ZA200601963B - 2,4 Di (hetero)-arylamino-pyrimidine derivatives as ZAP-70 and/or Syk inhibitors - Google Patents
2,4 Di (hetero)-arylamino-pyrimidine derivatives as ZAP-70 and/or Syk inhibitors Download PDFInfo
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- ZA200601963B ZA200601963B ZA200601963A ZA200601963A ZA200601963B ZA 200601963 B ZA200601963 B ZA 200601963B ZA 200601963 A ZA200601963 A ZA 200601963A ZA 200601963 A ZA200601963 A ZA 200601963A ZA 200601963 B ZA200601963 B ZA 200601963B
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- 125000005842 heteroatom Chemical group 0.000 title claims description 19
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
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- -1 C-Cyalkaxy Chemical group 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
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- UBFZMLJERNWJCZ-UHFFFAOYSA-N 2-amino-6-(dimethylamino)benzenesulfonamide Chemical compound CN(C)C1=CC=CC(N)=C1S(N)(=O)=O UBFZMLJERNWJCZ-UHFFFAOYSA-N 0.000 description 3
- XEFRNCLPPFDWAC-UHFFFAOYSA-N 3,4,5-trimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1OC XEFRNCLPPFDWAC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- JZTKJPOXZXAMIJ-UHFFFAOYSA-N 2-(dimethylamino)-6-[[2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]benzenesulfonamide Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3C(=C(N(C)C)C=CC=3)S(N)(=O)=O)C=CN=2)=C1 JZTKJPOXZXAMIJ-UHFFFAOYSA-N 0.000 description 2
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- 125000003342 alkenyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
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- 125000001246 bromo group Chemical group Br* 0.000 description 2
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- 238000000605 extraction Methods 0.000 description 2
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- 125000004076 pyridyl group Chemical group 0.000 description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
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- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
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- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- BZKOZYWGZKRTIB-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-6-amine Chemical compound O1CCOC2=CC(N)=CC=C21 BZKOZYWGZKRTIB-UHFFFAOYSA-N 0.000 description 1
- LEWZOBYWGWKNCK-UHFFFAOYSA-N 2,3-dihydro-1h-inden-5-amine Chemical compound NC1=CC=C2CCCC2=C1 LEWZOBYWGWKNCK-UHFFFAOYSA-N 0.000 description 1
- YDMLBSFKMTXIDJ-UHFFFAOYSA-N 2-[[2-(3,4-dimethoxyanilino)pyrimidin-4-yl]amino]-6-(trifluoromethoxy)benzenesulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1NC1=NC=CC(NC=2C(=C(OC(F)(F)F)C=CC=2)S(N)(=O)=O)=N1 YDMLBSFKMTXIDJ-UHFFFAOYSA-N 0.000 description 1
- ZPYYPVIZCAFIBS-UHFFFAOYSA-N 2-[[2-(3,4-dimethoxyanilino)pyrimidin-4-yl]amino]-6-prop-2-enoxybenzenesulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1NC1=NC=CC(NC=2C(=C(OCC=C)C=CC=2)S(N)(=O)=O)=N1 ZPYYPVIZCAFIBS-UHFFFAOYSA-N 0.000 description 1
- GWYOWFXEAHLULA-UHFFFAOYSA-N 2-amino-6-(trifluoromethoxy)benzenesulfonamide Chemical compound NC1=CC=CC(OC(F)(F)F)=C1S(N)(=O)=O GWYOWFXEAHLULA-UHFFFAOYSA-N 0.000 description 1
- ACUFLNWNUQBRFN-UHFFFAOYSA-N 2-chloro-6-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=C(Cl)C=CC=C1[N+]([O-])=O ACUFLNWNUQBRFN-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- HFCFJYRLBAANKN-UHFFFAOYSA-N 2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=CC=C1[N+]([O-])=O HFCFJYRLBAANKN-UHFFFAOYSA-N 0.000 description 1
- UYHSQVMHSFXUOA-UHFFFAOYSA-N 2-methylthiouracil Chemical compound CSC1=NC=CC(O)=N1 UYHSQVMHSFXUOA-UHFFFAOYSA-N 0.000 description 1
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- UMYMICJAEFKYND-UHFFFAOYSA-N 5,6-dichloro-5-nitrocyclohexa-1,3-diene Chemical compound ClC1C=CC=CC1([N+](=O)[O-])Cl UMYMICJAEFKYND-UHFFFAOYSA-N 0.000 description 1
- MPVSHKRXVYRFHY-UHFFFAOYSA-N 5-[[2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,3-dihydro-1h-indene-4-sulfonamide Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3C(=C4CCCC4=CC=3)S(N)(=O)=O)C=CN=2)=C1 MPVSHKRXVYRFHY-UHFFFAOYSA-N 0.000 description 1
- AAPNMNWWBLOWLI-UHFFFAOYSA-N 5-amino-2,3-dihydro-1H-indene-4-sulfonamide Chemical compound NC1=C(C=2CCCC2C=C1)S(=O)(=O)N.NC1=C(C=2CCCC2C=C1)S(=O)(=O)N AAPNMNWWBLOWLI-UHFFFAOYSA-N 0.000 description 1
- JMCYMXIDMSCABY-UHFFFAOYSA-N 5-amino-2,3-dihydro-1h-indene-4-sulfonamide Chemical compound NC1=CC=C2CCCC2=C1S(N)(=O)=O JMCYMXIDMSCABY-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 102100035861 Cytosolic 5'-nucleotidase 1A Human genes 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 101000802744 Homo sapiens Cytosolic 5'-nucleotidase 1A Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- 101100391171 Schizosaccharomyces pombe (strain 972 / ATCC 24843) for3 gene Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- ACXOYRULDUFYJB-UHFFFAOYSA-N [N].O1CCOC2=CC(N)=CC=C21 Chemical compound [N].O1CCOC2=CC(N)=CC=C21 ACXOYRULDUFYJB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- HLNPDVKKRBWQAA-UHFFFAOYSA-M amino(trimethyl)azanium;iodide Chemical compound [I-].C[N+](C)(C)N HLNPDVKKRBWQAA-UHFFFAOYSA-M 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ZVYXEXAXXWINEH-UHFFFAOYSA-N n,n-diethyl-2-hydroxybenzamide Chemical compound CCN(CC)C(=O)C1=CC=CC=C1O ZVYXEXAXXWINEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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| EP1991532B1 (de) | 2006-02-24 | 2017-01-11 | Rigel Pharmaceuticals, Inc. | Zusammensetzungen und verfahren zur hemmung des jak-pfades |
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| ES2633318T3 (es) | 2006-10-23 | 2017-09-20 | Cephalon, Inc. | Derivados bicíclicos fusionados de 2,4-diaminopirimidina como inhibidores de ALK y c-Met |
| MY148427A (en) | 2006-12-08 | 2013-04-30 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
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