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WO2008143674A1 - Purinones et 1h-imidazopyridinones en tant qu'inhibiteurs de pkc-thêta - Google Patents

Purinones et 1h-imidazopyridinones en tant qu'inhibiteurs de pkc-thêta Download PDF

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Publication number
WO2008143674A1
WO2008143674A1 PCT/US2007/069530 US2007069530W WO2008143674A1 WO 2008143674 A1 WO2008143674 A1 WO 2008143674A1 US 2007069530 W US2007069530 W US 2007069530W WO 2008143674 A1 WO2008143674 A1 WO 2008143674A1
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Prior art keywords
alkyl
chosen
compound
salt
independently chosen
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PCT/US2007/069530
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English (en)
Inventor
Andrew Roughten
Yajing Rong
Koc Kan Ho
Michael Ohlmeyer
David Diller
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Pharmacopeia, Inc.
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Priority to CA002686485A priority Critical patent/CA2686485A1/fr
Priority to PCT/US2007/069530 priority patent/WO2008143674A1/fr
Priority to CN200780053087A priority patent/CN101679412A/zh
Priority to JP2010509317A priority patent/JP2010527999A/ja
Priority to MX2009012612A priority patent/MX2009012612A/es
Priority to EP07797679A priority patent/EP2152708A1/fr
Publication of WO2008143674A1 publication Critical patent/WO2008143674A1/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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • C07D473/32—Nitrogen atom
    • 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

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 6> appears to play a dual regulatory role in T-cell apoptosis.
  • PKC # in T-cells and its essential role in mature T- cell activation establish that 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.
  • autoimmune disease such as rheumatoid arthritis and lupus erythematosus
  • 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, PtI), 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 PKC0 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 0 inhibitors are useful in treatment of transplant rejection, gastrointestinal cancer, and diabetes. Summary of the Invention
  • the invention relates to compounds of the formula I:
  • Q is chosen from N and CH;
  • R 1 is chosen from nitrogen-attached heterocyclyl, substituted nitrogen- attached heterocyclyl and
  • n is an integer from 2 to 6;
  • R is chosen separately in each occurrence from -H, C 1 -C 4 alkyl and -
  • R is chosen separately in each occurrence from -H, C 1 -C 4 alkyl and a bond to R 24 ;
  • R 23 is chosen from -H, Ci-C 4 alkyl and a bond to R 24 ;
  • R 24 is chosen from -H, C 1 -C 4 alkyl or together with either of R 22 or R 23 forms a 5-7 membered nitrogen heterocycle optionally substituted with
  • R 2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted hetero arylalkyl.
  • R 2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted hetero arylalkyl.
  • the invention in another aspect relates to a method for treating 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 method comprises administering a therapeutically effective amount of a compound of formula I, or salt thereof.
  • R 1 is chosen from nitrogen-attached heterocyclyl, substituted nitrogen- attached heterocyclyl and
  • R 22 is chosen separately in each occurrence from -H, C 1 -C 4 alkyl and a bond to R 24 ;
  • R 23 is chosen from -H, C r C 4 alkyl and a bond to R 24 ;
  • R 24 is chosen from -H, Ci-C 4 alkyl or together with either of R 22 or R 23 forms a 5-7 membered nitrogen heterocycle optionally substituted with
  • R 2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted hetero arylalkyl.
  • R 21 is chosen separately in each occurrence from -H, Ci-C 4 alkyl and -OH.
  • R 22 is chosen separately in each occurrence from -H, C 1 -C 4 alkyl" is intended to
  • H CH, H for example.
  • R 1 when it is said that R 22 may be a bond to R 24 when n is 3, for example, then R 1 may be
  • R is chosen from (CH2 > « (CH *- s and (CH 2 ) ⁇ 3 wherein R 9 is chosen from amino(Ci-C6)alkyl, (Ci-C6)alkylamino(C 1 -C6)alkyl and di[(C 1 -C 6 )alkyl]amino(Ci-C 6 )alkyl.
  • R is
  • R 22 is chosen separately in each occurrence from -H and Ci-C 4 alkyl; and R 24 together with R 23 forms a 5-7 membered nitrogen heterocycle optionally substituted with C 1 -C 4 alkyl.
  • R 22 is chosen separately in each occurrence from -H and Ci-C 4 alkyl; R 23 is chosen from -H, Ci-C 4 alkyl; and R 24 is -H or C 1 -C 4 alkyl.
  • R 22 is chosen separately in each occurrence from H, C 1 -C 4 alkyl and a bond to R 24 ;
  • R 23 is chosen from H, Ci-C 4 alkyl; and
  • R 24 together with one occurrence of R 22 forms a 5-7 membered nitrogen heterocycle optionally substituted with Ci-C 4 alkyl.
  • R 2 is chosen from, H ⁇
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen,
  • L is a Co-Cio alkyl.
  • R is chosen from wherein
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen, -
  • R 15 and R 16 are independently chosen from -H and
  • the invention relates to compounds of the formula I, or salt thereof:
  • R is chosen from wherein
  • R 5 , R 6 , and R 9 are independently chosen from -H, Ci -C 4 alkyl, - OH, -OCH3, halogen, and aminoalkyl;
  • R 7 and R 8 are independently chosen from -H, C 1 -C 4 alkyl, and aminoalkyl;
  • L 1 is a Co-Cio alkyl optionally substituted with -OH, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • M is C 2 -Ci 0 alkyl optionally substituted with -OH, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 2 is chosen from, .
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen, -OCH 3 , -OCF 3 , -CF 3 , Ci-C 4 alkyl, and phenyl.
  • L is a Co-Cio alkyl.
  • R 4 is chosen from wherein
  • R 5 , R 6 , and R 9 are independently chosen from -H, Ci-C 4 alkyl, -
  • R 7 and R 8 are independently chosen from -H, Ci-C 4 alkyl, and aminoalkyl
  • R 13 and R 14 are independently chosen from -H, -OH, and Ci-C 4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N.
  • R 5 , R 6 , R 7 , and R 8 are independently chosen from -H and Ci-C 4 alkyl; R 9 is -R 17 -NR 7 R 8 ; wherein
  • R 17 is a C 1 -C 4 alkyl.
  • R 4 is chosen from R ⁇ and ⁇ y wherein
  • R 7 and R 8 are independently chosen from -H and -CH 3 ;
  • R » 18 is chosen from -H and -OH.
  • R 2 is chosen from wherein
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen, ⁇
  • R 15 and R 16 are independently chosen from -H and
  • the invention relates to compounds of the formula I, or salt thereof: (I)
  • Q is chosen from N and CH;
  • R is chosen from (CH 2 )I_ 5 (CH 2 J 1 5 (CH *! and
  • R 4 is chosen from wherein
  • R 5 , R 6 , and R 9 are independently chosen from -H, C 1 -C 4 alkyl, -
  • R 7 and R are independently chosen from -H, C 1 -C 4 alkyl, and aminoalkyl
  • R 13 and R 14 are independently chosen from -H, -OH, and Ci-C 4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
  • R 2 is chosen from,
  • R 10 , R 11 , and R 12 are independently chosen from -H, halogen,
  • R and R are independently chosen from -H and Ci-C 4 alkyl.
  • R 5 , R 6 , R 7 , and R 8 are independently chosen from -H and Ci-C 4 alkyl;
  • R > 1 1 7 ' is a C 1 -C 4 alkyl.
  • R 4 is chosen from wherein
  • R 7 and R 8 are independently chosen from -H and -CH 3 ;
  • R 18 is chosen from -H and -OH.
  • the invention is directed to a method of treatment of a T- cell mediated disease comprising administering a therapeutically effective amount of a compound of formula I, or salt thereof.
  • the T-cell mediated disease may be, for example, an autoimmune disease or an inflammatory disease.
  • the autoimmune disease may be, for example, rheumatoid arthritis or lupus erythematosus.
  • the inflammatory disease may be, for example, asthma or inflammatory bowel disease.
  • the invention is directed to a method of treatment of cancer, such as gastrointestinal cancer, comprising administering a therapeutically effective amount of a compound of formula I, or salt thereof.
  • the invention is directed to a method of treatment of diabetes comprising administering a therapeutically effective amount of a compound of formula I, or salt thereof.
  • Alkyl and alkane are intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl groups are those of C 2O or below.
  • Cycloalkjd is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c- butyl, c-pentyl, norbornyl and the like.
  • (Ci to C n ) Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof containing only hydrogen and one to n carbons. Examples include vinyl, allyl, cyclopropyl, propargyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Saturated (Ci to C n )hydrocarbon is identical in meaning to (Ci to C n )alkyl or (Ci to C n )alkane as used herein. Whenever reference is made to Co -n alkyl, (C 0 to C n )alkyl, or (C 0 to C n )alkane when number of carbon atoms is 0, a direct bond is implied.
  • 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.
  • 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, TJ196, but without the restriction of
  • 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 groups of from 1 to 8 carbon atoms of a straight, branched, 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 maybe 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.
  • Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
  • aryl 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. As commonly understood, when referring to arylalkyl as a substituent, it is intended that the point of attachment is the alkyl group. Examples of arylalkyl are benzyl, phenethyl, phenylpropyl and naphthylethyl. Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • Heterocycles also include spiroheterocycles. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
  • heterocyclyl residues additionally include piperazinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.
  • heterocycle contains at least one nitrogen, but may also contain additional nitrogen atom(s) and/or other heteroatoms such as O and/or S.
  • 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 S ) 2 CH 2 NH 2 , etc.
  • Alkylamino alkyl means a secondary amine bound to a core structure via an alkyl group, e.g., -CH 2 CH 2 NHCH 3 , -CH2CH2 CH 2 NHCH 2 CH 3 , etc.
  • Dialkyl aminoalkyl means a tertiary amine bound to a core structure via an alkyl group, e.g., -CH 2 N(CHs) 2 , -
  • Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with loweralkyl, halogen, haloalkyl, hydroxy, hydroxymethyl, loweralkoxy, perfluoroloweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkyl aminocarbonyl), sulfonamide, amino sulfonyl, alkylamino sulfonyl, cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, ureido, alkylureido, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl
  • halogen means fluorine, chlorine, bromine or iodine.
  • 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” refer to administering a medicament beforehand to forestall or obtund an attack. Persons of ordinary skill in the medical art (to which the present method claims are directed) recognize that the term “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.
  • Boc t-butyloxy carbonyl
  • CDI carbonyl diimidazole
  • DIEA N,N-diisopropylethyl amine
  • EEDQ 2-ethoxy-l-ethoxycarbonyl- 1,2-dihydroquinoline
  • FCC flash column chromography
  • HOBt hydroxybenzotriazole
  • 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 purinone analogs of the invention may be prepared on solid support (Scheme 2).
  • an acid cleavable linker can be attached to the Argogel- NH 2 resin.
  • the resin with the linker is first reductive aminated with a R'NH 2 .
  • the pyrimidine 2a which is similarly prepared from the first step in Scheme 1, is then attached to the resin bound amine by a nucleophilic displacement reaction. Reduction of the nitro group, followed by ring closure with 4-nitrophenyl chloroformate, yields the purinone.
  • the product can then be released from the solid support by treatment with acid such as trifloroacetic acid.
  • lH-imidazopyridinone analogs of the invention can be prepared by the method shown in Scheme 3. Sequential displacement of the chlorides of 2,6-dichloro- 3-nitropyridine 6 yields compound 8. Reduction of nitro group by reagents well known in the art, followed by cyclization using, for example, triphosgene affords the lH-imidazopyridinones 10.
  • Step 1 reductive amination with a primary amine
  • the shaking vessel was then drained, and the resin was washed with CH 3 OH (IX), CH 2 Cl 2 (2X), CH 3 OH (IX), CH 2 Cl 2 (2X), CH 3 OH (IX), CH 3 OH (1X30 min) and CH 2 Cl 2 (2X).
  • the resulting resin-bound secondary amine 20 gave a positive result with the bromophenol blue staining test.
  • the resin was dried in vacuo.
  • Step 2 N-arylation with 4-amino-2-chloro-5-nitropyrimidine
  • resin-bound secondary amine 20 in 25 mL of DMF and 2.18 mL of N,N-diisopropylethylamine (12.5 mmol, 0.25 M, 3.4 eq.) in a 100 mL shaking vessel was added a solution of 12.5 mmol (0.25 M, 3.4 eq.) of an 4-amino-2-chloro-5-nitropyrimidine in 25 mL of DMF. The mixture was shaken at 25 0 C for 16 h.
  • the shaking vessel was drained and the resin was washed with DMF (2X), CH 2 Cl 2 (IX), DMF (IX), CH 2 Cl 2 (2X), CH 3 OH (2X) and CH 2 Cl 2 (2X).
  • the resulting resin-bound nitropyrimidine 21 gave a negative result with the bromophenol blue staining test.
  • the resin was dried in vacuo.
  • Step 3 reduction of the nitro group
  • the shaking vessel was recharged with 60 mL of a freshly prepared 0.5 M solution of sodium hydrosulf ⁇ te in 40 mL of H 2 O and 20 mL of 1,4-dioxane and 0.93 mL of a saturated aqueous solution of ammonia that was prepared as described above.
  • the resin suspension was shaken for 16 h at 25 0 C.
  • the shaking vessel was drained and the resin was washed with H20: 1,4-dioxane 2:1 (v/v) (2X), anhydrous CH 3 OH (2X), anhydrous DMF (2X), CH 2 Cl 2 (2X) and anhydrous THF (2X).
  • the resulting resin- bound 5-aminopyrimidine 22 gave a positive result with the bromophenol blue staining test.
  • the resin was dried in vacuo.
  • Step 4 formation of purinone ring
  • the shaking vessel was then drained and the resin was washed with CH 2 Cl 2 (2X), CH3OH (2X), CH 2 Cl 2 (2X), CH 3 OH (2X) and CH 2 Cl 2 (2X).
  • the resulting resin gave a negative result with the bromophenol blue staining test and was used without drying.
  • To this resin was added 60 mL of a solution of 1.68 g (30 mmol, 0.5 M, 32.2 eq.) of KOH in 15 mL of H 2 0 and 45 mL of DMSO. The resulting resin suspension was shaken for 18 h.
  • Step 5 cleavage from resin
  • 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 PKCO via fluorescent polarization using commercially available IMAP reagents.
  • the PKC ⁇ used was made from full-length, human cDNA (accession number LO 1087) with an encoded His-6 sequence at the C-terminus. PKC ⁇ was expressed using the baculo virus 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 LHQRRGS IKQ AKVHHVK (FITC)-NH 2 . The stock solution of the peptide is 2 mM in water.
  • the IMAP reagents come from the MAP Assay Bulk Kit, product #R8063 or #R8125 (Molecular Devices, Sunnyvale, CA).
  • 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 7.4 with 5 mM MgCl 2 , and 0.01% Tween-20. Additionally, 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 PKCO consists of 20 mM HEPES, pH 7.4 with 0.01% Tween-20. This buffer also contains.2 ng/ ⁇ L PKCO and 2 mM DTT which are added fresh just prior to use.
  • the plates used are Corning 3710 (Corning Incorporated, Corning, NY). These are non-treated black polystyrene, 384-well with flat-bottoms. The serial dilutions are performed Nunc V-bottom 96-well plates (Cat#442587, Nunc A/S, Roskilde, Denmark).
  • 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.
  • entries identified with "1” had values above 15 iiM; entries identified with "2” had values above 100 tiM; entries identified with "3” had values above 1 ⁇ M; entries identified with "4" had values above 10 ⁇ M.
  • Table 2 also shows selectivity of the compounds of the invention by showing their IC50 values for kinase SGK. Entries identified with “1” had values above 15 nM; entries identified with “2” had values above 100 nM; entries identified with “3” had values above 1 ⁇ M; entries identified with "4" had values above 10 ⁇ M. In Table 2, “nd” stands for “not determined.” Table 2.
  • IL-2 is a T cell-derived lymphokine that modulates immunological effects on many cells of the immune system, including cytotoxic T cells, natural killer cells, activated B cells and lymphokine-activated cells. It is a potent T cell mitogen that is required for the T cell proliferation, promoting their progression from Gl to S phase of the cell cycle. It is a growth factor for all subpopulations of T lymphocytes, as well as stimulating the growth of NK cells. It also acts as a growth factor to B cells and stimulates antibody synthesis.
  • IL-2 Due to its effects on both T and B cells, IL-2 is a major central regulator of immune responses. It plays a role in anti- inflammatory reactions, tumor surveillance, and hematopoiesis. It also affects the production of other cytokines, inducing IL-I, TNF - ⁇ and TNF- ⁇ secretion, as well as stimulating the synthesis of IFN- ⁇ in peripheral leukocytes. IL-2, although useful in the immune response, also causes a variety of problems. IL-2 damages the blood-brain barrier and the endothelium of brain vessels. These effects may be the underlying causes of neuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue, disorientation and depression. It also alters the electrophysiological behavior of neurons.
  • T cells that are unable to produce IL-2 become inactive (anergic). This renders them potentially inert to any antigenic stimulation they might receive in the future.
  • agents which inhibit IL-2 production may be used for immunosupression or to treat or prevent inflammation and immune disorders. This approach has been clinically validated with immunosuppressive drugs such as cyclosporin, FK506, and RS61443.
  • Tables 1-3 demonstrates utility of the compounds of the invention in inhibition of PKC ⁇ and their utility for treatment of 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.
  • autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and multiple sclerosis
  • inflammatory diseases such as asthma and inflammatory bowel disease
  • transplant rejection transplant rejection
  • gastrointestinal cancer gastrointestinal cancer
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereo isometric 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 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, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically 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.
  • 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.
  • AU methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the 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.
  • 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.
  • Formulations for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacterio stats 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.
  • 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.
  • compositions will usually 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.
  • the compounds of formula (I) are preferably administered orally or by injection (intravenous or subcutaneous).
  • 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.

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Abstract

L'invention concerne un genre chimique de purinones et de 1H-imidazopyridinones qui sont utiles en tant qu'inhibiteurs de PKCΘ, et leurs procédés d'utilisation. Le genre est représenté par la formule (I). Un exemple représentatif est: (II).
PCT/US2007/069530 2007-05-23 2007-05-23 Purinones et 1h-imidazopyridinones en tant qu'inhibiteurs de pkc-thêta WO2008143674A1 (fr)

Priority Applications (6)

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CA002686485A CA2686485A1 (fr) 2007-05-23 2007-05-23 Purinones et 1h-imidazopyridinones en tant qu'inhibiteurs de pkc-theta
PCT/US2007/069530 WO2008143674A1 (fr) 2007-05-23 2007-05-23 Purinones et 1h-imidazopyridinones en tant qu'inhibiteurs de pkc-thêta
CN200780053087A CN101679412A (zh) 2007-05-23 2007-05-23 作为PKC-θ抑制剂的嘌呤酮类和1H-咪唑并吡啶酮类
JP2010509317A JP2010527999A (ja) 2007-05-23 2007-05-23 ＰＫＣ−θ阻害剤としてのプリノン類および１Ｈ−イミダゾピリジノン類
MX2009012612A MX2009012612A (es) 2007-05-23 2007-05-23 Purinonas e inhibidores 1h-imidazopiridinonas como pkc-theta.
EP07797679A EP2152708A1 (fr) 2007-05-23 2007-05-23 Purinones et 1h-imidazopyridinones en tant qu'inhibiteurs de pkc-thêta

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WO2009062059A3 (fr) * 2007-11-08 2009-11-12 Pharmacopeia, Llc Purinones et 1h-imidazopyridinones isomères comme inhibiteurs de pkc-thêta
US7897600B2 (en) 2008-12-16 2011-03-01 Eli Lilly And Company Amino pyrazole compound
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7989459B2 (en) * 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US8501735B2 (en) 2009-10-29 2013-08-06 Palau Pharma, S.A. N-containing heteroaryl derivatives as JAK3 kinase inhibitors
US10189841B2 (en) 2015-11-20 2019-01-29 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors

Families Citing this family (3)

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GB201321737D0 (en) * 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic Agents
IL281391B2 (en) * 2018-09-13 2025-04-01 Kissei Pharmaceutical Imidazopyridinone compound
JP7383818B2 (ja) * 2019-11-25 2023-11-20 ザイ ラボ （シャンハイ） カンパニー、リミテッド． Ｄｎａ－ｐｋ阻害剤としてのピリミドイミダゾル系化合物

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WO2006108103A1 (fr) 2005-04-05 2006-10-12 Pharmacopeia, Inc. Derives de purine et d'imidazopyridine en vue d'une immunosuppression
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WO2007035873A1 (fr) 2005-09-21 2007-03-29 Pharmacopeia, Inc. Dérivés de purinone pour le traitement de maladies neurodégénératives

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WO2001019828A2 (fr) 1999-09-17 2001-03-22 Basf Aktiengesellschaft Inhibiteurs de kinase utilises comme agents therapeutiques
WO2006108103A1 (fr) 2005-04-05 2006-10-12 Pharmacopeia, Inc. Derives de purine et d'imidazopyridine en vue d'une immunosuppression
DE102005042742A1 (de) 2005-09-02 2007-03-08 Schering Ag Substituierte Imidazo[1,2b]pyridazine als Kinase-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
WO2007035873A1 (fr) 2005-09-21 2007-03-29 Pharmacopeia, Inc. Dérivés de purinone pour le traitement de maladies neurodégénératives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7989459B2 (en) * 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
WO2009062059A3 (fr) * 2007-11-08 2009-11-12 Pharmacopeia, Llc Purinones et 1h-imidazopyridinones isomères comme inhibiteurs de pkc-thêta
US7897600B2 (en) 2008-12-16 2011-03-01 Eli Lilly And Company Amino pyrazole compound
US8501735B2 (en) 2009-10-29 2013-08-06 Palau Pharma, S.A. N-containing heteroaryl derivatives as JAK3 kinase inhibitors
US8946257B2 (en) 2009-10-29 2015-02-03 Vectura Limited N-containing heteroaryl derivatives as JAK3 kinase inhibitors
US10189841B2 (en) 2015-11-20 2019-01-29 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors
US10399980B2 (en) 2015-11-20 2019-09-03 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors
US11161848B2 (en) 2015-11-20 2021-11-02 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors
US12043623B2 (en) 2015-11-20 2024-07-23 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors

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JP2010527999A (ja) 2010-08-19

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