WO2002018380A1 - 7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire - Google Patents

7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire Download PDF

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WO2002018380A1
WO2002018380A1 PCT/EP2001/009689 EP0109689W WO0218380A1 WO 2002018380 A1 WO2002018380 A1 WO 2002018380A1 EP 0109689 W EP0109689 W EP 0109689W WO 0218380 A1 WO0218380 A1 WO 0218380A1
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compound
mmol
alkyl
added
cycloalkyl
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PCT/EP2001/009689
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Jian Jeffrey Chen
James Patrick Dunn
David Michael Goldstein
Julie Anne Lim
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F. Hoffmann-La Roche Ag
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Priority to KR1020037002936A priority Critical patent/KR100571339B1/ko
Priority to AU2001293784A priority patent/AU2001293784B2/en
Priority to AU9378401A priority patent/AU9378401A/xx
Priority to BR0113628-3A priority patent/BR0113628A/pt
Priority to MXPA03001821A priority patent/MXPA03001821A/es
Priority to JP2002523895A priority patent/JP4141830B2/ja
Priority to CA002420286A priority patent/CA2420286A1/fr
Priority to EP01974206A priority patent/EP1315726A1/fr
Publication of WO2002018380A1 publication Critical patent/WO2002018380A1/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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to 7-oxo-pyridopyrimidines.
  • the present invention provides 2,6-disubstituted 7-oxo-pyrido[2,3-d]pyrimidines, a process for their manufacture, pharmaceutical preparations comprising the same, and methods for using the same.
  • Mitogen-activated protein kinases is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation.
  • the kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines.
  • One group of MAP kinases is the p38 kinase group that includes various isoforms (e.g., p38 , p39 ⁇ , p38 ⁇ and p38 ⁇ ).
  • the p38 kinases are responsible for phosphorylating and activating transcription factors as well as other kinases, and are activated by physical and chemical stress, pro- inflammatory cytokines and bacterial lipopolysacchari.de. More importantly, the products of the p38 phosphorylation have been shown to mediate the production of inflammatory cytokines, including TNF and EL-1, and cyclooxygenase-2. Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF- ⁇ is a cytokine produced primarily by activated monocytes and macrophages. Its excessive or unregulated production has been implicated as playing a causative role in the pathogenesis of rheumatoid arthritis.
  • TNF has also been implicated in viral infections, such as HTV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein- Barr virus, human herpes virus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
  • HSV-1 herpes simplex virus type-1
  • HSV-2 herpes simplex virus type-2
  • CMV cytomegalovirus
  • VZV varicella-zoster virus
  • Epstein- Barr virus Epstein- Barr virus
  • human herpes virus-6 HHV-6
  • HHV-7 human herpesvirus-7
  • HHV-8 human herpesvirus-8
  • pseudorabies rheumatoid arthritis
  • p38 has been implicated in stroke, Alzheimer's disease, osteoarthritis, lung injury, septic shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis, see e.g. J. Exp. Opin. Ther. Patents, (2000) 10(1).
  • Certain pyrido[2,3-d]pyrimidines have been disclosed as inhibitors of protein tyrosine kinase mediated cellular proliferation, see WO 96/34867.
  • One aspect of the present invention provides compounds represented by the Formula:
  • R 1 is hydrogen or alkyl
  • R is substituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl, heterocyclyl, heterocyclyl spiro cycloalkyl, aralkoxy, alkoxy, alkyl-S(O) n -alkylene- (where n is 1 or 2) or SO 2 Ar 2 ;
  • the compounds of Formula I and their aforementioned salts are inhibitors of protein kinases, and exhibit effective activity against p38 in vivo. Therefore, the compounds can be used for the treatment of diseases mediated by the pro-inflammatory cytokines such as TNF and IL-1.
  • cytokines such as TNF and IL-1.
  • another aspect of the present invention provides methods for the treatment of p38 mediated diseases or conditions in which a therapeutically effective amount of a compound of Formula I is administered to a patient in need of such treatment.
  • Yet another aspect of the present invention provides methods for preparing the compounds described above.
  • Still yet another aspect of the present invention provides methods for preparing medicaments useful for the treatment of the p38 mediated diseases and conditions. Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
  • Acyl means a radical -C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.
  • Acylamino means a radical -NR'C(O)R, where R' is hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein.
  • Representative examples include, but are not limited to formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like.
  • Alkoxy means a radical -OR where R is an alkyl as defined herein e.g., methoxy, ethoxy, propoxy, butoxy and the like.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, wo-butyl, tert-butyl, pentyl, and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkylsulfonyl-alkyl means a radical R -S(O) 2 -R b - where R a is alkyl and R b is alkylene as defined herein.
  • Alkylthio means a radical -SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
  • Aralkoxy means a radical -O-R a -R b , where R a is alkylene and R b is aryl as defined above.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical which is optionally substituted independently with one or more substituents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano, amino, monoalkylamio, dialkylamino, methylenedioxy, ethylenedioxy and acyl. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, methoxyphenyl, 1 -naphthyl, 2-naphthyl, and the derivatives thereof.
  • Cycloalkyl refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl- cyclohexyl, and the like.
  • Cycloalkylalkyl means a radical -R a R D where R a is an alkylene group and R D is cycloalkyl group as defined herein, e.g., cyclohexylmethyl, and the like.
  • Substituted cycloalkyl means a cycloalkyl radical as defined herein with one, two or three (preferably one) ring hydrogen atoms independently replaced by cyano or -Y-C(O)R (where Y is absent or an alkylene group and R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, or optionally substituted phenyl).
  • Dialkylamino means a radical -NRR' where R and R' independently represent an alkyl, hydroxyalkyl, cycloalkyl, or cycloalkylalkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(l-methylethyl)amino, (methyl)(hydroxymethyl)amino,
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
  • Haloalkyl means alkyl substituted with one or more same or different halo atoms, e.g., -CH 2 C1, -CF 3 , -CH 2 CF 3 , -CH 2 CC1 3 , and the like.
  • Heteroalkyl means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of -OR a , -NR b R c , and -S(O) n R d (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R a is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R b and R c are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R d is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamin
  • Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-l-hydroxymethylethyl, 2,3- dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2- hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
  • Heteroalkylsubstituted cycloalkyl means a cycloalkyl radical as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a heteroalkyl group with the understanding that the heteroalkyl radical is attached to the cycloalkyl radical via a carbon-carbon bond.
  • Representative examples include, but are not limited to, 1-hydroxymethylcyclopentyl, 2-hydroxymethylcyclohexyl, and the like.
  • Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, 2-, 3-, or 4-aminocyclohexyl, 2-, 3-, or 4- methanesulfonamido-cyclohexyl, and the like, preferably 4-hydroxycyclohexyl, 2- aminocyclohexyl or 4-methanesulfonamido-cyclohexyl.
  • Heterosubstituted cycloalkyl-alkyl means a radical R a R b - where R a is a heterosubstituted cycloalkyl radical and R is an alkylene radical.
  • Heterocyclyl means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0) n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, -(X) n -C(O)R (where X is O or NR' , n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxy (when n is 0), alkoxy, amino, monoalkylamino, dialkylamino, or optionally substituted phenyl, and R' is H or alkyl), -alkylene-C(O)R (where R is OR or NR'R'and R is hydrogen, alkyl or haloalkyl, and R' and R" are independently hydrogen or alkyl, or R' and R" together with the nitrogen atom to which they are attached
  • heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N- methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino- 1- oxide, thiomorpholino- 1,1 -dioxide, pyrrolinyl, imidazolinyl, N-methanesulfonyl- piperidin-4-yl, and the derivatives thereof.
  • heterocyclyl has the same meaning as specified hereinbefore, however in addition the heterocyclyl ring can also be substituted by four substituents, whereby the substituents can be as specified herein before.
  • substituent -alkylene-C(O)R can also have the meaning R is NR'R" whereby R' and R" together with the nitrogen atom to which they are attached form a ring and in the substituent -S(O) n R with n is 1 or 2, R can have also the meaning haloalkyl.
  • heterocyclyl can, in addition to the meanings as specified above also have the meaning tetrahydrothiopyranyl, tetrahydrothiofuryl and tetrahydrofuryl and even more specifically piperidin-4-yl, pi ⁇ eridin-1-yl, tetrahydropyran-4-yl, py ⁇ olidin-3-yl, morpholino, piperzin-1-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-3-yl or tetrahydrofur-3-yl, preferably piperidin-4-yl, whereby as stated above each specifically named heterocyclyl substituent can itself be substituted as defined above, preferably by any of the specific substituents exemplified in the table 1 and the specific examples.
  • Heterocyclylalkyl means a radical -R a R D where R a is an alkylene group and R D is a heterocyclyl group as defined above with the understanding that R b is attached to R a via a carbon atom of the heterocyclyl ring, e.g., tetrahydropyran-2- ylmethyl, 2- or 3-piperidinylmethyl, and the like.
  • Heterocyclyl spiro cycloalkyl means a spiro radical consisting of a cycloalkyl ring and a heterocyclic ring with each ring having 5 to 8 ring atoms and the two rings having only one carbon atom in common, with the understanding that the point of attachment of the heterocyclyl spiro cycloalkyl radical is via the cycloalkyl ring.
  • the spiro radical is formed when two hydrogen atoms from the same carbon atom of the cycloalkyl radical are replaced with a heterocyclyl group as defined herein, and may be optionally substituted with alkyl, hydroxy, hydroxyalkyl, or oxo.
  • Examples include, but are not limited to, for example, l,4-dioxaspiro[4.5]decan-8-yl, l,3-diazaspiro[4.5]decan- 8-yl, 2,4-dione-l,3-diaza-spiro[4.5]decan-8-yl, l,5-dioxa-spiro[5.5]undecan-9-yl, (3- hydroxymethyl-3-methyl)-l,5-dioxa-spiro[5.5]undecan-9-yl, and the like, preferably 1,4- dioxaspiro[4.5]decan-8-yl and l,5-dioxa-spiro[5.5]undecan-9-yl.
  • Hydroalkyl means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy- 1 -hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and l-(hydroxymethyl)-2-hydroxyethyl.
  • hydroxyalkyl is used to define a subset of heteroalkyl groups.
  • "Leaving group” has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulf onyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O- dimethylhydroxylamino, and the like.
  • halo such as chloro, bromo, and iodo
  • alkanesulfonyloxy arenesulfonyloxy
  • alkylcarbonyloxy e.g., ace
  • “Monoalkylamino” means a radical -NHR where R is an alkyl, hydroxyalkyl, cycloalkyl, or cycloalkylalkyl group as defined above, e.g., methylamino, (l-methylethyl)amino, hydroxymethylamino, cyclohexylamino, cyclohexylmethylamino, cyclohexylethylamino, and the like.
  • Optionally substituted phenyl means a phenyl ring which is optionally substituted independently with one or more substituents, preferably one or two substituents selected from the group consisting of alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano, amino, methylenedioxy, ethylenedioxy, and acyl.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulf
  • pro-drug and “prodrug” are used interchangeably herein and refer to any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula I are prepared by modifying one or more functional group(s) present in the compound of Formula I in such a way that the modification(s) may be cleaved in vivo to release the parent compound.
  • Prodrugs include compounds of Formula I wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters groups (e.g.
  • ethyl esters, morpholinoethanol esters of carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the like, See Bundegaard, H. "Design of Prodrugs" ⁇ l-92, Elesevier, New York-Oxford (1985).
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Green and P.G. Futs, Protective Groups in Organic Chemistry, (Wiley, 2 nd ed. 1991) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996).
  • Representative amino protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2- trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro- veratryloxycarbonyl (NVOC), and the like.
  • hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Treating" or “treatment” of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a therapeutically effective amount means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • One aspect of the present invention provides compounds represented by the formula:
  • R 1 is hydrogen or alkyl
  • R 2 is substituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl, heterocyclyl, heterocyclyl spiro cycloalkyl, aralkoxy, alkoxy, alkyl-S(O) n -alkylene- (where n is 1 or 2) or SO ⁇ -Ar 2 ;
  • n is 1 or 2, preferably 1, and X is hydrogen, alkyl, halo, nitro, cyano or methoxy, particularly halo, alkyl or methoxy, with substitution (fluoro, chloro, methyl and methoxy) at the 2-position being preferred.
  • R 1 is hydrogen or alkyl, e.g. methyl. More preferably,
  • R 1 is hydrogen .
  • R 2 is alkylsulfonyl-alkyl, aralkoxy, e.g. benzyloxy, alkoxy, heterosubstituted cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl or heterocyclyl. More preferably R is heterosubstituted cycloalkyl, preferably 4-heterosubstituted cyclohexyl, e.g.
  • R 2 can also be alkyl-sulfonylalkyl, e.g. (1,1- dimethyl-2-methylsulfonyl)ethyl or (l,l-dimethyl-3- methylsulfonyl)propyl.
  • the present invention includes all tautomeric forms. Furthermore, the present invention also includes all pharmaceutically acceptable salts of those compounds along with prodrug forms of the compounds and all stereoisomers whether in a pure chiral form or a racemic mixture or other form of mixture.
  • R 1 is hydrogen or alkyl
  • R is substituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl, heterocyclyl, heterocyclyl spiro cycloalkyl or SO 2 Ar 2 ;
  • R 3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, -alkylene-C(O)-R (where R is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and each of Ar 1 and Ar 2 is independently an aryl.
  • n 1 or 2 and X is hydrogen, alkyl, halo, nitro, cyano or methoxy, particularly halo, alkyl or methoxy, with substitution at the 2-position being prefe ⁇ ed.
  • R 1 is hydrogen or alkyl. More preferably, R 1 is hydrogen .
  • R 2 is heterosubstituted cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl or heterocyclyl. More preferably R 2 is heterosubstituted cycloalkyl or heterocyclyl, e.g. 4-substituted cyclohexyl, substituted piperidinyl, or tetrahydropyranyl.
  • R 3 of compounds of Formula I is hydrogen, alkyl, haloalkyl, cycloalkyl, cyanomethyl, heteroalkyl, aryl, aralkyl or -alkylene-C(O)-R (where R is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino).
  • R 3 is hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyanomethyl, 2- hydroxyethyl, 4-fluorophenyl, benzyl, carboxymethyl or methoxycarbonylmethyl.
  • R 3 is hydrogen or methyl.
  • the present invention provides compounds as defined in:
  • R 1 is hydrogen or alkyl
  • R 2 is substituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl, heterocyclyl, heterocyclyl spiro cycloalkyl, or -SO 2 Ar 2 ;
  • R 3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, -alkylene-C(O)-R (where R is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and each of Ar 1 and Ar 2 is independently aryl.
  • the IC 50 of Compounds of Formula I in the in vitro p38 assay is less than 10 ⁇ M, preferably less than 5 ⁇ M, more preferably less than 3 ⁇ M, and most preferably less than 1 ⁇ M.
  • Compounds of Formula I in Table I have IC50 in the in vitro p38 assay of from about 4.76 ⁇ M to about 0.0003 ⁇ M.
  • the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the present invention also includes all pharmaceutically acceptable salts of those compounds along with prodrug forms of the compounds and all stereoisomers whether in a pure chiral form or a racemic mixture or other form of mixture.
  • the compounds of Formula I are capable of further forming pharmaceutically acceptable acid addition salts. All of these forms are within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, Iactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge et al., "Pharmaceutical Salts,” J. of Pharmaceutical Science, 1977, 66, 1-19).
  • the acid addition salts of the basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts can be formed with metal ions or amines, such as alkali and alkaline earth metal ions or organic amines.
  • metal ions which are used as cations include sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al , "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977, 66, 1-19).
  • the base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
  • the free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • the compounds of the present invention can be prepared by a variety of methods, using procedures well known to those of skill in the art. In one aspect of the present invention, a method for preparing compounds of Formula I is shown in Scheme 1 below.
  • Treatment of a compound of Formula la (the person skilled in the art is familiar with its preparation and/or the commercial source from which he can purchase it) with a primary amine (R 3 -NH 2 ) provides a compound of Formula lb.
  • This reaction is conveniently carried out in a solvent which is inert under the reaction conditions, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, an optionally halogenated aromatic hydrocarbon, or an open-chain or cyclic ether such as tetrahydrofuran, a formamide or a lower alkanol.
  • the reaction is carried out at about -20 °C to about 120 °C.
  • Reduction of a compound of Formula lb provides an alcohol of Formula lc.
  • This reduction is typically carried out using lithium aluminum hydride in a manner well known to those of skill in the art (e.g., in a solvent which is inert under the conditions of the reduction, preferably an open-chain or cyclic ether, especially tetrahydrofuran, at about -20 °C to about 70 °C, preferably at about 0 °C to about room temperature).
  • Oxidation of an alcohol of Formula lc in the next step provides a carboxaldehyde of Formula Id.
  • the oxidation is typically ca ⁇ ied out with manganese dioxide, although numerous other methods can also be employed (see, for example, Advanced Organic Chemistry, 4TM Ed., March, John Wiley & Sons, New York (1992)).
  • the reaction is carried out conveniently in a solvent which is inert under the specific oxidation conditions, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, or an optionally halogenated aromatic hydrocarbon.
  • a solvent which is inert under the specific oxidation conditions, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, or an optionally halogenated aromatic hydrocarbon.
  • the oxidation is ca ⁇ ied out at about 0 °C to about 60 °C.
  • Reaction of a carboxaldehyde of Formula Id with an aryl substituted acetate, Ar 1 -CH 2 -CO 2 R (where R is an alkyl group) in a presence of a base provides a compound of Formula Ie.
  • a base Any relatively non-nucleophilic base can be used including carbonates, such as potassium carbonate, lithium carbonate, and sodium carbonate; bicarbonates, such as potassium bicarbonate, lithium bicarbonate, and sodium bicarbonate; amines, such as secondary and tertiary amines; and resin bound amines such as l,3,4,6,7,8-hexahydro-2H pyrimido[l,2-a]pyrimidine.
  • the reaction is ca ⁇ ied out in a solvent which is relatively polar but inert under the reaction conditions, preferably an amide such as dimethyl formamide, N-substituted pyrrolidinone, especially l-methyl-2-py ⁇ olidinone, and at a temperature of about 70 °C to about 150 °C, especially at or near the reflux temperature of the solvent to assist in the noted azeotropic removal of water.
  • a solvent which is relatively polar but inert under the reaction conditions, preferably an amide such as dimethyl formamide, N-substituted pyrrolidinone, especially l-methyl-2-py ⁇ olidinone, and at a temperature of about 70 °C to about 150 °C, especially at or near the reflux temperature of the solvent to assist in the noted azeotropic removal of water.
  • Oxidation of Ie with an oxidizing agent e.g. a peracid such as 3- chloroperbenzoic acid (i.e., MCPBA) or Oxone ® , provides a sulfone (If) which can be converted to a variety of target compounds.
  • an oxidizing agent e.g. a peracid such as 3- chloroperbenzoic acid (i.e., MCPBA) or Oxone ®
  • MCPBA 3- chloroperbenzoic acid
  • Oxone ® a peracid
  • the oxidation of Ie is carried out in a solvent which is inert under the conditions of the oxidation.
  • the solvent is preferably a halogenated aliphatic hydrocarbon, especially chloroform.
  • the solvent can be water, methanol or a mixture of an organic solvent (such as methanol, acetonitrile or tetrahydrofuran) and water.
  • the reaction temperature depends on the solvent used. For an organic solvent, the reaction temperature is generally at about -20 °C to about 50 °C, preferably about 0 °C to about room temperature. When water is used as the solvent, the reaction temperature is generally from about 0 °C to about 50 °C, preferably about 0 °C to about room temperature.
  • the oxidation can be ca ⁇ ied out under catalytic conditions with rhenium/peroxide based reagents.
  • Reaction of the compound If with an amine provides the compounds of Formula F (i.e. compounds I, wherein R 1 is hydrogen). Further alkylation of I' then provides compounds of Formula I, where R 1 is not hydrogen.
  • the reaction can be carried out in the presence or absence of solvent. Conveniently, the reaction is carried out at temperatures of from about 0 °C to about 200 °C, more preferably about room temperature to about 150 °C.
  • the sulfide Ie or the co ⁇ esponding sulfoxide can be reacted directly an amine (R'-NHa) to provide the compounds of Formula I' .
  • R'-NHa an amine
  • the present invention provides a method of preparing compounds of Formula I, by treating a compound of general Formula Ie or If with an amine (R ⁇ ISfflb) and optionally reacting the resulting product with R*-L, where R 1 is defined above, but excludes hydrogen, and L is a leaving group.
  • Suitable bases include alkoxides, such as tert-butoxides, and other relatively non-nucleophilic bases that are capable of deprotonating the compound of Formula Il-a. Cyclization of a compound of Formula Il-b with thiourea in the presence of a base affords a pyrimidine of Formula II-c. Typically, this cyclization reaction is conducted in an alcoholic solvent under refluxing conditions using a corresponding alkoxide as a base.
  • Suitable bases include a relatively non- nucleophilic bases including carbonates, such as potassium carbonate, lithium carbonate, and sodium carbonate; and bicarbonates, such as potassium bicarbonate, lithium bicarbonate, and sodium bicarbonate.
  • the reaction is carried out in a relatively polar solvent that inert under the reaction conditions, preferably acetone, dimethylformamide (DMF) or methylpy ⁇ olidinone (MP).
  • Alkylation of the amine group of a compound of Formula II-e with an alkylating agent R 3 -X 2 (where R 3 is those defined above and X 2 is a leaving group, such as halide) then provides a compoud of Ie which can be further converted to a compound of Formula F as described in Scheme I.
  • R 3 is those defined above and X 2 is a leaving group, such as halide
  • another aspect of the present invention provides a method of preparing a pyrimidine compound of Formula II-c by reacting an acetal of the Formula II- a with with an alkyl formate and reacting the resulting product with a thiourea.
  • Yet another aspect of the present invention provides a method for preparing a compound of Formula II-e, by reacting a compound of Formula II-c with an alkylating agent or an aryl substituted acetate, and reacting the resulting product with an aryl substituted acetate or an alkylating agent, respectively.
  • the compounds of Formula I and the pharmaceutically acceptable salts of basic compounds of Formula I with acids can be used as medicaments, e.g., in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered enterally, e.g., orally in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, e.g., in the form of nasal sprays, or rectally, e.g., in the form of suppositories.
  • they may also be administered parenterally, e.g., in the form of injection solutions.
  • the compounds of Formula I and their aforementioned pharmaceutically acceptable salts can be processed with pharmaceutically inert, organic or inorganic carriers for the production of pharmaceutical preparations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can
  • __ also contain therapeutically valuable substances other than the compounds of Formula I and their aforementioned pharmaceutically acceptable salts.
  • Medicaments which contain a compound of Formula I or a pharmaceutically acceptable salt of a basic compound of Formula I with an acid in association with a compatible pharmaceutical carrier material are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more of these compounds or salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with a compatible pharmaceutical carrier.
  • the compounds of Formula I and their aforementioned pharmaceutically acceptable salts can be used in accordance with the invention as therapeutically active substances, especially as antiinflammatory agents or for the prevention of graft rejection following transplant surgery.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a convenient daily dosage should be about 0.1 mg/kg to about 100 mg/kg, preferably about 0.5 mg/kg to about 5 mg/kg.
  • the daily dosage may be administered as a single dose or in divided doses and, in addition, the upper dosage limit referred to earlier may be exceeded when this is found to be indicated.
  • the use of compounds of Formula I and their aforementioned pharmaceutically acceptable salts for the production of medicaments especially in the treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, in the treatment of asthma, central nervous system disorders or diabetic complications or for the prevention of graft rejection following transplant surgery, is also an object of the invention.
  • the present invention provides a method of treating a cytokine- mediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula I, or a pharmaceutically acceptable salt or tautomer thereof.
  • Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for use as antipyretics for the treatment of fever.
  • Compounds of the invention would be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions.
  • Such compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease.
  • the compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes virus.
  • the compounds are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs.
  • cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection.
  • the compounds are also useful for the treatment of Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE), skin- related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, and scar tissue formation.
  • Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
  • the compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue.
  • Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemangiomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis.
  • the compounds of the invention may also be useful for preventing the production of cyclooxygenase-2.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiinflammatories, such as together with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB 4 antagonists and LTA hydrolase inhibitors.
  • TNF mediated disorder refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8.
  • TNF a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.
  • p38 mediated disorder refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8.
  • IL-1 IL-6
  • IL-8 another factor to be released
  • TNF- ⁇ has close structural homology with TNF- ⁇ (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF- ⁇ and TNF- ⁇ are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
  • Mpts. are in degrees Celsius (°C).
  • Sulfone 1 This example illustrates a method for preparing sulfone 1 from ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate. Step 1 Preparation of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate
  • Sulfone 2 This example illustrates a method for producing 6-(2-chlorophenyl)-2- methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol (Sulfone 2) starting with ethyl 4-chloro-2- methylthiopyrimidine-5-carboxylate.
  • Step 2.1 Preparation of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate
  • sulfone 1 (0.36 g, 1.0 mmol) in 10 mL of l-methyl-2- pyrrolidinone was added tran_.-l,4-diaminocyclohexane (1.05 g, 9.20 mmol).
  • the reaction mixture was sti ⁇ ed at 80 °C for 20 minutes, cooled, and diluted with ethyl acetate. A small amount of precipitate formed and the suspension was filtered. Water was added to the organic layer and extracted with 3x60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give a yellow liquid.
  • Example 16 This example illustrates the synthesis 2-(tr ⁇ ns-4-methanesulfonylamido- cyclohexylamino)-6-(2-chloro ⁇ henyl)-pyrido[2,3-d]pyrimidin-7-one starting with of 6-(2- chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol.
  • 2-py ⁇ olidinone was added sodium hydride (0.31 g, 7.75 mmol, 60 % dispersion in mineral oil). The reaction mixture was sti ⁇ ed for 10 minutes until gas evolution subsided, then 2-(trimethylsilyl)ethoxymethyl chloride (0.10 mL, 5.7 mmol) was added dropwise over a period of 5 minutes. The reaction mixture was stirred for 1.5 hours, after which a solution of tra.M-l,4-diaminocyclo_ ⁇ exane (6.24 g, 54.6 mmol) in 20 mL of dry 1- methyl-2-pyrrolidinone was added to the reaction mixture. The resulting reaction mixture was sti ⁇ ed for 30 minutes and poured into 60 mL of water.
  • the SEM-protected pyridone 16B (320 mg, 0.553 mmol) was suspended in 20 mL of methanol and treated with 10 mL of 10% hydrochloric acid. The reaction mixture was refluxed for 26 hours, cooled, then concentrated in vacuo until precipitate began to form. The resulting suspension was filtered, washed with water and ethyl acetate, then dried to give a white solid.
  • Example 17 This example illustrates the synthesis 2-(tr-.?.-?-4-NN-dimethylsulfonyl- aminocyclohexylamino)-6-(2-chlorophenyl)-pyrido[2,3-d]pyrimidin-7-one starting with the SEM-protected pyridone.
  • the purified ethyl carbamate (0.617 g, 1.40 mmole) was added to a hot ethanolic solution of potassium hydroxide (6.58 g, 117 mmole; 37 mL EtOH) and stirred at 80 °C for 3 hours.
  • the reaction mixture was then chilled in an ice bath and quenched with an aqueous solution of citric acid (6.6 g, 31.4 mmole; 37 mL H 2 O).
  • the resulting solution was concentrated in vacuo to provide a thick aqueous solution, which was extracted with ethyl acetate.
  • the organic layers were combined, dried with sodium carbonate, and concentrated in vacuo.
  • the residue was purified by flash chromatography on silica gel (10-30% methanol/dichloromethane). The column fractions containing product were combined and concentrated in vacuo to provide 30B.
  • the mixture was purified by flash chromatography on silica gel (10-40% methanol/dichloromethane + 1% ammonium hydroxide). The column fractions containing product were combined and concentrated in vacuo. The residue was dissolved in methanol and treated with hydrochloric acid (1.0 M/Et 0, 1.0 equivalent). The mixture was concentrated, washed with ethyl ether, filtered, and dried to give 0.013 g of the hydroehloride salt of Compound 32 (mp 150-168; M+.442).
  • the compound 30B (0.050g, 0.135 mmole) was taken up in 1 mL of THF with trimethylsilyl isocyanate (0.021 mL, 0.149 mmole) and stirred at room temperature for 3 hours, then evaporated in vacuo. The residue was purified by flash chromatography on silica gel (10% [1:9 ammonium hydroxide / methanol] / dichloromethane). The column fractions containing product were combined and concentrated in vacuo.
  • 35A 35B The ethyl carbamate was made from the corresponding benzyl sulfone in the manner already described, and cleaved to the piperidine intermediate 35A (mp >300.0) with iodotrimethylsilane.
  • Step 1 Alkylation To a suspension of the silyl protected alcohol 44A (483 mg, 1.0 mmole) in
  • Step 4 Preparation of6-(2-chlorophenyl)-2-(N-2-cyanoethylpiperidyl-4-amino)- pyrido[2,3- d]-pyrimidin-7-ol.
  • reaction mixture was purified and the isomers separated by chromatography on silica gel in 5% methanol/dichloromethane.
  • the less polar product fraction was assigned as the tra-M-isomer (i.e., compound 56 A) and was found to be pure by reverse phase HPLC.
  • the more polar product fraction was assigned as the c «-isomer (i.e., compound 56B) and was found to have a cis:trans ratio of 98:2 by reverse phase HPLC.
  • Each product fraction was separately dissolved in dichloromethane, treated with 1 equivalent of 1 M HCl in ether, and evaporated to a foamy residue. 13 mg of the trans- isomer, HCl salt of compound 56A (mass spec.
  • Butyl lithium (10.2 mL, 2.5 M solution in hexanes) was added to 55 mL of THF (distilled from sodium/benzophenone) at -30 °C.
  • the butyl lithium solution was moved to an ice bath and diisopropylamine (4 mL, 28.9 mmol) was added dropwise.
  • the reaction was stirred for 30 minutes and then cooled to approximately -80 °C in a dry ice/ether bath.
  • a solution of 4-fluoro-2-methylthiopyrimidine (1.6 g, 11.1 mmol) in 4 mL THF was added dropwise and the resulting reaction mixture was sti ⁇ ed for 2 hours.
  • Step 3 The product of Step 3 (1.66 g, 4.82 mmol) was dissolved in 20 mL THF and cooled in an ice bath. A solution of Oxone ® (5.9 g, 9.64 mmol) in water was added dropwise. The ice bath was removed and the reaction was sti ⁇ ed overnight. The reaction was filtered, approximately 40 mL of water was added and the mixture was sti ⁇ ed for 30 minutes. Solids were filtered off, resuspended in water and stirred for another 60 minutes. The mixture was filtered, rinsed with water and 20% ether/hexanes and dried to yield 1.08 g of the product. Step 5
  • reaction was purified by flash chromatography (1-5% (1:9 ammonium hydroxide/methanol)/dichloromethane), and the column fractions containing product 60 were combined and concentrated in vacuo.
  • the final product was taken up in methanol, treated with hydrochloric acid (1.0 M/Et 2 0, 1.0 equivalent) and re- evaporated to dryness, washed with ethyl ether, filtered, and dried to give 0.054 g of the hydroehloride salt of compound 60 (mp 143.0-158.5 °C).
  • Example 63 This example illustrates an alternative method of synthesizing compound
  • the methyl sulfide (15 g, 49.4 mmole) was taken up in 70 mL of NMP and stirred at room temperature; to this solution was added a solution of N-chlorosuccinimide (7.6 g, 56.8 mmole) in 6 mL of NMP with added water (0.87 mL, 48.1 mmole). The initial slurry quickly dissolved to a clear yellow solution. After 20 minutes at room temperaturethe sulfoxide 30C was then treated with ethyl 4-amino-l- piperidinecarboxylate (12.7 mL, 74.1 mmole). The reaction quickly darkened, warmed to the touch, and was left to stir at room temperature for 4 days.
  • the opaque yellow suspension was transferred to a large Erlenmeyer flask with 250 mL of water and stirred in an ice bath for 4 hours. The suspension was then filtered to collect a yellow cake, which was rinsed with water and hexanes and dried in vacuo. The ethyl carbamate intermediate showed excess mass, not reducing below 31.6 g despite prolonged drying.
  • Potassium hydroxide (111 g, 1.98 mol) was taken up in 400 mL of ethanol and heated until dissolved, and then cooled slightly before adding the carbamate intermediate from above (theoretically 49.4 mmole). The solution was stirred at reflux for 3 hours, then cooled to rt before placing in an ice bath for neutralization with aqueous citric acid (111 g, 577 mmole, dissolved in 400 mL of water). The solution was sti ⁇ ed for 30 minutes, then evaporated in vacuo to an aqueous syrup.
  • the opaque yellow suspension was transferred to a large Erlenmeyer flask with 250 mL of water and sti ⁇ ed in an ice bath for 4 hours. The suspension was then filtered to collect a yellow cake, which was rinsed with water and hexanes and dried in vacuo. The ethyl carbamate intermediate showed excess mass, not reducing below 31.6 g despite prolonged drying.
  • Potassium hydroxide (111 g, 1.98 mol) was taken up in 400 mL of ethanol and heated until dissolved, and then cooled slightly before adding the carbamate intermediate from above (theoretically 49.4 mmole). The solution was sti ⁇ ed at reflux for 3 hours, then cooled to rt before placing in an ice bath for neutralization with aqueous citric acid (111 g, 577 mmole, dissolved in 400 mL of water). The solution was sti ⁇ ed for 30 minutes, then evaporated in vacuo to an aqueous syrup. This syrup was extracted with methylene chloride (x 3); the combined extracts were washed with saturated brine, dried with sodium carbonate, and evaporated in vacuo to yield 12 g yellow foam (32.4 mmole).
  • Example 69 This example illustrates the synthesis 2-(tra «5-4-methoxycarboxamido- cyclohexylamino)-6-(2-chlorophenyl)-8H-pyrido[2,3--i]pyrimidin-7-one starting with the SEM-protected pyridone.
  • the SEM-protected pyridone (320 mg, 0.553 mmol) from Step 1 was suspended in 10 mL of methanol and treated with 10 mL of 10% hydrochloric acid. The reaction mixture was refluxed for 24 hours, cooled, then concentrated in vacuo until precipitate began to form.
  • Example 71 This example illustrates the synthesis 2-(tr_.n5-4-amidocarboxamido- cyclohexyla ⁇ tino)-6-(2-chlorophenyl)-8H-pyrido[2,3-_flpyrimidin-7-one starting with the SEM-protected pyridone.
  • Example 72 This example illustrates the synthesis 2-(c...-4-methanesulfonylamido- cyclohexylamino)-6-(2-chlorophenyl)-pyrido[2,3--i]pyrimidin-7-one starting with 6-(2- chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol. Step 1
  • reaction mixture was stirred for 30 minutes, then was added to a 0 °C cooled flask containing d_.-l,4-diaminocyclohexane (6.27 g, 54.9 mmol, TCI America, Portland, OR, mixture of cis and trans isomers).
  • the reaction mixture was sti ⁇ ed for 3 hours at ambient temperature. 100 mL of water and 100 mL of ethyl acetate were added, the layers were partitioned and the aqueous layer was extracted with another 100 mL portion of ethyl acetate. The combined organic layers were washed with 4x200 mL of brine, dried over sodium sulfate and concentrated in vacuo to give a crude yellow liquid.
  • the SEM-protected pyridone (0.29 g, 0.50 mmol) from Step 2 was suspended in 10 mL of methanol and treated with 10 mL of 10% hydrochloric acid. The reaction mixture was refluxed for 5 hours, cooled, then concentrated in vacuo until precipitate began to form.
  • Example 80 This example illustrates an alternative method for producing 6-(2- chlorophenyl)-8-methyl-2-methylthio-8-hydropyridino[2,3-d]pyrimidin-7-one (VI) N N H f *
  • Step 1 A mixture of S-3-(N-tritylamino)tetrahydrofuran (prepared according to the literature procedure, Barlos, Kleomenis; Papaioannou, Dionysios; Patrianakou, Stella; Sanida, Chariklia; Tsegenidis, Theodoras; J.Chem.Soc.Chem.Commun.; EN; 6; 1987; 474-475) (5.12 g, 0.0155 mol) and concentric hydrochloric acid (5 mL) was heated in ethanol (60 mL) to reflux for 15 min, and concentrated. The residue was sti ⁇ ed in hot ether (100 mL), filtered, washed with ether and dried in vacuo to afford (S)-3- aminotetrahydrofuran hydroehloride.
  • Lithium aluminum hydride (3.0 g) was sti ⁇ ed in dry tetrahydrofuran (300 mL) at 5 °C and treated dropwise with a solution of ethyl 4-(4-fluorophenyl) amino- 2-methylthio-pyrimidine-5-carboxylate (22.5 g) in dry tetrahydrofuran (250 mL). The reaction mixture was sti ⁇ ed overnight at room temperature. Additional 1.0 M solution of lithium aluminum hydride in THF (55 mL) was added at 5 °C and the mixture was stirred for three hours at room temperature.
  • Step 4 The aldehyde (8.6 g, 0.033 mol), ethyl o-chlorophenylacetate (8 g) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2a]pyrimidine polymer bound (base from Aldrich, 2.5 g) were mixed in NMP (60 mL) and stirred at 120 °C for 4 days. Additional 1.4 g of the base was added and the mixture was stirred at 120 °C for additional 3 days. The reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with NMP (10 mL). The filtrate was poured to water (600 mL) and extracted with EtOAc (3x500 mL).
  • the sulfide hydrazide 91 (250 mg, 0.78 mmol) and 4-amino- tetrahydropyran (397 mg, 5 equivalents) were combined and stirred at 150 °C for 10 hours.
  • the reaction mixture was cooled to room temperature and diluted with ethyl acetate (35 mL) and water (25 mL).
  • the organic layer was separated, washed with water (2X25 mL) and brine (1X25 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product (300 mg).
  • Step A Preparation of benzyl l-benzylpiperidin-4-ylcarbamate
  • Step 2 To a 0 °C solution of the N,N-dialkylated sulfide hydrazide (37 mg, 0.107 mmol) in tetrahydrofuran (3 mL) was added dropwise a solution of Oxone ® (66 mg, 1 equivalent) in water (3 mL). The resulting mixture was gradually warmed to room temperature over a 4 hour period, stored overnight at 0 °C, and diluted with ethyl acetate (35 mL) and water (20 mL).
  • Step 3 A mixture of the N,N-dialkylated sulfoxide hydrazide (35 mg, 0.0965 mmol), 4-amino-tetrahydropyran (39 mg, 4equivalents) and NMP was stirred at 80 °C for 35 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (35 mL) and water (25 mL).
  • Example 103 Q This example illustrate an assay protocol for determining in vitro inhibition of p-38 (MAP) Kinase.
  • the p-38 MAP kinase inhibitory activity of compounds of this invention in vitro was determined by measuring the transfer of the ⁇ -phosphate from ⁇ - 33 P-ATP by p-38 kinase to Myelin Basic Protein (MBP), using the a minor modification of the method described in Ahn, N. G.; et al. J. Biol. Chem. Vol. 266(7), 4220-4227, (1991).
  • the phosphorylated form of the recombinant p38 MAP kinase was expressed with SEK-1 and ME K in E. Coli and then purified by affinity chromatography using a Nickel column.
  • the phosphorylated p38 MAP kinase was diluted in kinase buffer (20 mM 3-(N-morpholino)propanesulfonic acid, pH 7.2, 25 mM ⁇ -glycerol phosphate, 5 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, ImM sodium vanadate, ImM dithiothreitol, 40mM magnesium chloride).
  • Test compound dissolved in DMSO or only DMSO (control) was added and the samples were incubated for 10 min at 30 °C.
  • the kinase reaction was initiated by the addition of a substrate cocktail containing MBP and ⁇ - 33 P-ATP. After incubating for an additional 20 min at 30 °C, the reaction was terminated by adding 0.75% phosphoric acid. The phosphorylated MBP was then separated from the residual ⁇ - 33 P-ATP using a phosphocellulose membrane (Millipore, Bedford, MA) and quantitated using a scintillation counter (Packard, Meriden, CT).
  • p-38 inhibitory activities (expressed as IC 50 , the concentration causing 50 % inhibition of the p-38 enzyme being assayed) of some compounds of the invention are:
  • Example 104 This example illustrates an in vitro assay to evaluate the inhibition of LPS- induced TNF- ⁇ production in THP1 cells.
  • THP-1 cells were suspended in culture medium [RPMI (Gibco-BRL, Gailthersburg, MD) containing 15% fetal bovine serum, 0.02 mM 2-mercaptoethanol], at a concentration of 2.5 x 10 ⁇ cells/mL and then plated in 96 well plate (0.2 mL aliquots in each well). Test compounds were dissolved in DMSO and then diluted with the culture medium such that the final DMSO concentration was 5%. Twenty five ⁇ L aliquots of test solution or only medium with DMSO (control) were added to each well. The cells were incubated for 30 min., at 37 °C. LPS (Sigma, St.
  • the amount of human TNF- ⁇ present was determined by a specific trapping ELISA assay using two anti-TNF- ⁇ antibodies (2TNF-H12 and 2TNF-H34) described in Reimund, J. M., et al. GUT. Vol. 39(5), 684-689 (1996).
  • Polystyrene 96-well plates were coated with 50 ⁇ l per well of antibody 2TNF-H12 in PBS (10 ⁇ g/mL) and incubated in a humidified chamber at 4 °C overnight. The plates were washed with PBS and then blocked with 5% nonfat-dry milk in PBS for 1 hour at room temperature and washed with 0.1% BSA (bovine serum albumin) in PBS.
  • BSA bovine serum albumin
  • TNF standards were prepared from a stock solution of human recombinant TNF- ⁇ (R&D Systems, Minneapolis, MN). The concentration of the standards in the assay began at 10 ng/mL followed by 6 half log serial dilutions.
  • the IC50 value was defined as the concentration of the test compound corresponding to half -maximal reduction in 450 nm absorbance.
  • Example 105 This example illustrates an in vivo assay to evaluate the inhibition of LPS- induced TNF- ⁇ production in mice (or rats).
  • mice Female BALB/c mice weighing 18-21 grams (Charles River, Hollister, CA) were acclimated for one week. Groups containing 8 mice each were dosed orally either with the test compounds suspended or dissolved in an aqueous vehicle containing 0.9% sodium chloride, 0.5% sodium carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol (CMC vehicle) or only vehicle (control group). After 30 min., the mice were injected intraperitoneally with 20 ⁇ g of LPS (Sigma, St. Louis, MO). After 1.5 h, the mice were sacrificed by CO2 inhalation and blood was harvested by cardiocentesis.
  • LPS Long Benzyl alcohol

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Abstract

L'invention concerne des composés de formule (I), dans laquelle R1 représente un hydrogène ou un alkyle, R2 représente un cycloalkyle substitué, un cycloalkyle hétérosubstitué, un cycloalkyle hétéroalkylsubstitué, un cycloalkyl-alkyle hétérosubstitué, un hétérocyclyle, un spiro cycloalkyle hétérocyclyle, un aralcoxy, un alcoxy, un -alkylène-S(O)¿n?-alkyle (dans lequel n est égal à 1 ou 2) ou -SO2Ar?2; R3¿ représente un hydrogène, un amino, un monoalkylamino, un dialkylamino, un acylamino, -Nra.C(=O)-Rb (dans lequel Ra désigne un hydrogène ou un alkyle et Rb désigne un hétérocyclyle ou un hétéroalkyle), un alkyle, un cycloalkyle, un aryle, un aralkyle, un haloalkyle, un hétéroalkyle, un cyanoalkyle, un -alkylène-C(O)-R (dans lequel R désigne un hydrogène, un alkyle, un hydroxy, un alcoxy, un amino, un monoalkylamino ou un dialkylamino), un acyle ou un phtalimidoalkyle; Ar?1 et Ar2¿ représentent, de manière indépendante, un aryle. L'invention concerne également l'utilisation de ces composés dans le traitement de maladies sélectionnées dans le groupe comprenant l'arthrite, la maladie de Crohn, la maladie d'Alzheimer, le syndrome du côlon irritable, la détresse respiratoire adulte et la maladie respiratoire obstructive chronique.
PCT/EP2001/009689 2000-08-31 2001-08-22 7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire WO2002018380A1 (fr)

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AU2001293784A AU2001293784B2 (en) 2000-08-31 2001-08-22 7-OXO pyridopyrimidines as inhibitors of a cellular proliferation
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BR0113628-3A BR0113628A (pt) 2000-08-31 2001-08-22 7-oxo-piridopirimidinas como inibidores de uma proliferação celular
MXPA03001821A MXPA03001821A (es) 2000-08-31 2001-08-22 7-oxo-piridopirimidinas como inhibidores de prolieferacion celular.
JP2002523895A JP4141830B2 (ja) 2000-08-31 2001-08-22 細胞増殖の阻害剤としての７−オキソ−ピリドピリミジン類
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WO2002018379A2 (fr) * 2000-08-31 2002-03-07 F. Hoffmann-La Roche Ag 7-oxo pyridopyrimidines
US6518276B2 (en) 2000-08-31 2003-02-11 Syntex (U.S.A.) Llc 7-oxo-pyridopyrimidines (II)
WO2003082871A1 (fr) * 2002-04-03 2003-10-09 F. Hoffmann-La Roche Ag Composes imidazo-fusionnes
WO2004046152A1 (fr) * 2002-11-18 2004-06-03 F. Hoffmann La Roche Ag Diazyinopyrimidines
WO2005007193A2 (fr) * 2003-07-07 2005-01-27 Vande Woude, George, F. Inhibition de l'angiogenese tumorale par combinaison de la thrombospondine-1 et des inhibiteurs du facteur de croissance endotheliale vasculaire
WO2005047284A1 (fr) * 2003-11-13 2005-05-26 F. Hoffmann-La Roche Ag Pyrido-7-pyrimidin-7-ones substitues hydroxyalkyle
JP2005529877A (ja) * 2002-04-19 2005-10-06 スミスクライン・ビーチャム・コーポレイション 新規化合物
WO2005105097A2 (fr) * 2004-04-28 2005-11-10 Gpc Biotech Ag Derives de pyridopyrimidine
WO2006056863A1 (fr) * 2004-11-23 2006-06-01 Ranbaxy Laboratories Limited Pyrido'2, 3-d!pyrimidines utilisees comme agents anti-inflammatoires
US7084270B2 (en) 2002-08-14 2006-08-01 Hoffman-La Roche Inc. Pyrimido compounds having antiproliferative activity
WO2006082492A1 (fr) * 2005-02-02 2006-08-10 Ranbaxy Laboratories Limited Derives azabicyclo utilises comme agents anti-inflammatoires
US7098332B2 (en) 2002-12-20 2006-08-29 Hoffmann-La Roche Inc. 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones
US7112676B2 (en) 2002-11-04 2006-09-26 Hoffmann-La Roche Inc. Pyrimido compounds having antiproliferative activity
US7115740B2 (en) 2003-04-10 2006-10-03 Hoffmann-La Roche Inc. Pyrimido compounds having antiproliferative activity
WO2007036791A1 (fr) * 2005-09-28 2007-04-05 Ranbaxy Laboratories Limited Dérivés de pyrido-pyrimidine pouvant être employés en tant qu'agents anti-inflammatoires
EP1878725A2 (fr) 2002-08-21 2008-01-16 Glaxo Group Limited Dérivés de la pyrimidine et leur utilisation comme modulateurs de CB2
WO2008078249A1 (fr) * 2006-12-21 2008-07-03 Ranbaxy Laboratories Limited Agents anti-inflammatoires
EP2112150A1 (fr) 2008-04-22 2009-10-28 GPC Biotech AG Inhibiteurs Raf améliorés
US7645764B2 (en) 2006-11-09 2010-01-12 Roche Palo Alto Llc Kinase inhibitors and methods for using the same
US8058283B2 (en) 2006-01-31 2011-11-15 Hoffmann-La Roche Inc. 7H-pyrido[3,4-D]pyrimidin-8-ones, their manufacture and use as protein kinase inhibitors
US8518958B2 (en) 2006-10-16 2013-08-27 Forma Therapeutics, Inc. Pyrido [2,3-D] pyrimidines and their use as kinase inhibitors
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10280162B2 (en) 2014-09-12 2019-05-07 Biolab Sanus Farmaceutica Ltda Pyridopyrimidines derivatives compounds
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
WO2020142612A1 (fr) * 2019-01-03 2020-07-09 Genentech, Inc. Composés de pyrido-pyrimidinone et de ptéridinone utilisés en tant qu'inhibiteurs de l'enzyme nécessitant l'inositol i (ire i alpha) à activité endoribonucléase pour le traitement de maladies cancéreuses
WO2020243376A1 (fr) * 2019-05-31 2020-12-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
RU2809987C2 (ru) * 2018-12-27 2023-12-20 Ле Лаборатуар Сервье Гетероциклические ингибиторы mat2a и способы применения для лечения рака
US12071425B2 (en) 2018-09-12 2024-08-27 Genentech, Inc. Phenoxy-pyridyl-pyrimidine compounds and methods of use
US12077534B2 (en) 2018-12-27 2024-09-03 Les Laboratoires Servier Aza-heterobicyclic inhibitors of MAT2A and methods of use for treating cancer

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KR101106162B1 (ko) * 2010-04-20 2012-01-20 주식회사 청용산기 포장박스 제조장치용 스티칭 장치에 있어서의 하역가이드 지지유닛
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WO2002018379A2 (fr) * 2000-08-31 2002-03-07 F. Hoffmann-La Roche Ag 7-oxo pyridopyrimidines
WO2002018379A3 (fr) * 2000-08-31 2002-07-25 Hoffmann La Roche 7-oxo pyridopyrimidines
US6518276B2 (en) 2000-08-31 2003-02-11 Syntex (U.S.A.) Llc 7-oxo-pyridopyrimidines (II)
US6753427B2 (en) 2000-08-31 2004-06-22 Syntex (U.S.A.) Llc 7-oxo-pyridopyrimidines (II)
WO2003082871A1 (fr) * 2002-04-03 2003-10-09 F. Hoffmann-La Roche Ag Composes imidazo-fusionnes
CN1293078C (zh) * 2002-04-03 2007-01-03 霍夫曼-拉罗奇有限公司 咪唑并稠合化合物
JP2005529877A (ja) * 2002-04-19 2005-10-06 スミスクライン・ビーチャム・コーポレイション 新規化合物
US7084270B2 (en) 2002-08-14 2006-08-01 Hoffman-La Roche Inc. Pyrimido compounds having antiproliferative activity
EP1878725A2 (fr) 2002-08-21 2008-01-16 Glaxo Group Limited Dérivés de la pyrimidine et leur utilisation comme modulateurs de CB2
US7112676B2 (en) 2002-11-04 2006-09-26 Hoffmann-La Roche Inc. Pyrimido compounds having antiproliferative activity
US7129351B2 (en) 2002-11-04 2006-10-31 Hoffmann-La Roche Inc. Pyrimido compounds having antiproliferative activity
US6943158B2 (en) 2002-11-18 2005-09-13 Roche Palo Alto Llc Diazinopyrimidines
CN100357293C (zh) * 2002-11-18 2007-12-26 霍夫曼-拉罗奇有限公司 二嗪并嘧啶类
WO2004046152A1 (fr) * 2002-11-18 2004-06-03 F. Hoffmann La Roche Ag Diazyinopyrimidines
US7098332B2 (en) 2002-12-20 2006-08-29 Hoffmann-La Roche Inc. 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones
US7115740B2 (en) 2003-04-10 2006-10-03 Hoffmann-La Roche Inc. Pyrimido compounds having antiproliferative activity
WO2005007193A2 (fr) * 2003-07-07 2005-01-27 Vande Woude, George, F. Inhibition de l'angiogenese tumorale par combinaison de la thrombospondine-1 et des inhibiteurs du facteur de croissance endotheliale vasculaire
WO2005007193A3 (fr) * 2003-07-07 2005-06-30 Vande Woude George F Inhibition de l'angiogenese tumorale par combinaison de la thrombospondine-1 et des inhibiteurs du facteur de croissance endotheliale vasculaire
JP2007510686A (ja) * 2003-11-13 2007-04-26 エフ．ホフマン−ラ　ロシュ　アーゲー ヒドロキシアルキル置換ピリド−７−ピリミジン−７−オン類
KR100816321B1 (ko) * 2003-11-13 2008-03-24 에프. 호프만-라 로슈 아게 히드록시알킬 치환 피리도-7-피리미딘-7-온
WO2005047284A1 (fr) * 2003-11-13 2005-05-26 F. Hoffmann-La Roche Ag Pyrido-7-pyrimidin-7-ones substitues hydroxyalkyle
WO2005105097A2 (fr) * 2004-04-28 2005-11-10 Gpc Biotech Ag Derives de pyridopyrimidine
WO2005105097A3 (fr) * 2004-04-28 2006-12-21 Gpc Biotech Ag Derives de pyridopyrimidine
WO2006056863A1 (fr) * 2004-11-23 2006-06-01 Ranbaxy Laboratories Limited Pyrido'2, 3-d!pyrimidines utilisees comme agents anti-inflammatoires
WO2006082492A1 (fr) * 2005-02-02 2006-08-10 Ranbaxy Laboratories Limited Derives azabicyclo utilises comme agents anti-inflammatoires
WO2007036791A1 (fr) * 2005-09-28 2007-04-05 Ranbaxy Laboratories Limited Dérivés de pyrido-pyrimidine pouvant être employés en tant qu'agents anti-inflammatoires
US8058283B2 (en) 2006-01-31 2011-11-15 Hoffmann-La Roche Inc. 7H-pyrido[3,4-D]pyrimidin-8-ones, their manufacture and use as protein kinase inhibitors
US8518958B2 (en) 2006-10-16 2013-08-27 Forma Therapeutics, Inc. Pyrido [2,3-D] pyrimidines and their use as kinase inhibitors
US7645764B2 (en) 2006-11-09 2010-01-12 Roche Palo Alto Llc Kinase inhibitors and methods for using the same
WO2008078249A1 (fr) * 2006-12-21 2008-07-03 Ranbaxy Laboratories Limited Agents anti-inflammatoires
EP2112150A1 (fr) 2008-04-22 2009-10-28 GPC Biotech AG Inhibiteurs Raf améliorés
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US9695132B2 (en) 2013-03-15 2017-07-04 Celgene Car Llc Heteroaryl compounds and uses thereof
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10189794B2 (en) 2013-03-15 2019-01-29 Celgene Car Llc Heteroaryl compounds and uses thereof
US10618902B2 (en) 2013-03-15 2020-04-14 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10774052B2 (en) 2013-03-15 2020-09-15 Celgene Car Llc Heteroaryl compounds and uses thereof
US10280162B2 (en) 2014-09-12 2019-05-07 Biolab Sanus Farmaceutica Ltda Pyridopyrimidines derivatives compounds
US10822333B2 (en) 2014-09-12 2020-11-03 Biolab Sanus Farmaceutica Ltda Pyridopyrimidines derivatives compounds
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4
US12071425B2 (en) 2018-09-12 2024-08-27 Genentech, Inc. Phenoxy-pyridyl-pyrimidine compounds and methods of use
RU2809987C2 (ru) * 2018-12-27 2023-12-20 Ле Лаборатуар Сервье Гетероциклические ингибиторы mat2a и способы применения для лечения рака
US12077534B2 (en) 2018-12-27 2024-09-03 Les Laboratoires Servier Aza-heterobicyclic inhibitors of MAT2A and methods of use for treating cancer
WO2020142612A1 (fr) * 2019-01-03 2020-07-09 Genentech, Inc. Composés de pyrido-pyrimidinone et de ptéridinone utilisés en tant qu'inhibiteurs de l'enzyme nécessitant l'inositol i (ire i alpha) à activité endoribonucléase pour le traitement de maladies cancéreuses
TWI748317B (zh) 2019-01-03 2021-12-01 美商建南德克公司 吡啶并－嘧啶酮與喋啶酮化合物及使用方法
US20230047209A1 (en) * 2019-01-03 2023-02-16 Genentech, Inc. Pyrido-pyrimidinone and pteridinone compounds and methods of use
WO2020243376A1 (fr) * 2019-05-31 2020-12-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer

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CN1451005A (zh) 2003-10-22
KR100571339B1 (ko) 2006-04-17
BR0113628A (pt) 2003-07-01
MXPA03001821A (es) 2003-06-04
ZA200301079B (en) 2004-05-07
JP2004507541A (ja) 2004-03-11
CA2420286A1 (fr) 2002-03-07
AU2001293784B2 (en) 2007-08-30
UY26918A1 (es) 2002-02-28
AU9378401A (en) 2002-03-13

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