MX2011002362A

MX2011002362A - Inhibidores heterociclicos de cinasa pim.

Inhibidores heterociclicos de cinasa pim.

Info

Publication number: MX2011002362A
Authority: MX; Mexico
Prior art keywords: amino; piperidin; pyridin; cycloalkyl; phenyl
Prior art date: 2008-09-02

Application number

MX2011002362A

Other languages

English (en)

Spanish (es)

Inventor

Jiong Lan

Matthew Burger

Original Assignee

Novartis Ag

Priority date

2008-09-02

Filing date

2009-08-31

Publication date

2011-04-04

2009-08-31 Application filed by Novartis Ag filed Critical Novartis Ag

2011-04-04 Publication of MX2011002362A publication Critical patent/MX2011002362A/es

Links

125000000623 heterocyclic group Chemical group 0.000 title description 13
229940043355 kinase inhibitor Drugs 0.000 title 1
239000003757 phosphotransferase inhibitor Substances 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 135
238000000034 method Methods 0.000 claims abstract description 70
239000000203 mixture Substances 0.000 claims abstract description 39
238000011282 treatment Methods 0.000 claims abstract description 35
206010028980 Neoplasm Diseases 0.000 claims abstract description 30
230000000694 effects Effects 0.000 claims abstract description 25
201000011510 cancer Diseases 0.000 claims abstract description 24
239000003795 chemical substances by application Substances 0.000 claims abstract description 23
101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 claims abstract description 21
108091000080 Phosphotransferase Proteins 0.000 claims abstract description 21
102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 claims abstract description 21
102000020233 phosphotransferase Human genes 0.000 claims abstract description 21
-1 aminocarbonyloxy, amino-sulfonyl Chemical group 0.000 claims description 173
125000000753 cycloalkyl group Chemical group 0.000 claims description 88
125000000217 alkyl group Chemical group 0.000 claims description 72
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 45
229910052739 hydrogen Inorganic materials 0.000 claims description 43
239000001257 hydrogen Substances 0.000 claims description 43
125000003118 aryl group Chemical group 0.000 claims description 42
125000003545 alkoxy group Chemical group 0.000 claims description 37
229910052736 halogen Inorganic materials 0.000 claims description 36
150000002367 halogens Chemical class 0.000 claims description 36
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
125000004093 cyano group Chemical group *C#N 0.000 claims description 31
125000001072 heteroaryl group Chemical group 0.000 claims description 30
150000003839 salts Chemical class 0.000 claims description 29
125000001424 substituent group Chemical group 0.000 claims description 28
125000003342 alkenyl group Chemical group 0.000 claims description 25
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
125000000304 alkynyl group Chemical group 0.000 claims description 22
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
125000004432 carbon atom Chemical group C* 0.000 claims description 18
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 18
125000002252 acyl group Chemical group 0.000 claims description 15
125000004442 acylamino group Chemical group 0.000 claims description 15
125000004423 acyloxy group Chemical group 0.000 claims description 15
125000004104 aryloxy group Chemical group 0.000 claims description 15
125000000000 cycloalkoxy group Chemical group 0.000 claims description 15
239000003814 drug Substances 0.000 claims description 15
125000005553 heteroaryloxy group Chemical group 0.000 claims description 15
125000005844 heterocyclyloxy group Chemical group 0.000 claims description 15
230000010354 integration Effects 0.000 claims description 15
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
229920006395 saturated elastomer Polymers 0.000 claims description 13
125000004001 thioalkyl group Chemical group 0.000 claims description 13
125000003441 thioacyl group Chemical group 0.000 claims description 12
150000003573 thiols Chemical class 0.000 claims description 11
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
125000003386 piperidinyl group Chemical group 0.000 claims description 9
125000001188 haloalkyl group Chemical group 0.000 claims description 8
ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 7
125000005518 carboxamido group Chemical group 0.000 claims description 7
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
230000002401 inhibitory effect Effects 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
125000004193 piperazinyl group Chemical group 0.000 claims description 7
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 claims description 6
229940124597 therapeutic agent Drugs 0.000 claims description 6
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
WAISNUDWNYJNMT-UTKZUKDTSA-N (3r,4s)-3-amino-1-[3-[[2-(2,6-difluorophenyl)quinazolin-8-yl]amino]pyridin-4-yl]piperidin-4-ol Chemical compound C1C[C@H](O)[C@H](N)CN1C1=CC=NC=C1NC1=CC=CC2=CN=C(C=3C(=CC=CC=3F)F)N=C12 WAISNUDWNYJNMT-UTKZUKDTSA-N 0.000 claims description 3
JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
108010081348 HRT1 protein Hairy Proteins 0.000 claims description 3
102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 3
ODHWZXUUXOFUQZ-DOTOQJQBSA-N n-[4-[(3r,5s)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl]-2-(2,6-difluorophenyl)quinazolin-8-amine Chemical compound C1[C@@H](C)C[C@@H](N)CN1C1=CC=NC=C1NC1=CC=CC2=CN=C(C=3C(=CC=CC=3F)F)N=C12 ODHWZXUUXOFUQZ-DOTOQJQBSA-N 0.000 claims description 3
125000001207 fluorophenyl group Chemical group 0.000 claims description 2
OAYLGJMFKMEJKI-HNNXBMFYSA-N n-[4-[(3s)-3-aminopiperidin-1-yl]pyridin-3-yl]-2-(1,3-thiazol-2-yl)quinazolin-8-amine Chemical compound C1[C@@H](N)CCCN1C1=CC=NC=C1NC1=CC=CC2=CN=C(C=3SC=CN=3)N=C12 OAYLGJMFKMEJKI-HNNXBMFYSA-N 0.000 claims description 2
BMYXNSDMYMRNAW-INIZCTEOSA-N n-[4-[(3s)-3-aminopiperidin-1-yl]pyridin-3-yl]-2-(2,6-difluorophenyl)quinazolin-8-amine Chemical compound C1[C@@H](N)CCCN1C1=CC=NC=C1NC1=CC=CC2=CN=C(C=3C(=CC=CC=3F)F)N=C12 BMYXNSDMYMRNAW-INIZCTEOSA-N 0.000 claims description 2
AJEKKBSRNRYYET-KRWDZBQOSA-N n-[4-[(3s)-3-aminopiperidin-1-yl]pyridin-3-yl]-2-(2-fluorophenyl)quinazolin-8-amine Chemical compound C1[C@@H](N)CCCN1C1=CC=NC=C1NC1=CC=CC2=CN=C(C=3C(=CC=CC=3)F)N=C12 AJEKKBSRNRYYET-KRWDZBQOSA-N 0.000 claims description 2
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
YSMODUONRAFBET-UHFFFAOYSA-N 5-hydroxylysine Chemical group NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 claims 1
125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 1
XPBFQTIASOFUJQ-HNNXBMFYSA-N n-[4-[(3s)-3-aminopiperidin-1-yl]pyrimidin-5-yl]-2-(2,6-difluorophenyl)quinazolin-8-amine Chemical compound C1[C@@H](N)CCCN1C1=NC=NC=C1NC1=CC=CC2=CN=C(C=3C(=CC=CC=3F)F)N=C12 XPBFQTIASOFUJQ-HNNXBMFYSA-N 0.000 claims 1
CJCNVDWBDYXQMZ-YJBOKZPZSA-N n-[4-[(3s,4s)-3-amino-4-fluoropiperidin-1-yl]pyridin-3-yl]-2-(2,6-difluorophenyl)quinazolin-8-amine Chemical compound C1C[C@H](F)[C@@H](N)CN1C1=CC=NC=C1NC1=CC=CC2=CN=C(C=3C(=CC=CC=3F)F)N=C12 CJCNVDWBDYXQMZ-YJBOKZPZSA-N 0.000 claims 1
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 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
241001465754 Metazoa Species 0.000 abstract description 11
230000005764 inhibitory process Effects 0.000 abstract description 5
230000001404 mediated effect Effects 0.000 abstract description 3
208000005623 Carcinogenesis Diseases 0.000 abstract description 2
230000036952 cancer formation Effects 0.000 abstract description 2
231100000504 carcinogenesis Toxicity 0.000 abstract description 2
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239000004473 Threonine Substances 0.000 abstract 1
230000010469 pro-virus integration Effects 0.000 abstract 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 abstract 1
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230000015572 biosynthetic process Effects 0.000 description 66
238000003786 synthesis reaction Methods 0.000 description 65
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235000019439 ethyl acetate Nutrition 0.000 description 50
239000000243 solution Substances 0.000 description 50
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238000004895 liquid chromatography mass spectrometry Methods 0.000 description 44
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
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210000004027 cell Anatomy 0.000 description 26
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238000006243 chemical reaction Methods 0.000 description 21
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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 description 14
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JOTRPRKONYTVBV-UHFFFAOYSA-N 4-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CN=CC=C1Cl JOTRPRKONYTVBV-UHFFFAOYSA-N 0.000 description 10
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JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
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IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
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