CA2978828A1 - 7-(morpholin-4-yl)pyrazole[1,5-a]pyrimidine derivatives which are useful for the treatment of immune or inflammatory diseases or cancer - Google Patents
7-(morpholin-4-yl)pyrazole[1,5-a]pyrimidine derivatives which are useful for the treatment of immune or inflammatory diseases or cancer Download PDFInfo
- Publication number
- CA2978828A1 CA2978828A1 CA2978828A CA2978828A CA2978828A1 CA 2978828 A1 CA2978828 A1 CA 2978828A1 CA 2978828 A CA2978828 A CA 2978828A CA 2978828 A CA2978828 A CA 2978828A CA 2978828 A1 CA2978828 A1 CA 2978828A1
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- CA
- Canada
- Prior art keywords
- alkyl
- compound
- formula
- morpholin
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 208000026278 immune system disease Diseases 0.000 title claims abstract description 16
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 13
- 201000011510 cancer Diseases 0.000 title claims abstract description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
- 150000003230 pyrimidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- -1 dioxothiomorpholino moiety Chemical group 0.000 claims abstract description 51
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 29
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 20
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 20
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 abstract 1
- 125000003386 piperidinyl group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 101150041968 CDC13 gene Proteins 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- 125000000217 alkyl group Chemical group 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 30
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical compound N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 239000000126 substance Substances 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000009835 boiling Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 108091000080 Phosphotransferase Proteins 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 16
- 102000020233 phosphotransferase Human genes 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 102000038030 PI3Ks Human genes 0.000 description 15
- 108091007960 PI3Ks Proteins 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 239000002274 desiccant Substances 0.000 description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 230000026731 phosphorylation Effects 0.000 description 8
- 238000006366 phosphorylation reaction Methods 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 102000001708 Protein Isoforms Human genes 0.000 description 7
- 108010029485 Protein Isoforms Proteins 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PHSWWKXTGAJPCQ-UHFFFAOYSA-N ethyl 2-phenylmethoxyacetate Chemical compound CCOC(=O)COCC1=CC=CC=C1 PHSWWKXTGAJPCQ-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
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- 230000001747 exhibiting effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
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- 229910052763 palladium Inorganic materials 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- ZSZXYWFCIKKZBT-IVYVYLGESA-N 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@@H]1[C@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O ZSZXYWFCIKKZBT-IVYVYLGESA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- ZLKVDWDBYSJPDP-UHFFFAOYSA-N 3-phenyl-6-pyridin-2-ylpyrazolo[1,5-a]pyrimidine Chemical compound C1=NN2C=C(C=3N=CC=CC=3)C=NC2=C1C1=CC=CC=C1 ZLKVDWDBYSJPDP-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- GLHXYSFEVOAOSL-UHFFFAOYSA-N 4-(azetidin-3-yl)morpholine Chemical compound C1NCC1N1CCOCC1 GLHXYSFEVOAOSL-UHFFFAOYSA-N 0.000 description 3
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 3
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 3
- 239000012828 PI3K inhibitor Substances 0.000 description 3
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
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- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 3
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- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 3
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 3
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- 238000006268 reductive amination reaction Methods 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- AOYSLJHKVBSXRU-UHFFFAOYSA-N 1-(oxetan-3-yl)piperazine Chemical compound C1OCC1N1CCNCC1 AOYSLJHKVBSXRU-UHFFFAOYSA-N 0.000 description 2
- PVMNSAIKFPWDQG-UHFFFAOYSA-N 1-tert-butylpiperazine Chemical compound CC(C)(C)N1CCNCC1 PVMNSAIKFPWDQG-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 2
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 2
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 2
- MJOUJKDTBGXKIU-UHFFFAOYSA-N 4,4-difluoropiperidine Chemical compound FC1(F)CCNCC1 MJOUJKDTBGXKIU-UHFFFAOYSA-N 0.000 description 2
- NZHLZEPECDCTFH-UHFFFAOYSA-N 4-pyrazolo[1,5-a]pyrimidin-7-ylmorpholine Chemical class C1CN(CCO1)C1=CC=NC2=CC=NN12 NZHLZEPECDCTFH-UHFFFAOYSA-N 0.000 description 2
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 2
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 2
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- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical class N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 description 1
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
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- 150000003904 phospholipids Chemical class 0.000 description 1
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- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical class CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
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- 229920000053 polysorbate 80 Polymers 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 239000012286 potassium permanganate 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
- 150000003141 primary amines Chemical class 0.000 description 1
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- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
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- IGPJYNUPSNKQTA-XVKPBYJWSA-N tert-butyl (1s,4s)-2,5-diazabicyclo[2.2.1]heptane-4-carboxylate Chemical compound C1N[C@]2(C(=O)OC(C)(C)C)CN[C@@]1([H])C2 IGPJYNUPSNKQTA-XVKPBYJWSA-N 0.000 description 1
- BZORURUBWYXNAX-UHFFFAOYSA-N tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1COC1 BZORURUBWYXNAX-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- FQIWHPALNIWULM-UHFFFAOYSA-N thiomorpholine-2,3-dione Chemical compound O=C1NCCSC1=O FQIWHPALNIWULM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL411864 | 2015-04-02 | ||
| PL411864A PL236355B1 (pl) | 2015-04-02 | 2015-04-02 | Pochodne 7-(morfolin-4-ylo)pirazolo[1,5-α]pirymidyny jako inhibitory kinazy PI3 |
| PCT/IB2016/051792 WO2016157091A1 (en) | 2015-04-02 | 2016-03-30 | 7-(morpholin-4-yl)pyrazole[1,5-a]pyrimidine derivatives which are useful for the treatment of immune or inflammatory diseases or cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2978828A1 true CA2978828A1 (en) | 2016-10-06 |
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Family Applications (1)
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|---|---|---|---|
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| EP (1) | EP3277687B1 (enExample) |
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| CN (1) | CN107743489B (enExample) |
| AU (1) | AU2016241568B2 (enExample) |
| BR (1) | BR112017020131B1 (enExample) |
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| DK (1) | DK3277687T3 (enExample) |
| EA (1) | EA032826B1 (enExample) |
| ES (1) | ES2765642T3 (enExample) |
| HR (1) | HRP20192195T1 (enExample) |
| HU (1) | HUE047822T2 (enExample) |
| MX (1) | MX2017011423A (enExample) |
| PL (2) | PL236355B1 (enExample) |
| PT (1) | PT3277687T (enExample) |
| SI (1) | SI3277687T1 (enExample) |
| WO (1) | WO2016157091A1 (enExample) |
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| AU2021207804A1 (en) | 2020-01-13 | 2022-09-01 | Verge Analytics, Inc. | Substituted pyrazolo-pyrimidines and uses thereof |
| CN114599653B (zh) * | 2020-09-28 | 2025-12-16 | 第一生物治疗股份有限公司 | 作为造血祖细胞激酶1(hpk1)抑制剂的吲唑及其使用方法 |
| CN114957261B (zh) * | 2022-05-17 | 2023-06-23 | 重庆文理学院 | 一种具有抗头颈癌作用的化合物及其制备方法和应用 |
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| PL191271B1 (pl) * | 1996-02-07 | 2006-04-28 | Neurocrine Biosciences Inc | Pochodna pirazolopirymidyny i jej zastosowanie oraz kompozycja farmaceutyczna |
| AU2004308399A1 (en) | 2003-12-23 | 2005-07-14 | Activbiotics, Inc. | Rifamycin analogs and uses thereof |
| AU2006212457B2 (en) * | 2005-02-11 | 2011-04-14 | F. Hoffmann-La Roche Ag | Pyrazolo-pyrimidine derivatives as mGLuR2 antagonists |
| KR101088239B1 (ko) * | 2006-09-20 | 2011-11-30 | 일라이 릴리 앤드 캄파니 | Ｃｒｆ１ 수용체 길항제로서의 티아졸 피라졸로피리미딘 |
| EP2215090B1 (en) * | 2007-10-26 | 2015-03-04 | F. Hoffmann-La Roche AG | Purine derivatives useful as pi3 kinase inhibitors |
| AU2009218515A1 (en) | 2008-02-26 | 2009-09-03 | Novartis Ag | Heterocyclic compounds as inhibitors of CXCR2 |
| EP2279188B1 (en) * | 2008-05-30 | 2015-01-28 | Genentech, Inc. | Purine pi3k inhibitor compounds and methods of use |
| WO2010037765A2 (en) * | 2008-10-03 | 2010-04-08 | Merck Serono S.A. | 4-morpholino-pyrido[3,2-d]pyrimidines |
| JP5578490B2 (ja) * | 2008-12-26 | 2014-08-27 | 味の素株式会社 | ピラゾロピリミジン化合物 |
| MX2011010915A (es) * | 2009-04-16 | 2012-01-27 | Ct Nac Investigaciones Oncologicas Cnio | Imidazopirazinas para usarse como inhibidores decinasa. |
| BRPI1009022A2 (pt) | 2009-05-27 | 2016-03-08 | Hoffmann La Roche | "composto, composição farmacêutica, processo para produzir uma composição farmacêutica, uso de um composto, método para tratamento de uma doença ou transtorno e kit" |
| CA2772371A1 (en) * | 2009-05-27 | 2010-12-02 | F. Hoffmann-La Roche Ag | Bicyclic indole-pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use |
| GB0912745D0 (en) | 2009-07-22 | 2009-08-26 | Wolfson Microelectronics Plc | Improvements relating to DC-DC converters |
| MX2012009059A (es) | 2010-02-22 | 2012-09-07 | Hoffmann La Roche | Compuestos inhibidores de fosfoinositida 3-cinasa delta (pi3k) pirido [3,2-d]pirimidina y metodos de uso. |
| PT2542084T (pt) | 2010-03-04 | 2018-03-23 | Merck Sharp & Dohme | Inibidores de catecol o-metil transferase e sua utilização no tratamento de distúrbios psicóticos |
| US9096605B2 (en) * | 2011-08-24 | 2015-08-04 | Glaxosmithkline Llc | Pyrazolopyrimidine derivatives as PI3 kinase inhibitors |
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2015
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- 2016-03-30 CN CN201680017259.4A patent/CN107743489B/zh not_active Expired - Fee Related
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- 2016-03-30 PL PL16714019T patent/PL3277687T3/pl unknown
- 2016-03-30 PT PT167140193T patent/PT3277687T/pt unknown
- 2016-03-30 HU HUE16714019A patent/HUE047822T2/hu unknown
- 2016-03-30 CA CA2978828A patent/CA2978828A1/en active Pending
- 2016-03-30 JP JP2017551627A patent/JP6665201B2/ja not_active Expired - Fee Related
Also Published As
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|---|---|
| WO2016157091A1 (en) | 2016-10-06 |
| EA201792087A1 (ru) | 2018-03-30 |
| MX2017011423A (es) | 2018-05-17 |
| CN107743489A (zh) | 2018-02-27 |
| JP6665201B2 (ja) | 2020-03-13 |
| HRP20192195T1 (hr) | 2020-03-06 |
| SI3277687T1 (sl) | 2020-02-28 |
| AU2016241568B2 (en) | 2019-09-26 |
| PL411864A1 (pl) | 2016-10-10 |
| KR102559190B1 (ko) | 2023-07-25 |
| EP3277687B1 (en) | 2019-10-30 |
| DK3277687T3 (da) | 2019-12-16 |
| HUE047822T2 (hu) | 2020-05-28 |
| BR112017020131A2 (pt) | 2018-05-29 |
| PT3277687T (pt) | 2020-01-10 |
| PL236355B1 (pl) | 2021-01-11 |
| EA032826B1 (ru) | 2019-07-31 |
| BR112017020131B1 (pt) | 2023-02-28 |
| US10138247B2 (en) | 2018-11-27 |
| PL3277687T3 (pl) | 2020-09-21 |
| KR20170132275A (ko) | 2017-12-01 |
| CN107743489B (zh) | 2021-05-04 |
| AU2016241568A1 (en) | 2017-10-19 |
| ES2765642T3 (es) | 2020-06-10 |
| US20180111939A1 (en) | 2018-04-26 |
| JP2018510192A (ja) | 2018-04-12 |
| EP3277687A1 (en) | 2018-02-07 |
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