CA2929650C - 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use - Google Patents
4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use Download PDFInfo
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- CA2929650C CA2929650C CA2929650A CA2929650A CA2929650C CA 2929650 C CA2929650 C CA 2929650C CA 2929650 A CA2929650 A CA 2929650A CA 2929650 A CA2929650 A CA 2929650A CA 2929650 C CA2929650 C CA 2929650C
- Authority
- CA
- Canada
- Prior art keywords
- pyrazol
- fluoro
- indol
- indole
- 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.)
- Expired - Fee Related
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- 238000000034 method Methods 0.000 title claims abstract description 51
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- LAUZGQFZTMIABE-UHFFFAOYSA-N 3-(1h-pyrazol-4-yl)-1h-indole Chemical class C1=NNC=C1C1=CNC2=CC=CC=C12 LAUZGQFZTMIABE-UHFFFAOYSA-N 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 494
- 150000003839 salts Chemical class 0.000 claims abstract description 94
- 239000012453 solvate Substances 0.000 claims abstract description 75
- 230000008569 process Effects 0.000 claims abstract description 28
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 101
- -1 carboxy, amino Chemical group 0.000 claims description 100
- 150000002367 halogens Chemical class 0.000 claims description 96
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 91
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 86
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 59
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 52
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000004043 oxo group Chemical group O=* 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 34
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 32
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 150000001336 alkenes Chemical class 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical class C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 101100519284 Cercospora nicotianae PDX1 gene Proteins 0.000 claims description 16
- 101100277598 Sorghum bicolor DES3 gene Proteins 0.000 claims description 16
- 101150073238 sor1 gene Proteins 0.000 claims description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 10
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 8
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 8
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical class O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 6
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical class O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical class C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- 101100496169 Arabidopsis thaliana CLH1 gene Proteins 0.000 claims 13
- 101100044057 Mesocricetus auratus SYCP3 gene Proteins 0.000 claims 13
- 101100080600 Schizosaccharomyces pombe (strain 972 / ATCC 24843) nse6 gene Proteins 0.000 claims 13
- 101150111293 cor-1 gene Proteins 0.000 claims 13
- 101000892398 Homo sapiens Tryptophan 2,3-dioxygenase Proteins 0.000 claims 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 2
- 150000001539 azetidines Chemical class 0.000 claims 2
- MFNYBOWJWGPXFM-UHFFFAOYSA-N cyclobutanecarboxamide Chemical compound NC(=O)C1CCC1 MFNYBOWJWGPXFM-UHFFFAOYSA-N 0.000 claims 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 2
- VHPXEAACOOIPKU-UHFFFAOYSA-N 4-[4-(6-fluoro-1H-indol-3-yl)pyrazol-1-yl]-N,N-dimethylpiperidine-1-carboxamide Chemical compound CN(C)C(=O)N1CCC(CC1)n1cc(cn1)-c1c[nH]c2cc(F)ccc12 VHPXEAACOOIPKU-UHFFFAOYSA-N 0.000 claims 1
- FQEYRPXCAJOPMZ-UHFFFAOYSA-N 4-[4-(6-fluoro-1H-indol-3-yl)pyrazol-1-yl]piperidine-1-carboxamide methyl 4-[4-(6-fluoro-1H-indol-3-yl)pyrazol-1-yl]piperidine-1-carboxylate Chemical compound NC(=O)N1CCC(CC1)n1cc(cn1)-c1c[nH]c2cc(F)ccc12.COC(=O)N1CCC(CC1)n1cc(cn1)-c1c[nH]c2cc(F)ccc12 FQEYRPXCAJOPMZ-UHFFFAOYSA-N 0.000 claims 1
- FYDSQCNZPGPMIC-UHFFFAOYSA-N 4-[[4-(6-fluoro-1H-indol-3-yl)pyrazol-1-yl]methyl]thiane 1,1-dioxide Chemical compound Fc1ccc2c(c[nH]c2c1)-c1cnn(CC2CCS(=O)(=O)CC2)c1 FYDSQCNZPGPMIC-UHFFFAOYSA-N 0.000 claims 1
- VSUNRZUEHFDYIN-UHFFFAOYSA-N 5,6-difluoro-3-(1H-pyrazol-4-yl)-1H-indole 6-fluoro-3-(1-methylpyrazol-4-yl)-1H-indole 6-fluoro-3-(1H-pyrazol-4-yl)-1H-indole 3-(1H-pyrazol-4-yl)-6-(trifluoromethyl)-1H-indole Chemical compound FC1=CC=C2C(=CNC2=C1)C=1C=NN(C1)C.N1N=CC(=C1)C1=CNC2=CC(=CC=C12)C(F)(F)F.FC=1C=C2C(=CNC2=CC1F)C=1C=NNC1.FC1=CC=C2C(=CNC2=C1)C=1C=NNC1 VSUNRZUEHFDYIN-UHFFFAOYSA-N 0.000 claims 1
- LLQCXKQXBNKZEJ-UHFFFAOYSA-N 6-fluoro-3-(1-pyridin-4-ylpyrazol-4-yl)-1H-indole Chemical compound Fc1ccc2c(c[nH]c2c1)-c1cnn(c1)-c1ccncc1 LLQCXKQXBNKZEJ-UHFFFAOYSA-N 0.000 claims 1
- UZUGZALEDIVFRR-UHFFFAOYSA-N CC1=NN(C(=C1C1=CNC2=CC(=CC=C12)F)C)CC1CCNCC1.FC1=CC=C2C(=CNC2=C1)C=1C=NN(C1)CC1CCN(CC1)S(=O)(=O)C Chemical compound CC1=NN(C(=C1C1=CNC2=CC(=CC=C12)F)C)CC1CCNCC1.FC1=CC=C2C(=CNC2=C1)C=1C=NN(C1)CC1CCN(CC1)S(=O)(=O)C UZUGZALEDIVFRR-UHFFFAOYSA-N 0.000 claims 1
- SMKHTRDMAMTDFH-UHFFFAOYSA-N CN(CC(=O)N1CCC(CC1)N1N=CC(=C1)C1=CNC2=CC(=CC=C12)F)C.FC1=CC=C2C(=CNC2=C1)C=1C=NN(C1)C1CCN(CC1)C(CC)=O Chemical compound CN(CC(=O)N1CCC(CC1)N1N=CC(=C1)C1=CNC2=CC(=CC=C12)F)C.FC1=CC=C2C(=CNC2=C1)C=1C=NN(C1)C1CCN(CC1)C(CC)=O SMKHTRDMAMTDFH-UHFFFAOYSA-N 0.000 claims 1
- YLLBBZDSZSABEY-UHFFFAOYSA-N FC1=CC=C2C(=CNC2=C1)C=1C(=NN(C1)CCC(=O)N)C.FC1=CC=C2C(=CNC2=C1)C=1C(=NN(C1C)CCC(=O)N)C Chemical compound FC1=CC=C2C(=CNC2=C1)C=1C(=NN(C1)CCC(=O)N)C.FC1=CC=C2C(=CNC2=C1)C=1C(=NN(C1C)CCC(=O)N)C YLLBBZDSZSABEY-UHFFFAOYSA-N 0.000 claims 1
- ALVXQAFUCMWOJW-UHFFFAOYSA-N FC1=CC=C2C(=CNC2=C1)C=1C(=NN(C1C)C)C.CN1N=C(C(=C1)C1=CNC2=CC(=CC=C12)F)C.CN1N=CC(=C1C)C1=CNC2=CC(=CC=C12)F Chemical compound FC1=CC=C2C(=CNC2=C1)C=1C(=NN(C1C)C)C.CN1N=C(C(=C1)C1=CNC2=CC(=CC=C12)F)C.CN1N=CC(=C1C)C1=CNC2=CC(=CC=C12)F ALVXQAFUCMWOJW-UHFFFAOYSA-N 0.000 claims 1
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- 206010028980 Neoplasm Diseases 0.000 abstract description 60
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- 102000057288 Tryptophan 2,3-dioxygenases Human genes 0.000 abstract description 38
- 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 abstract description 33
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Molecular Biology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13192224.7 | 2013-11-08 | ||
US14/076,016 US9126984B2 (en) | 2013-11-08 | 2013-11-08 | 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use |
US14/076,016 | 2013-11-08 | ||
EP13192224 | 2013-11-08 | ||
BE2014/0845 | 2014-11-03 | ||
BE201400845 | 2014-11-03 | ||
PCT/EP2014/074099 WO2015067782A1 (en) | 2013-11-08 | 2014-11-07 | 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use |
Publications (2)
Publication Number | Publication Date |
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CA2929650A1 CA2929650A1 (en) | 2015-05-14 |
CA2929650C true CA2929650C (en) | 2017-08-22 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA2929650A Expired - Fee Related CA2929650C (en) | 2013-11-08 | 2014-11-07 | 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use |
Country Status (4)
Country | Link |
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EP (1) | EP3066090A1 (ja) |
JP (1) | JP2016535097A (ja) |
CA (1) | CA2929650C (ja) |
WO (1) | WO2015067782A1 (ja) |
Families Citing this family (5)
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TWI695831B (zh) | 2014-09-13 | 2020-06-11 | 香港商南北兄弟藥業投資有限公司 | Crth2拮抗劑化合物及其用途 |
MA44759B1 (fr) * | 2016-04-29 | 2024-01-31 | Bayer Pharma AG | Forme polymorphe de n-(6-(2-hydroxypropan-2-yl)-2-[2-(méthylsulfonyl)éthyl]-2h-indazol-5-yl)-6-(trifluorométhyl)pyridine-2-carboxamide |
EP3269714A1 (en) | 2016-07-13 | 2018-01-17 | Netherlands Translational Research Center B.V. | Inhibitors of tryptophan 2,3-dioxygenase |
US10882856B2 (en) | 2016-09-24 | 2021-01-05 | Beigene, Ltd. | 5 or 8-substituted imidazo [1,5-a] pyridines as selective inhibitors of indoleamine and/or tryptophane 2,3-dioxygenases |
US20230391786A1 (en) * | 2022-06-02 | 2023-12-07 | Eli Lilly And Company | cGAS INHIBITORS |
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FR2862647B1 (fr) * | 2003-11-25 | 2008-07-04 | Aventis Pharma Sa | Derives de pyrazolyle, procede de preparation et intermediaires de ce procede a titre de medicaments et de compositions pharmaceutiques les renfermant |
GB0516156D0 (en) * | 2005-08-05 | 2005-09-14 | Eisai London Res Lab Ltd | JNK inhibitors |
US20110159017A1 (en) * | 2008-04-11 | 2011-06-30 | Ludwig Institute For Cancer Research Ltd. | Trytophan catabolism in cancer treatment and diagnosis |
SG182247A1 (en) | 2009-05-27 | 2012-08-30 | Hoffmann La Roche | Bicyclic indole-pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use |
BR112012006956A2 (pt) | 2009-10-12 | 2015-09-15 | Bayer Cropscience Ag | 1- (pirida-3-il) -pirazóisol e 1- (pirimida-5-il) - pirazóisol como pesticidas |
AU2011270807A1 (en) * | 2010-06-23 | 2013-01-31 | Vertex Pharmaceuticals Incorporated | Pyrrolo- pyrazine derivatives useful as inhibitors of ATR kinase |
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- 2014-11-07 JP JP2016551052A patent/JP2016535097A/ja active Pending
- 2014-11-07 CA CA2929650A patent/CA2929650C/en not_active Expired - Fee Related
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WO2015067782A1 (en) | 2015-05-14 |
JP2016535097A (ja) | 2016-11-10 |
CA2929650A1 (en) | 2015-05-14 |
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