ES2686500T3 - Compuestos de piridilo sustituidos con heterocíclicos, útiles como inhibidores de cinasas - Google Patents

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Publication number

ES2686500T3

ES2686500T3 ES13700828.0T ES13700828T ES2686500T3 ES 2686500 T3 ES2686500 T3 ES 2686500T3 ES 13700828 T ES13700828 T ES 13700828T ES 2686500 T3 ES2686500 T3 ES 2686500T3

Authority

ES

Spain

Prior art keywords

substituted

alkyl

hydrogen

solvent

membered

Prior art date

2012-01-13

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.)

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• 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 37
• 125000004076 pyridyl group Chemical group 0.000 title claims abstract description 13
• 229940043355 kinase inhibitor Drugs 0.000 title description 4
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
• -1 pyrazolopyridinyl Chemical group 0.000 claims abstract description 242
• 150000001875 compounds Chemical class 0.000 claims abstract description 238
• 150000003839 salts Chemical class 0.000 claims abstract description 90
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 70
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 68
• 239000001257 hydrogen Substances 0.000 claims abstract description 65
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 58
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 54
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 51
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 42
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 40
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 33
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 31
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 29
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 29
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 28
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 27
• 101150105130 RORB gene Proteins 0.000 claims abstract description 23
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 16
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 13
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 12
• 125000005843 halogen group Chemical group 0.000 claims abstract description 10
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 8
• 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims abstract description 8
• 125000001624 naphthyl group Chemical group 0.000 claims abstract description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 7
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims abstract description 7
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims abstract description 7
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims abstract description 7
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims abstract description 7
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims abstract description 6
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims abstract description 6
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 6
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 6
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 6
• 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 claims abstract description 6
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims abstract description 6
• 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 claims abstract description 6
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
• 150000002367 halogens Chemical class 0.000 claims abstract description 6
• 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims abstract description 6
• 125000001041 indolyl group Chemical group 0.000 claims abstract description 6
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims abstract description 6
• 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 6
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract description 6
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims abstract description 6
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 5
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 5
• 125000005872 benzooxazolyl group Chemical group 0.000 claims abstract description 5
• 125000005874 benzothiadiazolyl group Chemical group 0.000 claims abstract description 5
• 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims abstract description 5
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims abstract description 5
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims abstract description 5
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims abstract description 5
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims abstract description 5
• 125000006085 pyrrolopyridyl group Chemical group 0.000 claims abstract description 5
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims abstract description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 125000003118 aryl group Chemical group 0.000 claims description 20
• 239000003814 drug Substances 0.000 claims description 18
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 125000001188 haloalkyl group Chemical group 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 239000003085 diluting agent Substances 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 208000027866 inflammatory disease Diseases 0.000 claims description 8
• 208000023275 Autoimmune disease Diseases 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
• 230000002757 inflammatory effect Effects 0.000 claims description 3
• AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
• 241000272522 Anas Species 0.000 claims 1
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 466
• 239000002904 solvent Substances 0.000 description 444
• 201000006417 multiple sclerosis Diseases 0.000 description 291
• 230000014759 maintenance of location Effects 0.000 description 279
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 236
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 230
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 225
• 238000005160 1H NMR spectroscopy Methods 0.000 description 157
• 230000015572 biosynthetic process Effects 0.000 description 131
• 238000003786 synthesis reaction Methods 0.000 description 129
• 239000008186 active pharmaceutical agent Substances 0.000 description 122
• 239000011541 reaction mixture Substances 0.000 description 107
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 82
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
• 238000000034 method Methods 0.000 description 76
• 239000000243 solution Substances 0.000 description 75
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 71
• 238000006243 chemical reaction Methods 0.000 description 65
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
• 239000013058 crude material Substances 0.000 description 42
• 239000000741 silica gel Substances 0.000 description 42
• 229910002027 silica gel Inorganic materials 0.000 description 42
• 239000003480 eluent Substances 0.000 description 41
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 39
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
• 229910052938 sodium sulfate Inorganic materials 0.000 description 36
• 235000011152 sodium sulphate Nutrition 0.000 description 36
• 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 description 35
• 239000007832 Na2SO4 Substances 0.000 description 35
• 235000019439 ethyl acetate Nutrition 0.000 description 35
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
• 238000004440 column chromatography Methods 0.000 description 34
• 201000010099 disease Diseases 0.000 description 32
• 239000012044 organic layer Substances 0.000 description 30
• 150000001412 amines Chemical class 0.000 description 29
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
• 230000002829 reductive effect Effects 0.000 description 23
• 101710199010 Interleukin-1 receptor-associated kinase 4 Proteins 0.000 description 22
• 229940002612 prodrug Drugs 0.000 description 21
• 239000000651 prodrug Substances 0.000 description 21
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
• 239000010410 layer Substances 0.000 description 20
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• 239000000460 chlorine Substances 0.000 description 19
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• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 18
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 18
• 125000001424 substituent group Chemical group 0.000 description 18
• 239000002253 acid Substances 0.000 description 16
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
• 238000002953 preparative HPLC Methods 0.000 description 16
• KXVDSEWWEHKHAD-UHFFFAOYSA-N 6-chloro-4-(propan-2-ylamino)pyridine-3-carbohydrazide Chemical compound CC(C)NC1=CC(Cl)=NC=C1C(=O)NN KXVDSEWWEHKHAD-UHFFFAOYSA-N 0.000 description 15
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