteric coating can be used to prevent release from occurring until after passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine. Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule. Excipients that modify the solubility of the drug can also be used to control the release rate. Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween® and Pluronic®. Pore forming agents which add microstructure to the matrices (i.e., water soluble compounds such as inorganic salts and sugars) are added as particulates. The range should be between one and thirty percent (w/w polymer). 
     Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates). 
     It is to be understood and expected that variations in the principles of invention herein disclosed can be made by one skilled in the art and it is intended that such modifications are to be included within the scope of the present invention. The following Examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way. All references cited herein are hereby incorporated by reference in their entirety. 
     EXAMPLES 
     Example 1 
     All solvents and reagents were obtained commercially and used as received.  1 H NMR spectra were recorded on a Bruker instrument (300 MHz or 400 MHz) in the cited deuterated solvents. Chemical shifts are given in ppm, and coupling constants are in hertz. All final compounds were purified by flash chromatography using 220-400 mesh silica gel or reverse-phase HPLC with CH 3 CN/water as the solvents. Thin-layer chromatography was done on silica gel 60 F-254 (0.25-nm thickness) plates. Visualization was accomplished with UV light and/or 10% phosphomolybdic acid in ethanol. Nominal (low resolution) mass spectra were acquired on either a Waters LCT or an Applied Biosystems API 3000 mass spectrometer. High resolution mass spectra (HRMS) were acquired on either a Waters LCT or an Agilent TOF mass spectrometer. All other LC-MS experiments were done on an Agilent 1100 HPLC coupled with an Agilent single quadrupole mass spectrometer. Compound purity was determined by a LC-MS with 230 nM and 254 nM wavelengths. All final compounds reported here have purity ≥95%. 
     General Procedure A 
     
       
         
         
             
             
         
       
     
     EDCI coupling: compound of general structure 1 (1 equiv), EDCI (1 equiv), HOBt (0.2 equiv) and DIEA (2 equiv) were dissolved in DMF stirred at 25° C. for 5 min. Then to the mixture was added amine (1 equiv). The mixture was stirred at 25° C. for 16 hr. The mixture was poured into water and extracted with EtOAc. Combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to afford compound of general structure 2. 
     HATU coupling: compound of general structure 1 (1 equiv), HATU (1.25 equiv) and DIPEA (1.5 equiv) were dissolved in DMF stirred at 23° C. for 15 minutes. 1H-indazol-5-amine (1 equiv) was introduced to the reaction mixture and solution continued to stir at 23° C. for another 16 hours. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 2. 
     Boc-deprotection: compound of general structure 2 was dissolved in DCM and 4N HCl in dioxane was introduced to the solution. Reaction mixture was stirred at 23° C. for 1 hour. Reaction mixture was concentrated under reduced pressure to give a crude reaction mixture, which was purified via reverse phase preparative HPLC to afford the desired compound of general structure 3. 
     Benzyl group removal: compound of general structure 2 (1 equiv) and conc. HCl (1.2 equiv) were dissolved in MeOH and 10% dry Pd/C added. Reaction mixture was stirred under an atmosphere of H 2  (1 atm) at 50° C. for 5 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the crude product which was purified via reverse phase preparative HPLC to afford the desired compound of general structure 3. 
     General Procedure B 
     
       
         
         
             
             
         
       
     
     Amine HCl salt (2 equiv) was dissolved in methanol and tryethylamine added (2 equiv). The reaction solution was stirred for 15 min after which ketone or aldehyde of general structure 4 (1 equiv) along with HOAc (4 equiv) were added. The stirring was continued for another 15 min and NaBH 3 CN added. The reaction temperature was increased to 60° C. and stirring continued for 16 hours. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 5. 
     K 2 CO 3  (2 equiv), LiI (0.05 equiv) and benzylbromide were added to the solution of compound of general structure 5 (1 equiv) in MeCN at room temperature. Reaction temperature was elevated to 60° C. and stirring continued for 16 hours. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 6. 
     Solution of compound of general structure 6 (1 equiv), Pd(PPh 3 ) 4  (0.15 equiv)), K 3 PO 4  (3 equiv) in THF was purged with nitrogen for five minutes at room temperature. Reaction temperature was elevated to 120° C. and stirring continued for 48 hours. Solvent was removed under reduced pressure and residue purified via silica gel chromatography to afford the desired compound of general structure 7. 
     Compound of general structure 7 (1 equiv) was dissolved in methanol water mixture and NaOH (2 equiv) added. Reaction continued to stir at 30° C. for 16 hours. Reaction solution was acidified to pH=5. Purification of the crude residue was accomplished by reverse phase preparative HPLC to afford the desire compound of general structure 8. 
     Compound of general structure 8 (1 equiv), HATU (1.25 equiv) and DIPEA (1.5 equiv) were dissolved in DMF stirred at 23° C. for 15 minutes. 1H-indazol-5-amine (1 equiv) was introduced to the reaction mixture and solution continued to stirr at 23° C. for another 16 hours. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 9. 
     Compound of general structure 9 (1 equiv) and conc. HCl (1.2 equiv) were dissolved in MeOH and 10% dry Pd/C added. Reaction mixture was stirred under an atmosphere of H 2  (1 atm) at 50° C. for 5 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the crude product, which was purified via reverse phase preparative HPLC to afford the desired compound of general structure 10. 
     General Procedure C 
     
       
         
         
             
             
         
       
     
     Compound of general structure 11 (1 equiv) was dissolved in acetic acid and PtO 2  (0.1 equiv) added. Reaction solution was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 16 hours. The resulting solution was filtered off and concentrated under reduced pressure. The residue was basified with 2N NaOH to pH=9 and mixture extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 12. 
     Compound of general structure 12 (1 equiv) was dissolved in DCM and Boc 2 O (1.5 equiv), DIPEA (2 equiv) were added. Reaction continued to stir at room temperature for 16 hours. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 13. 
     Compound of general structure 13 (1 equiv) was dissolved in methanol water mixture and NaOH (2 equiv) added. Reaction continued to stir at 30′C for 16 hours. Reaction solution was acidified to pH=5. Purification of the crude residue was accomplished by reverse phase preparative HPLC to afford the desire compound of general structure 14. 
     Compound of general structure 14 (1 equiv), HATU (1.25 equiv) and DIPEA (1.5 equiv) were dissolved in DMF stirred at 23° C. for 15 minutes. 1H-indazol-5-amine (1 equiv) was introduced to the reaction mixture and solution continued to stir at 23° C. for another 16 hours. Reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude material, which was purified on silica gel to afford the desired compound of general structure 15. 
     Compound of general structure 15 was dissolved in DCM and 4N HCl in dioxane was introduced to the solution. Reaction mixture was stirred at 23° C. for 1 hour. Reaction mixture was concentrated under reduced pressure to give a crude reaction mixture which was purified via reverse phase preparative HPLC to afford the desired compound of general structure 16. 
     General Procedure D 
     
       
         
         
             
             
         
       
     
     A solution of compound of general structure 17 (1 equiv) and aldehyde or ketone (1 equiv) in MeOH (3.00 mL) was stirred at 23° C. for 16 hr. After 16 hours NaBH 3 CN (1.2 equiv) was added and mixture stirred for additional 3 hours. Reaction mixture was quenched by the addition of water and resulting mixture extracted with EtOAc. Combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Crude material was purified by preparative HPLC to afford compound of general structure 18. 
     General Procedure E 
     
       
         
         
             
             
         
       
     
     Compound of general structure 19 (1 equiv) was dissolved in CCl 4  and AIBN (0.1 equiv) followed by NBS (1.2 equiv) were added at room temperature. The reaction temperature was raised to 60° C. and stirring continued for 16 hours. Reaction mixture was filtered off and solvent removed under reduced pressure. Crude material 20 was used in the next step without additional purification. 
     Compound of general structure 20 (1 equiv) and alkyl amine (2 equiv) in THE was stirred at 70° C. for 16 hours. The reaction mixture was concentrated to under reduced pressure and material purified via silica gel chromatography to afford a compound of general structure 21. 
     NaOH (2 equiv) was introduced to a reaction vessel containing compound of general structure 21 (1 equiv) dissolved in MeOH/H 2 O mixture. Reaction was stirred at 20° C. for 16 hours. Solvent was removed under reduce pressure. The crude residue was dissolved in water (10 mL) and neutralized with 6 N HCl carefully until pH=8. The suspension was filtered and solids were collected and dried to afford compound of general structure 22. 
     Compound general of structure 22 (1 equiv), HATU (1.25 equiv) and DIPEA (2 equiv) were dissolved in DMF and stirred at 20° C. for 15 minutes. 1H-indazol-5-amine (1 equiv) was introduced to the reaction mixture and stirred at 20° C. for 15.8 hours. Reaction diluted with water and extracted with EtOAc. Combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Crude reaction mixture purified via reverse phase preparative HPLC to afford compound of general structure 23. 
     General Procedure F 
     
       
         
         
             
             
         
       
     
     Benzyl amine (1 equiv) was dissolved in dichloromethane. The corresponding aryl boronic acid 24 (1 equiv) was added to the reaction solution followed by glyoxylic acid (1 equiv) under an atmosphere of nitrogen. The reaction mixture was warmed up to 40° C. and temperature maintained for 16 hours. Reaction mixture was concentrated under reduced pressure. Crude reaction mixture purified via reverse phase preparative HPLC to afford compound of general structure 25. 
     Compound general of structure 25 (1 equiv), HATU (1.25 equiv) and DIPEA (2 equiv) were dissolved in DMF and stirred at 20° C. for 15 minutes. 1H-indazol-5-amine (1 equiv) was introduced to the reaction mixture and stirred at 20° C. for 16 hours. Reaction diluted with water and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Crude reaction mixture purified via normal phase silica gel chromatography to afford compound of general structure 26. 
     Compound of general structure 26 (1 equiv) and conc. HCl (1.2 equiv) were dissolved in MeOH and 10% dry Pd/C added. Reaction mixture was stirred under an atmosphere of H2 (1 atm) at 60° C. for 3 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the crude product, which was purified via reverse phase preparative HPLC to afford the desired compound of general structure 27. 
     Example 2 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-phenylacetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-phenylacetamide as an off-white solid (80%).  1 H NMR (400 MHz, CD 3 OD) δ 8.34 (s, 1H), 8.27 (s, 1H), 7.68-7.65 (m, 2H), 7.60-7.53 (m, 5H), 5.1 (s, 1H), 2.69 (s, 3H). MS (ES+) m/e 281.1 (M+H). 
     Example 3 
     N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroquinoline-3-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroquinoline-3-carboxamide as a yellow solid (23%).  1 H NMR (400 MHz, MeOD-d 3 ) δ 13.75 (s, 1H), 10.84 (s, 1H), 8.94 (s, 1H), 8.80 (s, 1H), 8.26 (m, 2H), 7.71 (m, 2H), 7.28 (m, 2H), 6.63 (s, 1H), 4.21 (m, 1H), 3.97 (m, 1H), 3.65 (m, 3H). MS (ES+) m/e 293.1 (M+H) + . 
     Example 4 
     N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide as a yellow solid (51%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (brs, 1H), 9.96 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.53-7.48 (m, 2H), 7.20-7.12 (m, 3H), 7.10-7.08 (m, 1H), 4.10-3.93 (m, 3H), 3.75-3.64 (m, 1H), 3.07-3.02 (m, 1H), 2.93-2.91 (m, 1H). MS (ES+) m/e 293.0 (M+H) + . 
     Example 5 
     N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide as a white solid (18%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.16 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.52-7.46 (m, 2H), 7.37-7.35 (m, 1H), 7.18-7.13 (m, 3H), 4.64 (d, J=4.0 Hz, 1H), 3.25-3.22 (m, 1H), 2.97-2.81 (m, 2H), 2.75-2.65 (m, 1H). MS (ES+) m/e 293.1 (M+H) + . 
     Example 6 
     N-(1H-indazol-5-yl)isoindoline-1-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol B. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)isoindoline-1-carboxamide as a white solid (10%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (brs, 1H), 10.09 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.56-7.44 (m, 3H), 7.34-7.20 (m, 3H), 4.96 (brs, 1H), 4.40-4.26 (m, 2H), 3.79 (brs, 1H). MS (ES+) m/e 279.1 (M+H) + . 
     Example 7 
     N-(2-(dimethylamino)ethyl)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(2-(dimethylamino)ethyl)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide as a white solid (50%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.28 (brs, 1H), 8.07 (brs, 1H), 7.78-6.91 (m, 5H), 6.54 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 4.01-3.67 (m, 3H), 3.61 (s, 3H), 2.32-2.11 (m, 3H), 2.11-2.10 (m, 9H). MS (ES+) m/e 382.1 (M+H) + . 
     Example 8 
     N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol C. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a light brown solid (46%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (brs, 1H), 10.59 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.50-7.48 (m, 1H), 7.44-7.42 (m, 1H), 7.29-7.22 (m, 1H), 7.20-7.13 (m, 3H), 4.05-4.00 (m, 1H), 3.95-3.85 (m, 1H), 3.79-3.75 (m, 1H), 3.37-3.33 (m, 1H), 3.22-3.19 (m, 1H). MS (ES+) m/e 293.0 (M+H)+. 
     Example 9 
     N-(1H-indazol-5-yl)-3-methylisoindoline-1-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol B. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-3-methylisoindoline-1-carboxamide as a white solid (29%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (brs, 1H), 10.04 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.53-7.42 (m, 3H), 7.35-7.21 (m, 3H), 4.89 (s, 1H), 4.58-4.57 (m, 1H), 4.01 (s, 1H), 1.47 (d, J=6.4 Hz, 3H). MS (ES+) m/e 293.0 (M+H)+. 
     Example 10 
     N-(1H-indazol-5-yl)pyrrolidine-2-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)pyrrolidine-2-carboxamide as a white solid (33%). MS (ES+) m/e 231.1 (M+H)+. 
     Example 11 
     N-(1H-indazol-5-yl)pyrrolidine-3-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)pyrrolidine-3-carboxamide as a white solid (41%). MS (ES+) m/e 231.1 (M+H) + . 
     Example 12 
     (2S,5R)-N-(1H-indazol-5-yl)-5-phenylpyrrolidine-2-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford (2S,5R)-N-(1H-indazol-5-yl)-5-phenylpyrrolidine-2-carboxamide carboxamide as a white solid (26%). MS (ES+) m/e 307.0 (M+H) + . 
     Example 13 
     N-(1H-indazol-5-yl)piperidine-2-carboxamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)piperidine-2-carboxamide as a white solid (39%). MS (ES+) m/e 245.0 (M+H) + . 
     Example 14 
     N-(1H-indazol-5-yl)-2-(4-(4-methoxyphenoxy)phenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(4-(4-methoxyphenoxy)phenyl)-2-(methylamino)acetamide as a white solid (7%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.05 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.47 (s, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.00-6.93 (m, 4H), 6.89 (d, J=8.4 Hz, 2H), 4.20 (d, J=7.2 Hz, 1H), 3.75 (s, 3H), 2.60 (m, 1H), 2.30 (d, J=4.8 Hz, 3H). MS (ES+) m/e 403.1 (M+H) + . 
     Example 15 
     N-(1H-indazol-5-yl)-2-(4-(3-methoxyphenoxy)phenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol A. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(4-(3-methoxyphenoxy)phenyl)-2-(methylamino)acetamide as a white solid (8%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 10.08 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.51-7.48 (m, 4H), 7.27 (t, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.72 (dd, J=8.4, 2.0 Hz, 1H), 6.58 (t, J=2.4 Hz, 1H), 6.53 (dd, J=8.0, 2.4 Hz, 1H), 4.23 (s, 1H), 3.73 (s, 3H), 2.31 (s, 3H). MS (ES+) m/e 403.1 (M+H) + . 
     Example 16 
     2-(4-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (7%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 10.10 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.52-7.40 (m, 6H), 4.24 (s, 1H), 2.72 (m, 1H), 2.28 (s, 3H). MS (ES+) m/e 315.0 (M+H) + . 
     Example 17 
     2-(4-chlorophenyl)-2-(ethylamino)-N-(1H-indazol-5-yl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (12%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.13 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.49-7.39 (m, 4H), 4.39 (s, 1H), 2.51-2.50 (m, 2H), 1.08 (t, J=6.4 Hz, 3H). MS (ES+) m/e 329.1 (M+H) + . 
     Example 18 
     2-(4-chlorophenyl)-N-(1H-indazol-5-yl)-2-(isopropylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-chlorophenyl)-N-(1H-indazol-5-yl)-2-(isopropylamino)acetamide as a white solid (49%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.18 (s, 1H), 8.21 (s, 1H), 8.09 (d, J=1.2 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.52-7.45 (m, 3H), 7.44-7.39 (m, 3H), 4.51 (s, 1H), 2.70-2.66 (m, 1H), 1.03 (t, J=6.4 Hz, 1H). MS (ES+) m/e 343.1 (M+H) + . 
     Example 19 
     2-(4-fluorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-fluorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (11%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.08 (s, 1H), 10.64 (s, 1H), 9.59-9.31 (m, 2H), 8.07 (d, J=9.2 Hz, 2H), 7.67-7.64 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.41-7.34 (m, 3H), 5.04 (s, 1H), 2.52 (s, 3H). MS (ES+) m/e 299.0 (M+H) + . 
     Example 20 
     2-(4-fluorophenyl)-N-(1H-indazol-5-yl)-2-(isopropylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-fluorophenyl)-N-(1H-indazol-5-yl)-2-(isopropylamino)acetamide as a white solid (54%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.17 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.52 (dd, J=8.4, 5.6 Hz, 2H), 7.49-7.39 (m, 2H), 7.17 (t, J=8.8 Hz, 2H), 4.51 (s, 1H), 2.72-2.66 (m, 1H), 1.04 (t, J=6.8 Hz, 6H). MS (ES+) m/e 327.1 (M+H) + . 
     Example 21 
     2-(ethylamino)-N-(1H-indazol-5-yl)-2-phenylacetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(ethylamino)-N-(1H-indazol-5-yl)-2-phenylacetamide as a white solid (39%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 10.17 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.52-7.45 (m, 4H), 7.35 (t, J=7.2 Hz, 2H), 7.30-7.28 (m, 1H), 4.43 (s, 1H), 2.63-2.52 (m, 2H), 1.09 (t, J=7.2 Hz, 3H). MS (ES+) m/e 295.0 (M+H) + . 
     Example 22 
     N-(1H-indazol-5-yl)-2-(isopropylamino)-2-phenylacetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(isopropylamino)-2-phenylacetamide as a white solid (63%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.17 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=1.2 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.52-7.41 (m, 4H), 7.34 (t, J=7.2 Hz, 2H), 7.30-7.27 (m, 1H), 4.51 (s, 1H), 2.72-2.69 (m, 1H), 1.04 (dd, J=7.6, 6.4 Hz, 6H). MS (ES+) m/e 309.1 (M+H) + . 
     Example 23 
     2-(ethylamino)-2-(4-fluorophenyl)-N-(1H-indazol-5-yl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(ethylamino)-2-(4-fluorophenyl)-N-(1H-indazol-5-yl)acetamide as a white solid (8%).  1 H NMR (400 MHz, CD 3 OD) δ 8.45 (s, 1H), 8.09 (d, J=1.2 Hz, 1H), 8.00 (s, 1H), 7.67-7.61 (m, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 1.6 Hz, 1H), 7.26-7.19 (m, 2H), 4.82 (s, 1H), 2.96-2.88 (m, 2H), 1.29 (t, J=7.2 Hz, 3H). MS (ES+) m/e 313.1 (M+H) + . 
     Example 24 
     N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)-2-(methylamino)acetamide as a white solid (4%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.96 (s, 1H), 10.01 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.46 (s, 2H), 7.39 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.15 (s, 1H), 3.72 (s, 3H), 2.28 (s, 3H). MS (ES+) m/e 311.1 (M+H) + . 
     Example 25 
     N-(1H-indazol-5-yl)-2-(isopropylamino)-2-(4-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)-2-(methylamino)acetamide as a white solid (52%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 10.11 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.48-7.39 (m, 4H), 6.90 (d, J=8.4 Hz, 2H), 4.45 (s, 1H), 3.72 (s, 3H), 2.72-2.68 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 1.02 (d, J=6.4 Hz, 3H). MS (ES+) m/e 339.1 (M+H) + . 
     Example 26 
     2-(ethylamino)-N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(ethylamino)-N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)acetamide as a white solid (5%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.10 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.50-7.41 (m, 4H), 6.91 (d, J=8.8 Hz, 2H), 4.37 (s, 1H), 3.73 (s, 1H), 2.60-2.53 (m, 2H), 2.27 (s, 3H), 1.08 (t, J=7.2 Hz, 3H). MS (ES+) m/e 325.1 (M+H) + . 
     Example 27 
     2-(cyclopropylamino)-N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(cyclopropylamino)-N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)acetamide as a white solid (10%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 10.07 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.49-7.41 (m, 2H), 7.39 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.39 (s, 1H), 3.72 (s, 3H), 2.05-2.00 (m, 1H), 0.42-0.33 (m, 4H). MS (ES+) m/e 337.0 (M+H) + . 
     Example 28 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-(p-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-(p-tolyl)acetamide as a white solid (7%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.04 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.46 (s, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 4.19 (s, 1H), 2.28 (d, J=7.2 Hz, 6H). MS (ES+) m/e 295.1 (M+H) + . 
     Example 29 
     N-(1H-indazol-5-yl)-2-(isopropylamino)-2-(p-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(isopropylamino)-2-(p-tolyl)acetamide as a white solid (44%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 10.17 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.48-7.37 (m, 4H), 7.16 (d, J=7.6 Hz, 2H), 4.51 (s, 1H), 2.76-2.70 (m, 1H), 2.27 (s, 3H), 1.05 (dd, J=8.4, 6.4 Hz, 6H). MS (ES+) m/e 323.1 (M+H) + . 
     Example 30 
     2-(ethylamino)-N-(1H-indazol-5-yl)-2-(p-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(ethylamino)-N-(1H-indazol-5-yl)-2-(p-tolyl)acetamide as a white solid (13%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.08 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.48-7.44 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 4.34 (s, 1H), 2.59-2.51 (m, 2H), 2.27 (s, 3H), 1.07 (t, J=7.2 Hz, 3H). MS (ES+) m/e 309.1 (M+H) + . 
     Example 31 
     2-(cyclopropylamino)-N-(1H-indazol-5-yl)-2-(p-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(cyclopropylamino)-N-(1H-indazol-5-yl)-2-(p-tolyl)acetamide as a white solid (23%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.96 (s, 1H), 10.07 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.48-7.42 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.40 (s, 1H), 2.26 (s, 3H), 2.07-1.99 (m, 1H), 0.42-0.29 (m, 4H). MS (ES+) m/e 321.1 (M+H) + . 
     Example 32 
     N-(1H-indazol-5-yl)-2-(2′-methoxy-[1,1′-biphenyl]-4-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(2′-methoxy-[1,1′-biphenyl]-4-yl)-2-(methylamino)acetamide as a yellow solid (16%).  1 HNMR (400 MHz, DMSO-d 6 ) δ 13.00 (brs, 1H), 10.13 (s, 2H), 8.28 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.53-7.43 (m, 6H), 7.33-7.30 (m, 1H), 7.27 (dd, J=7.6, 2.0 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.01 (t, J=6.4 Hz, 1H), 4.27 (s, 1H), 2.34 (s, 3H). MS (ES+) m/e 387.1 (M+H) + . 
     Example 33 
     2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (10%).  1 H NMR (400 MHz, DMSO-d 6 ) □ 12.98 (s, 1H), 10.14 (s, 1H), 8.31 (s, 2H), 8.14 (s, 1H), 8.00 (s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.54-7.48 (m, 5H), 7.42-7.38 (m, 1H), 7.33-7.26 (m, 2H), 4.30 (s, 1H), 2.33 (s, 3H). MS (ES+) m/e 375.1 (M+H) + . 
     Example 34 
     2-((2-(dimethylamino)ethyl)amino)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford 2-((2-(dimethylamino)ethyl)amino)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)acetamide as a white solid (27%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (brs, 1H), 10.19 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.49-7.43 (m, 2H), 7.27 (t, J=7.8 Hz, 1H), 7.07-7.04 (m, 2H), 6.86 (dd, J=8.0, 2.0 Hz, 1H), 4.36 (s, 1H), 3.75 (s, 3H), 2.65-2.57 (m, 2H), 2.55-2.53 (m, 2H), 2.25 (s, 6H). MS (ES+) m/e 368.1 (M+H) + . 
     Example 35 
     N-(1H-indazol-5-yl)-2-(2-methoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol D. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(2-methoxyphenyl)-2-(methylamino)acetamide as a pink solid (10%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03 (brs, 1H), 9.99 (brs, 1H), 8.20 (s, 2H), 8.13 (s, 1H), 8.01 (s, 1H), 7.52-7.46 (m, 2H), 7.40 (dd, J=7.6, 1.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 4.59 (s, 1H), 3.83 (s, 3H), 2.34 (s, 3H). MS (ES+) m/e 311.0 (M+H) + . 
     Example 36 
     2-(tert-butylamino)-N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford 2-(tert-butylamino)-N-(1H-indazol-5-yl)-2-(4-methoxyphenyl)acetamide as alight brown solid (35%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 9.14 (m, 2H), 8.06 (s, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.34 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 5.20-5.18 (m, 1H), 3.78 (s, 3H), 1.32 (s, 9H). MS (ES+) m/e 353.1 (M+H) + . 
     Example 37 
     2-(tert-butylamino)-N-(1H-indazol-5-yl)-2-phenylacetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford 2-(tert-butylamino)-N-(1H-indazol-5-yl)-2-phenylacetamide as a purple solid (4%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.26 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.49-7.46 (m, 4H), 7.32 (t, J=7.6 Hz, 2H), 7.26-7.22 (m, 1H), 4.50 (s, 1H), 1.10 (s, 9H). MS (ES+) m/e 323.1 (M+H) + . 
     Example 38 
     2-(tert-butylamino)-N-(1H-indazol-5-yl)-2-(p-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford 2-(tert-butylamino)-N-(1H-indazol-5-yl)-2-(p-tolyl)acetamide as a white solid (12%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 10.20 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.49-7.43 (m, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 4.44 (s, 1H), 2.26 (s, 3H), 1.09 (s, 9H). MS (ES+) m/e 337.1 (M+H) + . 
     Example 39 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-(pyridin-3-yl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-(pyridin-3-yl)acetamide as a white solid (9%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.02 (brs, 1H), 10.21 (s, 1H), 8.69 (d, J=1.6 Hz, 1H), 8.50 (dd, J=4.8, 1.6 Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.90-7.88 (m, 1H), 7.50-7.45 (m, 2H), 7.41-7.39 (m, 1H), 4.34 (s, 1H), 2.32 (s, 3H). MS (ES+) m/e 282.0 (M+H) + . 
     Example 40 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-(pyridin-2-yl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-(pyridin-2-yl)acetamide as an off-white solid (15%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (brs, 1H), 10.19 (s, 1H), 8.54 (dd, J=4.8, 0.8 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J=1.2 Hz, 1H), 8.00 (s, 1H), 7.84-7.79 (m, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.48 (s, 2H), 7.34-7.30 (m, 1H), 4.44 (s, 1H), 2.36 (s, 3H). MS (ES+) m/e 282.0 (M+H) + . 
     Example 41 
     N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide as an off-white solid (42%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.11 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.48-7.44 (m, 2H), 7.27 (t, J=8.0 Hz, 1H), 7.11-7.04 (m, 2H), 6.88-6.83 (m, 1H), 4.26 (s, 1H), 3.76 (s, 3H), 2.31 (s, 3H). MS (ES+) m/e 311.0 (M+H) + . 
     Example 42 
     2-(3-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford 2-(3-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as an off-white solid (63%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (brs, 1H), 10.16 (brs, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 7.51-7.43 (m, 3H), 7.42-7.31 (m, 2H), 4.31 (s, 1H), 2.30 (s, 3H). MS (ES+) m/e 315.0 (M+H) + . 
     Example 43 
     2-(4-ethoxyphenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-ethoxyphenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as an off-white solid (59%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.02 (brs, 1H), 10.11 (brs, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.49-7.43 (m, 2H), 7.40 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.26 (s, 1H), 4.00 (q, J=6.8 Hz, 2H), 2.31 (s, 3H), 1.31 (t, J=6.8 Hz, 3H). MS (ES+) m/e 324.1 (M+H) + . 
     Example 44 
     N-(1H-indazol-5-yl)-2-(4-isopropoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(4-isopropoxyphenyl)-2-(methylamino)acetamide as an off-white solid (67%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (brs, 1H), 10.10 (s, 1H), 8.23 (s, 1H), 8.14-8.13 (m, 1H), 8.01 (s, 1H), 7.47 (s, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.61-4.54 (m, 1H), 4.23 (s, 1H), 2.31 (s, 3H), 1.24 (d, J=6.0 Hz, 6H). MS (ES+) m/e 339.1 (M+H) + . 
     Example 45 
     N-(1H-indazol-5-yl)-2-(4′-methoxy-[1,1′-biphenyl]-4-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(4′-methoxy-[1,1′-biphenyl]-4-yl)-2-(methylamino)acetamide as a white solid (34%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (brs, 1H), 10.14 (s, 1H), 8.21 (s, 1H), 8.14 (t, J=1.6 Hz, 1H), 8.01 (s, 1H), 7.62-7.54 (m, 6H), 7.48-7.46 (m, 2H), 7.03-7.00 (m, 2H), 4.31 (s, 1H), 3.79 (s, 3H), 2.34 (s, 3H). MS (ES+) m/e 387.0 (M+H) + . 
     Example 46 
     N-(1H-indazol-5-yl)-2-((2-methoxyethyl)amino)-2-(3-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-((2-methoxyethyl)amino)-2-(3-methoxyphenyl)acetamide as an off-white solid (16%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.07 (s, 1H), 10.61 (s, 1H), 9.55 (s, 2H), 8.07 (d, J=7.6 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.45-7.36 (m, 2H), 7.25-7.21 (m, 2H), 7.07-7.04 (m, 1H), 5.07 (s, 1H), 3.80 (s, 3H), 3.78-3.59 (m, 2H), 3.31 (s, 3H), 3.11 (m, 1H), 2.99 (m, 1H). MS (ES+) m/e 355.0 (M+H) + . 
     Example 47 
     2-(2-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general protocol E. The final residue was purified by reverse phase preparative HPLC to afford 2-(2-chlorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as an off-white solid (32%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03 (brs, 1H), 10.14 (s, 1H), 8.17-8.14 (m, 2H), 8.02 (s, 1H), 7.61-7.58 (m, 1H), 7.50-7.46 (m, 3H), 7.37-7.30 (m, 2H), 4.67 (s, 1H), 2.35 (s, 3H). MS (ES+) m/e 315.0 (M+H) + . 
     Example 48 
     2-(4-fluoro-3-methoxyphenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford 2-(4-fluoro-3-methoxyphenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (49%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 10.15 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.50-7.44 (m, 2H), 7.34 (dd, J=8.4, 2.0 Hz, 1H), 7.21-7.16 (m, 1H), 7.07-7.03 (m, 1H), 4.31 (s, 1H), 3.86 (s, 3H), 2.32 (s, 3H). MS (ES+) m/e 329.1 (M+H) + . 
     Example 49 
     2-(ethylamino)-N-(1H-indazol-5-yl)-2-(m-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford 2-(ethylamino)-N-(1H-indazol-5-yl)-2-(m-tolyl)acetamide as a yellow solid (30%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.08 (s, 1H), 10.66 (s, 1H), 9.44-9.37 (m, 2H), 8.10-8.06 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.47-7.36 (m, 4H), 7.31 (d, J=7.6 Hz, 1H), 5.04 (t, J=6.0 Hz, 1H), 2.98-2.84 (m, 2H), 2.36 (s, 3H), 1.23 (t, J=7.2 Hz, 3H). MS (ES+) m/e 309.1 (M+H) + . 
     Example 50 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-(3-(trifluoromethoxy)-phenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-(3-(trifluoromethoxy)phenyl)acetamide as a white solid (27%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (brs, 1H), 10.18 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.54-7.44 (m, 5H), 7.30-7.28 (m, 1H), 4.34 (s, 1H), 2.30 (s, 3H). MS (ES+) m/e 365.0 (M+H) + . 
     Example 51 
     2-(ethylamino)-2-(3-fluorophenyl)-N-(1H-indazol-5-yl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford 2-(ethylamino)-2-(3-fluorophenyl)-N-(1H-indazol-5-yl)acetamide as a white solid (21%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.16 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.50-7.33 (m, 5H), 7.14-7.09 (m, 1H), 4.43 (s, 1H), 2.60-2.53 (m, 2H), 1.09 (t, J=7.2 Hz, 3H). MS (ES+) m/e 313.1 (M+H) + . 
     Example 52 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-(m-tolyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-(m-tolyl)acetamide as a white solid (11%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.11 (s, 1H), 8.20 (s, 2H), 8.13 (s, 1H), 8.01 (s, 1H), 7.49-7.45 (m, 2H), 7.32-7.23 (m, 3H), 7.11 (d, J=7.2 Hz, 1H), 4.25 (s, 1H), 2.31 (s, 6H). MS (ES+) m/e 295.1 (M+H) + . 
     Example 53 
     2-(3-fluorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford 2-(3-fluorophenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (11%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.14 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.50-7.32 (m, 5H), 7.14-7.10 (m, 1H), 4.30 (s, 1H), 2.30 (s, 3H). MS (ES+) m/e 299.1 (M+H) + . 
     Example 54 
     (R)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford (R)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide as a white solid (17%). Enantiomers were separated by SFC (DAICEL CHTRALPAK AD column). Mobile phase: 55% EtOH with 0.1% NH 4 OH in CO 2 , flow rate 70 g/min to afford the desired compound with 99% enantiomeric purity.  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.05 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.47 (s, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 6.85 (dd, J=8.0, 2.0 Hz, 1H), 4.21 (s, 1H), 3.76 (s, 3H), 2.30 (s, 3H). MS (ES+) m/e 311.1 (M+H). [α] 25 C D=+98.86 (c=0.2 in MeOH). 
     Example 55 
     (S)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford (S)-N-(1H-indazol-5-yl)-2-(3-methoxyphenyl)-2-(methylamino)acetamide as a white solid (12%). Enantiomers were separated by SFC (DAICEL CHTRALPAK AD column). Mobile phase: 55% EtOH with 0.1% NH 4 OH in CO 2 , flow rate 70 g/min to afford the desired compound with 99% enantiomeric purity.  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97 (s, 1H), 10.05 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.47 (s, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 6.85 (dd, J=8.0, 2.4 Hz, 1H), 4.20 (s, 1H), 3.75 (s, 3H), 2.30 (s, 3H). MS (ES+) m/e 311.1 (M+H) + . [α] 25° C.   D =−96.44 (c=0.2 in MeOH). 
     Example 56 
     N-(1H-indazol-5-yl)-2-(methylamino)-2-(4-(trifluoromethoxy)phenyl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford N-(1H-indazol-5-yl)-2-(methylamino)-2-(4-(trifluoromethoxy)phenyl)acetamide as a brown solid (19%).  1 H NMR (400 MHz, DMSO-d 6 ) δ12.99 (s, 1H), 10.15 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.50-7.45 (m, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.30 (s, 1H), 2.30 (s, 3H). MS (ES+) m/e 365.1 (M+H) + . 
     Example 57 
     2-(3-fluoro-4-methoxyphenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford 2-(3-fluoro-4-methoxyphenyl)-N-(1H-indazol-5-yl)-2-(methylamino)acetamide as a white solid (29%).  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 10.07 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.49-7.44 (m, 2H), 7.35 (dd, J=12.8, 1.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.16-7.12 (m, 1H), 4.21 (s, 1H), 3.82 (s, 3H), 2.28 (s, 3H). MS (ES+) m/e 329.0 (M+H) + . 
     Example 58 
     2-(3-chlorophenyl)-2-(ethylamino)-N-(1H-indazol-5-yl)acetamide 
     
       
         
         
             
             
         
       
     
     The reaction was conducted following general procedure F. The final residue was purified by reverse phase preparative HPLC to afford 2-(3-chlorophenyl)-2-(ethylamino)-N-(1H-indazol-5-yl)acetamide as a brown solid (19%).  1 H NMR (400 MHz, CD 3 OD) δ 8.53 (s, 1H), 8.08 (d, J=1.2 Hz, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.53-7.39 (m, 5H), 4.55 (s, 1H), 2.83-2.68 (m, 2H), 1.24 (t, J=7.2 Hz, 3H). MS (ES+) m/e 329.1 (M+H) + . 
     Comparative Example 1 
     
       
         
         
             
             
         
       
     
     Comparative Example 2 
     
       
         
         
             
             
         
       
     
     Comparative Example 3 
     
       
         
         
             
             
         
       
     
     Comparative Example 4 
     
       
         
         
             
             
         
       
     
     Comparative Example 5 
     
       
         
         
             
             
         
       
     
     Comparative Example 6 
     
       
         
         
             
             
         
       
     
     Comparative Example 7 
     
       
         
         
             
             
         
       
     
     Example 59 
     Determination of compounds ROCK inhibitory activity in vitro (Z&#39;lyte assay): recombinant ROCK1 (amino acids 1-535) and ROCK2 (amino acids 1-552) proteins were purchased from ThermoFisher Scientific. Compounds activities were measured by Z′-lyte kinase kit (ThermoFisher Scientific) and IC50s were calculated. 
     Determination of compounds ROCK inhibitory activity in A7R5 cells: rat aortic smooth muscle cell line A7R5 cells were maintained and treated in DMEM medium with 10% of fetal bovine serum. Cells were seeded with density of 5,000 cells/well in 96-well plates for 24 hours and subsequently treated 90 min with testing compounds. Cells were then fixed and processed according to the In-Cell ELISA Colorimetric Detection Kit manual (Thermo Scientific). Cellular phospho-myosin light chains (ppMlc, Thr18/Ser19) levels were determined after treatments of DMSO control or test compounds using the In-Cell ELISA kit. The percent inhibition rate was calculated by applying the data obtained with 1 μM (or 10 μM) compound treatment to the formula, [1-(compound/DMSO)]×100%. ppMlc data obtained with 9 points 2-fold serial dilution of compounds were applied to the nonlinear regression curve fit function of the GraphPad Prism software to calculate the In cell IC50s. 
     NIH3T3 cells Acta2-promoter driven-luciferase assay: A NIH3T3 cell line stably expressing a luciferase reporter driven by the human ACTA2 gene promoter (−1000-1 bp) was established (NIH3T3-Acta2-luciferase). The cells were plated to confluence and treated with the test compounds plus TGF 1 for 24 hr. Cells were then lysed and luciferase activity was measured using the LightSwitch luciferase kit from Active Motif. 
     ROCK inhibitors potently inhibited ROCK kinase activity in vitro and in cells. As shown in  FIG. 1 , ROCK inhibitors of the invention, at lower than 20 nanomolar concentrations, potently inhibited both isoforms of ROCK kinases activity in vitro measured by Z′-Lyte kit. 
     Compounds of the invention inhibited ROCKs in cells as measured by A7R5 in-cell Elisa assay. A7R5 cells were treated with 9 points 2 fold serial dilution of compounds and ppMlc (T18/S19) levels were determined in order to calculate cellular IC50s of the compounds. Results are provided in Table 1, below. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                   
                 ppMIc IC50 
               
               
                   
                 Compound 
                 (nM) 
               
               
                   
                   
               
             
            
               
                   
                 Example 2  
                 304 
               
               
                   
                 Example 14 
                 207 
               
               
                   
                 Example 15 
                 124 
               
               
                   
                 Example 47 
                 461 
               
               
                   
                   
               
            
           
         
       
     
     ROCK inhibitors of the present invention inhibit both isoforms of ROCK. A CRISPR/CAS9 system was used to create HCT116 cells containing a knock out for either ROCK1 or ROCK2. The ROCK1KO and ROCK2KO cells were treated with the Example 2 compound for 90 min and pMypt (T853) levels were visualized by western blotting. The ROCK inhibitor efficiently blocked ROCK target MYPT1 phosphorylation at 110 nM. See  FIG. 2 . 
     Table 2, below, provides in vitro and cellular inhibition of ROCKs by compounds of the invention. Compounds activities were measured by Z′-lyte kinase kit (ThermoFisher Scientific). The percent inhibition rate was calculated by normalizing the kinase activity value obtained with 1 μM compound treatment against DMSO control value. IC50s were calculated using the GraphPad Prism software with kinase activities data that were collected from points 9 serial dilution of compounds treatment. The ROCK inhibition in A7R5 cells and NIH3T3 (Acta2-Luc) cells was performed as described above. 
     Two steps of measurements were adopted for pMLC/A7R5IC50. Percent inhibition rates were calculated with a single dose (1 μM or 10 μM) compounds treatment to screen for active compounds and then cellular IC50s were measured only in compounds that have over 50% of inhibition rates. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 pMLC 
                 NIH3T3, 
               
               
                   
                   
                   
                   
                   
                 % inh 
                 Acta2- 
               
               
                   
                 ROCK2 
                 ROCK2 
                 ROCK1 
                 ROCK1 
                 or IC 50    
                 luc, 
               
               
                   
                 % inh 
                 IC 50   
                 % inh 
                 IC50 
                 (nM) 
                 IC 50    
               
               
                 Ex. # 
                 (3 μM)* 
                 (nM) 
                 (3 μM)* 
                 (nM) 
                 A7R5 
                 (nM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 24 
                 98.8 
                 3.6 
                 99 
                 3.892 
                 224 
                 321 
               
               
                 29 
                 98.8 
                 6.3 
                 99 
                 65.7 
                 934 
                   
               
               
                 25 
                 98.8 
                 9.7 
                 99 
                 10.6 
                 633 
                   
               
               
                 36 
                 98.8 
                 9.9 
                 99 
                 24.7 
                 766 
                   
               
               
                 15 
                   
                 10 
                   
                 13 
                 124 
                 219 
               
               
                 26 
                 98.8 
                 12 
                 99 
                 24 
                 261 
                 845 
               
               
                 30 
                 98.8 
                 13 
                 99 
                 16 
                 502 
                 960 
               
               
                 16 
                 99 
                 15 
                 93.2 
                 3.8 
                 252 
                 915 
               
               
                   
                 @ 1 μM 
                   
                   
                   
                   
                   
               
               
                 42 
                   
                 16 
                   
                 8.8 
                 454 
                 882 
               
               
                 41 
                 99.5 
                 17 
                   
                 3.2 
                 304 
                 539 
               
               
                   
                 @ 1 μM 
                   
                   
                   
                   
                   
               
               
                 2 
                 98.7 
                 21 
                 98.8 
                 25 
                 304.0 
                 885 
               
               
                 50 
                 93 
                 21 
                 93 
                   
                   
                   
               
               
                   
                 @ 0.5 μM 
                   
                 @ 0.5 μM 
                   
                   
                   
               
               
                 28 
                 98.8 
                 21.2 
                 99 
                 17.78 
                 834 
                   
               
               
                 38 
                 100 
                 27.4 
                 100 
                 61.44 
                 1342 
                   
               
               
                 23 
                 95.3 
                 43 
                 94.3 
                 495 
                 1056 
                   
               
               
                 27 
                   
                 66 
                   
                 79 
                 2977 
                   
               
               
                 48 
                 76 
                 71 
                 87 
                   
                   
                   
               
               
                   
                 @ 0.5 μM 
                   
                 @ 0.5 μM 
                   
                   
                   
               
               
                 43 
                 98 
                 73 
                   
                   
                 4% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 37 
                 98.8 
                 74.3 
                 99 
                 98.1 
                 2601 
                   
               
               
                 5 
                   
                 77 
                   
                 38 
                 35810 
                   
               
               
                 49 
                 76 
                 87 
                 88 
                   
                   
                   
               
               
                   
                 @ 0.5 μM 
                   
                 @ 0.5 μM 
                   
                   
                   
               
               
                 47 
                   
                 135 
                   
                 8.3 
                 461 
                 659 
               
               
                 20 
                 94.6 
                 152 
                 18.4 
                 561 
                 2507 
                   
               
               
                 19 
                 96.6 
                 160 
                 21.4 
                 173 
                 1604 
                   
               
               
                 39 
                   
                 213 
                   
                 250 
                 4205 
                   
               
               
                 17 
                 96.3 
                 248 
                 93.3 
                 &lt;10 
                 556 
                   
               
               
                 34 
                   
                 438 
                   
                   
                 49% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 40 
                   
                 453 
                   
                 143 
                 37% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 44 
                   
                 455 
                   
                   
                 42% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 7 
                 11 
                 1628 
                 16 
                   
                 2% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                 @ 0.5 μM 
                   
                 @ 10 μtM 
                   
               
               
                 4 
                   
                 &gt;1000 
                   
                 &gt;1000 
                 18% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 31 
                   
                 &gt;1000 
                   
                 228 
                 35% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 6 
                   
                 &gt;1000 
                   
                 421 
                 1% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 32 
                   
                 &gt;1000 
                   
                 310 
                 5% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 21 
                 95.8 
                   
                 91.5 
                   
                 2386 
                   
               
               
                 22 
                 96.7 
                   
                 94.3 
                   
                 1802 
                   
               
               
                 18 
                 94.1 
                   
                 89.6 
                   
                 2507 
                   
               
               
                 8 
                 76.7 
                   
                   
                   
                 2620 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                   
                   
               
               
                 33 
                 66.5 
                   
                   
                   
                 48% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 45 
                 22 
                   
                   
                   
                 4% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 46 
                 67 
                   
                   
                   
                 27% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 14 
                 100 
                   
                   
                 32.6 
                 207 
                 678 
               
               
                   
                 @ 0.5 μM 
                   
                   
                   
                   
                   
               
               
                 35 
                 71 
                   
                   
                   
                 16% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 3 
                 0 
                   
                 0 
                   
                 25% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 13 
                   
                   
                   
                   
                 11% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 9 
                   
                   
                   
                   
                 4% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 10 
                   
                   
                   
                   
                 1% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 11 
                   
                   
                   
                   
                 1% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 12 
                   
                   
                   
                   
                 1% inh. 
                   
               
               
                   
                   
                   
                   
                   
                 @ 1 μM 
                   
               
               
                 51 
                   
                 53 
                   
                   
                 1660 
                 5453 
               
               
                 52 
                   
                 34 
                   
                   
                 532 
                 1512 
               
               
                 53 
                   
                 41 
                   
                   
                 914 
                 1159 
               
               
                 54 
                   
                 14 
                   
                   
                 200 
                 268 
               
               
                 55 
                   
                 30 
                   
                   
                 589 
                 773 
               
               
                 56 
                   
                 46 
                   
                   
                 546 
                 666 
               
               
                 57 
                 95% 
                 25 
                   
                   
                 339 
                 473 
               
               
                   
                 @ 0.5 
                   
                   
                   
                   
                   
               
               
                   
                 μM 
                   
                   
                   
                   
                   
               
               
                 58 
                 61% 
                 64 
                 85% 
                   
                 722 
                 1090 
               
               
                   
                 @ 0.5 μM 
                   
                 @ 0.5 μM 
                   
                   
                   
               
               
                 Comp1 
                 85.7 
                   
                 10.6 
                   
                 34% inh. 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                 @ 10 μM 
                   
               
               
                 Comp2 
                 97.5 
                   
                 92.2 
                   
                 4410 
                   
               
               
                 Comp3 
                 97.4 
                   
                 91.5 
                   
                 10920 
                   
               
               
                 Comp4 
                 96.5 
                   
                 95.8 
                   
                 6158 
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                   
                   
               
               
                 Comp5 
                 96.2 
                 33 
                 99 
                 1310 
                   
                   
               
               
                   
                 @ 1 μM 
                   
                   
                   
                   
                   
               
               
                 Comp6 
                 98.8 
                 41.76 
                 99 
                 41.32 
                 6990 
                   
               
               
                 Comp7 
                 100 
                 303 
                 100 
                 166 
                 18390 
               
               
                   
               
               
                 * % Inhibtion in ROCK1/ROCK2 assays was testing at 3 μM unless otherwise noted. 
               
            
           
         
       
     
     Comparative Examples lack an alkyl substituent on the 2-amino group (i.e., the 2-amino group is NH2 in the comparative compounds), which is present in compounds of the invention. The addition of the 2-alkylamino (i.e., R 1  is alkyl, etc.) is associated with enhanced cellular ROCK activity, particularly for lower alkyl amines at the 2-position (i.e., R 1  is lower alkyl). Compare, for example, Comparative Example 2 (with a primary 2-amino) with Examples 16, 17, and 18 that have a secondary 2-alkyl amino, and particularly where the alkyl group is small. All four compounds show high in vitro inhibition of ROCK1 and ROCK 2, but Examples 16, 17, and 18 have enhanced cellular ROCK inhibition as measured by phosphorylation of the ROCK target pMLC in A7R5 cells. For example, Example 2 provides cellular ROCK inhibition with an IC50 over 17 times lower than Comparative Example 1 (IC50s of 252 vs 4410, respectively). Similarly, the cellular IC50 for Examples 24, 25, 26, 27, and 36 are lower than Comparative Example 4, which has a primary 2-amino group. 
     Example 59 
     ROCK inhibitors improved oligodendrocyte process in human oligodendrocyte/neuron progenitor cells in culture. Human oligodendrocyte/neuron progenitor cells were cultured in vitro with or without ROCK inhibitor for 2 &amp; 14 days. Nestin and MAP2 proteins were visualized by staining with commercial antibodies to identify different stages of neuronal cell differentiation. ROCK inhibitors of the present invention significantly facilitated mature neuronal cell marker MAP2 expression while improved neurite outgrowth, as evidenced by strong increase in MAP2 signal in cells differentiated in the presence of ROCK inhibitor (compound of Example 2). See  FIG. 3 . 
     Example 60 
     ROCK inhibitor improved neurite extension and axon ensheathment in oligodendrocytes with rat dorsal root ganglia (DRG) explants co-culture system. Under co-cultured condition of rat oligodendrocytes with rat dorsal root ganglia (DRG) explants, ROCK inhibitor treatment, as shown in  FIG. 4 , changed cytoskeletal organization, producing many shorter, ordered myelin segments, which were identified by the neurofilament staining. At the same time, the ROCK inhibitor also facilitated axonal support of oligodentrocye by organized manner, which was visualized by staining the mature oligodendrocyte marker MBP. 
     Example 61 
     ROCK Inhibitors Penetrated Blood-Brain Barrier. 
     In a mouse pharmacokinetic study, 2 hours after dosing, animal tissues were harvested to determine the compound distribution. As shown in Table 3, the Example 2 Compound had excellent BBB penetrant property. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                 Dose 
                 Plasma 
                 Brain 
                 Brain/ 
               
               
                 Compound 
                   
                 (mg base/ 
                 Concentration 
                 Concentration 
                 Plasma 
               
               
                 ID 
                 Route 
                 kg) 
                 [ng/mL]* 
                 [ng/g]* 
                 Ratio 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Example 2 
                 IV 
                 10 
                 211 
                 699 
                 3.31 
               
               
                   
                 PO 
                 10 
                 405 
                 700 
                 1.73 
               
               
                   
                 PO 
                 30 
                 1400 
                 2856 
                 2.04 
               
               
                   
                 PO 
                 100 
                 9288 
                 19363 
                 2.08 
               
               
                   
               
               
                 * Plasma and brain were collected 2 hours post-dose 
               
            
           
         
       
     
     Brain and plasma concentrations of select ROCK inhibitors were also evaluated in mouse by IPLC/MS/MS at 15 min and 2 hrs following 2.5 mg/kg IV drug administration. The results are provided in Table 4, below. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                   
                   
                 Mean 
                 Mean 
                 Mean 
                 Mean 
               
               
                   
                   
                   
                   
                 Conc. 
                 Conc. 
                 Brain/ 
                 Brain/ 
               
               
                 Com- 
                   
                   
                   
                 at 0.25 hr 
                 at 2 hr 
                 Plasma 
                 Plasma 
               
               
                 pound 
                 Dose 
                   
                   
                 (ng/mL) 
                 (ng/mL) 
                 Ratio 
                 Ratio 
               
               
                 ID 
                 Level 
                 Route 
                 Site 
                 or (ng/g) 
                 or (ng/g) 
                 at 0.25 hr 
                 at 2 hr 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Exam- 
                 2.5 
                 IV 
                 Plasma 
                 394 
                 41.4 
                 2.17 
                 6.99 
               
               
                 ple 
                   
                   
                 Brain 
                 853 
                 288 
                   
                   
               
               
                 15 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Exam- 
                 2.5 
                 IV 
                 Plasma 
                 427 
                 2.14 
                 1.33 
                 8.41 
               
               
                 ple 
                   
                   
                 Brain 
                 566 
                 17.7 
                   
                   
               
               
                 41 
                   
                   
                 Brain 
                 541 
                 76.6 
                   
                   
               
               
                   
               
            
           
         
       
     
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