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WO2003028724A1 - Inhibiteurs de la kinase chk1 - Google Patents

Inhibiteurs de la kinase chk1 Download PDF

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Publication number
WO2003028724A1
WO2003028724A1 PCT/US2002/031842 US0231842W WO03028724A1 WO 2003028724 A1 WO2003028724 A1 WO 2003028724A1 US 0231842 W US0231842 W US 0231842W WO 03028724 A1 WO03028724 A1 WO 03028724A1
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pyrrolo
pyridin
phenyl
nicotinamide
butyramide
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Inventor
Robert A. Stavenger
Jason Witherington
Derek A. Rawlings
Dennis A. Holt
George. Chan
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SmithKline Beecham Ltd
SmithKline Beecham Corp
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SmithKline Beecham Ltd
SmithKline Beecham Corp
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B11/00—Diaryl- or thriarylmethane dyes
    • C09B11/04—Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
    • C09B11/10—Amino derivatives of triarylmethanes
    • C09B11/24—Phthaleins containing amino groups ; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes

Definitions

  • the present invention relates to damage response kinase inhibitors, especially checkpoint kinase ("chkl kinase”) inhibitors, pharmaceutical compositions comprising these compounds and methods of using these compounds to treat various forms of cancer and hyperproliferative disorders.
  • damage response kinase inhibitors especially checkpoint kinase ("chkl kinase”) inhibitors
  • pharmaceutical compositions comprising these compounds and methods of using these compounds to treat various forms of cancer and hyperproliferative disorders.
  • the cellular response to DNA damage involves cell cycle delays, increased repair and apoptosis (Zhou and Elledge Nature 2000. 408:433-439).
  • cell cycle delays also called checkpoints
  • repair activation which provides both the opportunity and capacity for cells to repair DNA damage. It is likely that approaches abrogating these survival DNA damage responses would have significant clinical utility.
  • Chkl was linked to survival responses including checkpoints.
  • Mice lacking CHK1 die in early embryogenesis (Liu et al.Gerce & Dev. 2000 14: 1448-1459; Takai et al, Gene & Dev. 2000. 14: 1439-1447).
  • ES cells expressing a conditional CHK1 gene die of p53-independent apoptosis after loss of CHK Prior to their death, these cells become incapable of preventing mitotic entry in response to IR (Liu et al.Gene & Dev. 2000 14: 1448-1459), demonstrating that Chkl is required for the G2 DNA damage checkpoint in mammals as previously observed in other organisms.
  • Chkl prevents mitotic entry as follows. Arrest in G2 is regulated by the maintenance of inhibitory phosphorylation of Cdc2 (Nurse Cell 1997. 91: 865-867). Cdc2 dephosphorylation and activation is catalyzed by the dual specificity phosphatase Cdc25 (Morgan Nature 1995. 374: 131-134). Recent evidence indicates that part of the G2/M D ⁇ A checkpoint mechanism involves inactivation and translocation of Cdc25C into the cytoplasm. This is at least partially mediated by phosphorylation on Ser-216 in Cdc25C and its consequent binding with 14-3-3 proteins (Peng et al., Science 1997. 277: 1501-1505; Dalai et al. Mol.
  • Chkl (Sanchez et al. Science 1997. 277: 1497-1501) has been shown to phosphorylate Cdc25C at Ser- 216 in vitro. This modification is thought to maintain Cdc25C phosphorylation in cells arrested at G2/M in response to DNA damage.
  • staurosporine-like kinase inhibitors UCN-01 and SB-218078, have been shown to be potent Chkl inhibitors (Jackson et al. Cancer Res. 2000. 60: 566-572; Graves et al. J. Biol. Chem. 2000. 275: 5600-5605).
  • Chkl inhibitor In vivo, they can abrogate the G2/M checkpoint induced by DNA damaging agents and enhance the cytotoxicities of the DNA damaging agents. Thus it is likely that a specific Chkl inhibitor could be used clinically in combination treatment with coventional therapies. Since Chkl is an essential kinase for regular cell cycle (Liu et al.Gene & Dev. 2000 14: 1448-1459), it is possible that Chkl inhibitor could also be used alone in cancer therapy.
  • the present invention involves pyrolo[2,3-b]pyridine compounds represented by Formula (I) hereinbelow, pharmaceutical compositions comprising such compounds and methods of inhibiting kinase as well as specific assays to detect inhibition of chkl kinase activity.
  • the present invention provides compounds of Formula (I), hereinbelow:
  • R 1 is aryl or heteroaryl, wherein aryl or heteroaryl may optionally be substituted by one or more of group A and on any position with the exception that R 1 is not 3,4- dichlorophenyl, with the preferred substitution being 3-,4- or 5-alkoxy- or hydroxy- or amino- or hydroxymethyl- or aminomethyl- or acetamido- or aminosulfamoyl- or dimethylamino- phenyl including di- and tri-substitution or 3-thienyl, with the more preferred substitution being 4-hydroxy-3-methoxyphenyl or 3-acetamidophenyl or 3,4-dimethoxyphenyl or 4-aminophenyl or 4-aminomethylphenyl or 4- dimethylaminomethylpheny 1 ;
  • R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, C,_ 10 alkyl, C, .10 alkanoyl, C 2.I0 alkenyl, C 2.10 alkynyl, C 3.10 cycloalkyl, C M alkylaryl, C M alkylheterocyclyl, and C 0.6 alkylheteroaryl; or R 3 and R 4 taken together with the nitrogen to which they are attached form a ring having 3 to 7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, sulfur, oxygen, or nitrogen, substituted with hydrogen, C, .6 alkyl or (CH 2 ) 0.3 aryl, wherein any of the foregoing may be optionally substituted by one or more of group C and on any position;
  • R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, C, . ,,, alkyl, C, .]0 alkanoyl, C 2.10 alkenyl, C 2.10 alkynyl, C 3.10 cycloalkyl, C 0.6 alkylaryl, C 0.6 alkylheterocyclyl, and C 0.6 alkylheteroaryl; or R 7 and R 8 taken together with the nitrogen to which they are attached form a ring having 3 to 7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, sulfur, oxygen, or nitrogen, substituted with hydrogen, C alkyl or (CH 2 ) 0.3 aryl; R" is selected from the group consisting of C ⁇ _ 8 alkyl, C 2 .
  • R 9 is hydrogen or . 6 alkyl, wherein any of the foregoing groups are optionally substituted with one or more of group D and at any position, with the exception that
  • R 9 is not tert-butyl
  • R 10 is selected from the group consisting of hydrogen, methyl and ethyl
  • R u is selected from the group consisting of hydrogen, C j hand6 alkyl, C 2.8 alkenyl and C 3 _ 6 cycloalkyl, wherein any of the foregoing groups are optionally substituted with one or more of group D and at any position;
  • R 10 and R u taken together with the nitrogen to which they are attached may form a ring having 3 to 7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, sulfur, oxygen, or nitrogen, substituted with hydrogen or C,_ 6 alkyl;
  • D is selected from the group consisting of C 6 alkyl, C 2.8 alkenyl, C 3.6 cycloalkyl,
  • OR 12 OC(O)NR 12 R 13 , NR 14 SO 2 R 12 R 13 , NR 14 C(O)OR 12 , NR 14 C(O)NR I2 R 13 , halo, cyano, trifluoromethyl, SR 12 , S(O)R 12 , SO 2 R 12 , SO 3 R 12 , SO 2 NR I2 R 13 , C(O)SR 12 , CONR 12 R 13 and PO 3 R 12 ;
  • R 12 , R 13 , R 14 are independently selected from the group consisting of hydrogen, C, .3 alkyl, C 2.3 alkanoyl, C 2.3 alkenyl, C 23 alkynyl, and C 3 5 cycloalkyl; or R 12 and R 13 taken together with the nitrogen to which they are attached form a ring having 3 to 7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, sulfur, oxygen, or nitrogen, substituted with hydrogen or C l _. alkyl;
  • E is selected from the group consisting of C M alkyl, OR 15 and NR I5 R 16 , with the exception that R 2 is not 3,4-dimethoxyphenyl or 3-methoxyphenyl,
  • F is selected from the group consisting of C ⁇ alkyl, C 2.8 alkenyl, C 3 6 cycloalkyl,
  • OR 12 OC(O)NR 12 R 13 , NR 12 R 13 , NR 14 SO 2 R 12 R 13 , NR 14 C(O)OR 12 , NR 14 C(O)NR 12 R 13 , halo, cyano, trifluoromethyl, SR 12 , S(O)R 12 , SO 2 R 12 , SO 3 R 12 , SO 2 NR 12 R 13 , C(O)SR 12 ,
  • R 15 and R 16 are independently selected from the group consisting of hydrogen, C,_ 3 alkyl, C 2.3 alkanoyl, C 2.3 alkenyl, C 23 alkynyl, and C 3 5 cycloalkyl; or R 15 and R 16 taken together with the nitrogen to which they are attached form a ring having 3 to 7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, sulfur, oxygen, or nitrogen, substituted with hydrogen or C,_ 3 alkyl.
  • alkanoyl is used herein at all occurrences to mean a C(0)alkyl group, wherein the alkyl portion is as defined below, including, but not limited to, acetyl, pivaloyl, and the like.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2- propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyI, and the like.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • alkyl refers to a saturated hydrocarbon group joined together by single carbon-carbon bonds.
  • the alkyl hydrocarbon group may be linear, or branched, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkylaryl is used herein at all occurrences to mean a aryl group as defined below attached to an alkyl group as defined above, including, but not limited to, benzyl and phenethyl, and the like.
  • alkylheterocyclyl is used herein at all occurrences to mean a heterocyclic group as defined below attached to an alkyl group as defined above, including, but not limited to, (tetrahydro-3-furanyl)methyl and 3-(4- morpholinyl)propyl, and the like.
  • alkylheteroaryl is used herein at all occurrences to mean a heteroaryl group as defined below attached to an alkyl group as defined above, including, but not limited to, 3-(mranyl)methyl and (2-pyridinyl)propyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2- propylene, and the like.
  • aryl is used herein at all occurrences to mean 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl, naphthalenyl, biphenyl, phenanthryl, anthracenyl, and the like.
  • aryloxy is used herein at all occurrences to mean an aryl group as defined above linked via an oxy group, including, but not limited to, phenoxy, and the like.
  • cycloalkyl is used herein at all occurrences to mean cyclic radicals, which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • heteroaryl is used herein at all occurrences to mean a 5-14- membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, which may be optionally substituted with hydrogen or C galkyl, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like.
  • heteroaryloxy is used herein at all occurrences to mean an heteroaryl group as defined above linked via an oxy group, including, but not limited to, 2-pyridinyloxy, and the like.
  • heterocyclic is used herein at all occurrences to mean a saturated or wholly or partially unsaturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which one or more rings contain one or more heteroatoms selected from nitrogen, which may be optionally substituted with hydrogen or C g alkyl, oxygen, and sulfur, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, 1,2,3,6- tetrahydropyridine, hexahydroazepine, and the like.
  • Compounds useful in the present invention include: 3-dimethylamino-N-(5-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-benzamide; 4-methoxy-N-(5-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-benzamide; 1 -ethyl-3-(5-phenyl- lH-pyrrolo[2,3-b]pyridin-3-yl)-urea; benzo[l ,3]dioxole-5-carboxylic acid (5 ⁇ phenyl-lH-pyrrolo[2,3-b] ⁇ yridin-3-yl)- amide;
  • Preferred compounds useful in the present invention include: N-(5-(thiophen-3-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-butyramide; N-(5-(4-hydroxy-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-butyramide;
  • More Preferred compounds useful in the present invention include: N-(5-(4-morpholinomethyl-phenyl-l ⁇ -pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide; N-(5-(4-piperidinomethyl-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide; N-(5-(4-pyrrolidinomethyl-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide; N-(5-(4-methylaminomethyl-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide; N-(5-(thiophen-3-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide; N-(5-(4-aminophenyl)-lH-pyrrol
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • the present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof.
  • Pharmaceutically acceptable salts are non- toxic salts in the amounts and concentrations at which they are administered.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • the boronic acid in the above example may be substituted for various boronic esters, for example pinacolate (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl) or related boronic esters with no change in the course of the reaction.
  • ⁇ itro compound 3 can then be reduced to the corresponding amine 4 using heterogeneous hydrogenation, for example with palladium on carbon in the presence of 1 atmosphere of hydrogen gas in methanol.
  • the amine 4 can then be acylated with a variety of acylating agents (many commercially available) to provide 5 by several standard methods, for example by treatment with acyl chorides or chloroformates in pyridine at various temperatures or by treatment with isocyanates in pyridine at various temperatures or by treatment with acid anhydrides in pyridine at various temperatures or by treatment with carboxylic acids in the presence of benzotraizol-1- yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and triethylamine in N,N-dimethylformamide.
  • acylating agents manufactured commercially available
  • the amine 6 can then be actylated with a variety of acylating agents (many commercially available) to provide 5 by several standard methods, for example by treatment with acyl chorides or chloroformates in pyridine at various temperatures or by treatment with isocyanates in pyridine at various temperatures or by treatment with acid anhydrides in pyridine at various temperatures or by treatment with carboxylic acids in the presence of benzotraizol-1- yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and triethylamine in N,N-dimethylformamide.
  • acylating agents manufactured commercially available
  • Amide 7 can then be transformed to 5 by the use of a variety of boronic acids (many commercially available) by standard procedures, for example using tetrakis(triphenylphosphine)palladium as catalyst in N,N-dimethylformamdide / ethanol / aqueous 2M potassium carbonate at 100 °C.
  • the boronic acid in the above example may be substituted for various boronic esters, for example pinacolate (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl) or related esters with no change in the course of the reaction.
  • R 1 boronic acids or boronic esters are not readily available, then 7 can be converted to 8, for example by bis(pinacolato)diboron, potassium acetate and [1,1 - bis(diphenylphosphino)-ferrocene]palladium(II) chloride in dimethylsulfoxide at 100 °C.
  • Boronate 8 can then be converted to 5 by the use of a variety of aryl or heteroaryl chlorides or bromides or iodides, (many commercially available) by standard procedures, for example using tetrakis(triphenylphosphine)palladium as catalyst in N,N-dimethylformamdide / ethanol / aqueous 2M potassium carbonate at 100 °C.
  • organoboron compounds could be replaced with other organometallic compounds suitable for cross-coupling reactions such as stannanes, silanes, oragnozincs, cuprates, or organomagnesium reagents.
  • Phenylboronic acid (1.10 g, 9.0 mmol, 1.5 equiv)
  • tetrakis(triphenylphosphine)palladium (346 mg, 0.3 mmol, 0.05 equiv)
  • 5-bromo- 3-nitro-lH-pyrrolo[2,3-b]pyridine (1.45 g, 6.0 mmol, 1.0 equiv) were combined in 2/1/1 DMF/EtO ⁇ /aq. 2M K 2 CO 3 (40 mL) and the mixture was heated to reflux for 16 h. The reaction mixture was cooled, poured into ⁇ 2 O and extracted with EtOAc.
  • Butyric anhydride (33 ⁇ l, 0.202 mmol, 1.0 equiv) was added to a solution of the 3-amino-5-phenyl-lH-pyrrolo[2,3-b]pyridine hydrochloride (50 mg, 0.203 mmol, 1.0 equiv) in pyridine (0.5 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated. Purification by column chromatography (2% MeO ⁇ in C ⁇ 2 C1 2 ) afforded 20 mg (36%) of the title compound.
  • Example 3 Preparation of (5-phenyl-lH-pyrrolor23-blpyridin-3-yl)-carbamic acid ethyl ester Following the procedure for Example Id, starting with 3-amino-5-phenyl- lH-pyrrolo[2,3-b]pyridine hydrochloride and ethyl chloroformate provided the title compund.
  • Example 14 Preparation of Pyrazine-2-carboxylic acid (5-phenyl-lH-pyrrolor2,3-b1pyridin-3-yl)- amide Following the procedure for Example Id, starting with 3-amino-5-phenyl- lH-pyrrolo[2,3-b]pyridine hydrochloride and pyrazine-2-carbonyl chloride provided the title compund.
  • ESIMS m/z 315.2 (M+).
  • Butyric anhydride (1.16 mL, 7.1 mmol, 1.0 equiv) was added to a solution of 3-amino-5-bromo-lH-pyrrolo[2,3-b]pyridine (1.50 g, 7.1 mmol, 1 equiv) in C ⁇ 2 CL, (10 mL) and pyridine (5 mL). The mixture was stirred at rt for 2 h, then the volatiles were removed and the residue was partitioned between H 2 O and EtOAc. The aqueous layer was extracted with EtOAc, the combined organic layers were washed with brine, dried over MgSO 4 and concentrated to give a solid which was triturated with EtOAc to provide 1.31 g (65%) of the title compound.
  • N-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-butyramide 28 mg, 0.1 mmol, 1.0 equiv
  • tetrakis(triphenylphosphine)palladium 5.8 mg, 0.005 mmol, 0.05 equiv
  • 3-acetamidobenzeneboronic acid 26.8 mg, 0.15 mmol, 1.5 equiv
  • Example 22 Preparation of N-(5-(3-methyl-phenyl)-lH-pyrroloF2,3-blpyridin-3-yl)-butyr amide Following the procedure for Example 17c, starting from N-(5-bromo-lH- pyrrolo[2,3-b]pyridin-3-yl)-butyramide and 3-methylbenzeneboronic acid provided the title compund.
  • N-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-butyramide 500 mg, 1.8 mmol, 1.0 equiv
  • bis(pinacolato)diboron 450 mg, 1.8 mmol, 1.0 equiv
  • potassium acetate 521 mg, 5.3 mmol, 3.0 equiv
  • Solid PdCl (dppf) 41 mg, 0.05 mmol, 0.03 equiv) was added and the mixture was heated to 100 °C for 16 h. The reaction mixture was then cool, poured into ⁇ 2 O and EtOAc and filtered through Celite.
  • N-(5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrrolo[3,2- b]pyridin-3-yl)-butyramide (36 mg, 0.1 mmol, 1.0 equiv), tetrakis(triphenylphosphine)palladium (5.8 mg, 0.005 mmol, 0.05 equiv) and 3- bromothiophene (15 ⁇ L, 0.15 mmol, 1.5 equiv) were combined in 2/1/1 DMF/EtO ⁇ /aq. 2M K 2 CO 3 (0.75 mL) and the mixture was heated to 100 °C for 15 h.
  • Example 37 Preparation of N-(5-(3-sulfamoylphenyl)-lH-pyrrolor2,3-b1pyridin-3-yl)-butyramide Following the procedure for Example 34b, starting from N-(5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-butyramide and 3-bromobenzenesulfonamide provided the title compund.
  • Example 38 Preparation of N-(5-(4-sulfamoylphenyl)- lH-pyrrolor2,3-blpyridin-3-yl)-butyramide Following the procedure for Example 34b, starting from N-(5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrrolo[3,2-b]pyridin-3-yl)-butyr amide and 4-bromobenzenesulfonamide provided the title compund.
  • Example 17b Following the procedure for Example 17b starting from 3-amino-5-bromo ⁇ lH-pyrrolo[2,3-b]pyridine and nicotinoyl chloride hydrochloride provided the title compound.
  • Example 17c Following the procedure for Example 17c, starting from N-(5-bromo-lH- pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide and 4-dimethylaminobenzeneboronic acid provided the title compund.
  • Example 51 Preparation of 4-methyl-N-(5-phenyl-lH-pyrrolor2,3-b1pyridin-3-yl)-nicotinamide Following the procedure for Example 50, starting from 3-amino-5-phenyl- lH-pyrrolo[2,3-b]pyridine and 4-methylnicotinic acid provided the title compund.
  • Example 52 Preparation of 6-methyl-N-(5-phenyl-lH-pyrrolor2.3-b1pyridin-3-yl)-nicotinamide Following the procedure for Example 50, starting from 3-amino-5-phenyl- lH-pyrrolo[2,3-b]pyridine and 6-methylnicotinic acid provided the title compund.
  • Example 56 Preparation of N-(5-(4-formylphenyl- l ⁇ -pyrrolor23-b1pyridin-3-yl)-butyramide Following the procedure for Example 17c, starting from N-(5-bromo-lH- pyrrolo[2,3-b]pyridin-3-yl)-butyramide and 4-formylbenzeneboronic acid provided the title compound.
  • ESIMS m/z 308.2 (M+l).
  • Example 92 Preparation of N-((5-(benzofuran-2-vD- lH-pyrroloF2,3-blpyridin-3-yl)-nicotinamide Following the procedure for Example 17c, starting from N-(5-bromo-lH- pyrrolo[2,3-b]pyridin-3-yl)-nicotinamide and benzofuran-2-yl-boronic acid provided the title compound.
  • ESIMS m/z 355.3 (M+l).
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC 50 , EC 50 , the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(I).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • diseases treatable using the present compounds include, but are not limited to leukemias, solid tumor cancers and metastases, lymphomas, soft tissue cancers, brain cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, lung cancer, bladder cancer, bone cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, kidney cancer, head cancer and neck cancer, chronic inflammatory proliferative diseases such as psoriasis and rheumatoid arthritis; proliferative cardiovascular diseases such as restenosis; prolifertive ocular disorders such as diabetic retinopathy; and benign hyperproliferative diseases such as hemangiomas.
  • Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromefhane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or.their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or.their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • Streptavidin coated SPA beads, ATP and 33 P-ATP were obtained from Amersham Pharmacia Biotech, Biotin labeled peptide KVSRSGLYRSPSMPENLNRK(Biotin-xx)NH 2 was obtained from Affiniti Research Products Ltd, assay buffer reagents were obtained from Sigma-Aldrich Co.Ltd. fff84 well assay plates were obtained from Corning Inc.
  • Assay buffer 50 mM HEPES, 50 mM KC1, 5% Glycerol, 1 mM EGTA, 0.001% Tween-20; enzyme/peptide mix: 25 nM Chkl, 2.5 ⁇ M biotin peptide, 7.5 mM 2- mercaptoethanol in assay buffer; ATP mix: 20 ⁇ M ATP at 650kBq/mL, 5mM MgCl 2 in assay buffer.
  • Inhibitors of decreasing concentration, from lOuM were incubated at room temperature for 1 hour together with 5 ⁇ L enzyme/peptide mix and 5 ⁇ L ATP mix. The reaction was stopped with 5 ⁇ L of 0.5M EDTA followed by a further addition of 65uL of 0.2mg/mL SPA beads.
  • a GST-Chkl expression construct was constructed which has the glutathione-S-transferase gene fused to the amino terminus of Chkl kinase via a linker containing a thrombin cleavage site. This construct was cloned into the Baculovirus expression vector, pFASTBAC, and this was used to make the viral stock for the subsequent infection. Spodoptera frugiperda cells (Sf9) were infected with the virus expressing the GST-Chkl and the cells were grown for 3 days, then harvested and frozen down. Purification of GST-Chkl:
  • the GST-Chkl protein was purified as follows: An Sf9 cell pellet expressing GST-Chkl was resuspended on ice in lysis buffer (50mM Tris-Cl, pH 7.5, 250mM NaCl2, ImM dithiothreitol (DTT), 0.1%Brij, 5% (v/v) protease inhibitor cocktail, lmM sodium orthovanadate), cells were lysed by sonication and centrifuged at 100,000xg for 30min The supernatant was added to Glutathione Sepharose 4B, beads, equilibrated in wash buffer (20mM Tris-Cl, pH 7.0, lOmM MgCl2, lOOmM NaCl2, ImM DTT, 0.5%(v/v) protease inhibitor cocktail, ImM sodium orthovanadate).
  • lysis buffer 50mM Tris-Cl, pH 7.5, 250mM NaCl2, ImM dithiothreitol (DTT), 0.1%
  • the mixture was rocked for 30min
  • the resin with the bound GST- Chkl was spun down at 500xg for 5min and washed with 14mls of wash buffer.
  • the beads were spun as above and resuspended in another 14mls of wash buffer.
  • the suspension was transferred into a column and allowed to pack, then the wash buffer was allowed to flow through by gravity.
  • the GST-Chkl was eluted from the column with lOmM Glutathione in 50rnM Tris-Cl, pH 8.0 in 500ul fractions. Protein concentrations were determined on the fractions using Bio-Rad's Protein assay kit as per instructions.
  • Synchronized cells were then returned to complete media containing a DNA-damaging drug such as 50nM topotecan (a dosage we have found to be sufficient to arrest cells in early G2 phase without inducing apoptosis) alone and in combination with test compounds for up to 18 hours.
  • a DNA-damaging drug such as 50nM topotecan (a dosage we have found to be sufficient to arrest cells in early G2 phase without inducing apoptosis) alone and in combination with test compounds for up to 18 hours.
  • Cell cycle profiles were then performed cytometrically using a procedure for propidium iodide staining of nuclei. (Vindelov et al, Cytometry Vol.3, No.5, 1983, 323-327)
  • CHK1 inhibitors would be expected to reverse the G2 arrest caused by the DNA damaging agent. Typical concentration ranges for such activity would be 0.001 to 10 uM.
  • Proliferation studies were performed in a variety of adherent and non- adherent cell lines including Hela S3, HT29, and Jurkat.
  • the proliferation assay utilized a colorimetric change resulting from reduction of the tetrazolium reagent XTT into a formazan product by metabolically active cells
  • CHK1 inhibitors are expected to enhance the cytotoxicity of DNA-damaging chemotherapeutic drugs. Typical concentration ranges for such activity would be 0.001 to 10 uM. Other assays for cellular proliferation or cytotoxicity could also be used with test compounds, and these assays are known to those skilled in the art.
  • Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below:

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Abstract

L'invention concerne de nouveaux composés utiles à l'inhibition de kinases de réaction au dommage.
PCT/US2002/031842 2001-10-04 2002-10-04 Inhibiteurs de la kinase chk1 Ceased WO2003028724A1 (fr)

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WO2004078756A3 (fr) * 2003-03-06 2005-03-24 Eisai London Res Lab Ltd Inhibiteurs des jun-kinases (jnk)
US7432375B2 (en) 2003-03-06 2008-10-07 Eisai R & D Management Co., Ltd. JNK inhibitors
US7652137B2 (en) 2003-03-06 2010-01-26 Eisai R & D Management Co., Ltd. Synthesis of 5 substituted 7-azaindoles and 7-azaindolines
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US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
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