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WO2005085252A1 - Composes de 1,2-a' pyrazine imidazo interagissant avec les proteines kinases - Google Patents

Composes de 1,2-a' pyrazine imidazo interagissant avec les proteines kinases Download PDF

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Publication number
WO2005085252A1
WO2005085252A1 PCT/GB2005/000842 GB2005000842W WO2005085252A1 WO 2005085252 A1 WO2005085252 A1 WO 2005085252A1 GB 2005000842 W GB2005000842 W GB 2005000842W WO 2005085252 A1 WO2005085252 A1 WO 2005085252A1
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optionally substituted
alkyl
aryl
alkoxy
hydroxy
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PCT/GB2005/000842
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English (en)
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Veronique Birault
Clifford John Harris
Stephen Anthony Harrison
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Biofocus Discovery Limited
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Priority claimed from GB0404889A external-priority patent/GB0404889D0/en
Priority claimed from GB0426259A external-priority patent/GB0426259D0/en
Application filed by Biofocus Discovery Limited filed Critical Biofocus Discovery Limited
Publication of WO2005085252A1 publication Critical patent/WO2005085252A1/fr

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    • 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
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in the inhibition of protein kinases, in particular serine/threonine kinases, more particularly mitogen activated protein kinase, more particularly the c-Jun NH2-teminal kinases (JNKs).
  • the invention also relates to the compounds for use in medicine and particularly in the prevention and/or treatment of a wide variety of diseases including inflammatory disorders, cancer, angiogenesis, diabetes, metabolic disease and neurological disorders.
  • JNK is known to be a c-Jun NH2-terminal kinase.
  • c-Jun N terminal kinases are intracellular stress activated signaling molecules.
  • the JNK family of serine- threonine kinases are derived from three distinct genes, jnkl, jnk2 and jnk3.
  • JNK belong to the family of stress-activated protein kinases that also include p38 protein kinase.
  • JNKs are regulated by a wide variety of cellular stresses, growth factors and pro-inflammatory cytokines (TNF ⁇ , IL-l ⁇ ), and have been implicated in the regulation of diverse biological processes such as immune response and apoptosis.
  • Down-stream substrates of JNKs include the transcription factors c-jun (crucial for API transcriptional activity), ATF-2, Elkl, p53 and the cell death domain protein (DENN) [Proc. Natl. Acad. Sci. USA,95, 2586-91 (1998)]. These factors regulate the expression of a variety of genes including inflammatory cytokines, MMPs, integrins and regulators of apoptosis, therefore are commonly associated with a number of human diseases. The potential of JNK inhibitors has therefore attracted considerable interest and evidence suggests that JNKs inhibitors would be useful in the treatment of inflammatory, vascular, neurodegenerative, metabolic, immunological and oncological human diseases [Nature Review Drug Discovery, 2, 554-565 (2003]. For example, JNK inhibitors may be useful in the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma, learning, memory and attention disorders, anxiety and panic disorders.
  • neurological disorders such as stroke, is
  • JNK inhibitors may also be useful in the treatment of inflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis.
  • inflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, septic shock and bronchitis.
  • JNK inhibitors may also be useful in the treatment of cardiovascular diseases, including stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure.
  • JNK inhibitors may also be useful in the treatment of metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
  • JNK antagonists may also be useful in the oncology area, in particular for the treatment of solid tumours (including breast, colorectal and pancreatic cancer), small cell lung cancer, ovarian cancer and prostate cancer.
  • Inhibitors of JNK activity have also been associated with opthalmic conditions including retinopathies and also macular degeneration.
  • JNK inhibitors may be useful in the treatment of a variety of diseases the development of non-peptide JNK inhibitors with good activity, selectivity and pharmacokinetic profiles is needed to fully exploit the clinical potential of this target.
  • the present invention provides a class of compounds which interact selectively with the JNK kinase.
  • a library designed to aid in the identification of kinase inhibitors comprising 6- aryl-imidazo[l,2-a]pyrazine-8-yl-amine analogues, has been disclosed (IBC conference 7 March 2002 - John Harris).
  • WO 02/060492 describes some compounds based on either a 2-amino-6-carba-disubstituted pyrazine scaffold or a 2-amino-6-carba-disubstituted pyridine scaffold, as JAK inhibitors for the treatment of immune disorders.
  • WO03/089434 describes certain imidazo[l,2- a]pyrazine-8-yl-amines as modulators of protein kinase.
  • the present invention relates to a selected class of compounds which interact selectively with the JNK kinase.
  • the above referenced prior art does not disclose the selected class of compounds of the present invention, nor compounds which interact selectively with the JNK kinase.
  • the invention provides a compound of formula I: x
  • X is -NHR6, -NR6R7 or -OR6;
  • R6 and R7 which may be the same or different are hydrogen, - heteroaryl-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 5 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 , and NO 2 , or heteroaryloxy-C ⁇ .
  • 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, Ci.
  • heteroarylamino-Ci-e-alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 - hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl , heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 and NO 2 , or aryl-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methyl
  • O-CF 3 amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocyclyl which is optionally substituted, heterocyclyl-Cl-6-alkyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 and NO 2 , or aryloxy-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocycl
  • 6 -alkylamino carboxy, CO 2 Me, SONH 2 and NO 2 , or aryl optionally independently substituted with one or more of C ⁇ - 6 - alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino- methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 -hydroxyalkyl, halogen, halo C ⁇ .
  • z is -NC(O)-, -C(O)N-, -NS(O) 2 -, S(O) 2 N-, -NC(O)N-, -NC(O)O- or -OC(O)N-, preferably wherein the third substituent on each N atom is H;
  • n 0 or 1
  • R3 is: - heteroaryl-C ⁇ . 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O- CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 - alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo C ⁇ - 6 -alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ - 6 -carboxyalkenyl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, d-e-alkyl, C
  • CF 3 amino-methyl, amino, C ⁇ . 6 -aminoalkyl, dimethylamino, C ⁇ _ 6 - alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyaIkyl, C ⁇ - 6 -alkenyl, halogen and halo C ⁇ - 6 -alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ .
  • R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ _ 6 -alkyl, C ⁇ - 6 -alkoxy, aryl, heteroaryl and C ⁇ - 6 -hydroxyalkyl; or heteroaryl optionally independently substituted with one or more of Ci- 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-alkyl, C ⁇ _ 6 -carboxyalkyl, C ⁇ _ 6 -carboxyalkyl, C ⁇ _ 6 -carboxyalkyl, C ⁇ _ 6 -carboxyalkyl,
  • 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ - 6 -carboxyalkenyl, CONR4R5, CO 2 H,
  • R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ - 6 -alkyl, C ⁇ . 6 -alkoxy, aryl, heteroaryl, C ⁇ _ 6 -hydroxyalkyl; or aryloxy-C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ _ 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, Ci- 6 -alkylamino, di-Ci- 6 -alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-alkyl, Ci.
  • R4 and R5 may be the same or different and are selected from hydrogen, Ci-e-alkyl, C ⁇ _ e-alkoxy, aryl, heteroaryl, C ⁇ - 6 -hydroxyalkyl; or aryl optionally independently substituted with one or more of C ⁇ - 6 - alkoxy, Ci-e-alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino- methyl, amino, C ⁇ - 6 -aminoalkyl, dimethylamino, C ⁇ - 6 -alkylamino, di-C ⁇ - 6 - alkylamino, hydroxy, C ⁇ - 6 -hydroxyalkyl, C ⁇ - 6 -alkenyl, halogen and halo Ci-e-
  • C ⁇ - 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ _ 6 -alkenyl, aryl, heteroaryl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ . 6 -alkyl, C ⁇ - 6 - alkoxy, aryl, heteroaryl and C ⁇ - 6 -hydroxyalkyl; or
  • C 3 . 8 -cycloalkyl optionally independently substituted with one or more of Ci-e-alkoxy, C ⁇ - 6 -alkenyl, aryl, heteroaryl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different and are selected from hydrogen, C ⁇ . 6 -alkyl, C ⁇ - 6 - alkoxy, aryl, heteroaryl and C ⁇ .
  • R6 and R7 are not both hydrogen.
  • R4 and R5 are not both hydrogen.
  • R 5 and R 4 are not both hydrogen.
  • R7 is hydrogen and preferably R6 is heteroaryl-Ci- 6 -alkyl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, Ci-6-aminoalkyl, hydroxy, Ci- 6 -hydroxyalkyl, halogen, halo C ⁇ - 6 -alkyl, heterocyclyl which is optionally substituted, CN, dimethylamino, C ⁇ - 6 - alkylamino, di-C ⁇ - 6 -alkylamino, carboxy, CO 2 Me, SONH 2 , heterocyclyl which is optionally substituted and heterocyclyl-Cl-6-alkyl which is optionally substituted.
  • R6 is pyridyl-alkyl which is optionally substituted, more preferably pyridin-3-ylmethyl or pyridine-3-ylethyl, and preferably R7 is hydrogen.
  • R6 and R7 which may be the same or different are selected from the following:
  • R3 is aryl or heteroaryl optionally independently substituted with one or more of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, methylenedioxy, aryl, trifluoromethyl, O-CF 3 , amino-methyl, amino, C ⁇ - 6 -aminoalkyl, hydroxy, C ⁇ - 6 - hydroxyalkyl, C ⁇ _ 6 -alkenyl, halogen and halo C ⁇ - 6 -alkyl, C ⁇ - 6 -carboxyalkyl, C ⁇ - 6 - carboxyalkenyl, CONR4R5, CO 2 H, NHCOR4, NHS(O) 2 R4, NC(O)NR4R5, NC(O)OR4 where R4 and R5 may be the same or different are either hydrogen, C ⁇ - 6 -alkyl, C ⁇ . 6 -alkoxy, aryl, heteroaryl, Ci- 6 -hydroxyalkyl;
  • R3 is phenyl, furan, phenylmethanol; hydroxymethyl-phenyl, optionally being 4- hydroxymethyl-phenyl or 3-hydroxymethyl-phenyl; or aminomethyl-phenyl optionally being 4-aminomethyl-phenyl.
  • the present invention provides a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier.
  • the invention provides a process for the preparation of a compound of formula I as mentioned above.
  • the invention provides a method for the prophylaxis or treatment of a JNK receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
  • the present invention provides a method for modulating JNK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I or a pharmaceutical formulation comprising a compound of formula I.
  • the present invention provides a compound of formula I for use in therapy, especially for use in the prophylaxis or treatment of a JNK receptor- related disorder.
  • the present invention provides the use of a compound of formula I for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor-related disorder.
  • X is:
  • the invention provides a compound of formula II:
  • R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, heteroarylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, or heteroarylalkynyl which is optionally substituted, alkyl, cycloalkyl; and
  • n 0 or 1;
  • R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, C ⁇ -C 6 alkyl which is optionally substituted, C 2 -C 6 alkenyl which is optionally substituted, C 2 -C 6 alkynyl which is optionally substituted or C 3 -C 8 cycloalkyl which is optionally substituted; and
  • R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted;
  • Rl and R2 are not both hydrogen.
  • R 5 and R 4 are not both hydrogen.
  • Rl is in the 3 or 4 position.
  • R2 is hydrogen, alkyl which is optionally substituted, alkoxy which is optionally substituted, aryloxy which is optionally substituted, halogen, hydroxy, CN, CO 2 H, NR 5 R 4 , CO 2 R 5 , CONR 5 R 4 , NR 5 (CO)R 4 , or S(O) p R 5 ; wherein R 5 and R 4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted and arylalkyl which is optionally substituted.
  • R2 is hydrogen
  • Rl is hydroxy or NR 5 R 4 where R 5 is hydrogen and R 4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted.
  • R3 is aryl which is optionally substituted or heteroaryl which is optionally substituted.
  • Z is -NC(O)-, -C(O)N-, -NS(O) 2 -, -S(O) 2 N-, -NC(O)N-, - NC(O)O- or -OC(O)N- and R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, C ⁇ -C 6 alkyl which is optionally substituted, C 2 -C 6 alkenyl which is optionally substituted, C 2 -C 6 alkynyl which is optionally substituted or C 3 -C 8 cycloalkyl which is optionally substituted.
  • R2 is hydrogen;
  • Rl is hydroxy or NR 5 R 4 where R 5 is an hydrogen and R 4 is alkyl which is optionally substituted, aryl which is optionally substituted, heteroarylalkyl which is optionally substituted or arylalkyl which is optionally substituted; and
  • R3 is aryl which is optionally substituted, heteroaryl which is optionally substituted, arylalkyl which is optionally substituted, heteroarylalkyl which is optionally substituted, arylalkenyl which is optionally substituted, arylalkynyl which is optionally substituted, C ⁇ -C 6 alkyl which is optionally substituted, C 2 -C 6 alkenyl which is optionally substituted, C 2 -C 6 alkynyl which is optionally substituted or C 3 -C 8 cycloalkyl which is optionally substituted.
  • R3 is selected from 4- hydroxymethyl-phenyl, 4-aminomethyl-phenyl and 3-hydroxymethyl-phenyl and perferably, Z is 0.
  • M is 2, R2 is H and Rl is 4-hydroxy.
  • the present invention provides a pharmaceutical formulation comprising a compound of formula II and a pharmaceutically acceptable diluent or carrier.
  • the invention provides a process for the preparation of a compound of formula II as mentioned above.
  • the invention provides a method for the prophylaxis or treatment of a JNK receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula II as mentioned above.
  • the present invention provides a method for modulating JNK receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula II or a pharmaceutical formulation comprising a compound of formula II.
  • the present invention provides a compound of formula II for use in therapy, especially for use in the prophylaxis or treatment of a JNK receptor-related disorder.
  • the present invention provides the use of a compound of formula II for the manufacture of a medicament for use in the prophylaxis or treatment of a JNK receptor-related disorder.
  • the compounds of formula I or II may be agonists, partial agonists or antagonists for the JNK receptor.
  • JNK receptor-related disorders are inflammatory and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis, transplant rejection, sceptic shock and bronchitis; cancer, in particular solid tumours, (including breast, colorectal and pancreatic cancer) small cell lung cancer, ovarian cancer and prostate cancer; vardiovascular diseases, including stroke, atherosclerosis, myocardial reperfusion injury, myocardial infarction and cardiac failure; angiogenesis; neurological disorders, such as stroke, ischaemia, head injury, Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injury, head trauma and also learning, memory and attention disorders, anxiety and panic disorders; opthalmic conditions including retinopathies and also macular degeneration and metabolic diseases such as diabetes, insulin resistance, obesity and metabolic syndrome.
  • inflammatory and autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoria
  • the compounds of the invention may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • optical isomers e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • the separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
  • the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein.
  • the compounds of the invention above may be prepared by, or in analogy with, conventional methods.
  • a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.
  • the necessary starting materials for preparing the compounds of the invention are either known or may be prepared in analogy with the preparation of known compounds.
  • alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms (“C ⁇ _ 6 - alkyl”).
  • alkyl examples include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C ⁇ - 6 -alkyl For parts of the range "C ⁇ - 6 -alkyl" all subgroups thereof are contemplated such as C ⁇ - 5 -alkyl, C ⁇ -alkyl, C ⁇ - 3 -alkyl, C ⁇ - 2 -alkyl, C 2 . 6 -alkyl, C 2 . 5 -alkyl, C 2 . 4 -alkyl, C 2 . 3 -alkyl, C 3 . 6 -alkyl, C 4 . 5 -alkyl, etc.
  • "Halo ⁇ C ⁇ - 6 -alkyl” means a C ⁇ - 6 -alkyl group substituted with one or more halogen atoms.
  • aryI-C ⁇ - 6 -alkyl means a C ⁇ - 6 -alkyl group substituted with one or more aryl groups.
  • cycloalkyl denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms.
  • examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl.
  • C 3 _ 8 - cycloalkyl all subgroups thereof are contemplated such as C 3 . 7 -cycloalkyl, C 3 . 6 -cycloalkyl, C 3 .
  • alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • C ⁇ - 6 -alkoxy all subgroups thereof are contemplated such as C ⁇ - 5 -alkoxy, C ⁇ - 4 -alkoxy, C ⁇ - 3 -alkoxy, C ⁇ - 2 -alkoxy, C 2 .
  • alkenyl means a straight chain or branched alkenyl radical of 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds and includes but is not limited to ethylene, ⁇ -propyl-1-ene, ⁇ -propyl-2-ene, isopropylene, etc.
  • alkynyl means a straight chain or branched alkynyl radical of 2 to 6 carbon atoms and containing one or more carbon-carbon triple bonds and includes but is not limited to ethynyl, 2-methylethynyl etc.
  • aryl refers to a 3- 10 membered hydrocarbon ring system having at least one aromatic ring or being fused to one or more saturated or unsaturated rings including, but not limited to phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl.
  • the aryl rings may optionally be substituted with C ⁇ - 6 -alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl.
  • aryloxy refers to an aryl group bonded to an oxygen atom.
  • heteroaryl refers to a 3-10 membered hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, indolyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl groups.
  • heterocyclyl means a 3-10 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl.
  • the heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl.
  • carbocyclyl or heterocyclyl groups include but are not limited to cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxa
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • substituted shall mean that one atom or group of atoms in a molecule is replaced by another atom or group and where optional substituents are referred to, but are not specified, suitable substituents include alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, hydroxy, NO 2 , CN, C ⁇ - 6 -alkyl-CN, aryl, acetyl, 1, 2, 4-oxadiazoiylmethyl, CHO, NR 3 R 4 , CO 2 R 3 , CONR 3 R 4 , NR 3 (CO) R 4 , S(O) p R 3 ; wherein R 3 and R 4 may be the same or different and are selected from hydrogen, alkyl which is optionally substituted, hydroxyalkyl which is optionally substituted, alkoxy which is optionally substituted, aryl which is optionally substituted,
  • leaving group refers to a group to be displaced from a molecule during a nucleophilic displacement reaction.
  • leaving groups are bromide, chloride and methanesulfonate, especially bromide and methanesulfonate.
  • “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • Treatment includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.
  • “An effective amount” refers to an amount of a compound that confers a therapeutic effect on the treated subject.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • prodrug forms means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug.
  • pharmacologically acceptable derivative such as an ester or an amide
  • ACN means acetonitrile
  • DEA diethylamine
  • DEPT distortion enhancement polarisation transfer
  • DMSO means dimethyl sulfoxide
  • ELS electron light scattering
  • HPLC means high performance liquid chromatography
  • Rt means retention time
  • TFA trifluoroacetic acid
  • THF means tetrahydrofuran
  • TLC means thin layer chromatography
  • the compounds of the formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
  • pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
  • Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
  • organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, tolu
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
  • the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
  • compositions suitable for administration typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the present invention provides a class of compounds which interact selectively with the JNK receptor and not significantly with other members of the gene family.
  • Table 5 the selectivity of a selection of compounds against a selection of kinases is presented.
  • the active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes.
  • the magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
  • 6,8-Dibromo-imidazo[l,2-a]pyrazine (A) can be aminated with amines.
  • the resultant compounds (B) are then Boc protected (C) and can then be reacted with the boronic acids and de-protected to yield the final compounds of formula (D) or be reacted with an amide in presence of copper iodide then de- protected to yield the final compounds of formula (E).
  • a suspension of copper(I)iodide (100 mg, 0.53 mmol), (6-Bromo-imidazo[l,2- a]pyrazin-8-yl)-pyridin-3-ylmethyl-amine (430mg, 1.06 mol), benzamide (150mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) was prepared in dry toluene (50 mL) and the mixture purged with nitrogen for 15 minutes. ⁇ /V'-dimethylethylenediamine (0.4 mL) was then added and the reaction stirred at room temperature for 15 minutes then heated to reflux for 16 hours.
  • 6,8-Dibromo-imidazo[l,2-a]pyrazine (A) can be aminated with amines.
  • the resultant compounds (B) can then be reacted with the boronic acids to yield the final compounds of formula (C) or be reacted with an amide in presence of cupper iodide to yield the final compounds of formula (D).
  • a suspension of copper(I)iodide (100 mg, 0.53 mmol), 4-(6-Bromo- imidazo[l,2-a]pyrazin-8-ylamino)-cyclohexanol (330 mg, 1.06 mol), thiophene-2-acetamide (190 mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) was prepared in dry toluene (50 mL) and the mixture purged with nitrogen for 15 minutes. ⁇ rVV'-dirnethylethylenediamine (0.4 mL) was then added and the reaction stirred at room temperature for 15 minutes then heated to reflux for 16 hours.
  • a JNK screening assay was performed in a 384-well and 96-well flashplate format. The kinetics of the reaction were determined under the following conditions: 0.2 ⁇ Ci; 33 P-ATP; 1.5 ⁇ M ATP; 2mU JNKl ⁇ l; 2 ⁇ M c-jun (1-79) peptide substrate incubated for 30 minutes at room temperature.
  • a standard ATP concentration of 0.1 x Km (Km previously defined as 15 ⁇ M) was employed.
  • Km for JNKl ⁇ l was derived as 4 ⁇ M (4.7 and 4.0 ⁇ M independent observations).
  • the kinetics of the reaction were determined under the following conditions 0.2 ⁇ Ci 33 P-ATP; 1.5 ⁇ M ATP; 2mU JNKl ⁇ l; 2 ⁇ M c-jun (1-79) peptide substrate incubated for 30 minutes at room temperature.

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Abstract

La présente invention concerne des nouveaux composés représentés par la formule (I), des composés pharmaceutiques, des procédés permettant de les préparer, ainsi que des procédés permettant d'utiliser ces composés pour inhiber les protéines kinases, en particulier les serines/thréonines kinases, plus particulièrement, une protéine kinase activée par un mitogène, plus particulièrement, les c-Jun kinases NH2-teminal (JNK). Cette invention concerne également des composés pouvant être utilisés à des fins médicales, et plus particulièrement, pour prévenir et/ou pour traiter une large gamme de maladies parmi lesquelles les troubles inflammatoires, le cancer, l'angiogenèse, les diabètes, une maladie métabolique, et des troubles neurologiques.
PCT/GB2005/000842 2004-03-04 2005-03-04 Composes de 1,2-a' pyrazine imidazo interagissant avec les proteines kinases WO2005085252A1 (fr)

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GB0404889A GB0404889D0 (en) 2004-03-04 2004-03-04 Compounds which interact with protein kinases
GB0404889.8 2004-03-04
GB0426259A GB0426259D0 (en) 2004-11-30 2004-11-30 Compounds which interact with protein kinases
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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008057512A3 (fr) * 2006-11-08 2008-06-26 Schering Corp Imidazopyrazines comme inhibiteurs de protéines kinases
WO2008082490A3 (fr) * 2006-12-20 2008-10-02 Schering Corp Nouveaux inhibiteurs de jnk
US7501411B2 (en) 2006-05-31 2009-03-10 Galapagos, Nv Triazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases
WO2010088368A2 (fr) 2009-01-29 2010-08-05 Schering Corporation Imidazopyrazines en tant qu'inhibiteurs de protéines kinases
US8173656B2 (en) * 2006-05-15 2012-05-08 Janssen Pharmaceutica Nv Imidazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases
JP2012510997A (ja) * 2008-12-08 2012-05-17 ギリアード コネチカット， インコーポレイテッド イミダゾピラジンＳｙｋ阻害剤
US8278337B2 (en) 2006-12-20 2012-10-02 Merck Sharp & Dohme Substituted pyridines that are JNK inhibitors
US8440667B2 (en) 2008-12-08 2013-05-14 Gilead Connecticut, Inc. Imidazopyrazine Syk inhibitors
US8450321B2 (en) 2008-12-08 2013-05-28 Gilead Connecticut, Inc. 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor
WO2013170112A1 (fr) * 2012-05-11 2013-11-14 Abbvie Inc. Inhibiteurs de nampt
US8697699B2 (en) 2008-02-13 2014-04-15 Gilead Connecticut, Inc. Imidazopyrazine SYK inhibitors
WO2015158283A1 (fr) * 2014-04-17 2015-10-22 Abbvie Inc. Inhibiteurs de kinase hétérocycliques
WO2015166370A1 (fr) 2014-04-28 2015-11-05 Pfizer Inc. Composés hétéroaromatiques et leur utilisation en tant que ligands de la dopamine d1
US9290505B2 (en) 2013-12-23 2016-03-22 Gilead Sciences, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
US9382256B2 (en) 2013-07-30 2016-07-05 Gilead Connecticut, Inc. Formulation of Syk inhibitors
US9562056B2 (en) 2010-03-11 2017-02-07 Gilead Connecticut, Inc. Imidazopyridines Syk inhibitors
CN106459067A (zh) * 2014-06-25 2017-02-22 豪夫迈·罗氏有限公司 用于治疗脊髓性肌萎缩的咪唑并[1，2‑a]吡嗪‑1基苯甲酰胺化合物
US9657023B2 (en) 2013-07-30 2017-05-23 Gilead Connecticut, Inc. Polymorph of Syk inhibitors
US9687492B2 (en) 2013-12-04 2017-06-27 Gilead Sciences, Inc. Methods for treating cancers
US9707236B2 (en) 2014-07-14 2017-07-18 Gilead Sciences, Inc. Combination methods for treating cancers
US9968601B2 (en) 2013-12-23 2018-05-15 Gilead Sciences, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
WO2021249417A1 (fr) * 2020-06-09 2021-12-16 赛诺哈勃药业（成都）有限公司 Composé hétérocyclique et son dérivé
US11339168B2 (en) 2019-02-22 2022-05-24 Kronos Bio, Inc. Crystalline forms of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine as Syk inhibitors
US11384082B2 (en) 2017-08-25 2022-07-12 Kronos Bio, Inc. Hydrates of polymorphs of 6-(1H-indazol-6-YL)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-A]pyrazin-8-amine bisemsylate as Syk inhibitors

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000491A1 (fr) * 1998-06-29 2000-01-06 The Regents Of The University Of California Antagonistes bifonctionnels des cascades d'activation des kinases sensibles aux cytokines et technique permettant de les utiliser comme anti-inflammatoires
WO2002060492A1 (fr) * 2001-01-30 2002-08-08 Cytopia Pty Ltd Procedes d'inhibition de kinases
WO2003018020A1 (fr) * 2001-08-23 2003-03-06 Takeda Chemical Industries, Ltd. Inhibiteurs de jnk
US20030153560A1 (en) * 1999-04-23 2003-08-14 Salituro Francesco G. Inhibitors of c-Jun N-terminal kinases (JNK)
WO2003089434A2 (fr) * 2002-04-19 2003-10-30 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines, leur procede de production et leur utilisation
WO2004022562A1 (fr) * 2002-09-09 2004-03-18 Cellular Genomics, Inc. 6-arykl-imidazo[1,2-a]pyrazin-8-ylamines, procede de preparation et procede d'utilisation correspondants
WO2004026310A1 (fr) * 2002-09-23 2004-04-01 Schering Corporation Nouvelles imidazopyrazines comme inhibiteurs de kinases dependant des cyclines
US20040220189A1 (en) * 2003-02-20 2004-11-04 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhbitors
WO2005005429A1 (fr) * 2003-06-30 2005-01-20 Cellular Genomics, Inc. Certaines imidazo[1,2-a]pyrazin-8-ylamines substituees heterocycliques et methodes d'inhibition de la tyrosine kinase de bruton utilisant ces composes
WO2005014599A1 (fr) * 2003-06-04 2005-02-17 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines et methodes d'inhibition de la tyrosine kinase de bruton par de tels composes
WO2005019220A2 (fr) * 2003-08-11 2005-03-03 Cellular Genomics Inc. Imidazo[1,2-a]pyrazines substituees utilisees comme modulateurs de l'activite d'une kinase
WO2005047290A2 (fr) * 2003-11-11 2005-05-26 Cellular Genomics Inc. Certaines imidazo[1,2-a]pyrazin-8-ylamines, procede de fabrication et methode d'utilisation

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000491A1 (fr) * 1998-06-29 2000-01-06 The Regents Of The University Of California Antagonistes bifonctionnels des cascades d'activation des kinases sensibles aux cytokines et technique permettant de les utiliser comme anti-inflammatoires
US20030153560A1 (en) * 1999-04-23 2003-08-14 Salituro Francesco G. Inhibitors of c-Jun N-terminal kinases (JNK)
WO2002060492A1 (fr) * 2001-01-30 2002-08-08 Cytopia Pty Ltd Procedes d'inhibition de kinases
WO2003018020A1 (fr) * 2001-08-23 2003-03-06 Takeda Chemical Industries, Ltd. Inhibiteurs de jnk
WO2003089434A2 (fr) * 2002-04-19 2003-10-30 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines, leur procede de production et leur utilisation
WO2004022562A1 (fr) * 2002-09-09 2004-03-18 Cellular Genomics, Inc. 6-arykl-imidazo[1,2-a]pyrazin-8-ylamines, procede de preparation et procede d'utilisation correspondants
WO2004026310A1 (fr) * 2002-09-23 2004-04-01 Schering Corporation Nouvelles imidazopyrazines comme inhibiteurs de kinases dependant des cyclines
US20040220189A1 (en) * 2003-02-20 2004-11-04 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhbitors
WO2005014599A1 (fr) * 2003-06-04 2005-02-17 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines et methodes d'inhibition de la tyrosine kinase de bruton par de tels composes
WO2005005429A1 (fr) * 2003-06-30 2005-01-20 Cellular Genomics, Inc. Certaines imidazo[1,2-a]pyrazin-8-ylamines substituees heterocycliques et methodes d'inhibition de la tyrosine kinase de bruton utilisant ces composes
WO2005019220A2 (fr) * 2003-08-11 2005-03-03 Cellular Genomics Inc. Imidazo[1,2-a]pyrazines substituees utilisees comme modulateurs de l'activite d'une kinase
WO2005047290A2 (fr) * 2003-11-11 2005-05-26 Cellular Genomics Inc. Certaines imidazo[1,2-a]pyrazin-8-ylamines, procede de fabrication et methode d'utilisation

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8173656B2 (en) * 2006-05-15 2012-05-08 Janssen Pharmaceutica Nv Imidazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases
US7501411B2 (en) 2006-05-31 2009-03-10 Galapagos, Nv Triazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases
WO2008057512A3 (fr) * 2006-11-08 2008-06-26 Schering Corp Imidazopyrazines comme inhibiteurs de protéines kinases
US8278337B2 (en) 2006-12-20 2012-10-02 Merck Sharp & Dohme Substituted pyridines that are JNK inhibitors
WO2008082490A3 (fr) * 2006-12-20 2008-10-02 Schering Corp Nouveaux inhibiteurs de jnk
US8697699B2 (en) 2008-02-13 2014-04-15 Gilead Connecticut, Inc. Imidazopyrazine SYK inhibitors
US8962835B2 (en) 2008-12-08 2015-02-24 Gilead Connecticut, Inc. Imidazopyrazine Syk inhibitors
TWI478922B (zh) * 2008-12-08 2015-04-01 Gilead Connenticut Inc 作為脾臟酪胺酸激酶（Ｓｙｋ）抑制劑之咪唑並吡化合物
US8440667B2 (en) 2008-12-08 2013-05-14 Gilead Connecticut, Inc. Imidazopyrazine Syk inhibitors
US8450321B2 (en) 2008-12-08 2013-05-28 Gilead Connecticut, Inc. 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor
US8455493B2 (en) 2008-12-08 2013-06-04 Gilead Connecticut, Inc. Imidazopyrazine Syk inhibitors
US9796718B2 (en) 2008-12-08 2017-10-24 Gilead Connecticut, Inc. 6-(benzo[d]thiazol-5-yl)-n-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine
JP2012510997A (ja) * 2008-12-08 2012-05-17 ギリアード コネチカット， インコーポレイテッド イミダゾピラジンＳｙｋ阻害剤
US8748607B2 (en) 2008-12-08 2014-06-10 Gilead Connecticut, Inc. Imidazopyrizine syk inhibitors
US8765761B2 (en) 2008-12-08 2014-07-01 Gilead Connecticut, Inc. 6-(1H-indazol-6-yl)-N-{4-[2-methyl-1-(morpholin-4-yl)propan-2-yl]phenyl}imidazo[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a syk inhibitor
US8796270B2 (en) 2008-12-08 2014-08-05 Gilead Connecticut, Inc. N-[6-(1H-indazol-6-yl)imidazo[1,2-A]pyridin-8-yl]-6-(morpholin-4-yl)pyridazin-3-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor
JP2017101090A (ja) * 2008-12-08 2017-06-08 ギリアード コネチカット， インコーポレイテッド イミダゾピラジンＳｙｋ阻害剤
US9212191B2 (en) 2008-12-08 2015-12-15 Gilead Connecticut, Inc. 6-(2,3-dihydro-1H-pyrido-[2,3-b][1,4]oxazin-7-yl)-N-(4-morpholinophenyl)imidazo[1,2-a] pyrazin-8-amine as a spleen tyrosine kinase inhibitor
CN102307474B (zh) * 2008-12-08 2015-04-01 吉利德康涅狄格股份有限公司 咪唑并吡嗪syk抑制剂
EP2373169A4 (fr) * 2008-12-08 2012-08-29 Gilead Connecticut Inc Inhibiteurs d'imidazopyrazine syk
US9120811B2 (en) 2008-12-08 2015-09-01 Gilead Connecticut, Inc. 6-(1H-indazol-6-YL)-N-(4-morpholinophenyl)imidazo[1,4-A]pyrazin-8-amine for treating leukemia or lymphoma
JP2015205935A (ja) * 2008-12-08 2015-11-19 ギリアード コネチカット， インコーポレイテッド イミダゾピラジンＳｙｋ阻害剤
US10093684B2 (en) 2008-12-08 2018-10-09 Gilead Connecticut, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
US9567348B2 (en) 2008-12-08 2017-02-14 Gilead Connecticut, Inc. Substituted pyrazolo[1,5-a]pyrimidines as Syk inhibitors
WO2010088368A2 (fr) 2009-01-29 2010-08-05 Schering Corporation Imidazopyrazines en tant qu'inhibiteurs de protéines kinases
US10842803B2 (en) 2010-03-11 2020-11-24 Kronos Bio, Inc. Imidazopyridines Syk inhibitors
US9562056B2 (en) 2010-03-11 2017-02-07 Gilead Connecticut, Inc. Imidazopyridines Syk inhibitors
US10092583B2 (en) 2010-03-11 2018-10-09 Gilead Connecticut, Inc. Imidazopyridines Syk inhibitors
JP2015516435A (ja) * 2012-05-11 2015-06-11 アッヴィ・インコーポレイテッド Ｎａｍｐｔ阻害薬
US9193723B2 (en) 2012-05-11 2015-11-24 Abbvie Inc. NAMPT inhibitors
US9187472B2 (en) 2012-05-11 2015-11-17 Abbvie Inc. NAMPT inhibitors
WO2013170112A1 (fr) * 2012-05-11 2013-11-14 Abbvie Inc. Inhibiteurs de nampt
US9382256B2 (en) 2013-07-30 2016-07-05 Gilead Connecticut, Inc. Formulation of Syk inhibitors
US10266539B2 (en) 2013-07-30 2019-04-23 Gilead Connecticut, Inc. Polymorph of Syk inhibitors
US9657023B2 (en) 2013-07-30 2017-05-23 Gilead Connecticut, Inc. Polymorph of Syk inhibitors
US9918939B2 (en) 2013-07-30 2018-03-20 Gilead Connecticut, Inc. Formulation of Syk inhibitors
US9949932B2 (en) 2013-07-30 2018-04-24 Gilead Connecticut, Inc. Formulation of syk inhibitors
US9687492B2 (en) 2013-12-04 2017-06-27 Gilead Sciences, Inc. Methods for treating cancers
US9974792B2 (en) 2013-12-04 2018-05-22 Gilead Sciences, Inc. Methods for treating cancers
US12263163B2 (en) 2013-12-23 2025-04-01 Kronos Bio, Inc. Crystalline succinate salt of 6-(6-aminopyrazin-2-yl)-n-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine as a Syk inhibitor
US11517570B2 (en) 2013-12-23 2022-12-06 Kronos Bio, Inc. Crystalline succinate salt of 6-(6-aminopyrazin-2-yl)-n-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine
US10828299B2 (en) 2013-12-23 2020-11-10 Kronos Bio, Inc. Crystalline monomesylate salt of 6-(6-aminopyrazin-2-yl)-n-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine
US9968601B2 (en) 2013-12-23 2018-05-15 Gilead Sciences, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
US10342794B2 (en) 2013-12-23 2019-07-09 Gilead Sciences, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
US9290505B2 (en) 2013-12-23 2016-03-22 Gilead Sciences, Inc. Substituted imidazo[1,2-a]pyrazines as Syk inhibitors
WO2015158283A1 (fr) * 2014-04-17 2015-10-22 Abbvie Inc. Inhibiteurs de kinase hétérocycliques
US10280184B2 (en) 2014-04-17 2019-05-07 Abbvie Inc. Heterocyclic kinase inhibitors
CN106459045A (zh) * 2014-04-17 2017-02-22 艾伯维公司 杂环激酶抑制剂
WO2015166370A1 (fr) 2014-04-28 2015-11-05 Pfizer Inc. Composés hétéroaromatiques et leur utilisation en tant que ligands de la dopamine d1
US9856263B2 (en) 2014-04-28 2018-01-02 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
CN106459067B (zh) * 2014-06-25 2019-05-31 豪夫迈·罗氏有限公司 用于治疗脊髓性肌萎缩的咪唑并[1，2-a]吡嗪-1基苯甲酰胺化合物
CN106459067A (zh) * 2014-06-25 2017-02-22 豪夫迈·罗氏有限公司 用于治疗脊髓性肌萎缩的咪唑并[1，2‑a]吡嗪‑1基苯甲酰胺化合物
US10080756B2 (en) 2014-07-14 2018-09-25 Gilead Sciences, Inc. Combination methods for treating cancers
US9707236B2 (en) 2014-07-14 2017-07-18 Gilead Sciences, Inc. Combination methods for treating cancers
US11384082B2 (en) 2017-08-25 2022-07-12 Kronos Bio, Inc. Hydrates of polymorphs of 6-(1H-indazol-6-YL)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-A]pyrazin-8-amine bisemsylate as Syk inhibitors
US12122781B2 (en) 2017-08-25 2024-10-22 Kronos Bio, Inc. Hydrates of polymorphs of 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-a]pyrazin-8-amine bis-mesylate as Syk inhibitors
US11339168B2 (en) 2019-02-22 2022-05-24 Kronos Bio, Inc. Crystalline forms of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine as Syk inhibitors
WO2021249417A1 (fr) * 2020-06-09 2021-12-16 赛诺哈勃药业（成都）有限公司 Composé hétérocyclique et son dérivé

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