DK2877177T3 - DERIVATIVES OF AZAINDAZOL OR DIAZAINDAZOL TYPE FOR TREATMENT OF PAIN - Google Patents

Info

Publication number

DK2877177T3

DK2877177T3 DK13745813.9T DK13745813T DK2877177T3 DK 2877177 T3 DK2877177 T3 DK 2877177T3 DK 13745813 T DK13745813 T DK 13745813T DK 2877177 T3 DK2877177 T3 DK 2877177T3

Authority

DK

Denmark

Prior art keywords

charom

pain

group

mmol

compound

Prior art date

2012-07-27

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• 208000002193 Pain Diseases 0.000 title claims description 107
• 230000036407 pain Effects 0.000 title claims description 97
• 238000011282 treatment Methods 0.000 title claims description 29
• VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims description 129
• 239000000203 mixture Substances 0.000 claims description 57
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 45
• 125000000217 alkyl group Chemical group 0.000 claims description 36
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
• 229910052717 sulfur Inorganic materials 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 23
• DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 16
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
• 125000005843 halogen group Chemical group 0.000 claims description 14
• 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 claims description 12
• 230000002265 prevention Effects 0.000 claims description 12
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
• 208000004296 neuralgia Diseases 0.000 claims description 11
• 208000021722 neuropathic pain Diseases 0.000 claims description 11
• 206010065390 Inflammatory pain Diseases 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 10
• 206010028980 Neoplasm Diseases 0.000 claims description 8
• 125000001188 haloalkyl group Chemical group 0.000 claims description 8
• 239000012453 solvate Substances 0.000 claims description 8
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 7
• 201000011510 cancer Diseases 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
• 208000001294 Nociceptive Pain Diseases 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 208000028389 Nerve injury Diseases 0.000 claims description 4
• 230000008764 nerve damage Effects 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 208000025747 Rheumatic disease Diseases 0.000 claims description 3
• 235000019256 formaldehyde Nutrition 0.000 claims description 3
• 230000001107 psychogenic effect Effects 0.000 claims description 3
• 125000003107 substituted aryl group Chemical group 0.000 claims description 3
• 101100212791 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) YBL068W-A gene Proteins 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 8
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims 2
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 1
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 179
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 149
• 238000000034 method Methods 0.000 description 144
• 239000000243 solution Substances 0.000 description 139
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 118
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 93
• 239000007787 solid Substances 0.000 description 90
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
• 238000005160 1H NMR spectroscopy Methods 0.000 description 81
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 77
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 74
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 70
• 239000012429 reaction media Substances 0.000 description 70
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
• 239000002904 solvent Substances 0.000 description 64
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 62
• 238000006243 chemical reaction Methods 0.000 description 61
• 239000012074 organic phase Substances 0.000 description 58
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 52
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
• 238000010586 diagram Methods 0.000 description 48
• 239000011541 reaction mixture Substances 0.000 description 48
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 45
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 44
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 35
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 34
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
• 235000019341 magnesium sulphate Nutrition 0.000 description 33
• -1 diazaindazole compound Chemical class 0.000 description 32
• 238000003756 stirring Methods 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
• 239000002798 polar solvent Substances 0.000 description 23
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 23
• 239000000047 product Substances 0.000 description 23
• 230000015572 biosynthetic process Effects 0.000 description 22
• 238000010898 silica gel chromatography Methods 0.000 description 22
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
• 239000000843 powder Substances 0.000 description 19
• 239000002244 precipitate Substances 0.000 description 19
• 239000007795 chemical reaction product Substances 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 17
• 229910000027 potassium carbonate Inorganic materials 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 238000012360 testing method Methods 0.000 description 16
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 15
• 150000007529 inorganic bases Chemical class 0.000 description 15
• 150000007530 organic bases Chemical class 0.000 description 15
• JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 14
• 108010025020 Nerve Growth Factor Proteins 0.000 description 14
• QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 14
• 229910052739 hydrogen Inorganic materials 0.000 description 14
• LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 13
• 102000015336 Nerve Growth Factor Human genes 0.000 description 13
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
• 238000005755 formation reaction Methods 0.000 description 13
• 229940053128 nerve growth factor Drugs 0.000 description 13
• 101150111783 NTRK1 gene Proteins 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 12
• WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 11
• 208000004454 Hyperalgesia Diseases 0.000 description 11
• 239000002253 acid Substances 0.000 description 11
• 229910052786 argon Inorganic materials 0.000 description 11
• 239000013078 crystal Substances 0.000 description 11
• 239000003480 eluent Substances 0.000 description 11
• 230000002829 reductive effect Effects 0.000 description 11
• 229920006395 saturated elastomer Polymers 0.000 description 11
• 229910000029 sodium carbonate Inorganic materials 0.000 description 11
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 10
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
• 101150056950 Ntrk2 gene Proteins 0.000 description 10
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
• 239000008346 aqueous phase Substances 0.000 description 10
• 239000003054 catalyst Substances 0.000 description 10
• 230000003197 catalytic effect Effects 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
• RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 10
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
• 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 9
• 239000012043 crude product Substances 0.000 description 9
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 9
• 230000005764 inhibitory process Effects 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 8
• 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 8
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
• 108091000080 Phosphotransferase Proteins 0.000 description 8
• 230000000202 analgesic effect Effects 0.000 description 8
• 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 8
• 238000005859 coupling reaction Methods 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• 230000006870 function Effects 0.000 description 8
• 239000003112 inhibitor Substances 0.000 description 8
• 239000007924 injection Substances 0.000 description 8
• 238000002347 injection Methods 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 238000007254 oxidation reaction Methods 0.000 description 8
• 102000020233 phosphotransferase Human genes 0.000 description 8
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
• 239000011591 potassium Substances 0.000 description 8
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
• 229910052938 sodium sulfate Inorganic materials 0.000 description 8
• 235000011152 sodium sulphate Nutrition 0.000 description 8
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
• AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 7
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
• XVIHGTRTKQZJAC-UHFFFAOYSA-N 6-chloro-3-nitropyridine-2-carbonitrile Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1C#N XVIHGTRTKQZJAC-UHFFFAOYSA-N 0.000 description 7
• 208000000094 Chronic Pain Diseases 0.000 description 7
• 241000700159 Rattus Species 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 230000009471 action Effects 0.000 description 7
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 238000004587 chromatography analysis Methods 0.000 description 7
• 238000010511 deprotection reaction Methods 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• 239000003814 drug Substances 0.000 description 7
• 239000002038 ethyl acetate fraction Substances 0.000 description 7
• 230000002757 inflammatory effect Effects 0.000 description 7
• 229910052763 palladium Inorganic materials 0.000 description 7
• 238000002360 preparation method Methods 0.000 description 7
• 239000000377 silicon dioxide Substances 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
• BYEUNDASYOFKIW-UHFFFAOYSA-N 5-iodo-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical class C1=C(I)C=C2C(N)=NNC2=N1 BYEUNDASYOFKIW-UHFFFAOYSA-N 0.000 description 6
• 206010005949 Bone cancer Diseases 0.000 description 6
• 208000018084 Bone neoplasm Diseases 0.000 description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
• 229910020008 S(O) Inorganic materials 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• 230000002378 acidificating effect Effects 0.000 description 6
• 125000000753 cycloalkyl group Chemical group 0.000 description 6
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
• 239000001257 hydrogen Substances 0.000 description 6
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
• 230000003647 oxidation Effects 0.000 description 6
• 235000011181 potassium carbonates Nutrition 0.000 description 6
• 238000006722 reduction reaction Methods 0.000 description 6
• 239000011734 sodium Substances 0.000 description 6
• 150000003462 sulfoxides Chemical class 0.000 description 6
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
• DDZGQYREBDXECY-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyrazine Chemical class C1=CN=C2C=NNC2=N1 DDZGQYREBDXECY-UHFFFAOYSA-N 0.000 description 5
• JPGXJOYWNKSCGX-UHFFFAOYSA-N 2-[(4,4-difluorocyclohexyl)-(2,2,2-trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C)CCN1C1=CC=C(C(O)=O)C(N(C2CCC(F)(F)CC2)C(=O)C(F)(F)F)=C1 JPGXJOYWNKSCGX-UHFFFAOYSA-N 0.000 description 5
• UQNVAKOELHOJFN-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-4-ium-1-yl)phenyl]acetate Chemical compound C1CN(C)CCN1C1=CC=C(CC(O)=O)C=C1 UQNVAKOELHOJFN-UHFFFAOYSA-N 0.000 description 5
• FYHRQFFVACXNTB-UHFFFAOYSA-N 2-chloro-5-iodopyridine-3-carbonitrile Chemical class ClC1=NC=C(I)C=C1C#N FYHRQFFVACXNTB-UHFFFAOYSA-N 0.000 description 5
• IHWZCGMZILLKFD-UHFFFAOYSA-N 2-methoxypyridine-3-carbonitrile Chemical compound COC1=NC=CC=C1C#N IHWZCGMZILLKFD-UHFFFAOYSA-N 0.000 description 5
• GPYNAAUDGBICPV-UHFFFAOYSA-N 3-amino-n-(3,5-difluorophenyl)-2h-pyrazolo[3,4-b]pyridine-5-sulfonamide Chemical compound C1=C2C(N)=NNC2=NC=C1S(=O)(=O)NC1=CC(F)=CC(F)=C1 GPYNAAUDGBICPV-UHFFFAOYSA-N 0.000 description 5
• JVIGDQVFRFSUKJ-UHFFFAOYSA-N 5-[(3,5-difluorophenyl)methoxy]-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C2C(N)=NNC2=NC=C1OCC1=CC(F)=CC(F)=C1 JVIGDQVFRFSUKJ-UHFFFAOYSA-N 0.000 description 5
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