WO2009062059A2 - Purinones et 1h-imidazopyridinones isomères comme inhibiteurs de pkc-thêta - Google Patents

Purinones et 1h-imidazopyridinones isomères comme inhibiteurs de pkc-thêta Download PDF

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WO2009062059A2
WO2009062059A2 PCT/US2008/082832 US2008082832W WO2009062059A2 WO 2009062059 A2 WO2009062059 A2 WO 2009062059A2 US 2008082832 W US2008082832 W US 2008082832W WO 2009062059 A2 WO2009062059 A2 WO 2009062059A2
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alkyl
compound according
chosen
substituted
hydrogen
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PCT/US2008/082832
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WO2009062059A3 (fr
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Andrew Roughton
Yajing Rong
Koc-Kan Ho
Michael Ohlmeyer
David Diller
Ray Jui-Hsiang Chan
Gaifa Lai
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Pharmacopeia, Inc.
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Publication of WO2009062059A2 publication Critical patent/WO2009062059A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom

Definitions

  • the present invention relates to a chemical genus of purinones and IH- imidazopyridinones which are useful as PKC ⁇ inhibitors.
  • PKC protein kinase C
  • PKC ⁇ is expressed predominantly in lymphoid tissue and skeletal muscle. It has been shown that PKC ⁇ is essential for T-cell receptor (TCR)-mediated T-cell activation but inessential during TCR-dependent thymocyte development. PKC ⁇ , but not other PKC isoforms, translocates to the site of cell contact between antigen- specific T-cells and antigen presenting cells (APC), where it localizes with the TCR in the central core of the T-cell activation. PKC ⁇ , but not the a, ⁇ , or ⁇ isoenzymes, selectively activated a FasL promoter-reporter gene and upregulated the mRNA or cell surface expression of endogenous FasL.
  • TCR T-cell receptor
  • APC antigen presenting cells
  • PKC ⁇ and ⁇ promoted T-cell survival by protecting the cells from Fas-induced apoptosis, and this protective effect was mediated by promoting p90Rsk-dependent phosphorylation of BAD.
  • PKC ⁇ appears to play a dual regulatory role in T-cell apoptosis.
  • PKC ⁇ inhibitors are useful for the treatment or prevention of disorders or diseases mediated by T lymphocytes, for example, autoimmune disease such as rheumatoid arthritis and lupus erythematosus, and inflammatory disease such as asthma and inflammatory bowel diseases.
  • PKC ⁇ is identified as a drug target for immunosuppression in transplantation and autoimmune diseases (Isakov et al. (2002) Annual Review of Immunology, 20, 761-794).
  • PCT Publication WO2004/043386 identifies PKC ⁇ as a target for treatment of transplant rejection and multiple sclerosis.
  • PKC ⁇ also plays a role in inflammatory bowel disease (The Journal of Pharmacology and Experimental Therapeutics (2005), 313 (3), 962-982), asthma (WO 2005062918), and lupus (Current Drug Targets: Inflammation & Allergy (2005), 4 (3), 295-298).
  • PKC ⁇ is highly expressed in gastrointestinal stromal tumors (Blay, P. et al. (2004) Clinical Cancer Research, 10, 12, Pt.1), it has been suggested that PKC ⁇ is a molecular target for treatment of gastrointestinal cancer (Wiedmann, M. et al. (2005) Current Cancer Drug Targets 5(3), 171).
  • small molecule PKC ⁇ inhibitors can be useful for treatment of gastrointestinal cancer.
  • PKC ⁇ inhibitors are useful in treatment of T-cell mediated diseases including autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and multiple sclerosis and inflammatory diseases such as asthma and inflammatory bowel disease.
  • PKC ⁇ inhibitors are useful in treatment of transplant rejection, gastrointestinal cancer, and diabetes. Description of the Invention
  • the invention relates to compounds of the formula I:
  • X 1 and X 2 are independently chosen from N and CH;
  • R 1 is chosen from
  • R is chosen from
  • M is C 2 -C 10 alkyl optionally substituted with -OH, with a proviso that - OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 7 and R 8 are independently chosen from -H and C 1 -C 4 alkyl;
  • A is chosen from carbocycle, substituted carbocycle, heterocycle and substituted heterocycle;
  • L 1 is a C 1 -C 10 alkyl optionally substituted with -OH, with the proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • Z is chosen from C 1 -C 6 alkyl, cyano, hydroxyalkyl, carboxamido and halo alkyl.
  • X 1 is CH and X 2 is N;
  • R 1 is chosen from
  • R 4 is chosen from
  • M is C 2 -C 10 alkyl optionally substituted with -OH, with a proviso that -
  • R 7 and R 8 are independently chosen from -H and C 1 -C 4 alkyl
  • A is chosen from carbocycle, substituted carbocycle, heterocycle and substituted heterocycle;
  • L 1 is a C 1 -C 10 alkyl optionally substituted with -OH, with the proviso that
  • R is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • Z is chosen from hydrogen, C 1 -C 6 alkyl, cyano, hydroxyalkyl, carboxamido and haloalkyl.
  • the invention relates to compounds of formula I wherein
  • X 1 and X 2 are independently chosen from N and CH; R 1 is -NHR 4 ;
  • R 5 represents one, two or three residues independently chosen from -H, C 1 -C 4 alkyl, acyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, hydroxyaminoalkyl and aminoalkyl;
  • R 6 represents one, two or three residues independently chosen from -H, C 1 -C 4 alkyl, -OCH 3 , hydroxy, amino, haloalkyl, acylamino, hydroxyalkyl, hydroxyaminoalkyl, hydroxyalkylamino, alkylamino, dialkylamino and aminoalkyl;
  • R 16 is chosen from -H, C 1 -C 4 alkyl, amino, and aminoalkyl;
  • R 17 represents one, two or three residues independently chosen from -H, fluoro, amino, aminoalkyl, alkoxy and optionally substituted heterocycloalkyl;
  • R 40 is chosen from -H, C 1 -C 4 alkyl, amino, alkylamino and dialkylamino;
  • R 25 is chosen from -H and C1-C4 alkyl
  • R 26 is chosen from -H and oxo
  • R 27 is chosen from -H, C 1 -C 4 alkyl, amino, and aminoalkyl; n is chosen from 1, 2 and 3;
  • L 1 is a C 1 -C 10 alkyl optionally substituted with -OH, with the proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
  • Z is chosen from hydrogen, C 1 -C 6 alkyl, cyano, hydroxyalkyl, carboxamido and haloalkyl.
  • the invention relates to compounds of formula I
  • X 1 and X 2 are independently chosen from N and CH;
  • R 1 is chosen from
  • R is chosen from
  • M is C 2 -C 10 alkyl optionally substituted with -OH, with a proviso that - OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 7 and R 8 are independently chosen from -H and C 1 -C 4 alkyl;
  • A is chosen from carbocycle, substituted carbocycle, heterocycle and substituted heterocycle;
  • L 1 is a C 1 -C 10 alkyl optionally substituted with -OH, with the proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • R is chosen from
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen, -CH 2 OCF 3 , -
  • R 18 represents one or two residues independently chosen from hydrogen and halogen
  • R 19 represents one or two residues independently chosen from hydrogen, hydroxy, halogen and C1-C4 alkyl, with the proviso that when R 19 is hydrogen, R 18 is not hydrogen;
  • R 30 represents one or two residues independently chosen from hydrogen, halogen, C 1 -C 6 alkyl, cyano and -OCF 3 ;
  • R 31 represents one or two residues independently chosen from hydrogen, halogen, C 1 -C 6 alkyl, cyano and -OCF 3 ;
  • D is C 0 -C 4 alkyl
  • R a represents one, two, or three residues independently chosen from hydrogen, halogen, alkoxy, haloalkoxy, haloalkyl, cyano, alkylthio, alkylsulfonyl, haloalkylthio, C 1 -C 4 alkyl, amino, and aminoalkyl;
  • R b represents one, two, or three residues independently chosen from hydrogen, halogen, alkoxy, haloalkoxy, haloalkyl, cyano, alkylthio, alkylsulfonyl, haloalkylthio, C 1 -C 4 alkyl, carboxamide, alkoxyalkyl, hydroxyalkyl, alkoxycarbonyl, amino, and aminoalkyl; and
  • Z is chosen from hydrogen, C 1 -C 6 alkyl, cyano, hydroxyalkyl, carboxamido and haloalkyl.
  • Z is hydrogen
  • the invention relates to compounds of formula Ib
  • R is chosen from
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen, -OCH 3 , -OCF 3 , - CH 2 OCF 3 , -CF 3 , -CN, alkylthio, -SO 2 Me, -SCF 3 , C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 acetate, C 1 -C 4 alkylamino, carboxamide, substituted carboxamide, aryl, substituted aryl, heterocycle, substituted heterocycle, aryloxy, and substituted aryloxy;
  • R is -H or halogen
  • R 19 is -H or hydroxyl
  • R 30 represents one or two residues independently chosen from hydrogen, halogen, C 1 -C 6 alkyl, cyano and -OCF 3 ;
  • R 31 represents one or two residues independently chosen from hydrogen, halogen, C 1 -C 6 alkyl, cyano and -OCF 3 ;
  • R a represents one, two, or three residues independently chosen from -H, halogen, -OCH 3 , -OCF 3 , -CF 3 , -CN, alkylthio, -SO 2 Me, -SCF 3 , C 1 -C 4 alkyl, amino, and aminoalkyl;
  • R b represents one, two, or three residues independently chosen from halogen, - OCH 3 , -OCF 3 , -CF 3 , -CN, -SMe, -SO 2 Me, -SCF 3 , C 1 -C 4 alkyl, carboxamide, alkoxyalkyl, amino, and aminoalkyl; and
  • D is C 0 -C 4 alkyl.
  • the invention relates to compounds of formula Ib in another embodiment, relates to compounds of formula Ib in
  • R is and D is Co-C 3 alkyl.
  • R 2 is In still another embodiment, R is .
  • R 10 is trifluoromethoxy, R 11 is halogen and R 12 is hydrogen.
  • D is Co, and in some embodiments, R 10 is trifluoromethoxy and R 12 is hydrogen.
  • the invention relates to compounds of formula Ib
  • R is in a further aspect, R is chosen from
  • Another aspect of the invention includes compounds of formula Ib in which R
  • the invention relates to compounds of formula I wherein
  • R is chosen from:
  • R 5 represents one, two or three residues independently chosen from -H, C 1 -C 4 alkyl, hydroxy, haloalkyl, hydroxyalkyl, hydroxyaminoalkyl and aminoalkyl;
  • R 6 represents one, two or three residues independently chosen from -H, C 1 -C 4 alkyl, -OCH3, halogen, hydroxy, amino, haloalkyl, acylamino, hydroxyalkyl, hydroxyaminoalkyl and aminoalkyl;
  • R 7 and R 8 are independently chosen from -H and C 1 -C 4 alkyl
  • R 13 and R 14 are independently chosen from -H, -OH, and C 1 -C 4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 16 is chosen from -H, C 1 -C 4 alkyl, amino, and aminoalkyl;
  • R 17 is chosen from -H, amino, aminoalkyl and optionally substituted heterocycloalkyl
  • R 40 is chosen from -H, C 1 -C 4 alkyl and amino
  • R 25 is chosen from -H and C 1 -C 4 alkyl
  • R 26 is chosen from -H and oxo
  • R 27 is chosen from -H, C 1 -C 4 alkyl, amino, and aminoalkyl; and n is chosen from 1 , 2 and 3.
  • Another aspect of the invention includes compounds in which L 1 is -CH 2 .
  • R 4 is ⁇ 1 .
  • Yet another aspect of the invention relates to compounds in which R 2 or R 2a is selected from
  • Still another aspect of the invention includes compounds in which L 1 is -CH 2 , R 4 is and R 2 or R 2a is selected from and
  • R 4 is [0021] Another aspect of the invention relates to compounds in which R 4 is
  • R 2 or R 2a is
  • the invention relates to compounds in which R is
  • R is .
  • R 4 is -M- NR R
  • M is C 2 -C 4 alkyl optionally substituted with -OH.
  • R 7 and R 8 are each independently hydrogen or methyl.
  • R or R a is
  • R a represents one, two, or three residues independently chosen from hydrogen, halogen, -alkoxy, haloalkoxy, haloalkyl, cyano, alkylthio, alkylsulfonyl, haloalkylthio, C 1 -C 4 alkyl, amino, and aminoalkyl; and R b represents one, two, or three residues independently chosen from hydrogen, halogen, alkoxy, haloalkoxy, haloalkyl, cyano, alkylthio, alkylsulfonyl, haloalkylthio, C 1 -C 4 alkyl, carboxamide, alkoxyalkyl, hydroxyalkyl, alkoxycarbonyl, amino, and aminoalkyl.
  • R a represents one, two, or three residues independently chosen from -H, halogen, -OCH 3 , -OCF 3 , -CF 3 , -CN, -SMe, -SO 2 Me, -SCF 3 , C 1 -C 4 alkyl, amino, and aminoalkyl;
  • R represents one, two, or three residues independently chosen from halogen, -OCH 3 , -OCF 3 , -CF 3 , -CN, -SMe, -SO 2 Me, -SCF 3 , C 1 -C 4 alkyl, carboxamide, alkoxyalkyl, amino, and aminoalkyl; and D is Co-C 6 alkyl.
  • R 4 is .
  • Still another embodiment includes compounds in which D is Co-C 2 alkyl. In a further embodiment, D is -CH 2 .
  • R z or R 2a is and D is C 0 -C 3 alkyl.
  • R 10 , R 11 , and R . 1 1 2 Z are independently chosen from -H, halogen, -OCH 3 , -OCF 3 , -CH 2 OCF 3 , -CF 3 , -CN, - SMe, -SO 2 Me, -SCF 3 , C 5 -C 6 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 acetate, C 1 -C 4 alkylamino, carboxamide, substituted carboxamide, aryl, substituted aryl, heterocycle, substituted heterocycle, aryloxy, and substituted aryloxy.
  • R 10 , R 11 , and R . 1 1 2 Z are independently chosen from -H, halogen, -OCH 3 , -OCF 3 , -CH 2 OCF 3 , -CF 3 , -CN, - SMe, -SO 2 Me, -S
  • R is and R is yet another embodiment of the invention
  • R a represents one, two, or three residues independently chosen from -H, -OCF 3 and C 1 -C 4 alkyl
  • R b represents one, two, or three residues independently chosen from hydrogen, halogen, C 1 -C 4 alkyl, alkoxycarbonyl, carboxamide, alkoxyalkyl, amide, hydroxyalkyl and aminoalkyl.
  • R a is chosen from C 1 -C 4 alkyl and hydrogen.
  • R is .
  • R is chosen from hydrogen, halogen and aminoalkyl.
  • R a is chosen from methyl and hydrogen and R b is selected from fluorine, chlorine or - CH 2 NH 2 .
  • the invention relates to compounds of formula I in wherein
  • R 4 is and R a is trifluromethoxy.
  • the invention relates to compounds of formula I wherein R is R 2 is ; and R 10 is selected from -CN and C 1 -C 4 alkynyl.
  • R 4 is chosen from and
  • R is and R 2 or R 2a is
  • the invention relates to compounds of formula I wherein X and X are both nitrogen; Z is hydrogen; R is and R 4 is
  • R 2 is and R 27 is methyl.
  • R 2 is ; R 27 is methyl; R 4 is
  • R 4 is L 1 is -CH 2 ; and R 6 is chosen from hydrogen, amino, aminoalkyl, hydroxyalkylamino, hydroxyl, acylamino and hydroxyalkyl.
  • R 4 is selected from and In
  • R is R6 , and in some of these compounds,
  • R 6 is selected from hydroxyl, amino and aminoalkyl.
  • R 4 is selected from and ;
  • L 1 is CH 2
  • the invention relates to compounds of formula I
  • R 2 or R 2a is In some of these compounds, R 10 is -
  • R 10 is -OCF 3
  • R 11 is halogen
  • R 12 is hydrogen
  • X 1 and X 2 are both nitrogen.
  • X 1 is CH and X 2 is nitrogen.
  • X 1 is nitrogen and X 2 is CH.
  • X 1 is CH; X 2 is nitrogen; R 4 is
  • the invention relates to compounds in which X 1 is CH; X 2 is nitrogen; R 4 is
  • R 2 or R 2a is L 1 is CH 2 and D is CH 2 .
  • compositions comprising a pharmaceutically acceptable carrier and a compound of formula I described herein.
  • the invention is directed to the use of a compound of the invention for the treatment of a T-cell mediated disease comprising administering a therapeutically effective amount of a compound of the invention, or salt or solvate thereof.
  • the T-cell mediated disease may be, for example, an autoimmune disease, an inflammatory disease or transplant rejection.
  • the autoimmune disease may be, for example, rheumatoid arthritis, psoriasis, multiple sclerosis or lupus erythematosus.
  • the inflammatory disease may be, for example, asthma or inflammatory bowel disease.
  • the invention is directed to a use of a compound of the invention for the treatment of diabetes comprising administering a therapeutically effective amount of a compound of formula I, or a salt or solvate thereof.
  • the invention is directed to a use of a compound of the invention for the treatment of cancer, such as gastrointestinal cancer, comprising administering a therapeutically effective amount of a compound of formula I, or a salt or solvate thereof.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl.
  • the term refers to alkyl of 10 or fewer carbons.
  • Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like.
  • Preferred alkyl and alkylene groups are those of C 10 or below (e.g.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • C 1 to C n Hydrocarbon (e.g. C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 ) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, vinyl, allyl, cyclopropyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • Saturated (C 1 to C n ) hydrocarbon is identical in meaning to (C 1 to C n ) alkyl or (C 1 to C n ) alkane as used herein. Whenever reference is made to Co- n alkyl, (Co to C n ) alkyl, or (Co to C n ) alkane when number of carbon atoms is 0, a direct bond is implied.
  • carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C 3 - C 10 carbocycle refers to such systems as cyclopropane, benzene and cyclohexene
  • C8-C12 carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. Similarly, aryloxy, cycloalkoxy and arylalkoxy are aryl, cycloalkyl and arylalkyl, respectively, bonded via an oxygen atom. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy. [0044] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
  • Fluoroalkyl refers to alkyl residues in which one or more hydrogens have been replaced by fluorine. It includes perfluoroalkyl, in which all the hydrogens have been replaced by fluorine. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and pentafluoroethyl.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society,
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched or cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • the double bonded oxygen when referred to as a substituent itself, is called "oxo".
  • Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14- membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
  • aryl As commonly understood, when referring to aryl as a substituent, it is intended that the point of attachment is a ring carbon of the aryl group (or ring carbon or heteroatom of the heteroaryl).
  • aryl and heteroaryl refer to systems in which at least one ring, but not necessarily all rings, are fully aromatic.
  • aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, benzocycloheptane and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, isoindoline, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, tetrahydrocarboline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl means an alkyl residue attached to an aryl ring.
  • arylalkyl As commonly understood, when referring to arylalkyl as a substituent, it is intended that the point of attachment is the alkyl group.
  • arylalkyl are benzyl, phenethyl, phenylpropyl, naphthylethyl and the like.
  • Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinyl ethyl and the like.
  • the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons.
  • heterocycle means a monocyclic, bicyclic or tricyclic residue with 1 to 13 carbon atoms and 1 to 5 heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • Heterocycles also include spiroheterocycles. Unless otherwise specified, a heterocycle may be non- aromatic or aromatic. The heterocycle may be fused to an aromatic hydrocarbon radical.
  • Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3 -oxadiazolyl, 1,2,3 -triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms. Examples include piperidine, piperazine, morpholine, pyrrolidine and thiomorpholine. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic; examples include pyridine, pyrrole and thiazole.
  • heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazol
  • Alkylthio means a lower alkyl group bound to a core structure via a sulfur atom, e.g. methylthio (-SCH 2 ), propylthio (-SCH 2 CH 2 CH 3 ).
  • Alkylamino means one lower alkyl group bound to a core structure via an amino group, e.g., methylamino, ethylamino, butylamino, etc.
  • Dialkylamino means two lower alkyl groups bound to a core structure via an amino group. Each lower alkyl group replaces one hydrogen on the nitrogen of the amino, e.g., dimethylamino (-NCH 3 CH 3 ).
  • Aminoalkyl means an amino group bound to a core structure via an alkyl group, e.g., aminomethyl, aminoethyl, aminopenthyl, etc.
  • the alkyl group, as defined above, could be straight or branched and, therefore, an aminoalkyl includes, e.g., - CH 2 CH 2 CH(CH 3 )CH 2 NH 2 , -CH 2 C(CH 3 ) 2 CH 2 NH 2 , etc.
  • Alkylaminoalkyl means a secondary amine bound to a core structure via an alkyl group, e.g., -CH 2 CH 2 NHCH 3 , -CH2CH2CH 2 NHCH 2 CH 3 , etc.
  • Dialkylaminoalkyl means a tertiary amine bound to a core structure via an alkyl group, e.g., -CH 2 N(CH 3 ) 2 , -CH2CH2CH 2 N(CH 3 )CH 2 CH 3 , etc.
  • alkyl group e.g., -CH 2 N(CH 3 ) 2 , -CH2CH2CH 2 N(CH 3 )CH 2 CH 3 , etc.
  • Haloakyl refers to an alkyl group in which one or more hydrogens are replaced by halogen, for example, trifluoromethyl, trifluoromethoxy, trichloroethyl, and difluoromethyl.
  • halogen for example, trifluoromethyl, trifluoromethoxy, trichloroethyl, and difluoromethyl.
  • Oxo is also included among the substituents referred to in "substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
  • 1 , 2 or 3 hydrogen atoms are replaced with a specified radical.
  • optionally substituted may be used interchangeably with "unsubstituted or substituted”.
  • treatment or “treating” a patient are intended to include prophylaxis.
  • the terms include amelioration, prevention and relief from the symptoms and/or effects associated with these disorders.
  • the terms "preventing” or “prevention” as used herein refer to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition, to diminish the likelihood or seriousness of the condition.
  • preventing or “prevention” refer to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition, to diminish the likelihood or seriousness of the condition.
  • prevent is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to diminish the likelihood or seriousness of a condition, and this is the sense intended.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, sulfur, and fluorine include 3 H, 14 C, 32 P, 35 S, and 18 F, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • solvate refers to a compound of Formula I in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
  • suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19 th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • the present invention includes compounds of formula I in the form of salts.
  • Suitable salts include those formed with both organic and inorganic acids. Such salts will normally be pharmaceutically acceptable, although non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, pamoic, pantothenic, phosphoric, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p- toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisometric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.
  • the present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using homo-chiral synthons or homo-chiral reagents, or optically resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both (E)- and (Z)- geometric isomers. Likewise, all tautomeric forms are intended to be included.
  • the graphic representation indicates either, or both, of the two trans enantiomers
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • the present invention provides a formulation comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques. “Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must, of course, be compatible with the compound of the invention to insure the stability of the formulation.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the invention [or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”)] and a pharmaceutically acceptable carrier, which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate- buffered saline (PBS) or the like, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers, such as cocoa butter or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the compounds of formula I are preferably administered orally or by injection (intravenous or subcutaneous).
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • R 2 is always chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted heteroarylalkyl, although, according to standard patent practice, in dependent claims it may be restricted to a subset of these values.
  • Superscripts are added to distinguish among residues that are attached similarly and that have overlapping Markush groups.
  • the substituent attached to the imidazolone ring at the nitrogen of the imidazolone can be R 2 or R 2a depending on the members of the Markush group defining it.
  • R 2 is intends to further limit, for example, the corresponding R a substituent in claim 4.
  • Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively.
  • a comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations,” is incorporated herein by reference.
  • T-cell mediated diseases including autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and multiple sclerosis, inflammatory diseases such as asthma and inflammatory bowel disease, transplant rejection, gastrointestinal cancer, and diabetes.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the intermediate 7 was prepared from 2 and tert-butyl (3- aminopropyl)carbamate in a similar method as described for the intermediate 3.
  • LC- MS Rt 6.15 min, m/e 414.2, 470.2; 1 H NMR (CDCl 3 ) ⁇ 8.97 (s, 1 H), 8.61 (s, broad, 1 H, NH), 7.42 (d, 1 H), 7.20 (m, 2 H), 5.25 (s, 1 H), 4.61 (d, 2 H), 3.35 (m, 2 H), 3.11 (m, 2 H), 1.82 (m, 2 H), 1.41 (s, 9 H).
  • the intermediate 9 was prepared from 8 in a similar method as described for the intermediate 5.
  • LC-MS Rt 5.29 min, m/e 466.2, 469.3; 1 H NMR (CDCl 3 ) ⁇ 7.81 (s, 1 H), 7.39 (d, 1 H), 7.10 (t, 1 H), 6.95 (d, 1 H), 5.83 (s, 1 H), 5.12 (s, 2 H), 3.25 (m, 2 H), 3.11 (m, 2 H), 1.70 (m, 2H), 1.42 (s, 9 H).
  • the target compound 10 was prepared from 9 in a similar method as described for the compound 6.
  • LC-MS Rt 3.90 min, m/e 366.1; 1 H NMR (CD 3 OD) ⁇
  • the intermediate 11 as a yellow solid was prepared from 1 and 2- (trifluoromethoxy)benzylamine in a similar method as described for the intermediate 2.
  • LC-MS Rt 7.47 min, m/e 394.1, 395.2; 1 H NMR (CDCl 3 ) ⁇ 9.00 (s, 1 H), 8.52 (s, broad, 1 H, NH), 7.42-7.28 (m, 4 H), 6.88 (s, 1 H), 4.61 (d, 2 H).
  • the intermediate 12 was prepared from 11 and (S)-tert-butyl 3- (aminomethyl)pyrrolidine- 1 -carboxylate in a similar method as described for the intermediate 3.
  • LC-MS Rt 6.36 min, m/e 512.3; 1 H NMR (CDCl 3 ) ⁇ 8.97 (s, 1 H), 8.59 (s, broad, 1 H, NH), 7.40-7.28 (m, 4 H), 5.22 (s, 1 H), 4.59 (d, 2 H), 3.50-3.10 (m, 6 H), 3.09-2.95 (m, 1 H), 2.29 (m, 1 H), 1.95 (m, 1 H), 1.41 (s, 9 H).
  • the intermediate 14 was prepared from 13 in a similar method as described for the intermediate 5.
  • LC-MS Rt 5.42 min, m/e 508.3; 1 H NMR (CDCl 3 ) ⁇ 7.81 (s, 1 H), 7.38-7.22 (m, 4 H), 5.86 (s, 1 H) 5.08 (s, 2 H), 4.55 (m, 1 H), 3.58- 3.00 (m, 6 H), 2.42 (m, 1 H), 1.98 (m, 1 H), 1.60 (m, 1 H), 1.42 (s, 9 H).
  • the target compound 15 was prepared from 14 in a similar method as described for the compound 6.
  • LC-MS Rt 3.98 min, m/e 408.3, 409.4; 1 H NMR (CD 3 OD) ⁇ 7.57 (s, 1 H), 7.40 (d, 1 H), 7.34-7.27 (m, 3 H), 6.37 (s, 1 H), 5.08 (s, 2 H), 3.42-3.08 (m, 5 H), 2.91 (m, 1 H), 2.60 (m, 1 H), 2.19 (m, 1 H), 1.71 (m, 1 H).
  • Step 8 9-((R)-1-(2,5-Dichlorophenyl)ethvn-2-((R)-pyrrolidin-3-ylmethylamino)- 7H-purin-8(9H)-one (45)
  • N4-(2,5-dichlorobenzyl)-2-chloropyrimidine-4,5-diamine (47) [00145] A mixture of N-(2,5-Dichlorobenzyl)-2-chloro-5-nitropyrimidin-4-amine [5.5 g, 16.5 mmol; Intermediate 46], THF (150 mL), and Raney-Ni (aqueous slurry) was placed under a hydrogen atmosphere (balloon; 1 ATM) at room temperature for 2.5 h.
  • a microwave tube was charged with 9-(2,5-dichlorobenzyl)-2-chloro-7H- purin-8(9H)-one (66 mg, 0.200 mmol; Intermediate 48), tert-Butyl ((lr,4r)-4- (aminomethyl)cyclohexyl)methylcarbamate (106 mg, 0.44 mmol), 1,4-Dioxane (0.5 ml) and 1-Butanol (0.5 ml). The mixture was sealed and irradiated in a microwave oven (Emrys "r Optimizer, Biotage) to 150°C for 4 hours.
  • a microwave tube was charged with 9-(2,5-dichlorobenzyl)-2-chloro-7H- purin-8(9H)-one (66 mg, 0.200 mmol; Intermediate 48), tert-butyl (ls,4s)-4- (aminomethyl)cyclohexylcarbamate (100 mg, 0.44 mmol), 1,4-Dioxane (0.5 ml) and 1-Butanol (0.5 ml). The mixture was sealed and irradiated in a microwave oven (Emrys 1 ' 1 Optimizer, Biotage) to 150°C in a microwave for 5 hours.
  • a microwave oven Emrys 1 ' 1 Optimizer, Biotage
  • the mixture was sealed and irradiated in a microwave oven (TimrysTM Optimizer, Biotage) to 150°C in a microwave for 5 hours.
  • the mixture was diluted with ethyl acetate (15 mL) and washed with saturated aqueous NH 4 Cl(I x 3 mL), brine(2 x 3mL), and dried over MgSO 4 .
  • the activity of the compounds described in the present invention may be determined by the following procedure. This procedure describes a kinase assay that measures the phosphorylation of a fluorescently- labeled peptide by full-length human recombinant active PKC ⁇ via fluorescent polarization using commercially available IMAP reagents.
  • the PKC ⁇ used was made from full-length, human cDNA (accession number LO1087) with an encoded His-6 sequence at the C-terminus. PKC ⁇ was expressed using the baculovirus expression system. The protein was purified with Ni- NTA affinity chromatography yielding a protein with 91% purity.
  • the substrate for this assay is a fluorescently-labeled peptide having the sequence LHQRRGSIKQ AKVHHVK (FITC)-NH 2 .
  • the stock solution of the peptide is 2 mM in water.
  • the IMAP reagents come from the IMAP Assay Bulk Kit, product
  • the kit materials include a 5X IMAP Binding Buffer and the IMAP Binding Reagent.
  • the Binding Solution is prepared as a 1:400 dilution of IMAP Binding Reagent into the IX IMAP Binding Buffer.
  • the substrate/ATP buffer for this assay consists of 20 mM HEPES, pH 8.
  • the buffer contains 100 nM substrate, 20 ⁇ M ATP, and 2 mM DTT which are added fresh just prior to use.
  • the kinase buffer containing the PKC ⁇ consists of 20 mM HEPES, pH 7.4 with 0.01% Tween-20. This buffer also contains.2 ng/ ⁇ L PKC ⁇ and 2 mM DTT which are added fresh just prior to use.
  • the plates used are Corning 3710 (Corning Incorporated, Corning,
  • the assay procedure starts the preparation of stock solutions of compounds at 10 mM in 100% DMSO.
  • the stock solutions and the control compound are serially diluted 1 :3.16 a total of 11 times into DMSO (37 ⁇ L of compound into 80 ⁇ L of DMSO).
  • a further dilution is performed by taking 4 ⁇ L compound and adding to 196 ⁇ L substrate/ATP Buffer.
  • 10 ⁇ L aliquots of the compounds are transferred to the Costar 3710 plate.
  • the kinase reaction is initiated by the addition of 10 ⁇ L PKC ⁇ . This reaction is allowed to incubate for 1 hour at ambient temperature.
  • the reaction is then quenched by the addition of 60 ⁇ L of Binding Solution.
  • the plate is incubated for an additional 30 minutes at ambient temperature.
  • the assay is measured using an AcquestTM Ultra- HTS Assay Detection System (Molecular Devices) in fluorescence polarization mode using 485 nm excitation and 530 nm emission.
  • Tables 1, 2 and 3 illustrate several examples of the compounds of the invention. These compounds were synthesized using one of the suitable procedures described above. The molecular weight of the compounds was confirmed by mass spectroscopy (m/z). The compounds of Tables 1, 2 and 3 were tested using the above-described PKC ⁇ IMAP assay.

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Abstract

L'invention porte sur un genre chimique de purinones et de 1H-imidazopyridinones, qui sont utiles comme inhibiteurs de PKC, et sur leurs procédés d'utilisation. Le genre est représenté par la Formule (I).
PCT/US2008/082832 2007-11-08 2008-11-07 Purinones et 1h-imidazopyridinones isomères comme inhibiteurs de pkc-thêta WO2009062059A2 (fr)

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