EP2303882A2 - Azacarbolinderivate, verfahren zu deren herstellung und deren therapeutische verwendung - Google Patents

Azacarbolinderivate, verfahren zu deren herstellung und deren therapeutische verwendung

Info

Publication number: EP2303882A2
Authority: EP; European Patent Office
Prior art keywords: pyrrolo; pyridin; fluoro; dipyridine; dipyridin
Prior art date: 2008-06-12
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP09761932A

Other languages

English (en)

French (fr)

Inventor

Christopher Arendt

Didier Babin

Olivier Bedel

Thierry Gouyon

Mikhail Levit

Serge Mignani

Neil Moorcroft

David Papin

Ronghua Li

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sanofi SA

Original Assignee

Sanofi Aventis France

Priority date (The priority date 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 date listed.)

2008-06-12

Filing date

2009-06-11

Publication date

2011-04-06

2009-06-11 Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France

2011-04-06 Publication of EP2303882A2 publication Critical patent/EP2303882A2/de

Status Withdrawn legal-status Critical Current

Links

238000002360 preparation method Methods 0.000 title claims description 17
230000001225 therapeutic effect Effects 0.000 title abstract description 5
-1 C(O)NR1aR1b Chemical group 0.000 claims abstract description 281
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 154
125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 92
125000004122 cyclic group Chemical group 0.000 claims abstract description 42
206010028980 Neoplasm Diseases 0.000 claims abstract description 30
239000002253 acid Substances 0.000 claims abstract description 22
125000003342 alkenyl group Chemical group 0.000 claims abstract description 19
201000011510 cancer Diseases 0.000 claims abstract description 19
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 17
238000011282 treatment Methods 0.000 claims abstract description 17
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 16
125000005842 heteroatom Chemical group 0.000 claims abstract description 16
150000003839 salts Chemical class 0.000 claims abstract description 16
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
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150000001408 amides Chemical class 0.000 claims abstract description 4
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125000003118 aryl group Chemical group 0.000 claims description 131
229910052757 nitrogen Inorganic materials 0.000 claims description 102
125000000753 cycloalkyl group Chemical group 0.000 claims description 88
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238000000034 method Methods 0.000 claims description 36
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125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 32
238000003786 synthesis reaction Methods 0.000 claims description 31
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125000000304 alkynyl group Chemical group 0.000 claims description 15
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
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229910052736 halogen Inorganic materials 0.000 claims description 9
150000002367 halogens Chemical class 0.000 claims description 9
WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 9
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 9
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239000003814 drug Substances 0.000 claims description 8
ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 claims description 8
125000003282 alkyl amino group Chemical group 0.000 claims description 7
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208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 7
QPMPQYGUAKDGAE-UHFFFAOYSA-N 1-phenoxy-3-piperidin-1-ylpropan-2-ol Chemical compound C1CCCCN1CC(O)COC1=CC=CC=C1 QPMPQYGUAKDGAE-UHFFFAOYSA-N 0.000 claims description 6
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 6
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ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 6
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
201000010099 disease Diseases 0.000 claims description 6
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
239000000546 pharmaceutical excipient Substances 0.000 claims description 6
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WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 6
125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 5
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
239000003112 inhibitor Substances 0.000 claims description 5
DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 claims description 5
HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 4
DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 4
125000005189 alkyl hydroxy group Chemical group 0.000 claims description 4
125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 4
230000008569 process Effects 0.000 claims description 4
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
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125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
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230000003831 deregulation Effects 0.000 claims description 3
125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 claims description 3
229940043355 kinase inhibitor Drugs 0.000 claims description 3
LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 claims description 3
LBTPIFQNEKOAIM-UHFFFAOYSA-N n-phenylmethanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC=C1 LBTPIFQNEKOAIM-UHFFFAOYSA-N 0.000 claims description 3
230000003647 oxidation Effects 0.000 claims description 3
238000007254 oxidation reaction Methods 0.000 claims description 3
239000003757 phosphotransferase inhibitor Substances 0.000 claims description 3
IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 3
ZOKPDCKJLXVQPL-UHFFFAOYSA-N pyridine;hydrochloride Chemical compound Cl.C1=CC=NC=C1.C1=CC=NC=C1 ZOKPDCKJLXVQPL-UHFFFAOYSA-N 0.000 claims description 3
125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
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238000002512 chemotherapy Methods 0.000 claims description 2
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JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
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125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 1
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238000001308 synthesis method Methods 0.000 abstract 1
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PFWWSGFPICCWGU-UHFFFAOYSA-N cyclopropanesulfonyl chloride Chemical compound ClS(=O)(=O)C1CC1 PFWWSGFPICCWGU-UHFFFAOYSA-N 0.000 description 1
230000017858 demethylation Effects 0.000 description 1
238000003745 diagnosis Methods 0.000 description 1
238000010586 diagram Methods 0.000 description 1
UIOXCPTYOYGESX-UHFFFAOYSA-N dibutyl(ethyl)phosphane Chemical compound CCCCP(CC)CCCC UIOXCPTYOYGESX-UHFFFAOYSA-N 0.000 description 1
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
WHOBZBLBTZHMGY-UHFFFAOYSA-N ditert-butyl(ethyl)phosphane Chemical compound CCP(C(C)(C)C)C(C)(C)C WHOBZBLBTZHMGY-UHFFFAOYSA-N 0.000 description 1
SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 1
IJVLPVWXJLKHID-UHFFFAOYSA-N docosanoyl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCCCC IJVLPVWXJLKHID-UHFFFAOYSA-N 0.000 description 1
229940079593 drug Drugs 0.000 description 1
150000002118 epoxides Chemical class 0.000 description 1
125000001033 ether group Chemical group 0.000 description 1
YUEZJHOSHBTWPV-UHFFFAOYSA-N ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate Chemical compound C1=NN(CC(=O)OCC)C=C1B1OC(C)(C)C(C)(C)O1 YUEZJHOSHBTWPV-UHFFFAOYSA-N 0.000 description 1
WFPSELYOOKTXKC-UHFFFAOYSA-N ethyl 6-amino-5-bromopyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C(N)C(Br)=C1 WFPSELYOOKTXKC-UHFFFAOYSA-N 0.000 description 1
UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
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150000002576 ketones Chemical class 0.000 description 1
230000003902 lesion Effects 0.000 description 1
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239000011777 magnesium Substances 0.000 description 1
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QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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239000002808 molecular sieve Substances 0.000 description 1
229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
235000019796 monopotassium phosphate Nutrition 0.000 description 1
DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
FQMAZOUBIAXCKR-UHFFFAOYSA-N n,n-diethyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine Chemical compound CCN(CC)CCOC1=CC=CC(B2OC(C)(C)C(C)(C)O2)=C1 FQMAZOUBIAXCKR-UHFFFAOYSA-N 0.000 description 1
YBEVQTSHMLBWFR-UHFFFAOYSA-N n,n-dimethyl-1-phenoxypropan-1-amine Chemical compound CCC(N(C)C)OC1=CC=CC=C1 YBEVQTSHMLBWFR-UHFFFAOYSA-N 0.000 description 1
DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
TXLHWPTUUBUVGG-UHFFFAOYSA-N n-(3-iodo-5-methoxypyridin-2-yl)-2,2-dimethylpropanamide Chemical compound COC1=CN=C(NC(=O)C(C)(C)C)C(I)=C1 TXLHWPTUUBUVGG-UHFFFAOYSA-N 0.000 description 1
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239000002777 nucleoside Substances 0.000 description 1
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239000002674 ointment Substances 0.000 description 1
231100000590 oncogenic Toxicity 0.000 description 1
230000002246 oncogenic effect Effects 0.000 description 1
125000002524 organometallic group Chemical group 0.000 description 1
AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
150000002940 palladium Chemical class 0.000 description 1
KDLHZDBZIXYQEI-VENIDDJXSA-N palladium-100 Chemical compound [100Pd] KDLHZDBZIXYQEI-VENIDDJXSA-N 0.000 description 1
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230000007170 pathology Effects 0.000 description 1
229940124531 pharmaceutical excipient Drugs 0.000 description 1
229940080469 phosphocellulose Drugs 0.000 description 1
PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
229960005235 piperonyl butoxide Drugs 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
229910000160 potassium phosphate Inorganic materials 0.000 description 1
235000011009 potassium phosphates Nutrition 0.000 description 1
LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
LJCNRYVRMXRIQR-UHFFFAOYSA-L potassium sodium tartrate Chemical compound [Na+].[K+].[O-]C(=O)C(O)C(O)C([O-])=O LJCNRYVRMXRIQR-UHFFFAOYSA-L 0.000 description 1
CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
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208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
201000001514 prostate carcinoma Diseases 0.000 description 1
208000023958 prostate neoplasm Diseases 0.000 description 1
238000000159 protein binding assay Methods 0.000 description 1
108060006633 protein kinase Proteins 0.000 description 1
AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
239000000376 reactant Substances 0.000 description 1
238000011160 research Methods 0.000 description 1
239000011347 resin Substances 0.000 description 1
229920005989 resin Polymers 0.000 description 1
230000004044 response Effects 0.000 description 1
XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
230000011664 signaling Effects 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
CEWQOBFWNPUNRO-UHFFFAOYSA-M sodium methoxyacetate Chemical compound [Na+].COCC([O-])=O CEWQOBFWNPUNRO-UHFFFAOYSA-M 0.000 description 1
239000001476 sodium potassium tartrate Substances 0.000 description 1
235000011006 sodium potassium tartrate Nutrition 0.000 description 1
239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
239000007901 soft capsule Substances 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
125000003003 spiro group Chemical group 0.000 description 1
201000000498 stomach carcinoma Diseases 0.000 description 1
239000000126 substance Substances 0.000 description 1
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238000006467 substitution reaction Methods 0.000 description 1
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238000012360 testing method Methods 0.000 description 1
238000012956 testing procedure Methods 0.000 description 1
GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
238000012546 transfer Methods 0.000 description 1
125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
150000008648 triflates Chemical class 0.000 description 1
JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
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239000004246 zinc acetate Substances 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals

Definitions

the present invention relates to ⁇ -aza- ⁇ -carboline derivatives, to their preparation and to their therapeutic application.
⁇ -aza- ⁇ -carbolines are defined by derivatives of 1,7 diaza carbazole or 8-aza- ⁇ -carboline; in official nomenclature the name of this tricyclic unit is 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine.
the present invention relates to compounds acting on protein kinases such as for example: CHK1, CDK1, CDK2, dyrk2, Flt3, GSK3 beta, MNK2, PDGFR beta, PI3K, PIM1, PIM2, PIM3, PLK, TrkB, all of which are involved in the cancer development. More particularly, the present invention relates to compounds acting on a target called Pim involved in the development of cancers.
Pim kinases encompassing Pim-1, Pim-2 and Pim-3, form a distinct family of serine / threonine kinases, and play a functional role in cell growth, differentiation and apoptosis.
One of the mechanisms by which Pim kinases can increase cancer cell survival and promote cancer progression is through the modulation of ADB activity, a key regulator of apoptosis.
Pim kinases are highly homologous to each other and display similar oncogenic behavior.
Pim kinases particularly Pim-1 and Pim-2, have been found to be abnormally expressed in a large number of hematological malignancies.
Amson et al. report the overexpression of Pim-1 in acute myeloid leukemia and acute lymphoid leukemia, and that overexpression of Pim-1 appears to result from inappropriate activation in various leukemias (Proc Natl Acad ScL, Vol 86, 8857-8861 (1989)).
Studies have demonstrated overexpression of Pim-1 in primary and metastatic CNS lymphoma, an aggressive form of non-Hodgkin lymphoma (Rubenstein et al., Blood, Vol 107, 9, 3716-3723 (2006)). ). Höttmann et al.
Pim-2 in B-cell chronic lymphocytic leukemia and suggest that upregulation of Pim-2 may be associated with a more aggressive course of the disease (Leukemia, 20, 1774- 1782 ( 2006)).
Abnormal expression of Pim-1 and Pim-2 has been linked to multiple myeloma (Claudio et al., Blood, v. 100, No. 6, 2175-2186 (2002)).
Pim-1 Hypermutation of Pim-1 has been identified in diffuse large cell lymphoma (Pasqualucci et al., Nature, Vol 412, 2001, pp 341-346 (2001)) and in Hodgkin's lymphoma classical and nodular predominantly lymphocytic (Liso et al., Blood, Vol.108, No. 3, 1013-1020 (2006)).
Pim-1 and Pim-2 have been implicated in prostate cancer (Chen et al., Mol Cancer Res, 3 (8) 443-451 (2005)).
Valdman et al. have demonstrated upregulation of Pim-1 in patients with prostate carcinoma and in high-grade prostatic intraepithelial neoplasia (precancerous lesions) (The Prostate, (60) 367-371 (2004) ), while Dai et al.
Pim-2 overexpression of Pim-2 in prostate cancer is associated with more aggressive clinical features (The Prostate, 65: 276-286 (2005)).
Xie et al. found that 44 kDa Pim-1 (Pim-IL) was significantly upregulated in human prostate tumor specimens, and indicate that Pim-IL has an anti-apoptotic effect on prostate cancer cells in response to chemotherapeutic drugs (Oncogene, 25, 70-78 (2006)).
Pim-2 is linked to the perineural invasion (PNI), during which cancer cells curl around the nerves, which are often found in certain cancers such as cancers of the prostate, pancreas, ducts biliary and head and neck (Ayala et al., Cancer Research, 64, 6082 - 6090 (2004)).
PNI perineural invasion
Pim-3 is aberrantly expressed in human and mouse hepatocarcinomas and human pancreatic cancer tissues (Cancer Res 66 (13), 6741-6747 (2006)).
Aberrant expression of Pim-3 has also been observed in gastric adenoma and metastatic sites of gastric carcinoma (Zheng et al., J Cancer Res Clin Oncol, 134: 481-488 (2008)).
Pim kinase inhibitors are useful for the treatment of cancer, including leukemias, lymphomas, myelomas, and various solid tumors, including head and neck cancers, colon cancer, prostate cancer, pancreatic cancer, liver cancer and oral cancer, for example. Since cancer remains a disease for which existing therapies are inadequate, it is clearly necessary to identify new inhibitors of Pim kinases that are effective in the treatment of cancer.
Z and Z2 may also represent C
Zl can finally represent C or N and
R 2 can represent a carbon bond or an alkylene radical each of which may be substituted by numerous possibilities, among which are heteroaryloxy, heteroaryl (C 1 -C 5) alkyl, heteroaryls and heterobicycloaryls.
B6, B7, B8, B9 may be C or N, and R7 is never heteroaryl.
the activity of the compounds of this invention is particularly directed to the treatment of cardiac problems.
the present invention relates to compounds of the following general formula:
R3, R4 can be independently of one another:
Sulfur at various oxidation levels such as sulfides, sulfoxides or optionally substituted sulfones;
Linear, branched or cyclic CpCio alkyl optionally comprising an optionally substituted heteroatom
R6 is a heteroaryl (5- or 6-membered with 1 to 4 heteroatom selected from N, S or O) linked to the azacarboline moiety either by a C or an N belonging to R6, R6 being optionally substituted; R6 may also represent C (O) NRIaRIb or an optionally substituted heterocycloalkyl or - C (O) optionally substituted heterocycloalkyl, such that RIa and RIb may be independently of one another:
the invention more specifically relates to compounds for which:
R3, R4 can be independently of one another:
aryl or heteroaryl optionally mono or di or tri substituted by R2a, R2b, R2c;
heterocycloalkyl optionally mono or di or tri substituted by R2a, R2b, R2c;
R 6 is a heteroaryl (5 or 6-membered with 1 to 4 heteroatoms (N, S or O) bonded to the azacarboline unit, either by a C or an N belonging to R 6, R 6 may also represent C (O) NRIaRIb or a heterocycloalkyl or -C (O) heterocycloalkyl, R6 being optionally mono or di or tri substituted by R2a, R2b, R2c wherein R2a, R2b and R2c are as described above or below and in particular in the examples.
RIa and RIb can be independently of one another:
R2a, R2b or R2c are chosen independently of one another from:
O-cycloalkyl (C 3 -C 7 ) optionally mono or poly substituted
N (aryl or heteroaryl) 2 each group being optionally mono or poly substituted
N aryl or heteroaryl (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted;
R3a, R3b or R3c groups are chosen from:
N (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl);
the present invention relates to all the compounds of the following general formula:
R3, R4 can be independently of one another: l.H;
aryl or heteroaryl optionally mono or di or tri substituted by R2a, R2b, R2c
heterocycloalkyl optionally mono or di or tri substituted by R2a, R2b, R2c
R6 is a heteroaryl (5 or 6-membered with 1 to 4 heteroatom N, S or O) linked to the azacarboline unit or by a C or N belonging to R6, R6 may also represent C (O) NRIaRIb or an optionally substituted heterocycloalkyl or -C (O) optionally substituted heterocycloalkyl; R6 being optionally mono or di or tri substituted by R2a, R2b, R2c; wherein:
-RIa and RIb can be independently of each other: 1. H; 2. CpCio linear or branched or cyclic (C3-C7) alkyl optionally mono or di substituted by R2a R2b;
Aryl optionally mono or di substituted with R2a R2b;
heteroaryl optionally mono or di substituted with R2a R2b;
O-cycloalkyl (C 3 -C 7 ) optionally mono or poly substituted with different R 3a;
Aryl optionally mono or poly substituted with different R3a;
heteroaryl optionally mono or poly substituted with different R3a;
heterocycloalkyl optionally mono or poly substituted with different R3a;
N (aryl or heteroaryl) 2 each group being optionally mono or poly substituted with different R3a;
N aryl or heteroaryl (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted with different R 3a;
N (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl);
the present invention thus relates to compounds of the following general formula:
R3, R4 can be independently of one another:
sulfur at different oxidation levels such as sulfide, sulfoxide or optionally substituted sulfone;
Linear, branched or cyclic CpCio alkyl optionally comprising an optionally substituted heteroatom
R6 is a heteroaryl (5 or 6-membered with 1 to 4 heteroatom selected from N, S or O) linked to the azacarboline unit either by a C or by an N belonging to R6, R6 being optionally substituted.
the invention more specifically relates to compounds for which:
R3, R4 can be independently of one another:
aryl or heteroaryl optionally mono or di or tri substituted by R2a, R2b, R2c;
heterocycloalkyl optionally mono or di or tri substituted by R2a, R2b, R2c;
R 6 is a heteroaryl (5 or 6-membered with 1 to 4 heteroatoms (N, S or O) bonded to the azacarboline unit, either by a C or an N belonging to R 6, R 6 being optionally mono or di or tri substituted with R 2a, R 2b; , R2c where R2a, R2b and R2c are as described in the examples.
RIa and RIb can be independently of one another:
R2a, R2b or R2c are chosen independently of one another from:
O-cycloalkyl (C 3 -C 7 ) optionally mono or poly substituted
N (aryl or heteroaryl) 2 each group being optionally mono or poly substituted
N aryl or heteroaryl (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted;
NC (O) (aryl or heteroaryl) 2 each group being optionally mono or poly substituted;
CN (O) (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl or heterocycloalkyl) each group being optionally mono or poly substituted;
N (C 1 -C 10 alkyl) S (O 2 ) R 3 a; 32. NHS ( ⁇ 2) - (alkyl (Ci-Cio) cycloalkyl or (C3-C 7) or heterocycloalkyl) each group being optionally mono or poly substituted;
NS ( ⁇ 2) alkyl (Ci-Cio) cycloalkyl or (C3-C 7) or heterocycloalkyl) 2 group each optionally mono or poly substituted;
NS ( ⁇ 2 ) (aryl or heteroaryl) 2 each group being optionally mono or poly substituted;
NS (O 2) (aryl or heteroaryl) (alkyl (Ci-Ci 0) cycloalkyl or (C 3 -C 7) or heterocycloalkyl) each group being optionally mono or poly substituted;
R3a, R3b or R3c groups are chosen from:
N (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl);
NC (0) alkyl (C r Cio) cycloalkyl or (C 3 -C 7) or heterocycloalkyl 2;
NC (O) (aryl or heteroaryl) 2
NC (O) (aryl or heteroaryl) (alkyl (Ci-Ci 0) cycloalkyl or (C 3 -C 7) or heterocycloalkyl);
NS (0 2) (alkyl (C r Cio) cycloalkyl or (C 3 -C 7) or heterocycloalkyl) 2;
NS (O 2 ) (aryl or heteroaryl) 2 ;
NS (O 2) (aryl or heteroaryl) (alkyl (Ci-Ci 0) cycloalkyl or (C 3 -C 7) or heterocycloalkyl);
the group R 6 is a 5- or 6-membered heteroaryl preferably chosen from pyridine, pyrazole, imidazole or triazole groups optionally substituted with R 2a.
the present invention relates to all the compounds of the following general formula:
R3, R4 can be independently of one another:
aryl or heteroaryl optionally mono or di or tri substituted by R2a, R2b, R2c;
heterocycloalkyl optionally mono or di or tri substituted by R2a, R2b, R2c;
R6 is a heteroaryl (5 or 6-membered with 1 to 4 N, S or O heteroatom) linked to the azacarboline unit or by a C or N belonging to R6, R6 being optionally mono or di or tri substituted by R2a, R2b, R2c; in which RIa and RIb can be independently of one another:
Aryl optionally mono or di substituted with R2a R2b;
heteroaryl optionally mono or di substituted with R2a R2b;
O-cycloalkyl (C 3 -C 7 ) optionally mono or poly substituted with different R 3a;
Aryl optionally mono or poly substituted with different R3a;
heteroaryl optionally mono or poly substituted with different R3a;
heterocycloalkyl optionally mono or poly substituted with different R3a;
N (aryl or heteroaryl) 2 each group being optionally mono or poly substituted with different R3a;
N aryl or heteroaryl (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted with different R 3a;
NC (O) (aryl or heteroaryl) 2 each group being optionally mono or poly substituted with different R3a;
NS (0 2) (alkyl (Ci-Cio) cycloalkyl or (C 3 -C 7) heterocycloalkyl or) 2 group each optionally mono or poly substituted with various R3a;
NS ( ⁇ 2) (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl or heterocycloalkyl) each group being optionally mono or poly substituted by different R 3a; COR3a;
R3a is selected from:
N (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl);
NC (0) alkyl (C r Cio) cycloalkyl or (C 3 -C 7) or heterocycloalkyl 2;
NC (O) (aryl or heteroaryl) 2
NC (O) (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl or heterocycloalkyl;
NS (0 2) (alkyl (C r Cio) cycloalkyl or (C 3 -C 7) or heterocycloalkyl) 2;
NS (O 2 ) (aryl or heteroaryl) 2 ;
NS (O 2 ) (aryl or heteroaryl) (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl or heterocycloalkyl;
Ci-Cio alkyl means all carbon chains of 1 to 10 carbons, saturated, linear or branched.
Aryl means phenyl or naphthyl.
Cycloalkyl (C3-C 7) means any non-aromatic rings consisting solely of carbon atoms, including cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane; but may also carry an unsaturation, for example cyclopentene, cyclohexene, cycloheptene ...
CpCio alkylhydroxy means all carbon chains of 1 to 10 carbons, saturated, linear or branched bearing at least one hydroxy group (OH).
CpCio alkoxy means all carbon chains of 1 to 10 carbons, saturated, linear or branched in which there is at least one ether function (C-O-C).
CpCio alkylamino means all carbon chains of 1 to 10 carbons, saturated, linear or branched in which there is at least one amine function (primary, secondary or tertiary).
Heteroaryl means any 5- or 6- or 7-membered aromatic mono-ring having at least one heteroatom (N, O, S), especially pyridine, pyrimidine, imidazole, pyrazole, triazole, thiophene, furan, thiazole, oxazole, and the like. that the bicyclic aromatic systems possessing at least one heteroatom (N, O, S) in particular indole, benzimidazole, azaindole, benzofuran, benzothiophene, quinoline, etc.
Heterocycloalkyl means all monocycles and bicycles (spiro or non-aromatic) having at least one heteroatom (N, O, S) with or without unsaturation, in particular: morpholine, piperazine, 4-methyl piperazine, 4-methylsulfonyl piperazine, piperidine, pyrolidine, oxetane, epoxide, dioxane, imidazolone, imidazolinedione ....
the compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the invention.
the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
the R 6 group is a 5- or 6-membered heteroaryl preferably chosen from pyridine, pyrazole, imidazole, thiophene, quinoline, thiazole or triazole groups, if appropriate. substituted by R2a.
R6 may also represent C (O) NRIaRIb or an optionally substituted heterocycloalkyl or optionally substituted C (O) heterocycloalkyl as indicated above or hereinafter.
a first group of compounds consists of the compounds for which: R3 represents
Aryl optionally mono or di substituted with R2a R2b;
Heteroaryl optionally mono or di substituted with R2a R2b; and / or R6 represents a heteroaryl group, especially a pyridine, pyrazole, imidazole thiophene, quinoline, thiazole or triazole group.
heteroaryl each being optionally substituted with R2a, R2b and R2c and / or R6 represents a heteroaryl group, especially a pyridine, pyrazole, imidazole or triazole group.
a third group of compounds consists of the compounds for which R2a, R2b and R2c are chosen from
each heterocycloalkyl is optionally substituted with R3a, R3b and R3c, selected from
a first group of compounds is constituted by the compounds for which: R 3 represents
CONRIaRIb ... and / or R6 represents a heteroaryl group, especially a pyridine, pyrazole imidazole or triazole group.
each heteroaryl is optionally substituted with R 2a, R 2b and R 2c and / or R 6 represents a heteroaryl group, especially a pyridine, pyrazole imidazole or triazole group.
R2a, R2b and R2c are selected from 1. F; 2. Cl:
the following compounds may be independently of one another:
the following compounds may also be independently of one another:
the subject of the present invention is also the processes for preparing the products of formula (I) as defined above and described in particular in Schemes 1 to 11 below.
the subject of the present invention is in particular the process for the preparation of the products of formula (I) as defined above and described in scheme 1 below in which the substituents R 3 and R 4 have the meanings indicated above or above.
R represents either the values of R6 as defined above or the following values: OH, OCH 3 , OS (O) 2 CF 3 , Cl, SCH 3 , CN.
the tricyclic nucleus synthesis strategy is based on two coupling reactions; a carbon-carbon bond is first created between two suitably chosen pyridines, then the formation of an intramolecular carbon-nitrogen bond leads to the 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine ( see Figure 1 below).
the starting products D1 and D2 of Scheme 1 can be commercial or can be prepared according to the usual methods known to those skilled in the art.
the subject of the present invention is also the processes for preparing Dl and / or D2 as defined in particular in Schemes 2 and 7 below.
the subject of the present invention is therefore also, as new industrial products, certain compounds D1 and / or D2 as defined above or hereinafter.
the subject of the present invention is also, as new industrial products, the synthetic intermediates D3 in which the substituents R3, R4 and R have the meanings indicated above or below.
the subject of the present invention is also, as new industrial products, synthetic intermediates D3 in which the substituent R3 represents a fluorine atom or a methoxy radical, and the substituent R4 represents a hydrogen atom, R being chosen from values defined above.
the compounds D4 represent products of formula (I) as defined above when R represents the values of R6 as defined above, R3 and R4 having any of the meanings indicated above.
the subject of the present invention is also, as new industrial products, the synthetic intermediates D4 in which R represents the following values: OH, OCH 3 ,
OS (O) 2 CF 3 , Cl, SCH 3 , CN, R 3 and R 4 having any of the meanings indicated above.
the process for preparing the compounds according to the invention consists in a first step of reacting the following products: Me 3 SnCl
the 3-position structure variations are made from the 3-bromo-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridine derivative obtained by the action of the dibrome in acetic acid on 6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine.
coupling reactions catalyzed by palladium complexes introduction of aryl or heteroaryl by reaction of Suzuki, introduction of amine by Hartwig-Buchwald type reaction
copper introduction of alkoxy group
the first step of the process for preparing the compounds having a unit other than the (3- pyridinyl) group at the 6-position according to the invention consists in one of the following two reactions:
the r-methyl-1 H-pyrazol-4'-yl unit (or any other aryl or heterorayl unit that can be introduced by a palladium complex catalyzed coupling reaction) is installed by means of a three-stage sequence comprising : a demethylation reaction, the formation of a triflate derivative and a Suzuki coupling reaction.
the 6-carboxamide group synthesis is also possible from triflate: a nitrile function is first introduced by reacting zinc cyanide in the presence of a palladium complex, in the next step the nitrile is hydrolyzed in an acid medium to give the corresponding carboxylic acid.
the last step is amide formation via the acyl chloride obtained by the action of thionyl chloride.
the 3-fluoro-6-methoxy-9H-pyrrolo [2,3-b: 5,4-c '] dipyridine derivative can also be used in a metalation-iodination reaction already described above. After a Suzuki reaction, the compound obtained can undergo the same sequence as before (demethylation, formation of triflate and introduction of heteroaryl by Suzuki coupling).
the variations in the 4-positions can be carried out via a triflate group obtained from the corresponding methoxy.
the coupling-cyclization sequence is carried out with the stannylated derivative described above and 2-amino-3-iodo-4-methoxypyridine.
the tricyclic dimethoxy compound is then converted to the corresponding ditriflate in two steps.
This ditriflate reacts preferentially in position 4 during a Suzuki coupling, which makes it possible to selectively and sequentially introduce an aryl group at the 4-position and a heteroaryl group at the 6-position.
the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient.
excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its salt, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the treatment of the above disorders or diseases.
Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
the compounds according to the invention can be used in creams, gels, ointments or lotions. These drugs find their therapeutic use, especially in the treatment of cancers sensitive to the deregulation of PIM kinases.
the inhibitors of Pim kinases that are the subject of the present invention are useful for the treatment of cancer, in particular leukemias, lymphomas and myelomas.
the subject of the present invention is therefore a medicinal product, characterized in that it comprises a compound of formula (I) as defined above, or a salt of addition of this compound to a pharmaceutically acceptable acid.
compositions containing, as active principle, a compound of formula (I) as defined above, as well as at least one pharmaceutically compatible excipient.
the present invention therefore relates to these pharmaceutical compositions used for the treatment of cancer.
the present invention therefore relates to the use of a compound of formula (I) as defined above for the preparation of a medicament for the treatment of diseases sensitive to the deregulation of PIM kinases.
the present invention therefore relates to the use of a compound of formula (I) as defined above for the preparation of a medicament for the treatment of cancer
the subject of the present invention is therefore the use of the products of formula (I) as defined above, for the preparation of medicaments intended for the chemotherapy of cancers.
the subject of the present invention is therefore the compounds of formula (I) as defined above as kinase inhibitors.
the subject of the present invention is therefore the compounds of formula (I) as defined above as inhibitors of PIM kinases.
the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.
a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.
the following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention.
the numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.
GENERALITIES All reactions are carried out with anhydrous solvents from the Acros Organics AcroSeal range.
the solvents used for extractions and chromatographies come from SDS.
the purifications on silica gel are carried out using silica cartridges (silica gel 60 15-40 .mu.m).
Preparative HPLC purifications are performed on Macherey-Nagel columns (NUCLEODUR Cl 8 phase) or other phases (Chiralcel OD-I or OJ-H or AS-H, Chiralpak, Kromasil Ci 8 ) with appropriate eluents.
the dilution solvents are: dimethylsulfoxide; methanol; acetonitrile; dichloromethane.
the reaction medium is hydrolyzed with 120 ml of a solution of 10% ammonium chloride and 30 ml of water. It is extracted twice with 50 ml of ethyl acetate and then dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. 3.2 g of a crude product are obtained which is purified by chromatography on silica gel using a gradient of heptane and ethyl acetate eluent (from 100/0 to 70/30 by volume), 1.7 (63%) g of 5-chloro 4-trimethylstannyl-2- (3'-pyridinyl) pyridine 2.
reaction mixture is poured into 200 ml of a solution of 10% sodium bicarbonate and 25 ml of water, extracted twice with 200 ml of ethyl acetate, dried over sodium sulphate and filtered. and concentrated to dryness under reduced pressure.
the crude product is purified by chromatography on silica gel using a gradient of eluent of ethyl acetate and methanol or of dichloromethane and methanol (100/0 to 90/10 by volume).
the coupled products 4a-h are obtained in yields of between 40 and 75%.
This catalyst solution is added to the solution of 3 as well as 7 to 12 mmol of potassium tert-butoxide. It is heated overnight at 100 ° C. After cooling, 10 ml of methanol and 150 ml of ethyl acetate are added. The organic phase is washed with an aqueous solution of sodium bicarbonate, dried and evaporated. The crude product is purified by chromatography on silica gel using a gradient of eluents of ethyl acetate and methanol or of dichloromethane and methanol (from 100/0 to 90/10 by volume). The cyclized products 5a-h are detailed in Table 1 (yield between 35 and 80% depending on the substrates).
the cyclization can also be carried out using another catalytic system, in this case the product 4 (1 mmol) is loaded into a 5 ml microwave tube with 0.05 mmol of tris (dibenzylideneacetone) dipalladium (0), 0.11 mmol of 2-dicyclohexylphosphino-2- (N, N-dimethylamino) biphenyl and 1.5 mmol of potassium fert-butoxide. The tube is sealed and then placed under an argon atmosphere, then 4 mL of 1,4-dioxane is added. The mixture is heated in the microwave for 1 hour at 150 ° C. The treatment and the purification of the compound 5 are carried out as described above. The yields are generally lower than those obtained with the Pd (OAc) 2 / Josiphos system. All the steps of this sequence can be carried out either by heating in the microwave (between 110 and 150 0 C) or conventional heating (reflux).
Step 1

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EP09761932A 2008-06-12 2009-06-11 Azacarbolinderivate, verfahren zu deren herstellung und deren therapeutische verwendung Withdrawn EP2303882A2 (de)

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FR0803262		2008-06-12
PCT/FR2009/051100 WO2009150381A2 (fr)	2008-06-12	2009-06-11	Derives d'azacarbolines, leur preparation et leur utilisation therapeutique

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US (1)	US20110178053A1 (de)
EP (1)	EP2303882A2 (de)
JP (1)	JP2011522867A (de)
KR (1)	KR20110016998A (de)
CN (1)	CN102124007A (de)
AR (1)	AR072084A1 (de)
AU (1)	AU2009259114B2 (de)
BR (1)	BRPI0915204A2 (de)
CA (1)	CA2725093A1 (de)
CO (1)	CO6280536A2 (de)
CR (1)	CR11814A (de)
DO (1)	DOP2010000366A (de)
EA (1)	EA018945B1 (de)
EC (1)	ECSP10010670A (de)
IL (1)	IL209840A0 (de)
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NI (1)	NI201000210A (de)
NZ (1)	NZ589839A (de)
PE (1)	PE20110122A1 (de)
SV (1)	SV2010003754A (de)
TW (1)	TW201002711A (de)
UA (1)	UA101668C2 (de)
UY (1)	UY31895A (de)
WO (1)	WO2009150381A2 (de)
ZA (1)	ZA201008387B (de)

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MX2010013726A (es)	2008-06-12	2011-01-14	Janssen Pharmaceutica Nv	Moduladores de diamino-piridina, pirimidina, y piridazina del receptor h4 de histamina.
FR2950891B1 (fr) *	2009-10-06	2012-11-09	Sanofi Aventis	Derives d'azacarbolines 9h-pyrrolo[2,3-b:5,4-c']dipyridine, leur preparation et leur utilisation therapeutique
AR073431A1 (es) *	2009-03-24	2010-11-03	Sanofi Aventis	Derivados de azacarbolinas 9h- pirrolo (2,3-b:5,4-c) dipiridina , su preparacion y si utilizacion terapeutica
FR2953838B1 (fr) *	2009-12-10	2012-02-24	Sanofi Aventis	Derives de 9h-beta-carboline (ou 9h-pyridino[3,4-b]indole) trisubstitues, leur preparation et leur utilisation therapeutique
US20110183938A1 (en) *	2009-12-16	2011-07-28	Genentech, Inc.	1,7-diazacarbazoles and methods of use
RS58514B1 (sr)	2012-06-13	2019-04-30	Incyte Holdings Corp	Supstituisana triciklična jedinjenja kao inhibitori fgfr
EP2970312B1 (de) *	2013-03-11	2017-11-15	The Regents of The University of Michigan	Bet-bromdomänenhemmer und therapeutische verfahren damit
KR101663864B1 (ko) *	2013-04-19	2016-10-07	영남대학교 산학협력단	아미도피리딘올 유도체 또는 이의 약제학적 허용가능한 염을 유효성분으로 함유하는 염증성 장질환의 예방 또는 치료용 약학조성물
CN103408573B (zh) *	2013-07-12	2015-12-23	上海工程技术大学	硼酸衍生物及其制备方法和应用
CN110198941B (zh) *	2017-01-25	2021-09-28	江苏豪森药业集团有限公司	吡咯并吡啶类n-氧化衍生物及其制备方法和应用
JP7365332B2 (ja) *	2017-08-07	2023-10-19	ジョイント・ストック・カンパニー “バイオキャド”	Ｃｄｋ８／１９阻害薬としての新規ヘテロ環式化合物
HRP20241288T1 (hr)	2018-05-04	2024-12-06	Incyte Corporation	Čvrsti oblici fgfr inhibitora i postupci za njihovu proizvodnju
AU2019262579B2 (en)	2018-05-04	2024-09-12	Incyte Corporation	Salts of an FGFR inhibitor
WO2020072675A1 (en)	2018-10-02	2020-04-09	Northwestern University	Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c)
JP7832891B2 (ja)	2019-12-04	2026-03-18	インサイト・コーポレイション	Ｆｇｆｒ阻害剤の誘導体
CN116693449A (zh)	2022-03-04	2023-09-05	上海致根医药科技有限公司	用作tyk2抑制剂的化合物、其制备方法及其在医药上的应用

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CO6280536A2 (es)	2011-05-20
US20110178053A1 (en)	2011-07-21
UY31895A (es)	2010-01-29
CN102124007A (zh)	2011-07-13
MX2010013699A (es)	2011-02-23
WO2009150381A3 (fr)	2010-02-18
BRPI0915204A2 (pt)	2019-01-15
JP2011522867A (ja)	2011-08-04
TW201002711A (en)	2010-01-16
AU2009259114A1 (en)	2009-12-17
KR20110016998A (ko)	2011-02-18
EA018945B1 (ru)	2013-11-29
CR11814A (es)	2011-01-10
AR072084A1 (es)	2010-08-04
PE20110122A1 (es)	2011-03-07
SV2010003754A (es)	2011-03-15
CA2725093A1 (fr)	2009-12-17
WO2009150381A2 (fr)	2009-12-17
MA32460B1 (fr)	2011-07-03
ECSP10010670A (es)	2011-01-31
EA201170002A1 (ru)	2011-08-30
IL209840A0 (en)	2011-02-28
ZA201008387B (en)	2012-02-29
DOP2010000366A (es)	2010-12-31
AU2009259114B2 (en)	2013-05-23
NI201000210A (es)	2011-05-09
NZ589839A (en)	2012-07-27
UA101668C2 (ru)	2013-04-25

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