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WO2008049919A2 - Inhibiteurs de kinase - Google Patents

Inhibiteurs de kinase Download PDF

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Publication number
WO2008049919A2
WO2008049919A2 PCT/EP2007/061542 EP2007061542W WO2008049919A2 WO 2008049919 A2 WO2008049919 A2 WO 2008049919A2 EP 2007061542 W EP2007061542 W EP 2007061542W WO 2008049919 A2 WO2008049919 A2 WO 2008049919A2
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alkyl
heteroaryl
aryl
heterocyclyl
cycloalkyl
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WO2008049919A3 (fr
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Olivier Defert
Dirk Leysen
Philippe Van Rompaey
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Devgen NV
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Devgen NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to new kinase inhibitors, more specifically AGC kinases inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease.
  • AGC-family protein kinases are named after their family members protein kinase A (PKA), protein kinase G (PKG), and protein kinase C (PKC).
  • PKA protein kinase A
  • PKG protein kinase G
  • PKC protein kinase C
  • Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK), which is believed to be an effector of Ras-related small GTPase Rho.
  • the Rho family consists of at least 10 members of small GTP binding proteins, including RhoA, B, C, D, E,
  • ROCKI shows highest expression levels in non-neuronal tissues, such as heart, lung and skeletal muscles; whereas ROCKII is preferentially expressed in brain (hippocampus, cortex and cerebellum).
  • Rho/Rho-kinase mediated pathway plays an important role in the signal transduction pathway of many agonists such as angiotensin II, 5-HT, NA, thrombin, endothelin-1 , urotensin II, platelet- derived growth factor and ATP/ADP.
  • Activation of ROCK leads to phosphorylation of various proteins: MLCP, MLC, LIMKs, CRMP2 and others.
  • One of the main substrates is the myosin light chain MLC.
  • Activation of MLC, together with the ROCK-induced inactivation of the MLCPhosphatase leads to stimulation of actin-myosin interactions and subsequent cell contraction and stress fiber formation.
  • ROCK also induces activation of LIMs resulting in an increase of actin filaments.
  • ROCK activates the ERM protein complex and other proteins involved in cytoskeletal regulation.
  • ROCK associates with and activates the IKK complex.
  • ROCK inhibitors prevent the degradation of the IKK complex and subsequent NF- ⁇ B activation induced by MPS and TNF.
  • ROCK inhibitors decrease NF- ⁇ B transcription stimulated by pro-inflammatory mediators.
  • NF- ⁇ B is a ubiquitously expressed family of transcription factors controlling the expression of numerous genes involved in immunity and inflammation. Therefore ROCK inhibitors provide a useful therapy to treat auto-immune and inflammatory diseases.
  • ROCKs play an important role in various cellular functions: such as smooth muscle contraction, actin cytoskeleton organization, platelet activation, downregulation of myosin phosphatase cell adhesion, -migration, -proliferation and -survival, thrombin-induced responses of aortic smooth muscle cells, hypertrophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle contraction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated anion channels, neurite retraction, neutrophil chemotaxis, wound healing and cell transformation and gene expression.
  • ROCK has been implicated in various diseases and disorders including hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, preterm labor, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease, benign prostatic hyperplasia and atherosclerosis.
  • the compounds described herein act as inhibitors of AGC-kinases and in particular of ROCK. These compounds and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of disorders, including allergic disorders such as asthma, cardiovascular diseases, vascular diseases, eye diseases, renal diseases, erectile dysfunction, inflammatory diseases, proliferative disorders; neurological disorders and diseases of the central nervous system (CNS), osteoporosis, renal diseases and AIDS.
  • allergic disorders such as asthma, cardiovascular diseases, vascular diseases, eye diseases, renal diseases, erectile dysfunction, inflammatory diseases, proliferative disorders; neurological disorders and diseases of the central nervous system (CNS), osteoporosis, renal diseases and AIDS.
  • CNS central nervous system
  • osteoporosis renal diseases and AIDS.
  • the invention provides a compound of Formula I or Il or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,
  • q is an integer selected from 0, 1 or 2
  • s is an integer selected from 1 or 2
  • Y is -C(R 3 )R 6 - or -NR 3 -, wherein R 3 is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl,
  • R 4 is selected from hydrogen, alkyl, alkoxy, cyano, nitro, halogen, R 5 is hydrogen ,
  • L in Formula I is -CR 9 R 10 - and L in Formula Il is selected from -CR 9 R 10 - Or -SO 2 -,
  • R 7 is hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalk
  • R 9 and R 10 are each independently selected from hydrogen or alkyl
  • R 11 and R 12 are each independently hydrogen or a group selected from alkyl, alkenyl, alkenyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylsulfonylaminoalkyl, alkylsulfonylamino, alkylcarbonyl, formylamino, formylaminoalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkoxyl, alkoxyalkyl, cyanoalkyl, aryloxyaralkyl, aralkylheteroaryl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aral
  • the invention provides a compound of the invention for use in human or veterinary medicine.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of at least one disease and/or disorder selected from the group comprising eye diseases; erectile dysfunction; cardiovascular diseases; vascular diseases; proliferative diseases; inflammatory diseases; neurological diseases and disease of the central nervous system (CNS); bronchial asthma; osteoporosis; renal diseases; and AIDS.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of eyes diseases including macular degeneration, retinopathy and glaucoma, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of inflammatory diseases, such as contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.
  • inflammatory diseases such as contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of cardiovascular and vascular diseases: including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, (pulmonary) hypertension, arteriosclerosis, thrombosis (including deep thrombosis); pulmonary vasoconstriction, and platelet related diseases, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith and/or alleviating complications and/or symptoms associated therewith.
  • cardiovascular and vascular diseases including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, (pulmonary) hypertension, arteriosclerosis, thrombosis (including deep thrombosis); pulmonary vasoconstriction, and
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention, treatment and/or management of neurological and CNS disorders: including but not limited to stroke, multiple sclerosis, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ' s disease, MS and neuropathic pain, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
  • neurological and CNS disorders including but not limited to stroke, multiple sclerosis, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ' s disease, MS and neuropathic pain, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of proliferative diseases including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate or thyroid; leukemia; sarcoma; lymphoma; melanoma; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.
  • proliferative diseases including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate or thyroid; leukemia; sarcoma; lymphoma; melanoma; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of erectile dysfunction, bronchial asthma, osteoporosis, renal diseases and AIDS, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
  • the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one kinase, in vitro or in vivo.
  • the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one ROCK kinase, for example ROCKII and/or ROCKI isoforms.
  • Undefined (racemic) asymmetric centers that may be present in the compounds of Formula I or Il are interchangeably indicated by drawing a wavy bonds or a straight bond in order to visualize the undefined steric character of the bond.
  • the present invention provides a compound of Formula I or Il having one of the Formula III, IV, V, Vl, VII, VIII, IX, or X,
  • IX X wherein r is an integer selected from 1 , 2, 3, 4 or 5, p is an integer selected from 0, 1 or 2, m is an integer selected from 0 or 1 ,
  • R 13 and R 14 are each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, alkoxy, amino, aminoalkyl, alkylaminoalkyl
  • R 15 and R 16 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl,
  • X and Z are each independently selected from -C(R 18 )R 19 - or -NR 18 -, wherein R 18 is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, and R 19 is selected from hydrogen or alkyl, wherein R 2 is selected from hydrogen or alkyl, said alkyl being optionally substituted with one or more substituents selected from amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino
  • R 3 is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, cycloalkyl,
  • R 4 is selected from hydrogen, alkyl, alkoxy, cyano, nitro, halogen,
  • R 5 is hydrogen
  • R 7 is hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalk
  • R 9 and R 10 are each independently selected from hydrogen or alkyl
  • R 11 and R 12 are each independently hydrogen or a group selected from alkyl, alkenyl, alkenyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylsulfonylaminoalkyl, alkylsulfonylamino, alkylcarbonyl, formylamino, formylaminoalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkoxyl, alkoxyalkyl, cyanoalkyl, aryloxyaralkyl, aralkylheteroaryl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aral
  • heterocyclyl is preferably selected from piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-
  • the present invention provides a compound of Formula I or Il having one of the Formula III, IV, V, Vl, VII, VIII, IX, or X
  • r is an integer selected from 1 , 2, 3, 4 or 5, preferably 1 , 2 or 3, more preferably 1 or 2
  • p is an integer selected from 0, 1 or 2
  • m is an integer selected from 0 or 1
  • R 13 and R 14 are each independently selected from hydrogen, hydroxyl, cyano, nitro, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 6 -ioaryl, C 6 -ioarylCi.
  • R 13 and R 14 are each independently selected from hydrogen, hydroxyl, cyano, nitro, Ci_ 6 alkyl, C 6 -ioaryl, C 6 -ioarylCi.
  • R 13 and R 14 are each independently selected from hydrogen, hydroxyl, cyano, nitro, Ci_ 6 alkyl, C 6 -ioaryl, halo, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, Ci_ 6 alkoxy, amino, aminoCi. 6 alkyl, Ci. 6 alkylaminoCi. 6 alkyl,
  • R 15 and R 16 are each independently selected from hydrogen, d- 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, C 3 . i O aryl, C 6 -ioarylCi_ 4 alkyl, C 3 . 6 cycloalkyl, Cs-ecycloalkylCi- ⁇ alkyl, heteroaryl, heteroarylCi_ 6 alkyl, heterocyclyl, heterocyclyld- ⁇ alkyl, haloCi_ 6 alkyl, preferably R 15 and R 16 are each independently selected from hydrogen, Ci_ 6 alkyl, C 6 -ioaryl, C 6 -ioarylCi_ 4 alkyl, C 3 .
  • R 15 and R 16 are each independently selected from hydrogen, Ci_ 6 alkyl, C 6 -ioaryl, C 6 -ioarylCi_ 4 alkyl, C 3 . 6 cycloalkyl, Cs-ecycloalkylCi- ⁇ alkyl, haloCi_ 6 alkyl, yet more preferably R 15 and R 16 are each independently selected from hydrogen, Ci_ 6 alkyl, haloCi_ 6 alkyl,
  • R 17 is selected from hydrogen, hydroxyl, amino, C 6 - i O aryl, C 6 -ioarylCi_ 4 alkyl, Ci_ 6 alkyl, aminoCi_ 6 alkyl, Ci_ 6 alkylamino, halogen, haloCi_ 6 alkyl, haloCi. 6 alkoxy, Ci_ 6 alkoxy, C 3 .
  • R 17 is selected from hydrogen, amino, C 6 -ioarylCi_ 4 alkyl, Ci_ 6 alkyl, aminoCi_ 6 alkyl, Ci_ 6 alkylamino, halogen, haloCi_ 6 alkyl, haloCi. 6 alkoxy, Ci_ 6 alkoxy,
  • X and Z are each independently selected from -C(R 18 )R 19 - or -NR 18 -, wherein R 18 is hydrogen or a group selected from d- 6 alkyl, d- 6 alkylcarbonyl, C 6 -ioaryl, C 6 -ioaryld- 6 alkyl, haloC 6 -ioarylCi. 6 alkyl, amino, aminod. 6 alkyl, C 3 .
  • R 19 is selected from hydrogen or d_ 6 alkyl, preferably R 18 is hydrogen or a group selected from d_ 6 alkyl, C 6 -ioaryl, C 6 -ioaryld- 6 alkyl, haloC 6 -ioaryld- 6 alkyl, amino, aminod_ 6 alkyl, C 3 .
  • R 18 is hydrogen or a group selected from d_ 6 alkyl, aryl, arylCi- 6 alkyl, haloaryld_ 6 alkyl, amino, aminod_ 6 alkyl, wherein R 2 is selected from hydrogen or d_ 6 alkyl, said d_ 6 alkyl being optionally substituted with one or more substituents selected from amino, C 6 -ioaryl, C 6 -ioarylCi_ 4 alkyl, d_ 6 alkyl, aminod_ 6 alkyl, Ci_ 6 alkylamino, heteroaryl, heteroaryld_ 6 alkyl, halogen, halod_ 6 alkyl, halod_ 6 alkoxy, heterocyclyl, Ci- 6 alkoxy, C 3
  • R 2 is selected from hydrogen or Ci_ 6 alkyl, said Ci_ 6 alkyl being optionally substituted with one or more substituents selected from amino, Ci -6 alkyl, aminoCi_ 6 alkyl, Ci_ 6 alkylamino, halogen, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, more preferably R 2 is selected from hydrogen or Ci_ 6 alkyl, R 3 is hydrogen or a group selected from C-
  • R 3 is hydrogen or a group selected from Ci- 6 alkyl, Ci_ 6 alkylcarbonyl, C 6 -ioaryl, C 6 -ioarylCi. 4 alkyl, haloC 6 -ioarylCi_ 4 alkyl, amino, aminoC-i- 6 alkyl, C 3 .
  • R 3 is hydrogen or a group selected from C-
  • R 4 is selected from hydrogen, C-
  • R 5 is hydrogen
  • R 6 is selected from hydrogen or C-
  • R 7 is hydrogen or a group selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, hydroxyCi_ 6 alkyl, Ci- 6 alkoxy, Ci. 6 alkoxyCi. 6 alkyl, hydroxyl, Ci_ 6 alkyloxycarbonyl, carboxyl, aminoCi_ 6 alkyl, amino, C 6 - i O aryl, C 6 -ioarylCi_ 4 alkyl, heteroaryl, heteroarylCi_ 4 alkyl, heterocyclyl, heterocyclylCi_ 4 alkyl, C 3 .
  • R 7 is hydrogen or a group selected from d- 6 alkyl, hydroxyd- 6 alkyl, d- 6 alkoxy, d. 6 alkoxyd. 6 alkyl, hydroxyl, Ci- 6 alkyloxycarbonyl, carboxyl, aminod.
  • R 11 and R 12 are each independently hydrogen or a group selected from C-
  • aryl i O aryl, heteroaryl, heteroarylC 2 .
  • 6 cycloalkyl, C 6 -ioaryl, heterocyclyl substituent or heteroaryl may be one or more C 3 .
  • R 11 and R 12 may together with the common nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring, said ring being optionally fused with one or more C 6 -ioaryl, heteroaryl, C 3 .
  • i 0 arylcarbonylamino, C 6 -ioaryloxy, cyano, cycloalkyl, haloCi_ 6 alkoxy, haloCi_ 6 alkyl, haloaryl, heteroaryl, heteroarylcarbonyl, heteroarylC 2 - 6 alkenylaminooxy, heteroarylCi_ 6 alkyl, heteroarylcarbonylamino, heterocyclyl, hydroxyd- 6 alkyl, nitro, oxo, sulfonyl, or fused to the C 3 .
  • scycloalkyl, aryl, heterocyclyl or heteroaryl substituent may be one or more cycloalkyl, C 6 -ioaryl, heterocyclyl or heteroaryl, each of said substituent being optionally substituted by one or more further substituent selected from halo, Ci_ 6 alkoxy, Ci_ 6 alkyl, Ci_ 6 alkylamino, Ci_ 6 alkylcarbonyl, Ci- 6 alkyloxycarbonyl, Ci_ 6 alkyl heteroaryl, Ci_ 6 alkylsulfonyl, C 6 -ioarylCi.
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H 2n+I wherein n is a number greater than or equal to 1.
  • alkyl groups of this invention comprise from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably 1 to 8 carbon atoms, in particular 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.
  • d- 4 alkyl means an alkyl of one to four carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers.
  • CrC 6 alkyl includes all linear, branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, and hexyl and its isomers.
  • optionally substituted alkyl refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, or example 1 , 2, 3 or 4 substituents or 1 to 2 substituents) at any available point of attachment.
  • Non-limiting examples of such substituents include halogen, hydroxyl, carbonyl, nitro, amino, oximes, imines, azido, hydrazino, cyano, alkyl, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thio, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamates, thioamides, urea, sulfonamides and the like.
  • alkyl When the term “alkyl” is used as a suffix following another term, as in “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one or two (preferably one) substituent(s) selected from the other, specifically-named group, also as defined herein.
  • hydroxyalkyl refers to a -R a -OH group wherein R a is alkylene as defined herein.
  • hydroxyalkyl includes 2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl, 3,4- dihydroxybutyl, and so forth.
  • Alkoxyalkyl refers to an alkyl group substituted with one to two of OR', wherein R' is alkyl as defined below.
  • aralkyl or arylalkyl refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is an aryl as defined below, such as benzyl.
  • heteroarylalkyl refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is a heteroaryl as defined below, such as pyridinyl.
  • cycloalkyl group is a cyclic alkyl group, that is to say, a monovalent, hydrocarbyl group having 1 , 2 or 3 cyclic structure.
  • Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic or polycyclic alkyl groups.
  • Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms.
  • the further rings of multi- ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms.
  • Cycloalkyl groups may also be considered to be a subset of homocyclic rings discussed hereinafter.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl with cyclopropyl being particularly preferred.
  • An "optionally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
  • alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed “alkylene” groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2- dimethylethylene, pentamethylene and hexamethylene.
  • alkenyl groups as defined above and alkynyl groups as defined above, respectively are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene” and “alkynylene” respectively.
  • alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts.
  • Cycloalkylene herein refers to a saturated homocyclic hydrocarbyl biradical of Formula C n H 2n - 2 - Cycloalkylene groups of this invention preferably comprise the same number of carbon atoms as their cycloalkyl radical counterparts. Where an alkylene or cycloalkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom, preferably a common carbon atom.
  • a C 3 alkylene group may be for example ⁇ CH 2 CH 2 CH 2 -*, *-CH(-CH 2 CH 3 )-* or *-CH 2 CH(-CH 3 )-*.
  • a C 3 cycloalkylene group may be
  • a cycloalkylene group is present, this is preferably a C 3 -C 6 cycloalkylene group, more preferably a C 3 cycloalkylene ( i.e. cyclopropylene group) wherein its connectivity to the structure of which it forms part is through a common carbon atom.
  • Cycloalkylene and alkylene biradicals in compounds of the invention may be, but preferably are not, substituted.
  • alkenyl refers to an unsaturated hydrocarbyl group, which may be linear, branched or cyclic, comprising one or more carbon-carbon double bonds. Alkenyl groups thus comprise two or more carbon atoms, preferably between 2 and 20 carbon atoms, more preferably between 2 and 10 carbon atoms, still more preferably between 2 and 8 carbon atoms, for example, between 2 and 6 carbon atoms. Similarly to cycloalkyl groups, cycloalkenyl groups may be considered to be a subset of homocyclic rings discussed hereinafter.
  • alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2-heptenyl and its isomers, 2-octenyl and its isomers, 2,4-pentadienyl and the like.
  • An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1 , 2 or 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
  • substituents for example 1 , 2 or 3 substituents, or 1 to 2 substituents
  • alkynyl refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon- carbon triple bonds.
  • Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Examples alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, 2-heptynyl and its isomers, 2-octynyl and its isomers and the like.
  • An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
  • substituents for example 1 to 4 substituents, or 1 to 2 substituents
  • cycloalkynyl groups may be considered to be a subset of homocyclic rings discussed hereinafter.
  • homocyclic ring is a ring wherein the ring atoms comprise only carbon atoms.
  • Examples of homocyclic rings thus include cycloalkyl, cycloalkenyl and cycloalkynyl, with cycloalkyl and cycloalkenyl being preferred.
  • a ring carbon atom is replaced with a heteroatom, preferably nitrogen, oxygen of sulfur, the heteroatom-containing ring resultant from such a replacement is referred to herein as a heterocyclic ring. More than one carbon atom in a ring may be replaced so forming heterocyclic ring having a plurality of heteroatoms.
  • Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined above for substituted aryl.
  • exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, indolinyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-o
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene) or linked covalently, typically containing 5 to 8 atoms; wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
  • Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-azulenyl, 1- or 2-naphthyl, 1-, 2- or 3-indenyl, 1-, 2- or 9-anthryl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1-, 2-, 3-, 4- or 10-phenanthryl, 1- or 2-pentalenyl, 1 , 2-, 3- or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8- tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, dibenzo[a,d]cylcoheptenyl, 1-, 2-, 3-,
  • the aryl ring can optionally be substituted by one or more aromatic substituents.
  • An "optionally substituted aryl” refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, or 1 to 2 substituents) at any available point of attachment.
  • Non-limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, - SO 2 -NH 2 , aryl, heteroaryl, arylalkyl, haloalkyl, haloalkoxy, alkyloxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO 2 R 15 , alkylthio, carboxy, and the like, wherein R 15 is alkyl or cycloalkyl.
  • arylene as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, pentalenylene, azulenylene and the like.
  • Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthylene, 1 ,4- dihydronaphthylene and the like.
  • heteroaryl ring where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • Non-limiting examples of a heterocyclyl include: pyrrolyl, furanyl (or furyl), thiophenyl (or thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thien
  • heteroaryl can be 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3- pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1-, -2-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3-, -A- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3-
  • an “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted aryl.
  • substituents for example 1 to 4 substituents, or 1 to 2 substituents
  • alkoxy refers to a radical having the Formula -OR wherein R is alkyl.
  • alkoxy is C 1 -C 10 alkoxy or CrC 6 alkoxy.
  • thioalkoxy is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halo.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above.
  • aroyl as used herein denotes a group -C(O)-aryl, wherein aryl is as defined above.
  • cycloalkylalkyl by itself or as part of another substituent refers to a group having one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains.
  • examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.
  • heterocyclyl-alkyl by itself or as part of another substituents refers to a group having one of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to a group -R b -R c wherein R b is alkylene or alkylene substituted by alkyl group and R c is a heterocyclyl group.
  • acyl by itself or as part of another substituent refers to an alkanoyl group having 2 to 6 carbon atoms or a phenylalkanoyl group whose alkanoyl moiety has 1 to 4 carbon atoms, i.e.
  • acyl therefore encompasses the group alkylcarbonyl (-COR 10 ), wherein R 10 is alkyl.
  • acyl is C 2 -C 11 acyl or C 2 -C 7 acyl.
  • Said acyl can be exemplified by acetyl, propionyl, butyryl, valeryl and pivaloyl, benzoyl, phenylacetyl, phenylpropionyl and phenylbutytyl.
  • amino refers to the group -NH 2 .
  • alkylamino by itself or as part of another substituent refers to a group consisting of an amino groups attached to one or two independently selected and optionally substituted alkyl groups, cycloalkyl groups, arylalkyl or cycloalkylalkyl groups i.e., alkyl amino refers to -N(R 8 )(R 9 ) wherein R 8 and R 9 are each independently selected from hydrogen, cycloalkyl, arylalkyl, cycloalkylalkyl or alkyl.
  • aminoalkyl refers to the group -R b -NR d R e wherein R b is alkylene or substituted alkylene, R d is hydrogen or alkyl or substituted alkyl as defined herein, and R e is hydrogen or alkyl as defined herein.
  • alkoxy by itself or as part of another substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group.
  • alkoxy group examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, hexanoxy and the like.
  • alkylthio by itself or as part of another substituent refers to a group consisting of a sulfur atom attached to one optionally substituted alkyl group.
  • alkylthio groups include methylthio (SCH 3 ), ethylthio (SCH 2 CH 3 ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio, and the like.
  • acylamino by itself or as part of another substituent refers to a group consisting of an amino group attached to one or two independently selected acyl groups as described before.
  • these represent imides such as phtalimides, maleimides and the like, and are encompassed in the meaning of the term acylamino.
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo or iodo.
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • Non- limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl and the like.
  • haloalkoxy alone or in combination refers to a group of Formula -O-alkyl wherein the alkyl group is substituted by 1 , 2 or 3 halogen atoms.
  • haloalkoxy includes -OCF 3 and -OCHF 2 .
  • alkylsulfonyl alone or in combination refers to a group of Formula -SO 2 -R Z wherein R z is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl as defined herein.
  • alkylsulfonyl is a group of formula -SO 2 -R Z wherein R z is alkyl.
  • sulfonamide alone or in combination refers to a group of Formula -SO 2 -NRR wherein each R independently is hydrogen or alkyl as defined herein.
  • substituted is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • groups may be optionally substituted, such groups may be substituted with once or more, and preferably once or twice.
  • Substituents may be selected from, for example, the group comprising halo, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
  • alkyl, aryl, or cycloalkyl each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.
  • the term "compounds of the invention” or a similar term is meant to include the compounds of general Formula I or Il and any subgroup thereof. This term also refers to the compounds as depicted in Tables 1 to 9 and their derivatives, ⁇ /-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues.
  • the N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called ⁇ /-oxide.
  • a compound means one compound or more than one compound.
  • L is -CR 9 R 10 - , R 9 and R 10 are each independently selected from hydrogen or alkyl, and heterocyclyl is selected from piperidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl,
  • L is CH 2 .
  • L is - SO 2 -, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , X, Y, Z, r, s, p, q, m have the same meaning as that defined above.
  • R 7 is hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy,
  • R 8 is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , L, X, Y, Z, r, s, p, q, m have the same meaning as that defined above.
  • R 8 is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino,
  • R 7 and R 8 are fused together and form an alkylene or alkyleneaminoalkylene optionally substituted with one or more substituent selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , L, X, Y, Z, r, s, p, q, m have the same meaning as that defined above.
  • some preferred compounds of Formula Il or V are compounds having one of the structural Formula V1 , V2, V3, V4:
  • R 3 , R 4 , R 5 , R 11 , R 12 , L and A have the same meaning as that defined above.
  • some preferred compounds of Formula II, V, V1 , V2, V3, V4 are compounds of Formula:
  • R 4 , R 5 , R 11 , R 12 have the same meaning as that defined above.
  • R 7 is preferably hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl
  • compounds of Formula I have structural Formula III or IV,
  • R 13 and R 14 are each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, alkoxy, amino, aminoalkyl, alkylaminoalkyl, preferably R 13 and R 14 are each independently selected from hydrogen or alkyl,
  • R 15 and R 16 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl, preferably R 15 and R 16 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,
  • R 17 is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cycloalkyl, heterocyclyl, preferably, R 17 is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl,
  • X and Z are each independently selected from -C(R 18 )R 19 - or -NR 18 -, wherein R 18 is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, and R 19 is selected from hydrogen or alkyl,
  • R 2 is selected from hydrogen or alkyl, said alkyl being optionally substituted with one or more substituents selected from amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, heterocyclyl, alkoxy, cycloalkyl,
  • R 4 is selected from hydrogen, alkyl, alkoxy, cyano, nitro, halogen,
  • R 5 is selected from hydrogen .
  • some preferred compounds of Formula II, V, V1 , V2, V3, V4 are compounds of Formula:
  • R 4 , R 5 are each independently hydrogen and R 11 is hydrogen or alkyl
  • R 12 is hydrogen or a group selected from alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroarylarylalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituent selected from halo, oxo, hydroxyl, nitro, cyano, alkyl, alkoxy, amino, alkylamino, haloalkyl, haloalkoxy, alkenylaminooxy.
  • some preferred compounds of Formula II, V, V1 , V2, V3, V4, are compounds of Formula V5, V6, V7, V8, V9, V10, V1 1 , V12, wherein aryl is phenyl or naphthyl, wherein heterocyclyl is selected from piperazinyl, piperidinyl, pyrrolidinyl, diazepanyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, indolinyl, dioxolanyl, and wherein heteroaryl is selected from indolyl, benzoxazolyl, furanyl, thiazolyl, piridinyl, thienyl, pyrazolyl, or imidazolyl.
  • some preferred compounds of Formula III or IV are compounds of Formula:
  • 1111 IV1 r is an integer selected from 1 or 2
  • p is an integer selected from 0, 1 or 2
  • m is an integer selected from 0 or 1 ,
  • R 13 and R 14 are each independently selected from hydrogen or alkyl
  • R 15 and R 16 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl
  • R 17 is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl,
  • X and Z are each independently selected from -C(R 18 )R 19 - or -NR 18 -, wherein R 18 is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, and R 19 is selected from hydrogen or alkyl,
  • R 4 is selected from hydrogen or halogen
  • L 1 is -CR 9 R 10 -, wherein R 9 and R 10 are each independently selected from hydrogen or CH 3 .
  • L is CH 2 .
  • the compounds of the invention may be in the form of pharmaceutically and/or veterinary acceptable salts, as generally described below.
  • suitable pharmaceutically acceptable organic and/or inorganic acids are as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the prior art referred to below).
  • pro-drug means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug.
  • the reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated.
  • Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component.
  • pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference.
  • Pro-drugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo.
  • pre-drug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre-drug reaches the area of the body where administration of the drug is indicated.
  • the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
  • the compounds of Formula I or Il may be prepared as described in the experimental section below using methods and chemistries with which those skilled in the art shall be familiar.
  • Suitable protective groups as well as methods and conditions for inserting them and removing them, will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, "Protective groups in organic synthesis", 3 rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety. It will also be clear to the skilled person that compounds of the invention in which one or more functional groups have been protected with suitable functional groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention.
  • the compounds of the invention can be prepared from aldehyde (such as, but not limited to isoquinoline-5-carbaldehyde) or carboxylic acid-containing intermediates 1 to 8 described hereinafter which may be reacted with complementary reactive molecules so as to form the desired compound.
  • aldehyde such as, but not limited to isoquinoline-5-carbaldehyde
  • carboxylic acid-containing intermediates 1 to 8 described hereinafter which may be reacted with complementary reactive molecules so as to form the desired compound.
  • the intermediates and complementary reactive molecules are either commercially available or may be easily prepared by the skilled person.
  • the compounds of the invention may be used for the inhibition of kinases in vitro or in vivo, preferably in vitro, for modulating biological pathways and/or processes in which such kinases are involved; and/or to prevent and/or treat diseases or disorders in which such kinases, pathways and/or processes are involved.
  • the compounds of the invention may be used to inhibit (at least one isoform of) ROCK; and as such may be used for any purposes known per se for inhibitors of ROCK.
  • the present invention also relates to the use of the compounds of Formula I or Il above in (the preparation of a composition for) inhibiting at least one kinase, in particular for inhibiting at least one isoform of ROCK, more in particular for inhibiting ROCK I and/or ROCK Il isoforms.
  • ROCKI can also be referred as ROK- ⁇ , p160ROCK, or Rho-kinase ⁇
  • ROCKM can also be referred as ROK- ⁇ or Rho-kinase ⁇ .
  • Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above.
  • the present invention also relates to a compound of Formula I or II, for use in the prevention and/or treatment of at least one disease and/or disorder selected from the group comprising eye diseases; erectile dysfunction; cardiovascular diseases; vascular diseases; inflammatory diseases; proliferative diseases; neurological diseases and disease of the central nervous system (CNS); bronchial asthma; osteoporosis; renal diseases; and AIDS.
  • at least one disease and/or disorder selected from the group comprising eye diseases; erectile dysfunction; cardiovascular diseases; vascular diseases; inflammatory diseases; proliferative diseases; neurological diseases and disease of the central nervous system (CNS); bronchial asthma; osteoporosis; renal diseases; and AIDS.
  • ROCK-mediated condition or “disease”, as used herein, means any disease or other deleterious condition in which is known to play a role.
  • ROCK-mediated condition or “disease” also means those diseases or conditions that are alleviated by treatment with a ROCK inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which ROCK is known to play a role.
  • the compounds of the invention are preferably used in the prevention and/or treatment of at least one disease or disorder, preferably in which at least one isoform of ROCK is involved.
  • the compounds of the invention may be used in the prevention and/or treatment of at least one disease or disorder in which the ROCK I or ROCK Il is involved, such as, such as inflammatory diseases, chronic obstructive bladder disease (COBD) and the related erectile dysfunction as well as in diabetes related ED.
  • COBD chronic obstructive bladder disease
  • the present invention relates to the use of a compound according to the invention for the preparation of a medicament for treating or lessening the severity of a disease or condition selected from eye disease or disorder (such as but not limited to retinopathy, glaucoma and degenerative retinal diseases such as macular degeneration and retinitis pigmentosa), kidney disease (such as but not limited to renal dysfunction), and bladder dysfunction (such as but not limited to chronic obstructive bladder disease), erectile dysfunction (such as but not limited to bladder disease related erectile dysfunction and diabetes related erectile dysfunction) neurological and CNS (brain) disease or disorder (such as but not limited to Alzheimer, meningitis, convulsions), hypertension, lung disease (such as but not limited to asthma, fibrosis, pneumonia, cystic fibrosis, respiratory distress syndrome), premature birth, cancer (such as but not limited to cancer of the brain (gliomas), breast, colon, head and neck, prostate, kidney, lung, intestine, nerve, skin, pancreas,
  • the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as:
  • Cardiovascular and vascular diseases including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, (pulmonary) hypertension, pulmonary vasoconstriction, arteriosclerosis, thrombosis (including deep thrombosis) and platelet related diseases.
  • Neurological and CNS disorders including but not limited to stroke, multiple sclerosis, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ' s disease, MS and neuropathic pain.
  • the present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders.
  • cancer including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate, or thyroid; leukemia; sarcoma; lymphoma; and melanoma.
  • Inflammatory diseases including but not limited to contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis.
  • the compound may be used in (the preparation of a medicament for ) the prevention and/or treatment of Inflammatory diseases selected from contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
  • the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as erectile dysfunction; bronchial asthma; osteoporosis; renal diseases; AIDS; eye diseases such as glaucoma, macular degeneration and retinopathy, .
  • the compound may be used in the prevention and/or treatment of glaucoma and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.
  • the present invention therefore relates to a method of treating or lessening the severity of a disease or condition selected from cardiovascular and vascular diseases: including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, pulmonary vasoconstriction, restenosis, hypertension, (pulmonary) hypertension, arteriosclerosis, thrombosis (including deep thrombosis) and platelet related diseases; neurological and CNS disorders: including but not limited to stroke, multiple sclerosis, spinal or brain cord injury, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ' s disease, MS and neuropathic pain; proliferative diseases such as cancer including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate or thyroid cancer; leukemia; sarcoma; lymphoma; melanom
  • the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester.
  • a pharmaceutically acceptable acid-addition and/or base-addition salt e.g. obtained with non-toxic organic or inorganic acid or base
  • solvate includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.
  • suitable inorganic solvent e.g. hydrates
  • organic solvent such as but not limited to alcohols, ketones, esters and the like.
  • the pharmaceutically acceptable salts of the compounds according to the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6,372,778,
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propy
  • the formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • cyclodextrins are o, ⁇ - or ⁇ -cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g.
  • ⁇ -CD randomly methylated ⁇ -CD
  • hydroxyalkyl particularly hydroxyethyl, hydroxypropyl or hydroxybutyl
  • carboxyalkyl particularly carboxymethyl or carboxyethyl
  • alkylcarbonyl particularly acetyl
  • alkoxycarbonylalkyl or carboxyalkoxyalkyl particularly carboxymethoxypropyl or carboxyethoxypropyl
  • alkylcarbonyloxyalkyl particularly 2-acetyloxypropyl.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6-dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2- hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD (2-HP- ⁇ -CD).
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
  • the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.
  • the present invention also encompasses cyclodextrin complexes consisting of a compound according to the invention and a cyclodextrin.
  • compositions, formulations (and carriers, excipients, diluents, etc. for use therein), routes of administration etc. which are known per se for analogous pyridinocarboxamides, such as those described in US-A-4,997,834 and EP-A-O 370 498.
  • the compounds of the invention may be used locally or systemically.
  • the compounds may advantageously be used in the form of a spray, ointment or transdermal patch or another suitable form for topical, transdermal and/or intradermal administration; and for systemic administration, the compounds of the invention may advantageously be administered orally.
  • solutions, gels, tablets and the like are often prepared using a physiological saline solution, gel or excipient as a major vehicle.
  • Ophthalmic formulations should preferably be prepared at a comfortable pH with an appropriate buffer system.
  • the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
  • a solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • a solid solution When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution".
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
  • the term "a solid dispersion” also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
  • the water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 2O 0 C solution.
  • Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC.
  • HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble.
  • Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule.
  • Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
  • Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal- coating polymer layer.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • the preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • a manner known per se which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred.
  • the at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of the Formula I or Il above that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • the invention relates to a composition, and in particular a composition for pharmaceutical use, that contains at least one compound of the invention (i.e. a compound that has been identified, discovered and/or developed using a nematode or method as described herein) and at least one suitable carrier (i.e. a carrier suitable for pharmaceutical use).
  • the invention also relates to the use of a compound of the invention in the preparation of such a composition.
  • said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation can be carried out both as dry and as moist granules.
  • suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • the compound according to the invention for subcutaneous or intravenous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion.
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these formulations When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compositions are of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. - enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal.
  • the invention relates to a composition for veterinary use that contains at least one compound of the invention (e.g. a compound that has been identified, discovered and/or developed using a nematode or method as described herein) and at least one suitable carrier (i.e. a carrier suitable for veterinary use).
  • a suitable carrier i.e. a carrier suitable for veterinary use.
  • the invention also relates to the use of a compound of the invention in the preparation of such a composition.
  • Mass spectrometer Micromass Platform LC. Ionization: electrospray (polarity: negative and positive). Unless indicated otherwise, purification by preparative HPLC, was performed on a Shimadzu SCL- 10A (UV detection at 215 and 254 nm, detector SPD-10A) using C-18 column (Nucleosil, 100A, 100 ⁇ m, 20 x 200 mm) and different gradients (water, acetonitrile, formic acid).
  • Chiral HPLC (analytical and preparative) was performed on a Shimadzu SCL-10A (UV detection at 215 and 254 nm, detector SPD-10A) using different column such as Chiralcel OD-H (tris-3,5- dimethylphenylcarbamate, 46 x 250 or 100 x 250 mm, 5 ⁇ m), Chiralcel OJ (tris-methylbenzoate, 46 x 250 or 100 x 250 mm, 5 ⁇ m), Chiralpak AD (tris-3,5-dimethylphenylcarbamate, 46 x 250 mm, 10 ⁇ m) and Chiralpak AS (tris-(S)-i-phenylethylcarbamate, 46 x 250 mm, 10 ⁇ m) from Chiral Technologies Europe (lllkirch, France):
  • Eluent mixture of solvent such as ethanol, 1-propanol, 2-propanol, methanol, butanol, pentane, hexane, heptane, cyclohexane, diisopropylethyamine, triethylamine.
  • the Cahn-lngold-Prelog system was used to attribute the absolute configuration of chiral center, in which the four groups on an asymmetric carbon are ranked to a set of sequences rules. Reference is made to Cahn; Ingold; Prelog Angew. Chem. Int. Ed. Engl. 1966, 5, 385-415.
  • the methyl ester (1.0 g) was dissolved in a mixture of MeOH (20 ml) and water (20 ml). Lithium hydroxide hydrate (5 eq.) was added and the reaction mixture was stirred at 6O 0 C for 30 minutes and then, was concentrated. The resulting solution, was diluted with aqueous citric acid solution (pH 5, 50 ml) and then slowly acidified to pH 4-5 with 2N hydrochloric acid. The compound was extracted with DCM (250 ml). The organic layer was dried over magnesium sulfate, filtered off and evaporated. The title compound was obtained as a white powder (72 % yield) and was used without further purification (mp: 119-121 0 C).
  • tert-butoxycarbonylamino group a mixture of DCM and trifluoroacetic acid (1 / 1 ; 100 ⁇ l) was added to the residue. The solution was stirred at RT for 2 hours, and then evaporated under reduced pressure. Compounds were used without further purification.
  • Protocol C To a solution of the corresponding carboxylic acid (1 eq) in DMF (0.25 M) with DIEA (3 eq) was added TBTU (1.3 eq) and HOBt (0.3 eq). The reaction mixture was stirred at RT for 3 to 10 minutes and the corresponding amine (1 eq) was added. The reaction mixture was stirred at RT for 3 hours to 3 days. The solvent was evaporated. The residue was partitioned between EtOAc and 2N Na 2 CO 3 (or 1 N NaOH). The product was extracted with EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated.
  • the inhibition assays were performed with a fluorescence polarization (FP) assay using the commercially available ROCK IMAP Kit from Molecular Devices (Product ID. No. R8093), essentially in accordance with the protocol supplied by the manufacturer.
  • the S6 ribosomal protein- derived substrate used was (FI)-AKRRRLSSLRA, also obtained from Molecular Devices (Product ID No. R7184).
  • the enzyme mix ROCK ⁇ /ROCKII was obtained from Upstate Biotechnology (Product ID No 14-451 ).
  • the mixture thus obtained (total volume: 17 ⁇ l) was incubated for 60 minutes at RT, upon which the fluorescence polarization was measured using an automated plate reader (Perkin Elmer, Model Envision 2100-0010 HTS) with FP filters: excitation filter FITC FP 480 and emission filters FITC FP P-pol 535 and FITC FP S-pol 535 (Perkin-Elmer).
  • the results were fitted to a curve using the XL-Fit algorithm and IC50 values were calculated for each fitted curve, again using the XL-Fit algorithm.
  • the IC 50 value for the reference compound was 0.4 ⁇ M.
  • exemplary compounds of the invention are set out in tabulated form.
  • the name of the compound, an arbitrarily assigned compound number and structural information are set out.
  • the protocol by which the compounds were made is provided and the IC 50 value obtained (in accordance with the protocol set forth above) is represented as follows: "+++” means IC 50 below 0.1 ⁇ M; "++” means IC 50 between 0.1 and 1 ⁇ M; "+” means IC 50 between 1 and 50 ⁇ M.
  • Table 2 shows the results for compounds of Formula V5 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined”
  • Pr means "protocol”.
  • Compounds of Formula V5 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 1 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • Table 3 shows the results for compounds of Formula V7 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined” and Pr means “protocol”.
  • Compounds of Formula V7 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 2 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • Table 4 shows the results for compounds of Formula V6 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined”
  • Pr means "protocol”.
  • Compounds of Formula V6 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 3 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • Table 5 shows the results for compounds of Formula V8 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined” and Pr means “protocol”.
  • Compounds of Formula V8 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 4 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • Table 6 shows the results for compounds of Formula V9 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined”
  • Pr means "protocol”.
  • Compounds of Formula V9 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 5 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • Table 7 shows the results for compounds of Formula V11 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined” and Pr means “protocol”.
  • Compounds of Formula V11 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 6 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • Table 8 shows the results for compounds of Formula V10 wherein R 4 and R 5 are each independently hydrogen.
  • ND means “not determined”
  • Pr means "protocol”.
  • Compounds of Formula V10 wherein R 4 and R 5 are each independently hydrogen were prepared starting from Intermediate 7 and from the corresponding amine HNR 11 R 12 following the general protocol B or C.
  • the present invention encompasses compounds 1 to 431 and stereoisomers, tautomers, racemics or a pharmaceutically acceptable salt and/or solvate thereof.

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Abstract

La présente invention concerne de nouveaux inhibiteurs des kinases de la famille AGC, en particulier des composés de formule (I) ou (II), ou un stéréoisomère, un tautomère, un racémique, un métabolite, un pro ou pré-médicament, un sel, un hydrate ou un solvate de ceux-ci, dans lesquelles R1, R2, R4, R5, R7, R8, q s, L et Y ont le sens défini dans les revendications. La présente invention concerne en particulier des inhibiteurs de la ROCK, des compositions, en particulier des produits pharmaceutiques, comprenant de tels inhibiteurs et des utilisations de tels inhibiteurs pour le traitement et la prophylaxie de maladies.
PCT/EP2007/061542 2006-10-26 2007-10-26 Inhibiteurs de kinase Ceased WO2008049919A2 (fr)

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US7470787B2 (en) 2005-07-11 2008-12-30 Aerie Pharmaceuticals, Inc. Isoquinoline compounds
EP2009004A4 (fr) * 2006-04-18 2010-08-25 Japan Tobacco Inc Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
WO2011057784A1 (fr) * 2009-11-11 2011-05-19 Sygnis Bioscience Gmbh & Co. Kg Composés pour l'inhibition de la kinase pim et pour le traitement de malignité
WO2012146724A3 (fr) * 2011-04-29 2013-01-17 Amakem Nv Nouveaux inhibiteurs de rock
US8357699B2 (en) 2007-01-10 2013-01-22 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US8394826B2 (en) 2009-05-01 2013-03-12 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US8450344B2 (en) 2008-07-25 2013-05-28 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US8455514B2 (en) 2008-01-17 2013-06-04 Aerie Pharmaceuticals, Inc. 6-and 7-amino isoquinoline compounds and methods for making and using the same
EP2699546A4 (fr) * 2011-04-18 2014-09-24 Commw Scient Ind Res Org Procédé de capture de gaz
CN104254330A (zh) * 2012-01-09 2014-12-31 X-Rx公司 具有激酶抑制活性的tryptoline衍生物及其用途
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CN108084149A (zh) * 2017-12-31 2018-05-29 佛山市赛维斯医药科技有限公司 含异丙基萘和丙二醇噻吩酰胺类化合物、制备方法及其用途
WO2020047229A1 (fr) 2018-08-29 2020-03-05 University Of Massachusetts Inhibition de protéines kinases pour traiter la maladie de friedreich
US12281308B2 (en) 2018-08-29 2025-04-22 University Of Massachusetts Inhibition of protein kinases to treat Friedreich ataxia
US11427563B2 (en) 2018-09-14 2022-08-30 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
US11891376B2 (en) 2018-09-14 2024-02-06 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds

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