BR112019011847A2 - derivados de imidazo [1,5-a] pirazina como inibidores pi3kdelta - Google Patents

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Publication number

BR112019011847A2

BR112019011847A2 BR112019011847-0A BR112019011847A BR112019011847A2 BR 112019011847 A2 BR112019011847 A2 BR 112019011847A2 BR 112019011847 A BR112019011847 A BR 112019011847A BR 112019011847 A2 BR112019011847 A2 BR 112019011847A2

Authority

BR

Brazil

Prior art keywords

compound

ealkyl

heteroaryl

heterocyclyl

cycloalkyl

Prior art date

2016-12-07

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• MIFJMFOVENWQDP-UHFFFAOYSA-N imidazo[1,5-a]pyrazine Chemical class C1=CN=CC2=CN=CN21 MIFJMFOVENWQDP-UHFFFAOYSA-N 0.000 title description 28
• 239000003112 inhibitor Substances 0.000 title description 10
• 150000001875 compounds Chemical class 0.000 claims abstract description 531
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
• 150000003839 salts Chemical class 0.000 claims abstract description 40
• 238000000034 method Methods 0.000 claims abstract description 38
• 201000010099 disease Diseases 0.000 claims abstract description 24
• 208000035475 disorder Diseases 0.000 claims abstract description 24
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
• 201000006417 multiple sclerosis Diseases 0.000 claims description 245
• -1 hydrogen halogen Chemical group 0.000 claims description 238
• 125000000623 heterocyclic group Chemical group 0.000 claims description 123
• 125000001072 heteroaryl group Chemical group 0.000 claims description 103
• 125000003118 aryl group Chemical group 0.000 claims description 99
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 96
• 239000001257 hydrogen Substances 0.000 claims description 96
• 229910052739 hydrogen Inorganic materials 0.000 claims description 96
• 239000000460 chlorine Substances 0.000 claims description 64
• 125000001424 substituent group Chemical group 0.000 claims description 56
• 125000005842 heteroatom Chemical group 0.000 claims description 54
• 229910052757 nitrogen Inorganic materials 0.000 claims description 50
• 150000002431 hydrogen Chemical group 0.000 claims description 48
• 229910052736 halogen Inorganic materials 0.000 claims description 45
• 150000002367 halogens Chemical class 0.000 claims description 38
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
• 229910052717 sulfur Inorganic materials 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
• 229910052801 chlorine Inorganic materials 0.000 claims description 28
• 229910052760 oxygen Inorganic materials 0.000 claims description 28
• 229920006395 saturated elastomer Polymers 0.000 claims description 27
• 210000004027 cell Anatomy 0.000 claims description 25
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
• 229910052794 bromium Inorganic materials 0.000 claims description 19
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
• 210000003719 b-lymphocyte Anatomy 0.000 claims description 15
• 206010028980 Neoplasm Diseases 0.000 claims description 14
• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 11
• 230000000694 effects Effects 0.000 claims description 11
• 230000005764 inhibitory process Effects 0.000 claims description 11
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 10
• 201000011510 cancer Diseases 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 9
• 229910003827 NRaRb Inorganic materials 0.000 claims description 8
• 125000004043 oxo group Chemical group O=* 0.000 claims description 8
• 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 7
• 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 7
• 229910052731 fluorine Inorganic materials 0.000 claims description 7
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 7
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 6
• 210000001280 germinal center Anatomy 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 5
• 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 5
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
• 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 5
• 229940126540 compound 41 Drugs 0.000 claims description 5
• 201000003444 follicular lymphoma Diseases 0.000 claims description 5
• VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 4
• QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
• 208000023275 Autoimmune disease Diseases 0.000 claims description 4
• 208000003950 B-cell lymphoma Diseases 0.000 claims description 4
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
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• 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 4
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 4
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
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• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
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• 229940127573 compound 38 Drugs 0.000 claims description 4
• PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 4
• 208000011580 syndromic disease Diseases 0.000 claims description 4
• YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 3
• ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 3
• TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
• 206010018372 Glomerulonephritis membranous Diseases 0.000 claims description 3
• 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
• 241000721454 Pemphigus Species 0.000 claims description 3
• 206010047115 Vasculitis Diseases 0.000 claims description 3
• 230000001154 acute effect Effects 0.000 claims description 3
• XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 3
• 210000004556 brain Anatomy 0.000 claims description 3
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• 229940125851 compound 27 Drugs 0.000 claims description 3
• 229940125900 compound 59 Drugs 0.000 claims description 3
• 208000027866 inflammatory disease Diseases 0.000 claims description 3
• ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 3
• 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 claims description 3
• 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 3
• 208000021937 marginal zone lymphoma Diseases 0.000 claims description 3
• 201000008350 membranous glomerulonephritis Diseases 0.000 claims description 3
• 231100000855 membranous nephropathy Toxicity 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 2
• ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 2
• GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims description 2
• IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
• STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 2
• OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 claims description 2
• MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 2
• YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 2
• VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
• DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 claims description 2
• KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 claims description 2
• FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 2
• QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 2
• XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 claims description 2
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• QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 claims description 2
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• LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 2
• SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 2
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