WO2008054599A2 - Inhibiteurs de la rho kinase - Google Patents

Inhibiteurs de la rho kinase Download PDF

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WO2008054599A2
WO2008054599A2 PCT/US2007/021093 US2007021093W WO2008054599A2 WO 2008054599 A2 WO2008054599 A2 WO 2008054599A2 US 2007021093 W US2007021093 W US 2007021093W WO 2008054599 A2 WO2008054599 A2 WO 2008054599A2
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alkyl
independently selected
hydroxy
amino
halo
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PCT/US2007/021093
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WO2008054599A3 (fr
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Alessandra Bartolozzi
Stewart Campbell
Bridget Cole
James Ellis
Hope Foudoulakis
Brian Kirk
Siya Ram
Paul Sweetnam
Martin Hauer-Jensen
Marjan Boerma
Junru Wang
Qiang Fu
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Surface Logix, Inc.
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Priority to CA2700988A priority Critical patent/CA2700988A1/fr
Publication of WO2008054599A2 publication Critical patent/WO2008054599A2/fr
Publication of WO2008054599A3 publication Critical patent/WO2008054599A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to inhibitors of ROCKl and ROCK2, which may be selective for ROCK2, and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCKl and/or ROCK2. Also provided are treatments combining inhibitors of ROCKl and/or ROCK2 with statins.
  • Rho-associated kinase is a key intracellular regulator of cytoskeletal dynamics and cell motility. Rho-kinase 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.
  • Rho- kinase mediates calcium sensitization and smooth muscle contraction. Inhibition of Rho- kinase blocks 5-HT and phenylephrine agonist induced muscle contraction.
  • Rho kinase induces stress fiber formation and is required for the cellular transformation mediated by RhoA.
  • Rho kinase participates in a variety of cellular processes, including but not limited to Na/H exchange transport system activation, stress fiber formation, adducin activation. Rho kinase is involved in physiological processes such as vasoconstriction, bronchial smooth muscle constriction, vascular smooth muscle and endothelial cell proliferation, platelet aggregation, and others. [0005] Inhibition of Rho-kinase activity in animal models has demonstrated a number of benefits of Rho-kinase inhibitors for the treatment of human diseases.
  • 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 where inhibition of Rho-kinase 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 intraoccular pressure, and bone resorption.
  • the inhibition of Rho-kinase activity in patients has benefits for controlling cerebral vasospasms and ischemia following subarachnoid hemorrhage.
  • Rho-kinase In mammals, Rho-kinase consists of two isoforms, ROCKl (ROCK ⁇ ; pi 60- ROCK) and ROCK2 (ROCK ⁇ ). ROCKl and ROCK2 are differentially expressed and regulated in specific tissues. For example, ROCKl is ubiquitously expressed at relatively high levels, whereas ROCK2 is preferentially expressed in cardiac and brain tissues and in a developmental stage specific manner. ROCKl is a substrate for cleavage by caspase-3 during apoptosis, whereas ROCK2 is not. Smooth muscle specific basic calponin is phosphorylated only by R0CK2.
  • ROCKl is critical for the development of cardiac fibrosis, but not hypertrophy, in response to various pathological conditions and suggest that signaling pathways leading to the hypertrophic and profibrotic response of the heart are distinct.
  • Another recent report suggests that ROCK-I inhibtion may be pro-fibrogenic.
  • ROCK-I inhibtion may be pro-fibrogenic.
  • the lack of inhibitors specific for ROCKl or R0CK2 has impeded their respective roles to otherwise be distinguished.
  • ROCK specific kinase inhibitors including kinase inhibitors that are isoform specific.
  • Cholesterol synthesis is a multistep process catalyzed by a series of enzymes including hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Inhibition of catalysis of these enzymes or blocking HMG-CoA reductase gene expression is recognized as an effective means to reduce cholesterol biosynthesis ad can lead to a reduction in cholesterol levels.
  • HMG-CoA hydroxymethylglutaryl-coenzyme A
  • HMG-CoA reductase inhibitors include statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, rivastatin (cer(i)vastatin), pitavastatin (nisvastatin, itavastatin), rosuvastatin (visastatin), e.g. useful for the treatment of hypercholesterolemia.
  • statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, rivastatin (cer(i)vastatin), pitavastatin (nisvastatin, itavastatin), rosuvastatin (visastatin), e.g. useful for the treatment of hypercholesterolemia.
  • the invention provides compounds that are inhibitors of ROCKl and ROCK2.
  • the inhibitors are selective for ROCK2 and do not substantially inhibit ROCKl .
  • the invention provides ROCK inhibitors that have desirable pharmacokinetic and pharmacodynamic profiles.
  • the invention further provides a method of inhibiting ROCKl and ROCK2 in a cell by incubating the cell with a compound that inhibits ROCKl and ROCK2.
  • the inhibitors are selective for ROCK2 and do not substantially inhibit ROCKl.
  • the invention provides ROCK inhibitors that have desirable pharmacokinetic and pharmacodynamic profiles.
  • the invention provides a method for intervening in a disease comprising administering an effective amount of a ROCK inhibitor.
  • the disease interventions can prevent a disease or its effects or symptoms, halt or impede progression of a disease or its effects or symptoms, or reverse the course of the disease or its effects or symptoms.
  • the diseases is atherosclerosis.
  • the disease is lipidosis.
  • the inhibitor is selective for ROCK2.
  • the invention further demonstrates certain advantages in selectively targeting ROCK2.
  • selective inhibition of ROCK2 is used for intervention in fibrotic diseases.
  • the invention provides methods of treating or ameliorating a fibrotic disease which comprises administering an effective amount of a compound that inhibits ROCK2 but does not substantially inhibit ROCKl.
  • the invention further provides a method for reducing or inhibiting physiological changes associated with a disease or development of diesase by administering a ROCK inhibitor, hi certain embodiments, the inhibitor is selective for ROCK2.
  • the ROCK inhibitor which may be selective for ROCK2
  • a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor such as a statin
  • the invention provides a method of inhibiting activation of mesenchymal cells, hi another embodiment, the invention provides a method of inhibiting infiltration of macrophages, hi yet another embodiment, the invention provides a means of inhibiting cell motility.
  • the invention also provides for attenuation of cellular responses to stress or injury, such as expression of smooth muscle actin, expression of fibronectin, or expression of disease related cytokines such as MCP-I.
  • a method of preventing or treating a disorder associated with endothelial dysfunction and thrombomodulin deficiency comprising administering to said individual an effective amount of a selective ROCK2 inhibitor, and optionally a statin or other HMG coenzyme A reductase inhibitor.
  • a method of treating a radiation-exposed individual or preventing tissue injury in an individual who is subsequently exposed to ionizing radiation comprising administering to said individual an effective amount of a selective ROCK2 inhibitor, and optionally a statin or other HMG coenzyme A reductase inhibitor.
  • a method of treating an individual having a neoplastic disease comprising administering to said individual an effective amount of a ROCK inhibitor, and optionally an HMG coenzyme A reductase inhibitor, and treating said individual with radiation therapy.
  • the invention provides a method of identifying compounds that are selective inhibitors of ROCK2 which comprises screening for compounds that inhibit ROCK2, but do not substantially inhibit ROCKl. Accordingly, the invention provides methods for identifying compounds for treating or ameliorating fibrotic disease.
  • a method of treating an individual having a neoplastic disease comprising the steps of administering to said individual an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and an ROCK inhibitor and treating said individual with radiation therapy.
  • ring A is a 5- or 6-membered aromatic ring which may comprise 0-3 heteroatoms selected from N, O, and S;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C]-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 16 and R 17 independently selected from the group consisting of H, C]-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(C r C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Cj-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • Y is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 46 and R 47 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(C 1 -C 6 alkyl)-O-(d-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl; aralkyl, heteroaryl, C 1 -C 6 alkyl, -(C-C 6 alkyl)-O-(C,-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 46 R 47 , -(C 1 -C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C
  • R 53 and R 54 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C-C 3 perfluoro alkyl;
  • R 56 and R 57 independently selected from the group consisting of H, C-C 8 alkyl, C 2 -C 8 alkenyl, C-C 8 alkynyl, -(C-C 6 alkyl)-O-(C-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 56 and R 57 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 56 R 57 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • R 63 and R 64 are independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(C r C 6 alkyl)-O-(C !
  • R 63 and R 64 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 66 and R 67 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C r C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 66 and R 67 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 68 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C 1 -C 6 alkyl)-O-(C r C 6 alkyl), -(Ci-C 6 alkyl)-NR 66 R 67 , -(Ci-C 6 alkyl)-O- (CpC 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • the present invention includes pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier and/or diluents.
  • the present invention includes pharmaceutical compositions comprising a substantially pure compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, and a pharmaceutically acceptable excipient and/or diluents.
  • Figure 1 shows various compounds that represent embodiment of the present invention.
  • Figure 2 shows various compounds that represent embodiment of the present invention.
  • Figure 3 shows various compounds that represent embodiment of the present invention.
  • Figure 4 shows various compounds that represent embodiment of the present invention.
  • Figure 5 shows various compounds that represent embodiment of the present invention.
  • Figure 6 shows various compounds that represent embodiment of the present invention.
  • Figure 7 shows various compounds that represent embodiment of the present invention.
  • Figure 8 shows various compounds that represent embodiment of the present invention.
  • Figure 9 shows various compounds that represent embodiment of the present invention.
  • Figure 10 depicts the selective inhibition of ROCK2 by the compounds of Examples 82 and 201. Inhibition is compared to Y27632 and fasudil, which inhibit both ROCKl and ROCK2.
  • Figure 11 shows the effect of selective ROCK2 inhibitors on the morphology of pulmonary arterial smooth muscle cells. Untreated cells (A) and cells treated with 3 ⁇ M Compound “82" (B) display normal morphology with intact actin stress fibers. Stress fibers are reduced or not apparent in cells treated with compounds that inhibit ROCKl and ROCK2 (C: 3 ⁇ M Y27632; D: 3 ⁇ M Compound "138").
  • Figure 12 shows the effect of selective ROCK2 inhibitors on the morphology of human umbilical vein endothelial cells. A: untreated; B: 3 ⁇ M Compound "82”; C: 3 ⁇ M Y27632; D: 3 ⁇ M Compound "138".
  • Figure 13 shows the effect of selective ROCK2 inhibitors on cell motility.
  • Compound “82” is compared to Y27632 at various concentrations.
  • Figure 14 shows the effect of selective ROCK2 inhibitors on cell motility.
  • Panc-1 cells were cultured in transwell dishes. Cell motility in the presence of various concentrations of a selective ROCK2 inhibitor (Compound "82") and a non-selective ROCK inhibitor (Y-27632) was evaluated after 4 hours and after 24 hours.
  • a selective ROCK2 inhibitor Compound "82”
  • Y-27632 non-selective ROCK inhibitor
  • Figure 15 shows increased levels of ROCKl and ROCK2 protein in ipsilateral kidney tissue, as compared to contralateral kidney tissue, seven days after ureteral obstruction.
  • Figure 16 shows levels of smooth muscle actin in ipsilatral kidney tissue after ureteral obstruction. Test animals were treated with a selective ROCK2 inhibitor (Compound "201"). Control animals were treated with vehicle alone.
  • Figure 17 depicts a Western blot showing induction of fibronectin in the ipsilateral kidney (lanes Ii to 5i) after ureteral obstruction as compared to the contralateral kidney (lanes Ic to 5 c).
  • Test mice received no ROCK inhibitor (Ii) or various concentrations of a selective ROCK2 inhibitor (lanes 2i to 5i).
  • Figure 18 shows levels of CD68, a transmembrane glycoprotein expressed by macrophages, in ipsilateral kidney tissue after ureteral obstruction. Test animals were treated with a selective ROCK2 inhibitor (Compound "201"). Control animals were treated with vehicle alone.
  • FIG 19 shows levels of monocyte chemotactic protein- 1 (MCP-I) in ipsilateral and contralateral kidney tissue after ureteral obstruction. Test animals were treated with a selective ROCK2 inhibitor (Compound “201"). Control animals were treated with vehicle alone.
  • Figure 20 shows accumulation of atherosclerotic plaques in ApoE -/- mice maintained on a high fat diet and treated with vehicle alone (A) or 100 mg/kg of compound "82" (B). Dotted lines indicate the location of the aortic epithelium.
  • Figure 21 shows hepatic lipodosis in ApoE -/- mice maintained on a high fat diet and treated with vehicle alone (A) or 100 mg/kg of compound "82" (B).
  • the present invention relates to treatment or ameliorization of disease by selective inhibition of ROCK2 (ROCK ⁇ ).
  • the present invention provides inhibitors of ROCK2 that do not substantially inhibit ROCKl.
  • the invention identifies ROCK2 as an important target for intervention in diseases involving fibrosis. The desirability of selective ROCK2 inhibitors for disease intervention is further made evident by the absence of undesirable physiological effects that can now be attributed to ROCKl inhibition.
  • Fibrotic disese is characterized by increased expression of certain cellular components, such as ROCKl and ROCK2, that mediate physical and physiological changes in cells and tissue. Fibrotic disease development involves, for example, accumulation of actin and fibronectin, expression of chemokines and receptors, attraction and infiltration of monocytes, and activation of mesenchymal cells. As demonstrated herein, such physical and physiological changes are inhibited by inhibition of ROCK2. Further, by distinguishing the effects of ROCK2 inhibition from the effects of inhibition of both ROCKl and ROCK2, it is made evident that certain undesirable effects associated with ROCKl inhibition can be avoided.
  • ROCK2 selective compounds For example, cell motility is diminished or inhibited by R0CK2 selective compounds, but the inhibition is not evident when ROCKl is also inhibited.
  • adverse cardiovascular responses associated with nonselective ROCK inhibtion such as vascular smooth muscle cell relaxation, and tachycardia, are avoided by the use of ROCK2 selective compounds.
  • the attainment of therapeutic levels of a ROCK2 selective compound is not hindered by side effects common to non-selective ROCK inhibitors.
  • a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor such as a statin
  • the combination may provide increased, additive, or synergistic effect.
  • Statins in addition to inhibiting HMG-CoA reductase (a key enzyme in the cholesterol synthesis pathway), are observed to have other pleiotropic effects.
  • statins modulate fibrogenic factors such as connective tissue growth factor (CTGF) and inhibit fibrosis.
  • CTGF connective tissue growth factor
  • the pleitropic effects are beneficial in trauma, vascular diseases, diabetes, immune disorders and inflammatory disorders.
  • Statins can be used to reduce side effects of radiation after accidental exposure or in the context of radiological or nuclear terrorism. Furthermore, statins reduce pathophysiological manisfestations of combined injury (radiation exposure combined with other types of injury such as penetrating or blunt trauma, burns or blast injury).
  • the present invention relates to a compound having the formula I:
  • Ring A is a 5- or 6-membered aromatic ring which may comprise 0-3 heteroatoms selected from N, O, and S;
  • R 1 is selected from the group consisting of aryl, -(CH 2 ) ⁇ -NR 13 R 14 , -X-R 12 ,
  • R 12 is selected from the group consisting OfCi-C 6 alkyl, -(C 1 -C O alkyl)-O-(Ci-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 16 R 17 , -(C 1 -C 6 alkyl)-C(O)NR 16 R 17 , -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl; R 13 and R 14 are independently selected from the group consisting of H,
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Cj-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(C]-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C r C 8 alkynyl, -(Ci-C 6 alkyl)-O-(C r C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, CpC 6 alkyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -(C-C 6 alkyl)-O- (C-C 6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C-C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoroalkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • Y is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 46 and R 47 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C]-C 6 alkyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 46 R 47 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • R 53 and R 54 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C)-C 3 perfluoro alkyl;
  • R 55 is selected from the group consisting of H, aryl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 56 R 57 , -CO 2 R 58 , -O-(CH 2 ) e -CO 2 R 58 , and -C(O)NR 56 R 57 ,
  • R 56 and R 57 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C r C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 56 and R 57 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C]-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 58 is selected from the group consisting of H, afyl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C-C 6 alkyl)-O-(C,-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 56 R 57 , -(C 1 -C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(C]-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo
  • R 63 and R 64 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C-C 3 perfluoro alkyl;
  • R 65 is selected from the group consisting of H, aryl, -(C 1 -C 6 alkyl)-O-(C-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 66 R 67 , -CO 2 R 68 , -0-(CH 2 ) ⁇ -CO 2 R 68 , and -C(O)NR 66 R 67 ,
  • R 66 and R 67 independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 alkynyl, -(C 1 -C 6 alkyl)-O-(C-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl; or R 66 and R 67 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from hal
  • R is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 66 R 67 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • r is selected from 0 to 6; 5 is selected from 0 to 6;
  • Ring A is preferably selected from phenyl and pyridyl rings, and is most preferably phenyl.
  • the present invention relates to a compound having the formula I 3 that is a selective ROCK2 inhibitor
  • R 1 is selected from the group consisting of aryl, -(CH 2 VNR 13 R 14 , -X-R 12 , -O-(CH 2 ) r CO 2 R' 2 , -0-(CH 2 VC(O)NR 13 R 14 , -O-(CH 2 ) r heteroaryl, -O-(CH 2 ) r cycloalkyl, -0-C(O)-(CH 2 VNR 13 R 14 , -O-(CH 2 ) Z -NR 13 R 14 , -NH-C(O)-(CH 2 VNR 13 R 14 , -NH-C(O)-X-R 15 , -NH-(CH 2 ) r NR 13 R 14 ;
  • R 12 is selected from the group consisting of Ci-C 6 alkyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 16 R 17 , -(C 1 -C 6 ⁇ yI)-C(O)NR 16 R 17 , -(C 1 -C 6 alkyl)-O-(d-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C]-C 3 perfluoro alkyl;
  • R 13 and R 14 are independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-C(O)NR 16 R 17 , aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • each X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl;
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(C-C 6 alkyl)-O-(C,-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -(C-C 6 alkyl)-O- (C-C 6 alkyl)-O-(C-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C-C 6 alkoxy, hydroxy, amino, cyano and C-C 3 perfluoroalkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • R 42 is selected from the group consisting OfCpC 6 alkyl, -(Ci-C 6 alkyl)-O-(C
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C]-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, oxo, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • Y is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 46 and R 47 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 alkynyl, -(Ci-C 6 ⁇ yI)-O-(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Cj-C 6 alkyl, -(C 1 -C 6 alkyl)-O-(C,-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 46 R 47 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and CpC 3 perfluoroalkyl;
  • R 53 and R 54 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 55 is selected from the group consisting of H, aryl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 56 R 57 , -CO 2 R 58 , -O-(CH 2 ) e -CO 2 R 58 , and -C( ⁇ O)NR 56 R 57 ,
  • R 56 and R 57 independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 alkynyl, -(C r C 6 alkyl)-O-(d-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 56 and R 57 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C]-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C r C 6 alkyl)-O-(Ci-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 56 R 57 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • R 63 and R 64 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 66 and R 67 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 66 and R 67 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 66 R 67 , -(C 1 -C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • r is selected from O to 6; 5 is selected from O to 6;
  • R 4 and R 5 are independently selected from H and alkyl, and in more preferably H.
  • R 1 , R 2 , R 4 , n and/? are as for the compound of the formula I.
  • /? is 1.
  • n may be 0.
  • R 4 is selected from -Y-R 42 .
  • Y may be preferably selected to be O, and R 42 may be selected to be -(Ci-C 6 alkyl)-O-(Cj-C 6 alkyl).
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and CpC 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl.
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C]-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl; each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(C]-C 6 alkyl)-O-(d-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl.
  • R 13 and R 14 are independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyty-C ⁇ CONR 16 R 17 ,aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, CpC 6 alkoxy, hydroxy, amino, cyano and CpC 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl; R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 13 and R 14 are independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(C-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-C(O)NR' 6 R 1 ⁇ aTyI, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, C]-C 6 alkoxy, oxo, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, CpC 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl.
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and C]-C 3 perfluoro alkyl, or R 15 is selected from -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -O-(CH 2 ) ⁇ -CO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C r C 8 alkynyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl), -(C 1 -C 6 alkyl)-NR I6 R 17 , -(C-C 6 alkyl)-O- (C]-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoroalkyl;
  • x is selected from O to 6
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • X is a covalent bond.
  • R 15 is C 1 -C 8 alkyl.
  • X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl
  • R 15 is selected from the group consisting of H, C 1 -C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which maybe optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(Ci-C 6 alkyl)-O-(d-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl; or R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C
  • R is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C 1 -C 6 alkyl)-O-(d-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-O- (C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C]-C 6 alkoxy, hydroxy, amino, cyano and C]-C 3 perfiuoroalkyl; and
  • x is selected from 0 to 6.
  • R 12 is selected from the group consisting of Ci-C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 16 R 17 , -(C 1 -C 6 alkyl)-C(-O)NR 16 R 17 , -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Cj-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(C-C 6 alkyl)-O-(C-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C-C 8 alkynyl, -(C-C 6 alkyl)-O-(C-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C-C 6 alkyl, C 2 -C 6 , alkenyl, C-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl; or R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Cj-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and C]-C 3 perfluoroalkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, oxo, hydroxy, amino, cyano and CpC 3 perfluoro alkyl; R 46 and R 47 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C]-C 6 al
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, CpC 6 alkyl, - (C 1 -C 6 alkyl)-O-(C,-C 6 alkyl), -(C-C 6 alkyl)-NR 46 R 47 , -(C 1 -C 6 alkyl)-O-(C,-C 6 alkyl)- 0-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • c is selected from 2 to 6; n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 12 is selected from the group consisting OfCi-C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR I6 R 17 , -(C-C 6 ⁇ yI)-C(O)NR 16 R 17 , -(C 1 -C 6 alkyl)-O-(C,-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, oxo, hydroxy, amino, cyano and CpC 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Cj-C 6 alkyl;
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl, or R 15 is selected from -(Ci-C 6 alkyl)-O-(Cj-C 6 alkyl), -(Cj-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Cj-C 8 alkyl, C 2 -C 8 alkenyl, Cj-C 8 alkynyl, -(Cj-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 1 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, oxo, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Cj-C 6 alkyl, -(Cj-C 6 alkyl)-O-(C,-C 6 alkyl), -(Cj-C 6 alkyl)-NR 16 R 17 , -(Cj-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Cj-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • R 46 and R 47 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl;
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(Ci-C 6 alkyl)-O-(C-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(C-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(C-C 6 alkyl)-O-(C-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -(C-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(C-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and C-C 3 perfluoroalkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 46 and R 47 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, - (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(C-C 6 alkyl)-NR 46 R 47 , -(C 1 -C 6 alkyl)-O-(C-C 6 alkyl)- 0-(C-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoroalkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 12 is selected from the group consisting OfCi-C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alky ⁇ -C ⁇ OJNR 16 R 17 , -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(C 1 -C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C]-C 6 alkyl, -(C-C 6 alkyl)-O-(C,-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -(C-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which niay be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoroalkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfiuoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • Y is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 46 and R 47 independently selected from the group consisting of H, Cj-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(d-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and CpC 3 perfluoro alkyl;
  • R 46 and R may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C]-C 6 alkyl, -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 46 R 47 , -(C 1 -C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • R 53 and R 54 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 55 is selected from the group consisting of H, aryl, -(Cj-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 56 R 57 , -CO 2 R 58 , -O-(CH 2 ) e -CO 2 R 58 , and -C( ⁇ O)NR 56 R 57 ,
  • R 56 and R 57 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C]-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(C r C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 56 and R 57 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 56 R 57 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl; d is selected from O to 6; e is selected from 0 to 6;
  • R 63 and R 64 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 66 and R 67 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(d-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 66 and R 67 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, CpC 6 alkoxy, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6 alkyl, -(C-C 6 alkyl)-O-(C,-C 6 alkyl), -(C 1 -C 6 alkyl)-NR 66 R 67 , -(C 1 -C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(d-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Cj-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, CpC 6 alkyl, C 2 -C 6 , alkenyl, Cj-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(C-C 6 alkyl)-NR 16 R 17 , -CO 2 R 18 , -0-(CH 2 VCO 2 R 18 , and -C(O)NR 16 R 17 ;
  • R 16 and R 17 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, Ci-C 8 alkynyl, -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C]-C 6 alkoxy, hydroxy, amino, cyano and C]-C 3 perfluoro alkyl; or R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl,
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Cj-C 6 alkyl, -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoroalkyl;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • R 7 is selected from the group consisting of -(CH 2 VNR 13 R 14 , and X-R 15 ;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C]-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl, or R 15 is selected from -(Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR I6 R 17 ,
  • R 16 and R 17 independently selected from the group consisting of H, Cj-C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 alkynyl, -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and Ci-C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 , alkenyl, C]-C 6 alkoxy, oxo, hydroxy, amino, cyano and Cj-C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Cj-C 6 alkyl, -(Ci-C 6 alkyl)-O-(C,-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(C-C 6 alkyl)-O- (Ci-C 6 alkyl)-O-(Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, amino, cyano and C]-C 3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4; and m is selected from 0 to 3.
  • Preferred compounds according to the present invention include: 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)acetamide, 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)acetamide, 2-(3-(4-(l H-indazol-5-ylamino)quinazolin-2-yl)phen ⁇ xy)- 1 -(4-methylpiperazin- 1 - yl)ethanone,
  • the R 1 and/or the R 4 group modulates the pharmacokinetic and/or pharmacodynamic profile of the compound and may result in improved pharmacokinetic properties compared to the unmodified, i.e., parent compound.
  • the active agent has improved physicochemical properties, pharmacokinetics, metabolism, or toxicity profile.
  • the active agent has superior solubility, lower IC 50 , and/or is substantially less protein bound in vivo compared to the compound lacking the R 1 residue.
  • the compounds of the invention include but are not limited to inhibitors and activators of proteins and enzymes. Specifically, the compounds of the present invention may modulate the function of Rho-Kinase.
  • the compounds of the invention may be useful in the treatment of cancer, neuronal degeneration (peripheral or central), spinal cord injury, erectile dysfunction, atherosclerosis, hypertension, cerebral vasospasm, cerebral ischemia, restenosis, asthma, glaucoma, asthma, osteoporosis, fibrotic disease (liver and kidney), Kidney dialysis (epithelial stability), and neuronal degeneration inflammation.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Most preferred are nitrogen or oxygen.
  • 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.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to six carbons, and more preferably from one to four carbon atoms. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • cycloalkyl refers to saturated, carbocyclic groups having from 3 to 7 carbons in the ring.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • 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.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • 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, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls and/or heterocyclic groups.
  • heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
  • Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, ox
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycyclic group can be substituted with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • nitro means -NO 2 ;
  • halogen or “halo” designates -F, -Cl, -Br or -I;
  • sulfhydryl means -SH;
  • hydroxyl means -OH; and
  • sulfonyl means -SO 2 -.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R, R' and R" each independently represent a group permitted by the rules of valence, preferably H, alkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic groups.
  • alkoxyl or "alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • the term lower alkoxy refers to an alkoxy group having from 1 to 6 carbon atoms.
  • oxo refers to an oxygen atom that has a double bond to a carbon.
  • each expression e.g. alkyl, m, n, R, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • 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.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • 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.
  • 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.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • 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, 2 nd 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 cis- and tr ⁇ rts-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.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the general intermediate of formula (VII) may be prepared as illustrated in Scheme A.
  • anthralamide (2-aminobenzamide (I)) is coupled with an appropriately substituted acid chloride of formula (II) in the presence of a base such as pyridine to give the benzamide (III).
  • the reaction is run in an aprotic solvent such as chloroform (CHCl 3 ) at a temperature of -20 to 5O 0 C, preferably at room temperature for 1-24 hours, preferably for 6 hours.
  • the benzamide (III) may be formed by treatment of the anthralamide (2-aminobenzamide (I)) with the benzoic acid in the presence of a coupling agent.
  • Suitable coupling agents include N-cyclohexyl-N'-(4- diethylaminocyclohexyl)-carbodiimide (DCC), 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) and bromotripyrrolidino phosphonium hexafluorophosphate (PyBroP ® ), benzotriazolel-lyl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (PyBOP ® ) with suitable additives if necessary which include 1-hydroxybenzotriazole (HOBt) and 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine.
  • DCC N-cyclohexyl-N'-(4- diethylaminocyclohexyl)-carbodiimide
  • EDC 1 -(3-dimethylamino
  • the protected indazole (VI) can be prepared as depicted in Scheme B.
  • 5-Nitro- indazole is appropriately protected via methods known to those skilled in the art, preferably with a tert-butoxy carbonyl group.
  • the nitro group is the reduced to the amino group via hydrogenation using a metal catalyst such as Pd/C in an inert solvent such as methanol (MeOH), 1 ,2 dimethoxethane (DME), ethanol (EtOH) or acetic acid (AcOH) or a combination of solvents preferably in a combination of MeOH and DME.
  • the reaction can be carried out under balloon pressure or under a pressure of 20-50 pounds per square inch (p.s.i.).
  • the phenol (VII) is then alkylated with an electrophile of formula (X) in the presence of a base such as potassium carbonate (K 2 CO 3 ), potassium tert-butoxide (KO'Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3 to give the ether (XI).
  • a base such as potassium carbonate (K 2 CO 3 ), potassium tert-butoxide (KO'Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3
  • a base such as potassium carbonate (K 2 CO 3 ), potassium tert-butoxide (KO'Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium
  • Additives such as sodium iodide (NaI) or potassium iodide (KI) may be optionally added to the reaction.
  • Compounds of formula (XVII) may be synthesized as depicted in Scheme D.
  • the transformation is effected by use of a metal catalyst such as palladium on carbon (PdVC).
  • the compound of formula (XIII) can be treated with, preferably at room temperature, with a carboxylic acid of formula (XIV) in the presence of a coupling agent (e.g., PyBOP, PyBrOP, dicyclohexylcarbodiimide (DCC), 1 -(3 '-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a solvent such as dichloromethane, chloroform, or dimethylformamide.
  • a coupling agent e.g., PyBOP, PyBrOP, dicyclohexylcarbodiimide (DCC), 1 -(3 '-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propan
  • agents such as HOBt maybe added to the reaction.
  • the compound of formula (XVI) may be synthesized via treatment with an acid chloride of formula (XV) in the presence a tertiary amine base such as triethylamine or DMAP to give an amide of formula (XVI).
  • the acid chlorides of formula (XV) are commercially available or can be prepared from carboxylic acids by procedures known to those skilled in the art. If necessary the indazole protecting group can be removed at this point to reveal the final compounds (XVII) via methods known to those skilled in the art.
  • Compounds of formula (XX) can be prepared by reacting the amines of formula (XIII) with a chloro formate of formula (XVI) in the presence of a base such as triethylamine, DMAP, NMO, or sodium hydrogen carbonate in a suitable solvent such as dichloromethane, chloroform, aqueous or anhydrous tetrahydrofuran, or dimethylformamide or in a combination of such solvents.
  • a base such as triethylamine, DMAP, NMO, or sodium hydrogen carbonate
  • a suitable solvent such as dichloromethane, chloroform, aqueous or anhydrous tetrahydrofuran, or dimethylformamide or in a combination of such solvents.
  • the reaction can be run at 0 to 6O 0 C, though room temperature is preferred. If required the indazole protecting group may be removed to give compound of formula (XX) by methods known to those skilled in the art.
  • Ureas of formula (XXV) may be synthesized as depicted in Scheme F.
  • anilines of formula (XIII) may be treated with 4-nitrophenyl carbonochloridate followed by the sequential addition of an amine of formula (XXII).
  • the reaction is run in an inert solvent such as THF, DMF or CH 2 Cl 2 in the presence of an amine base such as Et 3 N, DIEA or NMO.
  • ureas of formula (XXIV) Another option of the synthesis of the ureas of formula (XXIV) is to treat the anilines of formula (XIII) with a carbamoyl chloride of formula (XXIII) in the presence of a base such as Et 3 N, DIEA or NMO. If appropriate protecting groups (e.g. indazole) may be removed by methods known to those skilled in the art.
  • a base such as Et 3 N, DIEA or NMO.
  • Carbamates of formula (XXVII) may be synthesized as depicted in Scheme G.
  • Treatment of a phenol of formula (VII) where X OH with an isocyanate of formula (XXII) in an inert solvent such as CH 2 Cl 2 in the presence of an amine base such as Et 3 N, DEEA or NMO.
  • the reaction is run in an inert solvent such as THF, DMF or CH 2 Cl 2 in the presence of an amine base such as Et 3 N, DIEA or NMO.
  • the phenol (XXX) is then alkylated with an electrophile of formula (XXIX) in the presence of a base such as potassium carbonate (K 2 CO 3 ), potassium tert-butoxide (KO 1 Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3 to give the ether (XXXI).
  • a base such as potassium carbonate (K 2 CO 3 ), potassium tert-butoxide (KO 1 Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3
  • a base such as potassium carbonate (K 2 CO 3 ), potassium tert-butoxide (KO 1 Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaH
  • Additives such as sodium iodide (NaI) or potassium iodide (KI) may be optionally added to the reaction.
  • Presently preferred protecting groups include methyl, benzyl, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, CBz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety.
  • the preferred protecting groups for the indazole moiety are BOC, CBz, trifluoroacetamide and benzyl.
  • the modification of protein binding is based on surface technology, i.e. the preparation and screening of surfaces for their ability to resist adsorption of proteins from solution.
  • Surfaces which are resistant to adsorption of proteins from solution are known to one of skill in the art as "protein resistant" surfaces.
  • Functional groups may be screened to identify the group(s) present in protein resistant surfaces, as described in e.g., Chapman et al. Surveying for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304; Ostuni et al.
  • protein binding is assessed by measuring the capacity of molecules of the invention to bind to one or more human serum components or mimics thereof.
  • suitable functional residues may be identified by screening of surfaces comprising such residues for their ability to resist adsorption of serum components, including, but not limited to serum proteins, and preferably human serum proteins.
  • Candidate residues can be screened directly by attaching them to a solid support and testing the support for protein resistance.
  • candidate residues are incorporated into, or linked to molecules of pharmaceutical interest. Such compounds may be synthesized on a solid support, or bound to a solid support after synthesis.
  • immobilized candidate functional residues or molecules incorporating such residues are tested for their ability to bind serum components.
  • the serum components can be labeled with a signaling moiety for detection, or a labeled secondary reagent that binds to such serum components can be used.
  • Protein resistant surfaces which are resistant to adsorption of proteins from solution are known as "protein resistant" surfaces. Functional groups may be screened to identify the group(s) present in protein resistant surfaces, as described in e.g., Chapman et al. Surveying for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304; Ostuni et al. A Survey of Structure-Property Relationships of Surfaces that Resist the Adsorption of Protein, Langmuir 2001, 17:5605-5620; Holmlin, et al.
  • a combinatorial library of compounds may be generated as described infra, wherein the compounds are modified compounds comprising a conjugate of an active site of the compound (an essential backbone of a compound having a particular desired activity), e.g. compound A and at least one functional residue attached thereto, wherein each conjugate has a different functional residue attached thereto, e.g. residues having formula C, wherein each R group is selected from the various groups described herein.
  • a library may be used to screen a plurality of different functional residues for improved pharmacokinetic and/or pharmacodynamic properties including non-specific protein binding of the modified compound.
  • the solid support itself is chosen or modified to minimize its interaction with the serum components.
  • examples of such supports and assay systems are described in International Application WO 02/48676, WO 03/12392, WO 03/18854, WO 03/54515, herein incorporated by reference.
  • the molecules of the invention may be mixed with one or more serum components in liquid phase, and the amount of unbound molecules determined.
  • test compounds can be mixed with one or more serum components in liquid phase, and the unbound molecules determined.
  • molecules having reduced protein binding are identified as follows: a self-assembled monolayer of thiol molecules terminated with anhydride groups is formed at a gold surface. A set of small molecules with amine groups at one end, and groups that are designed to resist binding to albumin, for example, at the other end are then attached to the surface via reaction between the amine and anhydride. The set of molecules are spotted onto spatially distinct regions on the gold surface to create an array of molecules that might resist protein binding. This array is then exposed to a solution containing albumin that is fluorescently labeled. After a suitable incubation period, the gold surface is washed and scanned on a fluorescent scanner.
  • the immobilized chemical groups that bound to albumin will be identified by the presence of a fluorescent signal; groups that resist albumin binding will have low fluorescence in that part of the array. If a fluorescent protein is not available then antibodies against the protein of interest in combination with fluorescent secondary antibodies can be used to detect protein binding to the chemical groups. If an antibody is not available then a labeless detection method such as surface plasmon resonance (SPR) or MALDI mass spectrometry can be used to identify the presence of the protein at individual elements in the array. SPR also has the advantage of providing kinetic information on the binding of protein to the chemical groups.
  • SPR surface plasmon resonance
  • albumin any protein of pharmacokinetic interest can be tested for binding potential.
  • blood proteins that bind small molecules such as ⁇ -acid glycoprotein (AAG, AGP) and lipoproteins, could be exposed to the array and protein binding detected.
  • AAG ⁇ -acid glycoprotein
  • AGP ⁇ -acid glycoprotein
  • chemical groups can be identified that resist binding to P-glycoprotein (PGP) and therefore have the potential to reduce efflux when appended to a small molecule therapeutic. This is particularly important for development of anti-cancer drugs provide effective treatment where multiple drug resistance (MDR) has developed.
  • PGP P-glycoprotein
  • the method could also be used to identify chemical groups that resist binding to proteins such as thrombin, anti-thrombin, and Factor Xa and therefore have the potential to control coagulation.
  • This method would also be useful for identifying groups that improve therapeutics that are designed as supplemental or replacement therapies where protein binding and PK properties are very important, e.g., hormones and their binding proteins, and steroids and their binding proteins such as testosterone and sex hormone binding globulin (SHBG).
  • SHBG testosterone and sex hormone binding globulin
  • a self-assembled monolayer of thiol molecules terminated with maleimide groups is formed at a gold surface.
  • a set of small molecules with thiol groups at one end, and groups that are hydrophilic at the other end are then attached to the surface via reaction between the thiol and maleimide.
  • the set of molecules are spotted onto spatially distinct regions on the gold surface to create an array of molecules that might increase the solubility of a small molecule. Droplets of both polar (e.g., water) and hydrophobic (e.g., octanol) liquids are then placed onto each element of the array.
  • the contact angles of the two liquids on each element are then measured at each element of the array using a goniometer.
  • the wettability of a particular liquid at a surface presenting a chemical group can be determined by measuring the area of the surface covered by a droplet when viewed from above (high contact angle will yield droplets of small area; low contact angles cover greater areas).
  • the contact angle of a liquid on a surface presenting a chemical group is inversely proportional to the miscibility of that chemical group with that liquid (solvent). For example, a chemical group for which water has a high contact angle when it is presented at the surface, such as methyl (CH 3 ), has low miscibility with water, i.e., it will tend to reduce the solubility of a small molecule.
  • a chemical group for which water has a low contact angle when it is presented at the surface such as carboxyl (COOH)
  • COOH carboxyl
  • Sets of chemical groups can therefore be screened rapidly using contact angles on surfaces to identify groups that improve solubility or reduce hydrophilicity. This approach can be used to evaluate the effect on solubility of chemical groups used according to the invention.
  • a common parameter for the ability of a small molecule to cross the lipid membrane of a cell is logP where P is the partition coefficient of the compound between octanol and water.
  • P is the partition coefficient of the compound between octanol and water.
  • the pH dependence of the solubility of small molecules can be addressed in this method by measuring the contact angles of solutions at different pHs.
  • the parameter equivalent to logP in this case is logD, where D is the distribution coefficient, defined as the ratio of the sum of the concentrations of all species of the compound in octanol to the sum of the concentrations of all species of the compound in water at various pHs.
  • D is the distribution coefficient, defined as the ratio of the sum of the concentrations of all species of the compound in octanol to the sum of the concentrations of all species of the compound in water at various pHs.
  • Contact angles measured at different pHs therefore offer the possibility of an equivalent measure to logD.
  • the brain is one of the most difficult tissues for small molecules to penetrate.
  • the neurovascular junctions are tight and contain very few active transporters that are mostly responsible for clearing small molecules out of the brain.
  • the paracellular route (between cell junctions) is not available to small molecules, but only the transcellular route is (through cell membranes).
  • molecules to target the brain such as benzodiazepines, are hydrophobic to allow them to penetrate cell membranes.
  • the instant invention is compatible with the search for chemical groups that confer protein resistant and alleviate the common problem of excessive protein binding associated with molecules such as the benzodiazepines; this requires high dosing to account for the large percentage of binding to serum proteins.
  • the approaches described earlier for the identification of binders of PGP will be of help to optimize molecules for improved residence time in the brain.
  • monolayers of Caco-2 intestinal epithelial cells can be used to evaluate active transport of substances between the intestine and the bloodstream. When plated on a surface which allows the flow of material from apical to basolateral and vice versa, such cells form a biological membrane which can be used to simulate physiological absorption and bio-availability.
  • mouse brain capillary endothelial cell (MBEC) lines have been established to evaluate active transport in and out of the central nervous system.
  • Another example of such cells is HT29 human colon carcinoma cells.
  • monolayers expressing particular transporter proteins can be established using transfected cells. For example, Sasaki et al (2002) J. Biol. Chem. 8:6497 used a double-transfected Madin-Darby canine kidney cell monolayer to study transport of organic anions.
  • Alternatives to cell monolayers may of course be utilized to examine permeability.
  • Alternatives typically comprise a biological structure capable of active transport and include, but are not limited to, organs of the digestive tract obtained from lab animals and reconstituted organs or membranes created in vitro from cells seeded in an artificial matrix.
  • the present invention provides a compound of the general formula I, wherein the compound is an inhibitor of Rho-kinase.
  • Rho kinase a serine/threonine kinase
  • Rho serves as a target protein for small GTP-binding protein Rho. It serves as an important mediator of numerous cellular functions, including focal adhesions, motility, smooth muscle contraction, and cytokinesis, hi smooth muscle, ROCK plays an important role in Ca 2+ sensitization and the control of vascular tone.
  • Rho kinase is found in two forms, ROCK 1 (ROCK ⁇ ; pi 60- ROCK) and ROCK 2 (ROCK ⁇ ). Since, for example, a ROCK-mediated pathway plays an important role in vascular smooth muscle contraction, cell adhesion, and cell motility, it has gained importance in the pathogenesis of atherosclerosis. ROCK inhibitors are shown to suppress coronary artery spasms. A long-term inhibition of ROCK is reported to block the development of coronary arteriosclerotic lesions.
  • ROCK mediated pathways mediate numerous different cellular functions and ROCK inhibitors can be useful in treatments of patients in need thereof suffering from 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 where inhibition of Rho-kinase has been shown to inhibit tumor cell growth and metastasis, angiogenesis, arterial thrombotic disorders such as platelet aggregation and leukocyte aggregation, asthma, regulation of intraoccular pressure, and bone resorption.
  • 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 where inhibition of Rho-kina
  • Such treatment often relies on administering a therapeutic agent to a patient, wherein the therapeutic agent has a high specificity for a particular pathway or enzyme which is in need of regulation in the patient, by the therapeutic agent such as an enzyme inhibitor.
  • the therapeutic agent such as an enzyme inhibitor.
  • a compound which is an inhibitor of a Rho kinase (ROCK) which is an inhibitor of a Rho kinase (ROCK).
  • Fibrotic diseases include any disease in which there is a component due to abnormal or excessive deposition of fibrous tissue.
  • Such diseases include, but are not limited to, pulmonary fibrosis including bronchopulmonary dysplasia due to inhaled environmental and occupational pollutants, sarcoidosis, silicosis, asbestosis, pneumoconiosis, cystic fibrosis, pancreatic fibrosis, hepatic fibrosis including cirrhosis and steatosis, glomerulonephritis, systemic fibrosis, rheumatoid arthritis, wound healing, scleroderma, lupus, atherosclerosis, keloid, systemic sclerosis, fibrocytic breast diseases, uterine fibroids, ovarian cysts, endometriosis, radiation fibrosis, myocardial fibrosis, valvular fibrosis, Riedel's thyroiditis.
  • pulmonary fibrosis including bronchopulmonary dysplasia due to inhaled environmental and occupational pollutants
  • sarcoidosis silicosis, asbestosis
  • the invention also provides a method of treating a patient suffering from a disease associated with inflammation, or having inflammation as a component.
  • Inflammation may be symptomatic of an underlying disorder, and/or cause further disease progression.
  • An initial inflammatory response usually involves migration of fluid ans cells to injured tissues. This is generally followed by a cascade of events involving the local vascular system, the immune system, and arious cells within the injured tissue.
  • Chronic inflammation leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
  • Examples of inflammatory disease include, but are not limited to, colitis, inflammatory bowel disease, and Crohn's disease.
  • Other diseases include cardiac or cerebral ischemia, atherosclerosis, pain, and chronic degenerative conditions such as ocular disease, venous disease, arterial hypertension, and diabetes.
  • selective ROCK2 inhibitors will be generally useful for indications such as are describe above, except where relaxation of smooth muscle is desired.
  • selective ROCK2 inhibitors would not be used for treatment of hypertension or chronic obstructive airway disease.
  • selective ROCK2 inhibitors can be especially desirable for treatment of the above indications (e.g., neural tissue disorders, endothelial dysfunction, tissue remodeling, inflammation, fibrotic cascade, insulin receptor related, oncologic, ophthalmologic, angiogenic) where it is desired to avoid side effects such as smooth muscle relaxation resulting in hypotension, or tachycardia.
  • the present invention provides a compound which is a selective inhibitor of ROCK2.
  • Examples are provided herein that distinguish the role of ROCK2 from ROCKl and demonstrate the desirability of selective ROCK2 inhibitors that do not substantially inhibit ROCKl for treatment of certain diseases.
  • Selective R0CK2 inhibitors are compounds that inhibit ROCK2 to a greater extent than ROCKl when an appropriate concentration is employed. Thus, the compounds can be used to modulate R0CK2 mediated physiological processes while ROCKl mediated processes are essentially maintained. Accordingly, selective ROCK2 inhibitors of the invention have an IC 50 for R0CK2 that is at least about 3-fold lower than for ROCKl. In another embodiment, selective R0CK2 inhibitors have an IC 50 for R0CK2 that is at least about 10-fold lower than for ROCKl .
  • selective R0CK2 inhibitors have an IC 50 for R0CK2 that is at least about 30-fold lower than for ROCKl .
  • selective ROCK2 inhibitors have an IC 50 for R0CK2 that is at least about 100-fold lower than for ROCKl .
  • the invention also provides a method for identifying a compound for treating or amelioating a disease that comprises screening for compounds that inhibit R0CK2, but do not substantially inhibit ROCKl.
  • the disease to be treated with a selective R0CK2 inhibitor is a fibrotic disease.
  • 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 can be employed.
  • 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.
  • the selective ROCK2 inhibitors also have prophylactic applications.
  • compounds of the invention can be incorporated into drug eluting stents (cardiac, urethral, and the like) in order to prevent occlusion subsequent to implantation.
  • ROCK2 inhibitors may be administered as a preventative measure to inhibit or reduce the occurrence of fibrosis, particularly following an event that is associated with the occurrence of fibrosis. Such an event may include, myocardial infarction, surgery, lung damage from particle inhalation, wound healing, and diseases of the skin.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of the present invention, including but not limited to the compounds described above and those shown in the Figures, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • 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.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets
  • terapéuticaally-effective amount 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.
  • phrases "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.
  • pharmaceutically-acceptable carrier 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.
  • a pharmaceutically-acceptable material 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.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transport
  • 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 hydrox
  • 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.
  • pharmaceutically-acceptable salts 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, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sd. 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.
  • 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.
  • 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.
  • pharmaceutically- acceptable salts 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.
  • 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, for example, Berge et al., supra).
  • wetting agents 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.
  • antioxidants examples 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.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • 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 per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • 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.
  • 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.
  • 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 (using a flavored basis, usually sucrose and acacia or tragacanth), 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.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, 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
  • 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 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.
  • compositions 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.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated 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.
  • 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.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants 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.
  • 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 nonirri taring 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.
  • suitable nonirri taring 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.
  • 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.
  • 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 are also contemplated as being within the scope of this invention.
  • 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.
  • aqueous and nonaqueous carriers examples 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • 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.
  • compositions may also contain adjuvants 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.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • 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.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • 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.
  • 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.
  • 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.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient'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.
  • 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.
  • 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.
  • 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.
  • 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, intracerebro ventricular 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.
  • 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. Preferred dosing is one administration per day.
  • composition While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition). [0187]
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • 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, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
  • treatment is intended to encompass also prophylaxis, therapy and cure.
  • 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 compound 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 therapeutical 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.
  • an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
  • 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 to improve bioavailability of some 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).
  • 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.
  • the formulations contain micelles formed from a compound of the present invention and at least one amphiphilic carrier, in which the micelles have an average diameter of less than about 100 ran. More preferred embodiments provide micelles having an average diameter less than about 50 nm, and even more preferred embodiments provide micelles having an average diameter less than about 30 nm, or even less than about 20 nm.
  • amphiphilic carriers While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastro-intestinal tract).
  • GRAS Generally-Recognized-as-Safe
  • amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
  • Particularly preferred amphiphilic carriers are saturated and monounsaturated polyethyleneglycolyzed fatty acid glycerides, such as those obtained from fully or partially hydrogenated various vegetable oils.
  • oils may advantageously consist of tri-. di- and mono-fatty acid glycerides and di- and mono-polyethyleneglycol esters of the corresponding fatty acids, with a particularly preferred fatty acid composition including capric acid 4-10, capric acid 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 and stearic acid 5-15%.
  • amphiphilic carriers includes partially esterified sorbitan and/or sorbitol, with saturated or mono-unsaturated fatty acids (SPAN- series) or corresponding ethoxylated analogs (TWEEN-series).
  • amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di- oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc (produced and distributed by a number of companies in USA and worldwide).
  • Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible).
  • Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol.
  • PEG polyethylene glycol
  • polylactic also termed polylactide
  • polyglycolic acid also termed polyglycolide
  • a polylactic-polyglycolic acid copolymer a polyvinyl alcohol.
  • Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons.
  • the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons.
  • the polymer is polyethyleneglycol of 750 daltons (PEG(750)).
  • the polymers used in the present invention have a significantly smaller molecular weight, approximately 100 daltons, compared to the large MW of 5000 daltons or greater that used in standard pegylation techniques. Polymers may also be defined by the number of monomers therein; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 daltons).
  • hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co- caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
  • a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and
  • 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 which 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. In all cases the amount should be between 0.1 and thirty percent (w/w polymer).
  • 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
  • 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.
  • 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).
  • the ROCK inhibitors of the invention can be coadministered with other agents commonly used to treat those disorders.
  • cholinesterase inhibitors may be coadministered for treatment of a neural tissue indication (e.g., Alzheimers, spinal cord repair).
  • a PDE5 inhibitor may be coadministered for an indication involving an endothelial dysfunction (e.g., erectile dysfunction) or tissue remodeling (e.g., cardiac hypertrophy).
  • a PDE5 inhibitor may be coadministered.
  • a ROCK inhibitor may be coadministered with a steroid, NSAID.
  • Lipid lowering therapies may be used in combination with ROCK inhibitors for treatment of fibrotic disease or metabolic syndrome.
  • cytotoxic agents may be coadministered.
  • a ROCK inhibitor can be coadministered with a VEGFR antagonist (e.g., Avastin).
  • a beta-blocker or prostaglandin may be coadministered.
  • Fibrotic diseases may be complex and include components such as, for example, an inflammatory component (e.g., pulmonary fibrosis), an autoimmune component (e.g., rheumatoid arthritis), or an estrogen mediated component (e.g., fibroids, endometriosis). Often, it is only that component of the fibrotic disease that is responsive to therapy. Further, accepted treatment for certain fibrotic diseases may be largely palliative. According to the invention, ROCK inhibitors are administered to treat or ameliorate such diseases and may be coadministered with the agents that would usually be directed to those other components.
  • an inflammatory component e.g., pulmonary fibrosis
  • an autoimmune component e.g., rheumatoid arthritis
  • an estrogen mediated component e.g., fibroids, endometriosis
  • ROCK inhibitors are administered to treat or ameliorate such diseases and may be coadministered with the agents that would usually be directed to those other components.
  • agents that may be coadministered with ROCK inhibitors include anti-inflammatory agents such as NSAIDs, corticosteroids and the like, antibiotics, anti-oxidants, immunosuppressants such as glucocorticoids, methotrexate, cyclosporine and the like, hormones and hormone analogs such as danazol, progestin and the like, and hormone agonists such as Gonadotropin-releasing hormone (GnRH) agonists and the like.
  • anti-inflammatory agents such as NSAIDs, corticosteroids and the like, antibiotics, anti-oxidants, immunosuppressants such as glucocorticoids, methotrexate, cyclosporine and the like, hormones and hormone analogs such as danazol, progestin and the like, and hormone agonists such as Gonadotropin-releasing hormone (GnRH) agonists and the like.
  • GnRH Gonadotropin-releasing hormone
  • Statins which are known to inhibit the enzyme 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase (a key enzyme in the cholesterol synthesis pathway), are observed to have other pleiotropic effects.
  • statins modulate fibrogenic factors such as connective tissue growth factor (CTGF) and inhibit fibrosis.
  • CTGF connective tissue growth factor
  • the pleitropic effects are beneficial in trauma, vascular diseases, diabetes, immune disorders and inflammatory disorders.
  • Particularly interesting applications of these drugs include reducing side effects of radiation after accidental exposure or in the context of radiological or nuclear terrorism.
  • statins reduce pathophysiological manisfestations of combined injury (radiation exposure combined with other types of injury such as penetrating or blunt trauma, burns or blast injury.
  • the present invention demonstrates the benefit of combinations of ROCK inhibitors and inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase on pathways involved in the pathophysiological mansifestations of radiation and combined injury.
  • Atorvastatin and a ROCK inhibitor e.g., compound "82" modulate expression of genes in the same biological processes, although the individual genes modulated by the two compounds are different.
  • the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is a statin.
  • Representative statins include, but are not limited to, pravastatin and its sodium salt, simvastatin, lovastatin, rosuvastatin, atorvastatin and fluvastatin.
  • Representative ROCK inhibitors include, but are not limited to, compound "82,” compound “138,”compound “210,” Y-27632, fasudil (Asahi Kasei) and H-1152P.
  • the ROCK inhibitor is selective for ROCK2. The inhibitors are administered orally or parenterally.
  • the present invention provides a method of treating a pathophysiological state in an individual in need of such treatment, comprising the step of administering to the individual an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and an effective amount of a ROCK inhibitor.
  • Representative pathophysiological states include cardiovascular diseases or disorders, disorders related to muscle relaxation properties, inflammatory diseases or disorders, states related to neurite outgrowth inducing effects or central nervous system dysfunction or neurodegeneration, diseases or disorders related to cell proliferation and cell migration, diseases or disorders related to microorganism invasion, or diseases or disorders related to insulin resistance and diabetes.
  • representative cardiovascular diseases include hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure or atherosclerosis.
  • Representative said disorder related to muscle relaxation is asthma, male erectile dysfunctions, female sexual dysfunction or over-active bladder syndrome.
  • Representative inflammatory disease or disorders include stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and inflammatory pain, rheumatoid arthritis, irritable bowel syndrome or inflammatory bowel disease.
  • Representative states related to neurite outgrowth inducing effects or central nervous system dysfunction or neurodegeneration include neuronal or axonal lesions, spinal cord injury, stroke, traumatic brain injury, Parkinson's disease or Alzheimers disease.
  • Representative states related to cell proliferation and cell migration include treating cancer and tumor metastasis.
  • Representative diseases or disorders related to microorganism invasion include infection caused by a virus or a bacteria.
  • the 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor is a statin.
  • the present invention is also directed to a method of preventing or treating a disorder associated with endothelial dysfunction and thrombomodulin deficiency, comprising the step of administering to a subject an effective amount of 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor and a ROCK inhibitor.
  • Disorders to be treated include, but are not limited to, sepsis, adult respiratory distress syndrome, and tissue radiation injury.
  • the present invention is also directed to a method of treating a radiation- exposed individual or preventing tissue injury in an individual who is subsequently exposed to ionizing radiation, comprising the step of administering to a subject an effective amount of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and a ROCK inhibitor.
  • an individual is treated for exposure to a therapeutic amount of radiation.
  • the individual has a cancerous or pre-cancerous condition.
  • the individual was exposed to a non-therapeutic ionizing radiation such as having been exposed to radiation in a radiation accident, in nuclear warfare, in an event of radiation terrorism or in a space flight or the individual may have been exposed to radiation produced by an explosive device.
  • the present invention is also directed to a method of treating an individual having a neoplastic disease, comprising the steps of administering to said individual an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and an inhibitor of Rho kinase and treating said individual with radiation therapy.
  • Agents coadministered according to the invention need not be administered together. For example, they may be administered by different routes and at different intervals.
  • Mass spectrometry was conducted by: SynPep Co., 6905 Sierra Ct. Dublin, CA 94568, or it was recorded on an LC-MS: Waters 2695 Separations Module with a Waters ZQ 2000 single quadrapole MS detector. Unless stated all mass spectrometry was run in ESI mode.
  • Preparative HPLC was performed on Waters Delta machine (600 and 515 Pumps ) using an YMC- Pack ProC18 (150 x 20 mm LD.) column using a combination of Buffer A (0.1% TFA/H 2 0) and Buffer B (0.0085% TFA/MeCN) as the mobile phase.
  • aqueous layer was basicified with 1 N NaOH, extracted with CHCl 3 (3x), dried under Na 2 SO 4 and concentrated in vacuo. The two organic layers were combined to afford tert-butyl 5-(2-(3-((R)- pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (65 mg, 79 %).
  • Example 61 isopropyl 2-(3-(4-(lH-indazol-5-yIamino)quinazolin-2-yl)phenoxy)acetate

Abstract

La présente invention concerne des inhibiteurs de ROCK1 et R0CK2 qui peuvent être sélectifs vis-à-vis de R0CK2 et des procédés de modulation des propriétés pharmacocinétiques et/ou pharmacodynamiques de ces composés. L'invention concerne également des procédés d'inhibition de ROCK1 et/ou de R0CK2. Elle concerne également des traitements qui combinent des inhibiteurs de ROCK1 et/ou de de R0CK2 avec des statines.
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