ES2487542T3 - Derivados de N-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d]pirimidinas y pirrol-3-il-pirrolo[2,3-d]pirimidinas como inhibidores de cinasas Janus - Google Patents
Derivados de N-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d]pirimidinas y pirrol-3-il-pirrolo[2,3-d]pirimidinas como inhibidores de cinasas Janus Download PDFInfo
- Publication number
- ES2487542T3 ES2487542T3 ES10720113.9T ES10720113T ES2487542T3 ES 2487542 T3 ES2487542 T3 ES 2487542T3 ES 10720113 T ES10720113 T ES 10720113T ES 2487542 T3 ES2487542 T3 ES 2487542T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- pyrimidin
- pyrrolo
- pyridin
- pyrrolidin
- 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.)
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- 229940122245 Janus kinase inhibitor Drugs 0.000 title description 25
- 125000005842 heteroatom Chemical group 0.000 title description 12
- PSJGZWCZKPCRFZ-UHFFFAOYSA-N 2-(1h-pyrrol-3-yl)-7h-pyrrolo[2,3-d]pyrimidine Chemical class N1C2=NC=CC2=CN=C1C=1C=CNC=1 PSJGZWCZKPCRFZ-UHFFFAOYSA-N 0.000 title 1
- -1 nitro, hydroxyl Chemical group 0.000 claims abstract description 604
- 150000001875 compounds Chemical class 0.000 claims abstract description 225
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 224
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 153
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 126
- 239000011737 fluorine Substances 0.000 claims abstract description 126
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 120
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 119
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 117
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 107
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 104
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 100
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 94
- 150000003839 salts Chemical class 0.000 claims abstract description 94
- 229910052736 halogen Chemical group 0.000 claims abstract description 63
- 150000002367 halogens Chemical group 0.000 claims abstract description 63
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 60
- 239000001257 hydrogen Substances 0.000 claims abstract description 59
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 53
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 49
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 48
- 229910021481 rutherfordium Inorganic materials 0.000 claims abstract description 48
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims abstract description 45
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 44
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 32
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 29
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 27
- 125000004429 atom Chemical group 0.000 claims abstract description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 20
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims abstract description 18
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims abstract description 15
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims abstract description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 15
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 12
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims abstract description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims abstract description 9
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 125
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 111
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 78
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 71
- 229910052717 sulfur Inorganic materials 0.000 claims description 66
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 55
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 54
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 45
- 239000003814 drug Substances 0.000 claims description 42
- 125000002619 bicyclic group Chemical group 0.000 claims description 40
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 34
- 125000002950 monocyclic group Chemical group 0.000 claims description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 31
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 29
- 239000000460 chlorine Substances 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 29
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 claims description 27
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 claims description 27
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 26
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 125000005605 benzo group Chemical group 0.000 claims description 24
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 24
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical group N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 claims description 18
- BRIOKNPDCPJCOD-UHFFFAOYSA-N [1,3]oxazolo[5,4-d]pyrimidine Chemical group N1=CN=C2OC=NC2=C1 BRIOKNPDCPJCOD-UHFFFAOYSA-N 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 16
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 14
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 13
- BFPLMTPHDFFMTG-UHFFFAOYSA-N [1,3]oxazolo[5,4-b]pyridine Chemical compound C1=CN=C2OC=NC2=C1 BFPLMTPHDFFMTG-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 208000027866 inflammatory disease Diseases 0.000 claims description 13
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 13
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical group C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 12
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
- FKZDJXVOWLWXHB-UHFFFAOYSA-N 4-(1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1C=1C=NNC=1 FKZDJXVOWLWXHB-UHFFFAOYSA-N 0.000 claims description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 11
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 10
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 claims description 10
- ZATXVRSLQDRAHZ-UHFFFAOYSA-N [1,3]oxazolo[4,5-c]pyridine Chemical group N1=CC=C2OC=NC2=C1 ZATXVRSLQDRAHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 10
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical group C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 9
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 claims description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 9
- 208000003476 primary myelofibrosis Diseases 0.000 claims description 9
- 208000017520 skin disease Diseases 0.000 claims description 9
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 9
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical group OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 claims description 8
- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical group C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 claims description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 8
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 7
- 206010028537 myelofibrosis Diseases 0.000 claims description 7
- 210000000056 organ Anatomy 0.000 claims description 7
- 229910052701 rubidium Inorganic materials 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 6
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 206010070834 Sensitisation Diseases 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000008313 sensitization Effects 0.000 claims description 5
- SRSKXJVMVSSSHB-UHFFFAOYSA-N 1h-pyrrolo[3,2-c]pyridine Chemical group N1=CC=C2NC=CC2=C1 SRSKXJVMVSSSHB-UHFFFAOYSA-N 0.000 claims description 4
- IFMHNXABCSMTFF-UHFFFAOYSA-N 2,3-dihydrofuro[2,3-b]pyridine Chemical group C1=CN=C2OCCC2=C1 IFMHNXABCSMTFF-UHFFFAOYSA-N 0.000 claims description 4
- QGRJPUCTZXMGAL-UHFFFAOYSA-N 3-[1-(1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile Chemical compound C1CN(C=2OC3=CC=CC=C3N=2)CC1C(CC#N)N(N=C1)C=C1C1=NC=NC2=C1C=CN2 QGRJPUCTZXMGAL-UHFFFAOYSA-N 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
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- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- ALJUMASAQKRVRM-UHFFFAOYSA-N pyridine-3,4-dicarbonitrile Chemical compound N#CC1=CC=NC=C1C#N ALJUMASAQKRVRM-UHFFFAOYSA-N 0.000 claims description 4
- SMZMHUCIDGHERP-UHFFFAOYSA-N thieno[2,3-b]pyridine Chemical group C1=CN=C2SC=CC2=C1 SMZMHUCIDGHERP-UHFFFAOYSA-N 0.000 claims description 4
- GDQBPBMIAFIRIU-UHFFFAOYSA-N thieno[2,3-c]pyridine Chemical group C1=NC=C2SC=CC2=C1 GDQBPBMIAFIRIU-UHFFFAOYSA-N 0.000 claims description 4
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical group C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 claims description 4
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical group N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 claims description 4
- WUSKTICHQHMRQJ-UHFFFAOYSA-N 3-[3-[2-cyano-1-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]ethyl]pyrrolidin-1-yl]-6-methylpyrazine-2-carbonitrile Chemical compound N#CC1=NC(C)=CN=C1N1CC(C(CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CC1 WUSKTICHQHMRQJ-UHFFFAOYSA-N 0.000 claims description 3
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- PMSVVUSIPKHUMT-UHFFFAOYSA-N cyanopyrazine Chemical compound N#CC1=CN=CC=N1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
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- WJDMEHCIRPKRRQ-UHFFFAOYSA-N furo[3,2-c]pyridine Chemical compound N1=CC=C2OC=CC2=C1 WJDMEHCIRPKRRQ-UHFFFAOYSA-N 0.000 claims description 3
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- SUFIWOYGKLNPIM-UHFFFAOYSA-N 2-[1-([1,3]oxazolo[5,4-b]pyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile Chemical compound N1=C(OC2=NC=CC=C21)N1CC(CC1)C(C#N)CN1N=CC(=C1)C=1C2=C(N=CN=1)NC=C2 SUFIWOYGKLNPIM-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Applications Claiming Priority (5)
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| PCT/US2010/035783 WO2010135650A1 (en) | 2009-05-22 | 2010-05-21 | N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS |
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| MY156727A (en) | 2016-03-15 |
| CN102458581A (zh) | 2012-05-16 |
| MX2011012353A (es) | 2011-12-14 |
| SG176130A1 (en) | 2011-12-29 |
| EA025520B1 (ru) | 2017-01-30 |
| CA2762174A1 (en) | 2010-11-25 |
| EA201171454A1 (ru) | 2012-06-29 |
| US20100298334A1 (en) | 2010-11-25 |
| WO2010135650A1 (en) | 2010-11-25 |
| CL2011002956A1 (es) | 2012-05-25 |
| CO6440524A2 (es) | 2012-05-15 |
| CN102458581B (zh) | 2016-03-30 |
| AU2010249380A1 (en) | 2011-12-08 |
| IL216463A0 (en) | 2012-02-29 |
| EP2432555A1 (en) | 2012-03-28 |
| NZ596479A (en) | 2014-01-31 |
| US8716303B2 (en) | 2014-05-06 |
| US9334274B2 (en) | 2016-05-10 |
| KR101771401B1 (ko) | 2017-08-25 |
| JP2012527483A (ja) | 2012-11-08 |
| AR076794A1 (es) | 2011-07-06 |
| TW201100429A (en) | 2011-01-01 |
| BRPI1012159A2 (pt) | 2020-09-15 |
| KR20120034665A (ko) | 2012-04-12 |
| AU2010249380B2 (en) | 2015-08-20 |
| IL216463A (en) | 2017-09-28 |
| BRPI1012159B1 (pt) | 2022-01-25 |
| JP5775070B2 (ja) | 2015-09-09 |
| CA2762174C (en) | 2018-02-20 |
| EP2432555B1 (en) | 2014-04-30 |
| ZA201108544B (en) | 2013-04-24 |
| CR20110620A (es) | 2012-02-02 |
| US20140221379A1 (en) | 2014-08-07 |
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