NZ612990B2 - Novel heterocyclic derivatives and their use in the treatment of neurological disorders - Google Patents
Novel heterocyclic derivatives and their use in the treatment of neurological disorders Download PDFInfo
- Publication number
- NZ612990B2 NZ612990B2 NZ612990A NZ61299012A NZ612990B2 NZ 612990 B2 NZ612990 B2 NZ 612990B2 NZ 612990 A NZ612990 A NZ 612990A NZ 61299012 A NZ61299012 A NZ 61299012A NZ 612990 B2 NZ612990 B2 NZ 612990B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkoxy
- alkyl
- amino
- halogen
- alkylthio
- Prior art date
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- 125000000623 heterocyclic group Chemical group 0.000 title claims description 12
- 208000009025 Nervous System Disease Diseases 0.000 title description 2
- 206010029305 Neurological disorder Diseases 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 283
- 239000000203 mixture Substances 0.000 claims abstract description 166
- 239000003814 drug Substances 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 206010001897 Alzheimer's disease Diseases 0.000 claims abstract description 15
- -1 cyano, amino Chemical group 0.000 claims description 288
- 125000000217 alkyl group Chemical group 0.000 claims description 270
- 125000003545 alkoxy group Chemical group 0.000 claims description 151
- 125000004414 alkyl thio group Chemical group 0.000 claims description 120
- 150000003839 salts Chemical class 0.000 claims description 87
- 239000011780 sodium chloride Substances 0.000 claims description 86
- 229910052736 halogen Inorganic materials 0.000 claims description 78
- 150000002367 halogens Chemical class 0.000 claims description 78
- 239000001257 hydrogen Substances 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 150000001408 amides Chemical class 0.000 claims description 64
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 54
- 125000004043 oxo group Chemical group O=* 0.000 claims description 49
- 239000002253 acid Substances 0.000 claims description 46
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 230000002265 prevention Effects 0.000 claims description 34
- 125000000304 alkynyl group Chemical group 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 27
- 125000004076 pyridyl group Chemical group 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 19
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 16
- 125000005842 heteroatoms Chemical group 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 229940035295 Ting Drugs 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- XOFXAOWIVZWNIB-UHFFFAOYSA-N 5-(cyanomethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(CC#N)C=N1 XOFXAOWIVZWNIB-UHFFFAOYSA-N 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 206010057668 Cognitive disease Diseases 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- MNNQIBXLAHVDDL-UHFFFAOYSA-N 5-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)C=N1 MNNQIBXLAHVDDL-UHFFFAOYSA-N 0.000 claims description 6
- ATQMNVZWKLJGKE-UHFFFAOYSA-N ClC=1C(=NC=CC=1C#N)C(=O)O Chemical compound ClC=1C(=NC=CC=1C#N)C(=O)O ATQMNVZWKLJGKE-UHFFFAOYSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- QBTHZBYYZUTCNC-UHFFFAOYSA-N 3,5-dimethylpyrazine-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)C(C)=N1 QBTHZBYYZUTCNC-UHFFFAOYSA-N 0.000 claims description 4
- HVEKARODEHTVSY-UHFFFAOYSA-N 3-amino-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid Chemical compound NC1=NC(OCC(F)(F)F)=CN=C1C(O)=O HVEKARODEHTVSY-UHFFFAOYSA-N 0.000 claims description 4
- NIPZZXUFJPQHNH-UHFFFAOYSA-N Pyrazinoic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 3
- RYKZGTYZYNIIMK-UHFFFAOYSA-N 3-amino-5-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=C(N)N=C2N(CCOC)C=CC2=N1 RYKZGTYZYNIIMK-UHFFFAOYSA-N 0.000 claims description 3
- WHUOIRNGRTWJQV-UHFFFAOYSA-N 3-amino-5-(3-fluoropropoxy)pyrazine-2-carboxylic acid Chemical compound NC1=NC(OCCCF)=CN=C1C(O)=O WHUOIRNGRTWJQV-UHFFFAOYSA-N 0.000 claims description 3
- OZMUCSYTBBYNTK-UHFFFAOYSA-N 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylic acid Chemical compound NC1=NC(C(F)(F)F)=CN=C1C(O)=O OZMUCSYTBBYNTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- QQNDJNHLMAFNJI-RHIBPKLGSA-N 5-chloro-4,6-dideuterio-3-(trideuteriomethyl)pyridine-2-carboxylic acid Chemical compound [2H]C1=NC(C(O)=O)=C(C([2H])([2H])[2H])C([2H])=C1Cl QQNDJNHLMAFNJI-RHIBPKLGSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 12
- GJLOKYIYZIOIPN-UHFFFAOYSA-N 5-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)C=N1 GJLOKYIYZIOIPN-UHFFFAOYSA-N 0.000 claims 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 2
- UFVVHKGSZWJGNA-UHFFFAOYSA-N 5-carbamothioylpyridine-2-carboxylic acid Chemical compound NC(=S)C1=CC=C(C(O)=O)N=C1 UFVVHKGSZWJGNA-UHFFFAOYSA-N 0.000 claims 1
- PFENLEKZZJZJBJ-UHFFFAOYSA-N 5-cyano-3-methylpyridine-2-carboxylic acid Chemical compound CC1=CC(C#N)=CN=C1C(O)=O PFENLEKZZJZJBJ-UHFFFAOYSA-N 0.000 claims 1
- HRLVPHGCEGTVLK-UHFFFAOYSA-N 5-cyanopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C#N)C=N1 HRLVPHGCEGTVLK-UHFFFAOYSA-N 0.000 claims 1
- RBYJWCRKFLGNDB-UHFFFAOYSA-N 5-methylpyrazine-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)C=N1 RBYJWCRKFLGNDB-UHFFFAOYSA-N 0.000 claims 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 40
- 206010012601 Diabetes mellitus Diseases 0.000 abstract description 11
- CDJHOYHFBRGWII-UHFFFAOYSA-N N-[6-[5-amino-3-(fluoromethyl)-2,6-dihydro-1,4-oxazin-3-yl]pyridin-2-yl]-5-chloropyridine-2-carboxamide Chemical compound C1OCC(N)=NC1(CF)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CC=2)=N1 CDJHOYHFBRGWII-UHFFFAOYSA-N 0.000 abstract 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
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- 235000019439 ethyl acetate Nutrition 0.000 description 168
- 239000011541 reaction mixture Substances 0.000 description 159
- 239000000243 solution Substances 0.000 description 158
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 136
- 238000005160 1H NMR spectroscopy Methods 0.000 description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- 238000004128 high performance liquid chromatography Methods 0.000 description 114
- 239000012071 phase Substances 0.000 description 111
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 86
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- SASWSEQJAITMKS-JJNNLWIXSA-N tert-butyl (2S)-2-[[(2S)-1-[[(2S)-1-[[(4S,5S,7S)-5-hydroxy-2,8-dimethyl-7-[[(2S,3S)-3-methyl-1-oxo-1-(pyridin-2-ylmethylamino)pentan-2-yl]carbamoyl]nonan-4-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-methylamino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]p Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)[C@@H](O)C[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC=1N=CC=CC=1)C(C)C)N(C)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H]1N(CCC1)C(=O)OC(C)(C)C)C1=CN=CN1 SASWSEQJAITMKS-JJNNLWIXSA-N 0.000 description 1
- LCZVKKUAUWQDPX-UHFFFAOYSA-N tert-butyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl]amino]acetate Chemical compound CC(=O)OC1=CC=CC=C1CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1=CC=CC=C1OC(C)=O LCZVKKUAUWQDPX-UHFFFAOYSA-N 0.000 description 1
- VJKLTOIZSJCFMS-UHFFFAOYSA-N tert-butyl 3-amino-5-cyanopyridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=NC=C(C#N)C=C1N VJKLTOIZSJCFMS-UHFFFAOYSA-N 0.000 description 1
- PIBXOBCFOCDTJF-UHFFFAOYSA-N tert-butyl 4-(1H-imidazol-5-ylmethyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CC1=CN=CN1 PIBXOBCFOCDTJF-UHFFFAOYSA-N 0.000 description 1
- VYEFIDLPUQXRNR-UHFFFAOYSA-N tert-butyl 5-bromo-3-methylpyridine-2-carboxylate Chemical compound CC1=CC(Br)=CN=C1C(=O)OC(C)(C)C VYEFIDLPUQXRNR-UHFFFAOYSA-N 0.000 description 1
- JKLUQTXMHJEXII-UHFFFAOYSA-N tert-butyl 5-cyano-3-nitropyridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=NC=C(C#N)C=C1[N+]([O-])=O JKLUQTXMHJEXII-UHFFFAOYSA-N 0.000 description 1
- ZQWLEEHQYOVHRA-JKSUJKDBSA-N tert-butyl N-[(3R,6R)-3-(6-amino-3-fluoropyridin-2-yl)-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-5-yl]carbamate Chemical compound C1O[C@](C(F)(F)F)(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)C1=NC(N)=CC=C1F ZQWLEEHQYOVHRA-JKSUJKDBSA-N 0.000 description 1
- CMBVABNFCTUWCQ-XZOQPEGZSA-N tert-butyl N-[(3R,6R)-3-[6-[(3-amino-5-cyanopyridine-2-carbonyl)amino]pyridin-2-yl]-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-5-yl]carbamate Chemical compound C1O[C@](C(F)(F)F)(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)C1=CC=CC(NC(=O)C=2C(=CC(=CN=2)C#N)N)=N1 CMBVABNFCTUWCQ-XZOQPEGZSA-N 0.000 description 1
- KXLJKFDODRECNS-OEMAIJDKSA-N tert-butyl N-[1-[(2R)-3-amino-1,1,1-trifluoro-2-methyl-3-oxopropan-2-yl]oxy-2-(6-bromopyridin-2-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)(CO[C@](C)(C(N)=O)C(F)(F)F)C1=CC=CC(Br)=N1 KXLJKFDODRECNS-OEMAIJDKSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229960002070 torsemide Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 102000035402 transmembrane proteins Human genes 0.000 description 1
- 108091005683 transmembrane proteins Proteins 0.000 description 1
- 230000000472 traumatic Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GNUHEWKSXCCLNW-UHFFFAOYSA-N triethyl(pyridin-2-yl)silane Chemical compound CC[Si](CC)(CC)C1=CC=CC=N1 GNUHEWKSXCCLNW-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000000381 tumorigenic Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 201000007117 withdrawal disease Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Disclosed herein are heterocyclic compounds of the Formula (I), in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's disease or diabetes via inhibition of BACE-1 or BACE-2. In one embodiment the compound is 5-chloro-pyridine-2-carboxylic acid [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide. of BACE-1 or BACE-2. In one embodiment the compound is 5-chloro-pyridine-2-carboxylic acid [6-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-pyridin-2-yl]-amide.
Description
Novel Heterocyclic Derivatives and Their Use in the Treatment of Neurological Disorders
FIELD OF THE INVENTION
The invention relates to novel heterocyclic derivatives and pharmaceutically able salts
thereof, pharmaceutical compositions f, pharmaceutical combinations thereof, and
their use as medicaments, particularly for the ent of neurodegeneration via inhibition of
BACE—1 or diabetes via inhibition of BACE—2.
BACKGROUND OF THE INVENTION
mer’s Disease is a devastating neurodegenerative er. Its sporadic forms affect
an elderly population (sharp increase in incidence at >75 years of age), in addition, there are
s familial forms with an onset of the disease in the fourth or fifth decade of life.
Pathologically, it is characterized by the ce of extracellular senile plaques, and
intracellular neurofibrillar s in patient’s brains. The core tuent of the senile
s are small, 4 kDa amyloid peptides. They are generated by the proteolytic processing
,1 5 of a large transmembrane protein, amyloid precursor protein (APP). Cleavage of APP by
beta-secretase (BACE—1) releases the soluble APP-beta fragment, while the 99-amino acid
long C—terminus remains tethered to the membrane. This C-terminal fragment is
subsequently proteolytically processed by gamma-secretase (a membrane multi-enzyme
complex) to generate amyloid peptides of various length, predominantly 40 and 42 amino
acids long (Hardy J, Selkoe DJ (2002) Science; 297 (5580):353-356).
lf, under pathologic conditions, the generation of these peptides occurs at an increased rate,
or if their removal from the brain is disturbed, increased brain d peptide concentrations
leads to the formation of oligomers, fibrils and eventually plaques (Farris W, et a/ (2007)
Am.J. Pathol.; 171 (1):241-25‘l). It has been shown, that deposition of amyloid peptides and
plaques in the brain is the first measurable event in the pathogenesis of mers Disease,
and that it is the trigger for loss of synapses, synaptic contacts, and neurons (Grimmer T, et
al (2009) Neurobiology of Aging; 30 (12):1902-1909). Brain atrophy caused by massive
neuron loss is followed by impairments in cognition, memory, orientation and the ability to
perform the tasks of daily living, i.e. clinically manifest dementia o A, et al (2009)
Neurology; 73 (10):754-760).
BACE-‘l, also known as Asp2 or Memapsin 2, is a transmembrane ic protease highly
expressed in neurons. It co-localizes with its substrate APP in Golgi and endocytic
compartments (Willem M, Lammich 8, Haass C (2009) 8emin.Cell Dev.Biol; 20 (2):175-182).
Knock-out studies in mice have demonstrated the absence of amyloid peptide formation,
while the animals are healthy and fertile (Ohno M, et a/ (2007) Neurobiol.Dis.; 26 (1):134-
145). Genetic ablation of BACE-1 in APP-overexpressing mice has demonstrated e of
plaque formation and the reversal of cognitive deficits (Ohno M, et al (2004) Neuron; 41
(1)127-33). BACE-1 levels are elevated in the brains of sporadic Alzheimer’s e patients
(Hampel H, Shen Y (2009) Scand. J. Clin. Lab. Invest; 69 (1)28-12).
Taken er, these findings suggest that the inhibition of BACE-‘l may be a favourable
therapeutic strategy for the treatment of Alzheimer’s Disease.
Beta-site amyloid precursor protein cleaving enzyme 2 (BACE-2) is a transmembrane
aspartic protease that is highly expressed in pancreatic B cells and other peripheral tissues
(Brian D. Bennett, Safura Babu-Khan, Richard Loeloff, Jean-Claude Louis, Eileen Curran;
Martin Citron, and Robert Vassar (2000) JJ. Biol. Chem. 275 (27) 20647—20651). BACE-2 is
closely related to BACE-1 or beta secretase. However, despite structural and sequence
similarities the substrate icity of BACE-1 and BACE—2 appear to be different. While AB
or B-amyloid peptide is the main substrate of BACE-1, BACE-2 does not generate either form
of AB (Vassar, R., Bennett, B. D., Babu-Khan, 8., Kahn, 8., Mendiaz, E. A., Denis, P.,
Teplow, D. 8., Ross, 8., Amarante, P., Loeloff, R., Luo, Y., Fisher, 8., Fuller, J., Edenson, 8.,
Lile, J., Jarosinski, M. A., Biere, A. L., Curran, E., Burgess, T., Louis, J.-C., Collins, F.,
Treanor, J., Rogers, 6., and Citron, M. (1999) e 286, 1).
Transmembrane protein 27 (TM EM27 or collectrin) plays an important role in B-cell
proliferation and insulin secretion (Pinar Akpinar, Satoru Kuwajima, Jan Krtitzfeldt, and
Markus 8toffel (2005) Tmem27: Cell Metabolism. 2(6) 385-397) and has been identified as a
ate for BACE-2 (). Tmem27 exists as a dimer and the ellular
domain is cleaved and shed from the plasma in a B pecific manner. Overexpression of
full-length Tmem27, but not the truncated or e n, increases B cell proliferation,
ting that the full length protein is required for this biological function. ch1 (hepatocyte
nuclear factor-1d, HNF-1q) ls the ription of TMEM27. Mice with targeted deletion
of ch1 exhibit sed B cell mass, and knockdown of Tmem27 using RNAi results in a
reduction of cell proliferation. Transgenic mice with increased expression of Tmem27 in
pancreatic B cells t increased B cell mass compared to their wild-type littermates. This
2012/050395
data indicates that TMEM27 plays a role in control of B cell mass and that inhibition of BACE-
2 which cleaves TMEM27 could be useful for treating loss of B cell mass and function, the
underlying cause of diabetes.
Taken together, these s suggest that the inhibition of BACE-2 may be a favourable
therapeutic gy for the treatment and prevention of metabolic disorders related to
decreased [3 cell mass and/or function, such as type 2 diabetes.
SUMMARY OF THE INVENTION
The present invention s to novel heterocyclic derivatives having BACE inhibitory
activity, to their preparation, to their medical use and to medicaments comprising them.
More particularly, in a first aspect, the invention relates to a compound of the formula
51/ \E2
R2 N
T T/X1fl\/J\N NH
l 2
Re (I),
in which
either
X1 is CR1 or N;
X3 is CR3 or N;
X, is CR4 or N;
X5 is CR5 or N;
wherein at least one of X1, X3, X4 and X5 is N and not more than 2 of X1, X3, X4 and X5
are N;
X1 is CR1 or N;
Xe, is CR3, N or 8;
X4 is a bond;
X5 is CR5, N or 8;
wherein at least one of X1, X3 and X5 is N or 8, not more than 2 of X1, X3 and X5 are N
and not more than 1 of X3 and X5 are 8;
R1 is hydrogen, cyano, halogen, (C1-a)alkyl, halogen-(C1.s)alkyl, (Ci.s)a|koxy, halogen-
(C1.8)alkoxy, (01.8)alkylthio, halogen-(01.8)alkylthio, alkoxy-(C1_8)alky|, (C1_g)alkoxy-(C1_
8)alkoxy, alkoxy—(C1.s)alkylthio, alkylthio-(C1.8)alkyl, (C1.s)a|kylthio-(C1.a)alkoxy, (C1.
8)alkylthio-(C1.e)a|kylthio, (Cz.s)alkenyl, or (02.3)alkynyl;
R2 is an aryl, heteroaryl or non-aromatic heterocyclyl group G1, which group G1 is
optionally substituted by 1', 2, 3 or 4 substituents independently selected from the group,
consisting of cyano, amino, amino-(C1_e)alkyl, N-(C1.4)alkyl—amino—(C1.8)alkyl, N,N-di(C1.
4)alkyl-amino-(C1.8)alky|, aminocarbonyl, thiocarbamoyl, halogen, (C1.e)a|kyl, halogen-(C1-
3)alky|, y, oxo, (01-8)alkoxy, halogen-(C1.e)a|koxy, (C1.a)alkylthio, halogen-(C1.
lthio, (01.8)alkoxy-(C1_8)alkyl, (03.8)cycloalkyl-(C1-3)alkoxy, (01-8)alkoxy-(C1.8)alkoxy, (C1.
8)alkoxy-(C1.s)alky|thio, (C1.s)alkylthio-(C1.8)alkyl, (C1.e)alkylthio-(C1-s)alkoxy, (C1.s)alkylthio-
(C1.s)alkylthio, (Cz.s)alkenyl, (Cz.s)alkynyl, (Cz.s)alkenoxy, (Cz.e)alkynoxy and a (Cs.
3)cycloa|kyl, aryl, heteroaryl or non-aromatic heterocyclyl group G2, which group Gz is
optionally substituted by 1, 2, 3, or 4 tuents independently selected from the group,
consisting of cyano, aminocarbonyl, halogen, (C1.B)alkyl, halogen-(C1.e)alkyl, hydroxy, (C1.
8)alkoxy, halogen-(01.8)alkoxy, (C1.s)alkylthio, halogen-(C1.s)alkylthio, (C1.s)alkoxy-(C1-s)alkyl,
(C1-a)alkoxy-(C1.s)alkoxy, (C1.s)alkoxy-(C1.a)alkylthio, (01-8)alkylthio-(C1.s)alkyl, (C1.e)alkylthio-
(01-8)alkoxy, alkylthio-(C1_8)alkylthio, (02.3)alkenyl and (02-8)alkynyl;
R3 is hydrogen, cyano, halogen, (C1.3)alkyl, halogen—(C1.s)alkyl, (C1-s)alkoxy; halogen-
(C1-s)alkoxy, (C1.8)alkylthio, halogen-(C1.s)alkylthio, (C1_8)a|koxy-(C1-a)alkyl, (C1-s)a|koxy-(C1-
xy, (C1.s)alkoxy-(C1-8)alkylthio, a|kylthio-(C1_8)alkyl, (C1-8)alkylthio-(C1-a)alkoxy, (C1.
8)alkylthio—(C1_8)alkylthio, (Cz_g)alkenyl, or (Cz_g)alkynyl;
R4 is hydrogen, cyano, halogen, (01.8)alkyl, halogen-(C1.s)a|kyl, (01.3)alkoxy, halogen-
(C1-a)alkoxy, (C1.s)a|kylthio, halogen-(01.8)alkylthio, (01-3)alkoxy-(C1.e)alkyl, (C1.s)alkoxy-(C1-
3)alkoxy, (C1.a)a|koxy-(C1-a)alkylthio, (C1-s)a|kylthio-(C1.s)alkyl, (C1-s)alkylthio-(C1.8)alkoxy, (C1.
lthio—(C1_8)alkylthio, (02.8)alkenyl, or (02.8)alkynyl;
R5 is en, cyano, halogen, (C1-s)alkyl, halogen—(01.8)alkyl, (C1.a)a|koxy, halogen-
(C1-e)alkoxy, (C1.8)alkylthio, halogen-(C1.s)alkylthio, (C1.s)a|koxy-(C1.a)alkyl, alkoxy-(C1.
8)alkoxy, (C1.s)a|koxy-(C1-8)a|kylthio, (C1-s)alkylthio-(C1.s)alkyl, (C1-s)a|kylthio—(C1-s)a|koxy, (C1.
8)a|kylthio-(C1.5)alkylthio, (Cz_s)alkenyl, or alkynyl;
R, and R5, taken together, are -C(H)=C(H)-C(H)=C(H)— or a (C1.s)a|kylene group, in
which (C1.s)alky|ene group 1 or 2 -CH2- ring members are optionally ed with hetero ring
members independently ed from the group, consisting of -N(H)—, -N[(C1_3)alkyl]-, -O—,
8-, -S(=O)- or -S(=O)2-;
R6 is (C1-e)alkyl, halogen-(C1.a)alkyl, hydroxy-(C1-s)alkyl, (C1.s)alkoxy-(C1-3)a|kyl,
mercapto-(C1-s)alkyl, (C1-a)alky|thio-(C1.8)alkyl, amino-(C1-e)alky|, N-(C1-4)a|ky|—amino-(C1-
8)alkyl, N,N-di(C1.4)alkyl-amino—(C1_8)alkyl, (02.8)alkenyl, or (Cz.a)a|kynyl;
R5 and R6, taken together, are a (01.4)alkylene group, in which (01.4)alkylene group 1
CH2- ring member is optionally replaced with a hetero ring member independently selected
from the group, consisting of -N(H)-, -N[(C1_4)alky|]-, -O-, -S—, - or -S(=O)2-;
E1 is -C(R7)(Rs)-, Ol' -C(R7)(Ra)-C(R9)(R1o)';
E2 is -C(R11)(R12)-, or -C(R11)(R12)‘C(R13)(R14)';
either
each of R7 and R8 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (C1.s)a|ky|, halogen-(C1.a)alkyl, (C1.e)a|koxy-(C1.s)alkyl and (C1.s)alkylthio-(C1.
1O 8)a|kyl§
R7 and R8, taken together, are oxo or H2-;
either
each of R9 and R10 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (C1.8)alkyl, halogen-(01.8)alkyl, (01.8)alkoxy—(C1.e)alkyl and (C1.s)alkylthio—(C1.
8)a|kyl;
R9 and R10, taken er, are oxo or -CH2-CH2-;
either
each of R11 and R12 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (C1.a)a|kyl, halogen-(C1.e)alkyl, (C1-s)a|koxy-(C1.s)alkyl and (C1.8)alkylthio-(C1.
8)alkyl;
R11 and R12, taken together, are oxo or —CR15R16-CR17R18-
wherein R15, R16, R17 and R18 are independently selected from hydrogen and fluoro;
either
each of R13 and R14 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (C1.s)a|kyl, halogen-(C1_8)alkyl, (C1.s)alkoxy-(C1.8)alkyl and alky|thio-(C1.
8)alkyl§
R13 and R14, taken together, are oxo or -CH2-CH2-;
or a pharmaceutically acceptable salt thereof.
In a second , the invention s to a compound of the formula
R, H x, A
\H/ Y fitN/ ”"2
(I).
in which
either
X1 is CR1 or N;
X3 is CR3 or N;
X4 is CR4 or N;
X5 is CR5 or N;
wherein at least one of X1, )9, X4 and X5 is N and not more than 2 of X1, X3, X4 and X5
are N;
o_r
X1 is CR1 or N;
X3 is CR3, N or 8;
X4 is a bond;
X5 is CR5, N or S;
n at least one of X1, X1, and X5 is N or 8, not more than 2 of X1, X3 and X5 are N
and not more than 1 ofXa and X5 are 8;
R1 is hydrogen, cyano, n, (C1-s)alky|, halogen-(C1-s)alkyl, (Ci.s)alkoxy, halogen-
(C1_8)alkoxy, (C1_8)alkylthio, halogen-(C1_8)alkylthio, (C1_B)alkoxy-(C1_8)alkyl, (C1_8)alkoxy-(C1_
8)alkoxy, (01.8)alkoxy-(C1-s)alkylthio, (01-8)alkylthio-(C1.s)alkyl, (C1.a)a|kylthio-(C1.8)alkoxy, (C1.
3)alkylthio-(C1.a)alkylthio, (Cz.a)alkenyl, or (02-3)alkynyl;
R2 is an aryl, heteroaryl or non-aromatic heterocyclyl group G1, which group G1 is
optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group,
consisting of cyano, amino, amino-(C1.s)alkyl, N-(C1.4)alkyl-amino—(C1-s)alkyl, N,N-di(C1.
4)alkyl—amino-(C1.8)alkyl, aminocarbonyl, thiocarbamoyl, halogen, alkyl, halogen-(C1.
8)alkyl, hydroxy, oxo, (C1.a)alkoxy, halogen—(C1-s)alkoxy, (C1.s)alkylthio, halogen-(C1.
lthio, (C1_e)alkoxy-(C1.8)alkyl, (03.8)cycloalkyl-(C1_g)alkoxy, (01-8)alkoxy-(C1_8)alkoxy, (C1.
8)alkoxy-(C1.s)a|kylthio, (C1.s)a|kylthio-(C1.s)alkyl, (C1.e)a|kylthio-(C1.s)alkoxy, (C1.s)a|kylthio-
(C1.a)a|kylthio, (C2-s)alkenyl, (C2-e)alkynyl, (Cz-e)alkenoxy, (Cz.s)alkynoxy and a (Ca.
8)cycloalkyl, aryl, heteroaryl or omatic heterocyclyl group 62, which group Gz is
ally substituted by 1, 2, 3, or 4 substituents independently selected from the group,
consisting of cyano, aminocarbonyl, halogen, (01.8)alkyl, halogen-(C1-s)alkyl, hydroxy, (C1.
8)alkoxy, halogen-(C1.s)alkoxy, (Ci.e)alkylthio, n-(01.8)alkylthio, (01.8)alkoxy-(C1.s)alkyl,
2012/050395
(01.8)alkoxy-(C1.s)a|koxy, (C1.8)alkoxy—(C1-s)alkylthio, (C1-e)a|kylthio-(C1.3)alkyl, (C1.a)a|kylthio-
(Ci—e)alkoxy, (C1.8)alkylthio-(C1.8)a|kylthio, (Cz.e)alkenyl and (Cz.s)alkynyl;
R3 is hydrogen, cyano, halogen, (01.8)alkyl, halogen-(C1-a)alkyl, (C1-e)alkoxy; halogen-
(C1_3)alkoxy, (C1_8)a|kylthio, halogen-(C1_8)alkylthio, (C1_s)alkoxy-(C1_8)alkyl, alkoxy-(C1_
8)alkoxy, (C1.8)a|koxy-(C1-s)a|kylthio, (C1-g)alkylthio-(C1.s)a|kyl, alkylthio-(C1-8)alkoxy, (C1.
8)alkylthio-(C1.8)alkylthio, (Cz.a)alkenyl, or (C2.a)a|kynyl;
R4 is hydrogen, cyano, halogen, (01.8)alkyl, halogen-(C1-s)alkyl, (C1.s)alkoxy, halogen-
(01-8)alkoxy, (C1_e)alkylthio, halogen-(C1_8)alkylthio, (01.8)alkoxy-(C1_8)alkyl, (C1-8)alkoxy-(C1_
8)alkoxy, (01-8)alkoxy-(C1-s)alkylthio, (C1-s)alkylthio-(01.e)a|kyl, (01-8)alkylthio-(C1-8)alkoxy, (C1.
1O 8)a|kylthio-(C1.s)alkylthio, (Cz.a)a|kenyl, or (C2.e)a|kynyl;
R5 is hydrogen, cyano, halogen, (C1.e)alkyl, halogen-(01.8)alkyl, (C1.s)alkoxy, halogen-
(C1_8)alkoxy, (01.8)alkylthio, halogen-(01.8)alkylthio, (C1.8)alkoxy-(C1_8)alkyl, alkoxy—(C1.
8)alkoxy, (C1.s)alkoxy-(C1-s)alkylthio, (C1.s)alkylthio-(C1.e)alkyl, alkylthio-(C1.s)alkoxy, (C1.
lthio-(C1-e)a|kylthio, alkenyl, or a|kynyl;
g
R4 and R5, taken together, are -C(H)=C(H)—C(H)=C(H)— or a (01.8)alkylene group, in
which (C1.e)alkylene group 1 or 2 -CH2- ring members are optionally replaced with hetero ring
members independently selected from the group, consisting of -N(H)-, -N[(C1.a)a|kyl]-, -O-,
S-, -S(=O)- or -S(=O)2-;
R6 is en, (C1.8)alkyl, halogen-(01-8)alkyl, y-(C1_8)alkyl, (C1_g)alkoxy—(C1_
8)alkyl, mercapto-(C1.e)alkyl, (C1.s)alkylthio-(C1_8)a|kyl, amino-(C1.e)alkyl, N-(C1.4)alkyl-amino-
(C1-8)alky|, N,N-di(C1.4)alkyl-amino-(C1.s)a|kyl, (C2.e)a|kenyl, or (Cz.e)a|kynyl;
R5 and R6, taken together, are a (01-4)alkylene group, in which (01.4)alkylene group 1
CH2- ring member is optionally replaced with a hetero ring member ndently selected
from the group, consisting of -N(H)-, -N[(C1.4)alkyl]-, -O-, -S-, -S(=O)- or -S(=O)2-;
E1 is -C(R7)(Rs)-, or -C(R7)(Rs)-C(R9)(R1o)-;
E2 is -C(R11)(R12)-, or -C(R11)(R12)-C(R13)(R14)-;
either
each of R7 and R8 is independently selected from the group, consisting of en,
cyano, halogen, (C1.s)alkyl, halogen-(C1.s)alkyl, (C1-e)alkoxy-(C1.s)alkyl and (C1.s)a|kylthio-(C1.
8)alky|;
R7 and R8, taken together, are oxo or -CH2-CH2-;
either
each of R9 and R10 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (C1.s)alkyl, halogen-(C1-s)alkyl, (C1.e)alkoxy-(C1.a)alkyl and (C1.s)alkylthio-(C1.
8)alkyl;
R9 and R10, taken together, are oxo or -CH2-CH2-;
either
each of R11 and R12 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (01.8)alkyl, halogen-(C1_8)alkyl, (01-8)alkoxy-(C1_8)alky| and alkylthio-(C1.
a)aIkyI;
g
R11 and R12, taken together, are oxo or —CR15R16-CR17R13-
n R15, R16, R17 and R18 are ndently selected from hydrogen and fluoro;
either
each of R13 and R14 is independently selected from the group, consisting of hydrogen,
cyano, halogen, (01.8)alkyl, halogen-(C1_8)alkyl, alkoxy-(C1_8)alkyl and (C1.s)a|kylthio-(C1.
SIaIkyI;
_o_r
R13 and R14, taken together, are oxo or -CH2—CH2-;
or a pharmaceutically acceptable salt thereof.
DEFINITIONS
Halogen denotes fluorine, chlorine, e or iodine.
A halogenated group or moiety, such as halogenalkyl, can be mono-, di-, tri-, poly- or per-
halogenated.
An aryl group, ring or moiety is a naphthyl or phenyl group, ring or moiety.
A heteroaryl group, ring or moiety is a monocyclic aromatic 5- or 6-membered structure, in
which structure 1, 2, 3 or 4 ring s are hetero ring s independently selected
from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur
ring member, such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, zinyl, pyrimidyl or pyridyl; or
2012/050395
a bicyclic aromatic 9- or 10— or membered structure, in which ure 1, 2, 3, 4 or 5 ring
members are hetero ring s independently selected from the group, consisting of a
nitrogen ring member, an oxygen ring member and a sulfur ring member. The fused rings
completing the bicyclic groups may contain only carbon atoms and may be saturated,
lly saturated, or unsaturated. Heteroaryl groups which are bicyclic include at least one
fully aromatic ring but the other fused ring may be aromatic or non-aromatic. Examples of
bicyclic heteroaryl groups include, benzofuranyl, benzothiophenyl, imidazopyridinyl,
indazolyl, indolyl, nolinyl, pyrazolopyridinyl, quinolinyl, pyrrolopyrazinyl (in particular
pyrrolo[2,3-b]pyrazinyl) and pyrrolopyridinyl (in particular pyrrolo[3,2—b]pyridinyl). The
heteroaryl l may be bonded via a carbon atom or heteroatom.
A non-aromatic heterocyclyl group, ring or moiety is a non-aromatic 4-, 5-, 6- or 7—membered
cyclic structure, in which structure 1, 2 or 3 ring members are hetero ring members
independently selected from the group, consisting of a nitrogen ring member, an oxygen ring
member and a sulfur ring member, such as azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl,
tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl or
perhydroazepinyl.
Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is ht-
chain or branched.
The terms "alkoxy", "alkenoxy" and "alkynoxy" respectively denote alkyl, alkenyl and alkynyl
groups when linked by oxygen.
A “N,N-di(01.4)alkyl-amino-(C1.a)alkyl” group may contain two identical or two different (01.4)
DETAILED DESCRIPTION OF THE INVENTION
The present ion provides nds of formula (I) as defined hereinbefore and
pharmaceutical compositions f that may be useful in the treatment or prevention of
diseases, conditions and/or disorders modulated by BACE inhibition.
On account of one or more than one trical carbon atom, which may be present in a
compound of the formula I, a corresponding compound of the formula I may exist in pure
optically active form or in the form of a mixture of optical isomers, e. g. in the form of a race-
mic e. All of such pure optical isomers and all of their mixtures, including the racemic
mixtures, are part of the present invention.
In one embodiment, the invention therefore relates to a compound of the formula
51/ \E2
R2 N
\n/ /x1o‘*\ A\l N
l NH2
R, (la),
0 x3§ /x5
x,
in which
E, E2, R2, R5, X1, X3, X4 and X5 are as defined hereinbefore in relation to the formula I,
or a pharmaceutically able salt thereof.
In one embodiment, the invention therefore relates to a compound of the formula
E1/ \E2
R2 N x1 /
\H/ _
/ s N
| NHZ
Rs (lb),
0 x3§ /x5
in which
E, E2, R2, R5, X1, X3, X4 and X5 are as defined hereinbefore in relation to the formula I,
or a pharmaceutically acceptable salt f.
In one ment, there is provided a compound of the Examples as an isolated
stereoisomer wherein the compound has one stereocenter and the stereoisomer is in the R
configuration.
in one ment, there is provided a compound of the Examples as an isolated
stereoisomer wherein the compound has one stereocenter and the stereoisomer is in the 8
configuration.
In one embodiment, there is ed a compound of the Examples as an isolated
stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the R
R configuration.
_11-
In one embodiment, there is provided a compound of the Examples as an isolated
stereoisomer wherein the compound has two stereocenters and the isomer is in the R
8 configuration.
In one embodiment, there is provided a compound of the es as an isolated
stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the S
R configuration.
In one embodiment, there is provided a compound of the Examples as an ed
stereoisomer wherein the nd has two stereocenters and the stereoisomer is in the S
8 configuration.
In one embodiment, there is provided a compound of the Examples, wherein the compound
has one or two stereocenters, as a racemic mixture.
As used , the term “isomers” refers to different compounds that have the same
molecular formula but differ in arrangement and uration of the atoms. Also as used
herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo
ic configurations which may exist for a given compound of the present invention and
includes geometric isomers. It is understood that a substituent may be attached at a chiral
center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or
racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non-
superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a
ic” mixture. The term is used to ate a racemic mixture where appropriate.
"Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which
are not mirror-images of each other. The absolute stereochemistry is specified according to
the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the
stereochemistry at each chiral carbon may be specified by either R or 8. Resolved
compounds whose absolute uration is unknown can be designated (+) or (-) depending
on the direction (dextro- or levorotatory) which they rotate plane polarized light at the
ngth of the sodium D line. Certain of the compounds described herein contain one or
more asymmetric s or axes and may thus give rise to enantiomers, diastereomers, and
other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-
or (S)-. The present invention is meant to include all such possible isomers, including
racemic mixtures, lly pure forms and intermediate mixtures. Optically active (R)- and
(S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using
conventional techniques. If the compound contains a double bond, the substituent may be E
or Z configuration. If the com pound contains a disubstituted cycloalkyl, the cycloalkyl
tuent may have a cis- or trans-configuration.
A compound of the formula I may exist in tautomeric form. All such tautomers are part of the
present invention.
A compound of the formula I may exist in free form or in salt form, for example a basic
compound in acid addition salt form or an acidic compound in the form of a salt with a base.
All of such free compounds and salts are part of the present invention.
In one embodiment, the invention relates to a compound of the formula I, la, lb, lc, Id or le in
free form. In another embodiment, the invention relates to a nd of the formula I, la,
lb, lc, Id or le as defined , in salt form. In another embodiment, the invention relates to
a compound of the a I, la, lb, Ic, Id or le as defined herein, in acid addition salt form. In
a further embodiment, the invention relates to a compound of the formula I, la, lb, lc, Id or le
as d herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the
invention relates to a nd of the formula I, la, lb, lc, Id or Ie as defined , in
hydrochloride salt form. In yet a further embodiment, the invention relates to any one of the
compounds of the Examples in free form. In yet a further embodiment, the invention relates
to any one of the compounds of the Examples in salt form. In yet a further embodiment, the
invention relates to any one of the compounds of the es in acid addition salt form. In
yet a further embodiment, the invention relates to any one of the compounds of the
Examples in pharmaceutically acceptable salt form. In yet a further ment, the
invention relates to any one of the compounds of the es in hydrochloride salt form.
As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a
compound of the invention. “Salts” include in particular “pharmaceutically acceptable salts”.
The term “pharmaceutically acceptable salts” refers to salts that retain the biological
effectiveness and ties of the compounds of this ion and, which lly are not
biologically or otherwise undesirable. In many cases, the compounds of the present
invention are e of forming acid and/or base salts by virtue of the presence of amino
and/or carboxyl groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and
organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide,
bicarbonate/carbonate, bisulfate/sulfate, rsulfornate, chloride/hydrochloride,
chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,
hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, ,
maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,
nitrate, canoate, oleate, e, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen ate, polygalacturonate, propionate, stearate, succinate,
sulfosalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts
can be derived include, for example, hydrochloric acid, hydrobromic acid, ic acid, nitric
acid and phosphoric acid. c acids from which salts can be derived include, for
example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid,
succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, ic acid,
methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and sulfosalicylic acid.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic
bases. nic bases from which salts can be derived include, for example, ammonium
salts and metals from columns | to XII of the periodic table. in certain embodiments, the salts
are derived from sodium, ium, ammonium, calcium, ium, iron, silver, zinc, and
copper; ularly suitable salts include ammonium, potassium, sodium, calcium and
magnesium salts.
Organic bases from which salts can be derived include, for example, primary, ary,
and ry amines, tuted amines including naturally occurring substituted amines,
cyclic amines and basic ion exchange resins. Certain organic amines include
isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine,
piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from a
parent compound, a basic or acidic moiety, by conventional chemical methods. Generally,
such salts can be prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide,
carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a
stoichiometric amount of the appropriate acid. Such reactions are typically carried out in
water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous
media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where
practicable. Lists of additional suitable salts can be found, e.g., in “Remington's
Pharmaceutical Sciences”, 20th ed., Mack Publishing y, Easton, Pa., (1985); and in
“Handbook of Pharmaceutical Salts: Properties, ion, and Use” by Stahl and Wermuth
(Vlfiley-VCH, Weinheim, Germany, 2002).
When both a basic group and an acid group are present in the same molecule, the
compounds of the present invention may also form internal salts, e.g., zwitterionic les.
Furthermore, the compounds of the present invention, including their salts, can also be
obtained in the form of their hydrates, or include other solvents used for their crystallization.
The compounds of the present invention may inherently or by design form solvates with
1O pharmaceutically acceptable solvents (including water); therefore, it is ed that the
invention embrace both ed and unsolvated forms. The term te" refers to a
molecular complex of a compound of the present invention (including pharmaceutically
acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are
those commonly used in the pharmaceutical art, which are known to be innocuous to the
recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the x where
the solvent molecule is water.
The compounds of the present ion, including salts, es and solvates thereof, may
inherently or by design form polymorphs. All such rphs are part of the present
invention.
The present invention es all pharmaceutically acceptable isotope—labeled nds
of the formula I, wherein one or more than one atom is / are replaced by one or more than
one atom having the same atomic number as, but an atomic mass different from, the one(s)
usually found in nature. Examples of such isotopes are those of carbon, such as "C, 13C or
14C, chlorine, such as ”Cl, fluorine, such as 18F, bromine, such as 76Br, hydrogen, such as 2H
or 3H, iodine, such as 123|,12‘*l, 125l or “1|, nitrogen, such as 13N or 15N, oxygen, such as 15O,
17O or 18O, phosphorus, such as 32P, or sulphur, such as 35S. An isotope-labeled compound
of the formula I can be prepared by a process analogous to those described in the Examples
or by a conventional que known to those skilled in the art using an appropriate
isotopically—labeled reagent or starting material. The incorporation of a heavier isotope, such
as 2H (deuterium or D), may provide greater metabolic stability to a compound of the formula
I, which may result in, for example, an increased in vivo-half-life of the compound or in
d dosage requirements. Certain isotope-labeled compounds of the a I, for
example those incorporating a radioactive isotope, such as 3H or 14C, may be used in drug or
substrate-tissue distribution studies. nds of the formula I with a positron emitting
isotope, such as 11C, 18F, 13N or 150, may be useful in positron emission tomography (PET)
or single photon emission computed tomography (SPECT) studies, e. g. to examine
substrate-receptor occupancies.
Pharmaceutically acceptable es in accordance with the ioninclude those wherein
the solvent of crystallization may be isotopically substituted, e.g. D20, de-acetone, de-DMSO.
Compounds of the invention, i.e. compounds of formula I, la, lb, lc, Id or le that contain
groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of
forming co-crystals with suitable co—crystal s. These co-crystals may be prepared from
compounds of formula I, la, lb, Ic, Id or le by known co-crystal forming procedures. Such
procedures include grinding, heating, co—subliming, ting, or contacting in solution
compounds of formula I, la, lb, lc, Id or Ie with the co-crystal former under crystallization
ions and isolating co-crystals thereby formed. Suitable co-crystal formers include those
bed in . Hence the invention further provides co-crystals comprising
a compound of formula I, la, lb, lc, Id or le.
In n embodiments, the invention relates to a compound of the a I, la, lb, lc, Id or
le, or a pharmaceutically acceptable salt thereof, in which:
(1) X1 is CR1 or N;
X3 is CR3 or N;
X4 is CR4 or N;
X5 is CR5;
wherein at least one of X1, X3 and X4 is N and not more than 2 of X1, X3 and X4 are N.
(2) X1 is CH or N;
X3 is OH or N;
X4 is CR4 or N;
X5 is CR5;
wherein one and not more than one of X1, X3 and X4 is N;
(3) X1 is N; X3 is CR3; X4 is CR4; and X5 is CR5.
(4) X1 is CR1; X3 is N; X4 is CR4; and X5 is CR5.
(5) X1 is CR1; X3 is CR3; X4 is N; and X5 is CR5.
(6) X1 is CR1; X3 is CR3; X4 is CR4; and X5 is N.
(7) X1 is N; X3 is N; X4 is CR4; and X5 is CR5.
—16-
(8) X1 is N; X3 is CR3; X4 is N; and X5 is CR5.
(9) X1 is N; X3 is CR3; X4 is CR4; and X5 is N.
(10) X1 is CR1; X3 is N; X4 is N; and X5 is CR5.
(11) X1 is CR1; X3 is N; X4 is CR4; and X5 is N.
(12) X1 is CR1; X3 is CR3; X4 is N; and X5 is N.
(13) R1 is hydrogen, cyano, halogen, (01.8)alkyl, halogen-(01.3)alkyl, (C1_8)alkoxy, halogen-
(C1-a)alkoxy, (01.8)alkylthio, n-(C1.s)alkylthio, (C1.s)alkoxy-(Ci-s)alkyl, (C1.e)alkoxy-(C1_
3)alkoxy, (C1.s)alkoxy-(C1-s)alkylthio, (Ci-s)a|kylthio-(C1.s)a|kyl, (Ci.s)alkylthio-(C1-8)alkoxy, (C1.
1O 8)alkylthio—(C1.8)aikylthio, (02.8)alkenyl, or (Cz.s)a|kynyl.
(14) R1 is hydrogen, cyano, halogen, (01.4)alkyl, halogen-(01.4)alkyl, (01.4)alkoxy, or halogen-
(C1—4)alkoxy.
(15) R1 is hydrogen.
(16) R2 is an aryl or heteroaryl group G, which group G1 is optionally substituted by 1, 2, 3 or
4 substituents ndently selected from the group, consisting of cyano, amino, amino-(C1-
6)a|ky|, (C1.3)a|kyl-amino-(C1_5)a|ky|, di(C1_4)alkyl-amino—(C1_6)alky|, aminocarbonyl,
thiocarbamoyl, halogen, (C1.e)alkyl, halogen-(C1.s)alkyl, hydroxy, oxo, (C1.s)alkoxy, halogen-
(C1.s)alkoxy, (C1.s)alkylthio, halogen-(C1.s)alkylthio, (C1.e)alkoxy-(C1-6)alkyl, (Cs-e)cycloa|kyl-
(C1-e)alkoxy, (C1.e)alkoxy-(C1-e)a|koxy, (C1.s)alkoxy-(C1-s)a|kylthio, alkylthio-(C1-6)alkyl,
(C1.6)alkylthio-(C1-6)alkoxy, (01.6)alkylthio-(C1_6)alkylthio, (02.3)alkenyl, (Cz_e)alkynyl, (CZ.
)alkenoxy, (Cz.e)alkynoxy and a (Cs-e)cycloalkyl, aryl, aryl or non-aromatic heterocyclyl
group 62, which group G2 is ally substituted by 1 to 4 substituents ndently
selected from the group, ting of cyano, aminocarbonyl, halogen, (Ci.e)alkyl, halogen-
(C1.3)alky|, hydroxy, (01-6)alkoxy, halogen-(C1_6)alkoxy, (C1-e)alkylthio, halogen-(C1.6)alkylthio,
(01.5)alkoxy-(C1.e)alky|, (C1.e)aikoxy-(01.e)alkoxy, (01.6)alkoxy-(Ci-e)a|kylthio, (C1.e)alkylthio-
(C1.e)alkyl, (C1.s)a|kylthio-(C1-e)alkoxy, (C1.e)alkylthio-(C1.e)a|kylthio, (Cz.e)alkeny| and (CZ.
)a|kynyl.
(17) R2 is a heteroaryl group, which is optionally substituted by 1, 2, 3 or 4 substituents
independently selected from the group, consisting of cyano, amino, amino-(01.6)alkyl, (C1.
s)a|kyl-amino-(C1-6)alkyl, di(C1.4)alkyI-amino-(C1.s)alkyl, aminocarbonyl, thiocarbamoyl,
halogen, (C1.e)alky|, halogen-(C1-e)a|kyl, y, oxo, a|koxy, n—(Ci.e)a|koxy, (C1.
|thio, halogen-(01.6)alkylthio, (C1_s)alkoxy-(C1.s)alky|, (Cs.e)cycloalkyl-(Ci-e)alkoxy, (C1.
6)a|koxy-(C1_6)alkoxy, (01.6)alkoxy-(C1_6)alkylthio, (01.6)alkylthio-(C1_6)alkyl, (C1_e)a|kylthio-(C1.
2012/050395
6)alkoxy, alkylthio—(C1.s)alkylthio, (C2.e)alkenyl, (Cz.s)alkynyl, (Cz-e)alkenoxy, (CZ.
)alkynoxy.
(18) R2 is a 9- or 10- or membered bicyclic heteroaryl group, which is optionally substituted
by 1, 2, 3 or 4 substituents independently selected from the group, consisting of cyano,
amino, (C1.e)alkyl, (C1.6)alkyl-amino-(C1_6)alkyl, di(01.4)alkyl-amino-(C1_6)alkyl,
aminocarbonyl, thiocarbamoyl, halogen, (01.6)alkyl, halogen-(C1.6)alkyl, hydroxy, oxo, (C1.
)alkoxy, halogen—(C1-s)alkoxy, (C1-5)alkylthio, halogen-(C1-e)alkylthio, (C1_e)alkoxy-(C1.e)alkyl,
(Cs—e)cycloalkyl-(C1.5)alkoxy, (C1-e)a|koxy-(C1.6)a|koxy, (01.e)a|koxy-(C1-e)alkylthio, (C1.
6)alkylthio-(C1_5)alkyl, (C1_6)alkylthio-(C1_6)alkoxy, (01-5)alkylthio-(C1_6)alkylthio, (Cz_e)alkenyl,
(02-6)alkynyl, (Cz-e)alkenoxy, (Cz.e)alkynoxy.
(19) R2 is a 9- or 10— or membered bicyclic heteroaryl group, which’is optionally substituted
by 1, 2, 3 or 4 tuents independently selected from the group, consisting of cyano,
amino, n, (01-4)alkyl, difluoromethyl, trifluoromethyl, hydroxy, oxo, (01-4)alkoxy, (C1-
4)alkoxy-(C1_4)a|kyl and halogen-(01.4)alkoxy.
(20) R2 is a 9-membered bicyclic heteroaryl group in which structure 1, 2 or 3 ring members
are nitrogen ring members, which is optionally substituted by 1, 2, 3 or 4 substituents
independently selected from the group, consisting of cyano, amino, (C1.e)a|kyl, (C1.
6)alkyl-amino-(C1.e)alkyl, di(C1-4)alkyl-amino-(C1.e)alkyl, aminocarbonyl, thiocarbamoyl,
halogen, (01-5)alkyl, halogen-(01-6)alkyl, hydroxy, oxo, (C1_s)alkoxy, n-(C1_e)alkoxy, (C1.
6)alky|thio, halogen—(C1.e)alkylthio, (C1.e)alkoxy-(C1-s)alkyl, (Cs.e)cycloalkyI-(C1-e)alkoxy, (C1.
6)alkoxy-(C1.s)alkoxy, (C1.e)alkoxy-(C1-e)alkylthio, (C1.s)alkylthio-(C1.e)alkyl, (C1.s)alkylthio-(C1.
6)a|koxy, (C1.s)a|kylthio—(C1-e)alkylthio, (Cz-e)alkenyl, (Cz-s)alkynyl, alkenoxy, (C2-
)alkynoxy.
(21) R2 is a 9-membered bicyclic heteroaryl group in which structure 1, 2 or 3 ring members
are en ring members, which is optionally substituted by 1, 2, 3 or 4 substituents
independently ed from the group, ting of cyano, amino, halogen, (01-4)alkyl,
difluoromethyl, trifluoromethyl, hydroxy, oxo, (01.4)alkoxy, (01.4)alkoxy-(C1.4)alkyl and
halogen-(C1_4)alkoxy.
(22) R2 is a 5- or 6-membered heteroaryl group in which structure 1, 2, 3, or 4 ring members
are hetero ring members independently selected from the group consisiting of a en ring
member, an oxygen ring member and a sulfur ring member, which group is optionally
substituted by 1, 2, 3 or 4 substituents independently selected from the group, consisting of
cyano, amino, aminocarbonyl, thiocarbamoyl, halogen, (01.4)alkyl, halogen-(01.4)alkyl,
y, oxo, (01.4)alkoxy, halogen-(01.4)alkoxy, (01.4)alkylthio, n—(01.4)alkylthio, (C1.
4)a|koxy-(C1-4)alkyl, (03.4)cycloalkyl-(C1-4)alkoxy, (01-4)alkoxy-(C1-4)alkoxy, (C1-4)alkoxy-(C1_
-18—
lthio, (01-4)alkylthio-(C1.4)alkyl, (C1.4)alkylthio-(C1-4)alkoxy, (01.4)alkylthio—(Ci.4)alkylthio,
(02.4)alkenyl, (02.4)alkynyl, alkenoxy, and (02-4)alkynoxy.
(23) R2 is a ered heteroaryl group in which structure 1, 2, 3, or 4 ring members are
hetero ring members independently selected from the group consisiting of a en ring
member, an oxygen ring member and a sulfur ring member, which group is optionally
substituted by 1, 2, 3 or 4 substituents independently selected from the group, consisting of
cyano, amino, aminocarbonyl, rbamoyl, halogen, (C1.4)a|kyl, halogen-(C1.4)alkyl,
hydroxy, oxo, (01.4)alkoxy, halogen-(01.4)alkoxy, (C1.4)a|kylthio, halogen-(01.4)alkylthio, (C1.
4)alkoxy-(C1_4)alkyl,1(C3_4)cycloalkyl-(C1.4)alkoxy, (C1_4)alkoxy-(C1.4)alkoxy, (01.4)alkoxy-(C1-
4)alkylthio, (C1.4)alkylthio-(Ci.4)alkyl, (01.4)alkylthio-(Ci.4)alkoxy, (01.4)alkylthio-(C1.4)alkylthio,
(Ca-4)alkenyl, (C2-4)alkynyl, alkenoxy, and (02-4)alkynoxy.
(24) R2 is a 6-membered heteroaryl group in which structure 1, 2, 3, or 4 ring members are
hetero ring members independently selected from the group consisiting of a en ring
member, an oxygen ring member and a sulfur ring member, which group is optionally
substituted by 1, 2, 3 or 4 substituents independently selected from the group, consisting of
cyano, amino, halogen, (01.4)alkyl, halogen-(01-4)alkyl, y, oxo, (01-4)alkoxy and
halogen-(01.4)alkoxy.
(25) R2 is a pyridyl or pyrazinyl group which is optionally substituted by 1, 2 or 3 substituents
independently selected from the group, consisting of cyano, amino, aminocarbonyl,
thiocarbamoyl, halogen, (C1.4)a|kyl, halogen-(01.4)alkyl, hydroxy, oxo, (C1_4)alkoxy, halogen-
(C1-4)alkoxy, (C1.4)alkylthio, n-(C1.4)alkylthio, (C1.4)alkoxy-(C1.4)alkyl, (Cs.4)cycloalkyl-
(Ci—4)alkoxy, (01-4)alkoxy—(01.4)alkoxy, alkoxy-(C1-4)a|kylthio, (C1.4)a|kylthio-(C1.4)alkyl,
(C1-4)a|kylthio-(C1_4)alkoxy, (01.4)alkylthio-(C1_4)alkylthio, (02.4)alkenyl, (02-4)alkynyl, (CZ-
4)alkenoxy, and alkynoxy.
(26) R2 is a pyridyl or pyrazinyl group which is optionally substituted by 1, 2 or 3 substituents
independently selected from the group, consisting of cyano, amino, halogen, alkyl,
halogen-(C1-4)alkyl, hydroxy, oxo, (01.4)alkoxy and halogen-(01.4)alkoxy.
(27) R2 is a pyridin—2—yl or pyrazin-2—yl group which is optionally substituted by 1, 2 or 3
substituents independently selected from the group, consisting of cyano, amino,
aminocarbonyl, thiocarbamoyl, halogen, (01.4)alkyl, halogen-(01-4)alkyl, hydroxy, oxo, (C1.
4)alkoxy, halogen-(01.4)alkoxy, (01.4)alkylthio, halogen-(C1.4)alkylthio, (C1.4)alkoxy-(C1-4)a|kyl,
(Cs—4)cycloalkyl-(C1-4)alkoxy, alkoxy—(Ci.4)alkoxy, (01.4)alkoxy-(Ci.4)alkylthio, (C1.
4)alkylthio-(C1_4)alkyl, (C1_4)alkylthio-(C1_4)alkoxy, (C1_4)alkylthio-(C1.4)alkylthio, (C2_4)alkenyl,
(Oz-4)alkynyl, (02.4)alkenoxy, and (C2.4)alkynoxy.
(28) R2 is a pyridinyl or pyrazinyl group which is optionally substituted by 1, 2 or 3
substituents independently selected from the group, consisting of cyano, amino, halogen,
(01.4)alkyl, halogen-(01.4)alkyl, hydroxy, oxo, (01-4)alkoxy and halogen-(01.4)alkoxy.
(29) R2 is a pyridinyl or pyrazinyl group which is optionally substituted by 1 or 2
substituents independently selected from the group, consisting of cyano, amino, fluoro,
bromo, chloro, hydroxyl, oxo, methyl, methyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy and trifluromethoxy.
(30) R2 is a pyridyl or pyrazinyl group which is substituted by 1, 2 or 3 substituents and
wherein one of the substituents is located at the para on of the pyridyl or pyrazinyl
group relative to the amide linker and wherein the substituents are independently selected
from the group, consisting of cyano, amino, aminocarbonyl, thiocarbamoyl, halogen, (C1.
4)alkyl, halogen-(01.4)alkyl, y, oxo, (01.4)alkoxy, halogen—(C1.4)alkoxy, (01.4)alkylthio,
halogen-(01.4)alkylthio, (C1.4)alkoxy—(C1-4)alkyl, (03.4)cycloalkyl-(C1.4)alkoxy, (01.4)alkoxy-(C1-
4)alkoxy, (C1.4)alkoxy-(C1-4)alkylthio, alkylthio-(C1.4)alkyl, (01.4)alkylthio-(C1.4)alkoxy, (C1.
4)alkylthio-(C1_4)alkylthio, (02.4)alkenyl, (02.4)alkynyl, alkenoxy, and (02-4)alkynoxy.
(31) R2 is a pyridyl or pyrazinyl group which is substituted by 1, 2 or 3 substituents and
n one of the tuents is located at the para position of the pyridyl or pyrazinyl
group relative to the amide linker and wherein the substituents are independently ed
from the group, consisting of cyano, amino, halogen, alkyl, halogen-(01.4)alkyl, hydroxy,
oxo, (C1_4)alkoxy and halogen-(01.4)alkoxy.
(32) R2 is a pyridin—2-yl or pyrazinyl group which is substituted by 1, 2 or 3 substituents
and wherein one of the substituents is d at the para position of the pyridinyl or
pyrazinyl group relative to the amide linker and wherein the substituents are independently
selected from the group, consisting of cyano, amino, halogen, (01.4)alkyl, halogen-(01-4)alkyl,
hydroxy, oxo, (01.4)alkoxy and halogen-(C1.4)alkoxy.
(33) R2 is a pyridyl or pyrazinyl group which is substituted by 2 or 3 substituents and wherein
one of the substituents is located at the para position and one of the substituents is located
at the ortho position of the pyridyl or pyrazinyl group relative to the amide linker and wherein
the substituents are independently selected from the group, consisting of cyano, amino,
aminocarbonyl, thiocarbamoyl, halogen, (01.4)alkyl, halogen-(C1_4)alkyl, hydroxy, oxo, (C1.
4)a|koxy, halogen-(01.4)alkoxy, alkylthio, halogen-(01.4)alkylthio, (01.4)alkoxy-(C1-4)alkyl,
(03.4)Cycloalkyl-(C1-4)alkoxy, alkoxy-(C1_4)alkoxy, (C1-4)alkoxy-(C1-4)a|kylthio, (C1.
lthio-(C1.4)alkyl, (C1.4)alkylthio-(C1.4)alkoxy, (C1.4)alkylthio-(C1.4)alkylthio, (C2.4)alkenyl,
(02.4)alkynyl, (02.4)alkenoxy, and (02-4)alkynoxy.
(34) R2 is a pyridyl or pyrazinyl group which is substituted by 2 or 3 substituents and wherein
one of the substituents is located at the para position and one of the substituents is d
at the ortho position of the pyridyl or pyrazinyl group relative to the amide linker and wherein
the substituents are independently selected from the group, consisting of cyano, amino,
halogen, (01.4)alkyl, halogen-(01-4)alkyl, hydroxy, oxo, (01-4)alkoxy and n-(01.4)alkoxy.
(35) R2 is a pyridinyl or pyrazinyl group which is substituted by 2 substituents and
wherein one of the substituents is located at the para position and one of the substituents is
d at the ortho position of the pyridin-2—yl or pyrazinyl group relative to the amide
linker and wherein the substituents are independently selected from the group, consisting of
1O cyano, amino, halogen, alkyl, halogen-(01.4)alkyl, hydroxy, oxo, (01.4)alkoxy and
n-(C1-4)alkoxy.
(36) R2 is a pyridin—2-yl or pyrazinyl group which is substituted by 2 substituents and
wherein one of the substituents is located at the para position and one of the substituents is
located at the ortho position of the pyridinyl or pyrazin-2—yl group relative to the amide
linker and wherein the substituents are ndently selected from the group, consisting of
cyano, amino, fluoro, bromo, chloro, hydroxyl, oxo, methyl, fluoromethyl, difluoromethyl,
oromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluromethoxy.
(37) R3 is hydrogen, cyano, halogen, (01.4)alkyl, halogen-(01-4)alkyl, (01.4)alkoxy, n-
(C1.4)alkoxy, (C1.4)alkylthio, halogen—(C1.4)alkylthio, (01.4)alkoxy-(C1-4)alkyl, (01-4)alkoxy-(C1-
4)alkoxy, (C1.4)alkoxy-(C1.4)alkylthio, (C1-4)alkylthio-(C1.4)alkyl, (01-4)alkylthio-(C1-4)alkoxy, (C1.
4)alkylthio-(C1.4)alkylthio, (C2.4)alkenyl, or alkynyl.
(38) R3 is hydrogen, cyano, halogen, (01.4)alkyl, halogen—(01-4)alkyl, (01.4)alkoxy, or halogen-
(01.4)alkoxy.
(39) R3 is hydrogen.
(40) R4 is en, cyano, halogen, (01.4)alkyl, halogen-(01.4)alkyl, alkoxy, halogen-
(C1-4)alkoxy, (01.4)alkylthio, halogen-(C1.4)alkylthio, (01.4)alkoxy-(C1.4)alkyl, (01-4)alkoxy-(C1.
4)alkoxy, (01-4)alkoxy-(C1.4)alkylthio, (01-4)alkylthio-(C1-4)alkyl, (C1-4)alkylthio-(C1-4)alkoxy, (c1.
4)alkylthio-(C1.4)alkylthio, (02.4)alkenyl, or (02-4)alkynyl.
(41) R4 is hydrogen, cyano, halogen, alky|, halogen-(01-4)alkyl, (C1.4)alkoxy, or halogen-
(C1.4)alkoxy.
(42) R4 is hydrogen or halogen.
(43) R4 is hydrogen.
(44) R4 is fluoro.
WO 95469
(45) R5 is hydrogen, cyano, halogen, (C1.4)alkyl, halogen-(01-4)alkyl, (01-4)alkoxy, halogen-
(C1-4)alkoxy, (01.4)alkylthio, halogen-(01.4)alkylthio, alkoxy-(C1-4)alkyl, (01.4)alkoxy-(C1_
4)alkoxy, (01.4)alkoxy-(C1.4)alkylthio, (01.4)alkylthio-(C1.4)alkyl, (C1.4)a|kylthio—(C1-4)alkoxy, (C1.
4)alkylthio-(C1_4)alkylthio, alkenyl, or (02.4)alkynyl.
(46) R5 is hydrogen, cyano, halogen, (C1.4)alkyl, halogen-(C1-4)alkyl, (01.4)alkoxy, or n-
(01.4)alkoxy.
(47) R5 is hydrogen or halogen.
(48) R5 is hydrogen or fluoro.
(49) R5 is halogen.
(50) R5 is fluoro;
(51) R5 is hydrogen.
(52) R5 is hydrogen, (01.4)alkyl, halogen—(01-4)alkyl, hydroxy—(C1-4)alkyl, alkoxy-(C1-
4)alkyl, mercapto-(C1.4)alky|, (C1.4)alkylthio—(C1.4)a|kyl, amino-(01.4)alkyl, (01-4)alkyl—amino-(C1-
l, di(01-4)alkyl-amino-(C1.4)alkyl, (02.4)alkenyl, or (02.4)alkynyl.
(53) R6 is alkyl, halogen-(01-4)alkyl, hydroxy-(C1-4)a|kyl, (C1.4)alkoxy-(C1.4)alkyl,
mercapto-(C1.4)alky|, (01.4)alkylthio-(C1.4)alkyl, amino-(01.4)alkyl, (C1.4)alkyl-amino-(C1.4)alkyl,
di(C1-4)alkyl-amino-(C1.4)alkyl, (02.4)alkenyl, or (C2.4)a|kynyl.
(54) R6 is (01.3)alkyl or halogen-(01-3)alkyl.
(55) R5 is (01-3)alkyl or fluoro—(C1-3)alkyl.
(56) R6 is methyl, fluoromethyl, difluoromethyl or trifluoromethyl.
(57) E1 is -C(R7)(Rs)-. 0r -C(R7)(Ra)-C(R9)(R1o)--
(58) E1 is -C(R7)(R3)-.
(59) E2 is -C(R11)(R12)-, or "C(R11)(R12)'C(R13)(R14)'-
(60) E2 is 'C(R11)(R12)'-
(61) either
each of R7 and R8 is independently selected from the group, consisting of hydrogen, cyano,
n, (01.8)alkyl, halogen-(C1.a)alkyl, (C1-a)alkoxy-(C1.s)alkyl and (01.8)alkylthio-(C1.s)alkyl;
R7 and R8, taken together, are oxo or —CH2-CH2-.
(62) either
each of R7 and R3 is ndently selected from the group, consisting of hydrogen, cyano,
halogen, (01.3)alkyl and halogen-(C1-s)alkyl;
R7 and R8, taken together, are oxo or -CH2-CH2-.
(63) e_ith_er
each of R7 and R8 is hydrogen;
R7 and R8, taken together, are oxo.
(64) each of R7 and R8 is hydrogen.
(65) either
each of R9 and R10 is ndently selected from the group, consisting of hydrogen, cyano,
halogen, alkyl, halogen-(01-8)alkyl, (01-8)alkoxy-(C1.s)alkyl and (01.8)alkylthio-(C1.s)alkyl;
R9 and R10, taken together, are oxo or -CH2-CH2-.
(66) each of R9 and R10 is hydrogen.
(67) either
each of R11 and R12 is independently selected from the group, consisting of hydrogen, cyano,
halogen, (01-8)alkyl, halogen-(C1-8)alkyl, (C1-e)alkoxy-(C1.e)alkyl and (C1.a)alkylthio-(C1.s)a|kyl;
R11 and R12, taken together, are oxo or -CH2-CH2-;
(68) each of R11 and R12 is independently selected from the group, consisting of hydrogen,
halogen, (C1.e)alkyl and halogen-(C1.a)alkyl;
each of R11 and R12 is independently ed from the group, consisting of hydrogen, (C1.
8)alkyl and halogen-(C1.8)alkyl;
(69) either
each of R11 and R12 is independently selected from the group, consisting of hydrogen, cyano,
n, (01.3)alkyl and halogen-(C1.s)alkyl;
g
R11 and R12, taken together, are oxo or —CR15R1e—CR17R18-
wherein R16, R17, R18 and R19 are independently selected from hydrogen and fluoro;
(70) either
each of R11 and R12 is ndently selected from the group, ting of hydrogen, (C1.
3)alky| and halogen-(01.3)alkyl;
R11 and R12, taken together, are oxo;
(71) either
each of R11 and R12 is independently selected from the group, ting of en, methyl
and ethyl;
R11 and R12, taken together, are 0x0;
(72) each of R11 and R12 is independently selected from the group, consisting of hydrogen,
(01.3)alkyl and halogen-(01-3)alkyl;
(73) R11 is (C1.s)a|kyl, and R12 is halogen-(Ci.e)alkyl;
(74) R11 is (C1.3)alkyl, and R12 is halogen-(01-3)alkyl;
(75) each of R11 and R12 is independently selected from the group, consisting of hydrogen,
(01.3)alkyl and fluoro-(C1_3)alkyl;
(76) each of R11 and R12 is independently selected from the group, consisting of en,
methyl, fluoromethyl, difluoromethyl and trifluoromethyl;
(77) R11 and R12 is hydrogen;
(78) R11 and R12, taken together, are 0x0;
(79) e_itn_e_c
each of R13 and R14 is independently ed from the group, consisting of hydrogen, cyano,
halogen, (01.3)alkyl, halogen-(C1_8)alkyl, (01-3)alkoxy-(C1_8)alkyl and (C1_8)alky|thio-(C1.8)alkyl;
R13 and R14, taken together, are 0x0 or H2-;
(80) each of R13 and R14 is en.
The skilled person would understand that the embodiments (1) to (80) may be used
independently, collectively or in any combination or sub-combination to the limit the scope of
the invention as described hereinbefore in relation to compounds of the formula I, la, lb, lc, Id
or Ie.
In one embodiment, the invention relates to a compound of the formula
Y | R,” ”H2
in which
X1 is CR1 or N;
X3 is CR3 or N;
X4 is CR4 or N;
wherein at least one of X1, X3 and X4 is N and not more than 2 of X1, X3 and X4 are N;
R1 is hydrogen, cyano, halogen, alkyl, n-(01-4)alkyl, (C1_4)alkoxy, or
halogen-(01.4)alkoxy;
R2 is a 5- or 6—membered heteroaryl group in which structure 1, 2, 3, or 4 ring members
are hetero ring members independently selected from the group consisiting of a nitrogen ring
member, an oxygen ring member and a sulfur ring member, which group is optionally
substituted by 1, 2, 3 or 4 substituents independently selected from the group, consisting of
cyano, amino, aminocarbonyl, thiocarbamoyl, halogen, (01.4)alkyl, n-(C1_4)alkyl,
hydroxy, oxo, (C1.4)alkoxy, halogen—(01.4)alkoxy, (01.4)alkylthio, halogen-(01.4)alkylthio, (C1.
4)a|koxy-(C1_4)alkyl, (01-4)alkoxy-(C1_4)alkoxy, (01.4)alkoxy—(C1_4)alkylthio, (01.4)alkylthio—(C1_
4)alkyl, (01.4)alkylthio-(C1.4)alkoxy, (01.4)alkylthio-(C1.4)alkylthio, (02.4)alkenyl, (02.4)alkynyl,
(Cz-4)alkenoxy, and (02-4)alkynoxy;
R3, R4 and R5 are independently selected from the group ting of hydrogen,
cyano, halogen, (C1_4)alkyl, halogen-(01.4)alkyl, (01.4)alkoxy, or halogen-(01.4)alkoxy;
R5 is (C1.s)alkyl or fluoro-(C1.3)a|kyl; and
each of R11 and R12 is ndently selected from the group, consisting of en,
(C1.s)a|kyl and halogen-(01.3)alkyl;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the ion relates to a compound of the formula lc
in which
X1 is CH or N;
X3 is CH or N;
X4 is CR4 or N;
wherein one and not more than one of X1, X3 and X4 is N;
R2 is a pyridyl or pyrazinyl group which is optionally substituted by 1, 2 or 3
substituents independently selected from the group, consisting of cyano, amino,
aminocarbonyl, rbamoyl, halogen, (01.4)alkyl, halogen-(C1.4)alkyl, hydroxy, oxo, (C1.
4)alkoxy, halogen-(01.4)alkoxy, (01.4)alkylthio, halogen-(01.4)alkylthio, alkoxy—(C1_4)alkyl,
(C1.4)alkoxy-(C1.4)alkoxy, (C1.4)alkoxy-(C1_4)alkylthio, (01.4)alkylthio-(C1_4)alkyl, (Ci—4)alkylthio-
alkoxy, (C1.4)alkylthio-(C1.4)a|kylthio, (C2.4)a|kenyl, (02.4)alkynyl, (C2-4)alkenoxy, and (Ca.
4)alkynoxy;
R4 and R5 are ndently hydrogen, or halogen;
R5 is (C1.3)alkyl or fluoro-(C1.3)a|kyl; and
each of R11 and R12 is ndently selected from the group, consisting of hydrogen,
(C1.s)a|ky| and fluoro-(C1.a)alkyl;
or a pharmaceutically acceptable salt thereof.
In a further embodiment, the invention relates to a compound of the a
0 R11
R N X1 IR12
2\n/ Y/ “ N
| NH2
Rs (Id).
in which
X1 is CH or N;
X3 is CH or N;
X4 is CR4 or N;
wherein one and not more than one of X1, X3 and X4 is N;
R2 is a pyridyl or pyrazinyl group which is substituted by 2 or 3 substituents and
wherein one of the substituents is located at the para position and one of the substituents is
located at the ortho position of the pyridyl or pyrazinyl group relative to the amide linker and
wherein the substituents are independently selected from the group, ting of cyano,
amino, halogen, (01.4)alkyl, halogen-(01-4)aikyl, hydroxy, oxo, (01-4)alkoxy and halogen-(C1.
4)alkoxy;
R4 and R5 are independently hydrogen, or halogen;
R6 is methyl, fluoromethyl, difluoromethyl or trifluoromethyl; and
each of R11 and R12 is independently selected from the group, ting of hydrogen,
methyl, fluoromethyl, difluoromethyl and trifluoromethyl;
or a pharmaceutically able salt thereof.
WO 95469
In a further embodiment, the invention relates to a compound of the formula
in which
R2 is a pyridin-2—yl or pyrazinyl group which is substituted by 2 substituents and
wherein one of the substituents is located at the para position and one of the substituents is
d at the ortho on of the pyridin-Z-yl or pyrazin-Z-yl group relative to the amide
linker and wherein the substituents are independently selected from the group, consisting of
cyano, amino, fluoro, bromo, chloro, hydroxyl, oxo, methyl, fluoromethyl, difluoromethyl,
trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluromethoxy;
R5 is hydrogen or fluoro;
R5 is , fluoromethyl or difluoromethyl; and
each of R11 and R12 is ndently selected from the group, ting of hydrogen,
methyl, fluoromethyl, difluoromethyl and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention relates to a compound of the invention which is
selected from:
-Bromo-pyridinecarboxylic acid [6-(5-aminomethyI-3,6-dihydro—2H-[1,4]-oxazinyl)-
pyridinyl]—amide;
-Chloro—pyridinecarboxylic acid [6-(5-aminofluoromethyl-3,6-dihydro—2H-[1,4]oxazin-3—
yl)-pyridin-2—yl]-amide;
-Bromo—pyridinecarboxylic acid [6-(5-aminofluoromethyl-S,6-dihydro-2H-[1,4]oxazin
yl)—pyridin-2—yl]-amide;
5-Cyano—3-methyl-pyridinecarboxylic acid aminofluoromethyl-3,6—dihydro-2H-
[1,4]oxazinyl)-pyridinyl]—amide;
4,6-Dideutero—5-chIorotrideuteromethyl-pyridine—2—carboxylic acid [6-(5-amino
fluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide;
-Thiocarbamoyl-pyridinecarboxylic acid [6-(5—amino—3—fluoromethyl-3,6—dihydro-2H-
[1 ,4]oxazinyl)-pyridin-2—yl]-amide;
-CyanomethyI-pyridinecarboxylic acid [6-(5-amino-3,6—dimethyI—6-trifluoro-methyl-3,6-
dihydro-2H-[1,4]oxazinyl)—pyridiny|]-amide;
o-pyridine—2—carboxylic acid [6-(5-amino—3,6-dimethyItrifluoromethyl-3,6-dihydro-
2H-[1,4]oxazinyI)-pyridinyI]-amide;
o—3-methyl-pyridine-2—carboxylic acid [6-(5-amino—3,6-dimethyltrifluoromethyI-3,6-
dihydro-2H-[1,4]oxazinyl)f|uoro-pyridinyl]—amide;
4,6-Dideutero—S-chlorotrideuteromethyl-pyridine—2—carboxylic acid [4-(5-amino
fluoromethyI-3,6-dihydro—2 H-[1,4]oxazinyl)-pyridin-2—yl]—amide;
-Chloro-pyridinecarboxylic acid [4-(5-amino—3-fluoromethyI-3,6-dihydro-2H-[1,4]oxazin
yI)—pyridinyl]-amide;
-Cyanomethyl-pyridinecarboxylic acid [4-(5-amino-3,6-dimethyltrifluoromethyl-3,6-
dihydro—2H-[1,4]oxazinyl)-5—fluoro—pyridin—Z-yfl-amide;
-Bromo—pyridinecarboxylic acid [5-(5-aminofluoromethyI-3,6-dihydro-2H-[1,4]oxazin
chloro—pyridinyl]-amide;
3-Amino—5-cyano-pyridinecarboxylic acid [6-(5-amino-3,6-dimethyltrifluoromethyl-3,6—
dihydro—2H-[1,4]oxazin-3—yl)—pyridin—2—yl]—amide;
3-Chloro—5-cyano-pyridine—2—carboxylic acid [6-(5-amino-3,6-dimethyl—6-trifluoromethyl-3,6-
dihydro-ZH-[1,4]oxazinyI)-pyridin-2—yI]—amide;
-Chloro—4,6—dideuteriotrideuteriomethyl-pyridinecarboxylic acid amino—3,6—
dimethyl-6—trifluoromethyI-3,6—dihydro-2H-[1,4]oxazinyI)-pyridinyl]—amide;
-Bromo-3—chloro-pyridinecarboxylic acid [6-(5-amino-3,6-dimethyItrifluoromethyI-3,6-
dihydro—2H-[1,4]oxazin-3—yI)-pyridin—2-yl]-amide;
3-Amino(2,2,2-trifluoro-ethoxy)-pyrazinecarboxylic acid amino-3,6—dimethyl
trifluoromethyl-3,6-dihydro-2H-[1 ,4]oxazinyl)—pyridinyI]-amide;
3-Chloro-5—cyano-pyridinecarboxylic acid [6-(5-amino-3,6-dimethyltrifluoromethyl-3,6-
dihydro-ZH-[1,4]oxazinyl)fluoro-pyridiny|]-amide;
-Methoxy-B—methyl-pyridine—Z-carboxylic acid [6-(5-amino-3,6-dimethyltrifluoromethyI-3,6-
dihydro-2H-[1,4]oxazinyl)fluoro-pyridin—2-yl]amide;
3-Amino(2,2,2-trifluoro—ethoxy)-pyrazinecarboxylic acid [6-(5-amino—3,6—dimethyI
trifluoromethyl-3,6-dihydro—2 H-[1,4]oxazin-3—yI)fluoro-pyridinyl]amide;
3-Aminocyano-pyridine—2-carboxylic acid [6-(5-amino—3,6—dimethyltrifluoromethyI-3,6-
dihydro—2H-[1,4]oxazin-3—yI)fluoro-pyridin-Z—yl]amide;
-Difluoromethoxymethyl-pyridinecarboxylic acid [6-(5-amino-3,6—dimethyl-6—
trifluoromethyl-3,6—dihydro-2 H-[1,4]oxazinyl)fluoro-pyridinyl]amide;
3-Chlorodifluoromethoxy-pyridine-Z-carboxylic acid amino-3,6-dimethyI
trifluoromethyI-B,6-dihydro-2H-[1,4]oxaziny|)f|uoro-pyridinyl]amide;
3,5-DichIoro-pyridine-Z-carboxylic acid [6—(5-amino—3,6—dimethyltrifluoromethyI-S,6-
dihydro-2H-[1,4]oxazinyI)fluoro-pyridinyl]amide;
-Fluoromethoxy—3-methyi-pyridine-Z-carboxylic acid [6-(5-amino-3,6-dimethyl-6—
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin—3-yl)—5-fluoro-pyridin-Z-yl]amide;
yl-pyrazine—2—carboxylic acid [6—(5-amino-3,6-dimethyl-6—trifluoromethyl-3,6-dihydro-
2H-[1,4]oxazinyl)fluoro-pyridinyl]amide;
3-Chlorotrifluoromethyl-pyridine-Z-carboxylic acid [6—(5-amino-3,6-dimethyI
trifluoromethyI-3,6-dihydro-2H-[1 ,4]oxazinyl)f|uoro-pyridinyl]amide;
3-Chlorocyano-pyridinecarboxylic acid [4-(5-amino-3,6-dimethyltrifiuoromethyI-3,6-
di hydro-2 H-[1,4]oxazin-3—yl)—5-fluoro-pyridinyI]—amide;
3-Chlorodifluoromethoxy-pyridinecarboxylic acid [4-(5-amino—3,6-dimethyl
trifluoromethyI-3,6-dihydro-2H—[1,4]oxazinyl)—5-fluoro-pyridin-2—yl]—amide;
-Cyano—3-methyl-pyridinecarboxylic acid [4-(5-amino—6,6-bis-fluoromethylmethyl-3,6-
dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]-amide;
5-Cyano—3-methyI-pyridine-2—carboxylic acid [6-( 5-amino—3-difluoromethyl-3,6—dihydro—2H-
[1,4] exazinyl)-5—fluoro-pyridin-2—yl]—amide;
3-Chlorocyano-pyridinecarboxylic acid [6-(5-amino-3—difluoromethyi-3,6-dihydro—2H-
[1,4] oxazin-S—yl)fluoro—pyridin—2—yl]—amide;
3,5-Dimethyl-pyrazinecarboxylic acid [6-(5-amino-3,6-dimethyl-6—trifluoromethyl-3,6-
dihydro—2H-[1 zinyl)fluoro—pyridinyl]amide;
3-Amino(3-fluoro-propoxy)-pyrazinecarboxylic acid [6—(5-amino—3,6—dimethyl-6—
trifluoromethyI-3,6-dihydro-2 H-[1,4]oxazinyI)f|uoro-pyridiny|]amide;
3-Amino(2-methoxy—ethyl)-5H-pyrrolo[2,3-b]pyrazine—2—carboxyiic acid [6—((5-amino-3,6-
dimethyI-6—trifl thyl-3,6-dihydro-2H-[1 ,4]oxazinyI)fl uoro-pyridin-Z-yflamide;
3-Amino—5-trifl uoromethyl-pyrazine-2—carboxylic acid amino—3,6-dimethyl
trifluoromethyl-3,6-dihydro-2 H-[1,4]oxazinyI)fluoro-pyridin-Z-yl]amide;
3-Amino(2,2-difluoro-ethyl)—5H-pyrrolo[2,3-b]pyrazinecarboxylic acid amino—3,6-
yl-6—trifluoromethyI-3,6-dihydro—2H-[1,4]oxaziny|)fluoro-pyridin-2—yl]—amide;
4-Chlorodif|uoromethy|—1H-pyrazole—S—carboxylic acid [6-(5-amino-3,6-dimethyl-6—
trifluoromethyI-S,6-dihydro-2H-[1 ,4]oxazinyl)—5-fluoro-pyridinyI]-amide;
6-Chloro(2,2-difluoro-ethyi)-1H-pyrrolo[3,2—b]pyridinecarboxylic acid [6-(5-amino-3,6-
dimethyItrifluoromethyI-S,6-dihydro-2H-[1,4]oxazinyI)-5—fluoro-pyridin-Z-yl]-amide; and
6-Chloro(2-methoxy—ethyl)-1H—pyrrolo[3,2—b]pyridine-5—carboxylic acid [6-(5-amino-3,6-
dimethyltrifluoromethyI-3,6-dihydro-2H-[1,4]oxazinyl)fluoro—pyridin-2—yI]-amide;
and pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to a compound of the invention which is
selected from:
-Bromo-pyridinecarboxylic acid [6-((R)aminomethyl-3,6-dihydro-2H-[1,4]-oxazin
yl)-pyridinyl]—amide;
-Chloro-pyridinecarboxylic acid [6-(5-aminofluoromethyi-3,6—dihydro-2H-[1,4]oxazin
yl)-pyridin-2—yl]—amide;
-Bromo-pyridine—2—carboxylic acid [6-(5-amino—3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin—3-
yl)-pyridinyi]-amide;
-Cyano—3-methyl-pyridinecarboxylic acid [6-(5-aminofluoromethyl-3,6-dihydro-2H—
[1,4]oxazinyl)—pyridin—2—yl]-amide;
4,6-Dideuterochlorotrideuteromethyl-pyridinecarboxylic acid [6-(5-amino—3-
fluoromethyI-3,6-dihydro-2H-[1,4]oxazinyI)-pyridinyl]-amide;
—Thiocarbamoyl-pyridine—2-carboxylic acid [6-(5-aminofluoromethyl-3,6-dihydro-2H—
xazinyl)-pyridin-2—yl]—amide;
o—3-methyI-pyridinecarboxylic acid [6-((3R,6R)—5-amino-3,6-dimethyl-6—trifluoro—
methyl-3,6—dihydro-2H—[1,4]oxazinyl)-pyridin-2—yl]—amide;
-Cyano-pyridine-2—carboxylic acid [6-((38,6R)—5—amino-3,6-dimethyl-6—trifiuoromethyI-3,6-
dihydro-2H-[1,4]oxazinyl)—pyridin-2—yI]-amide;
-Cyano—pyridinecarboxylic acid [6-((3R,6R)amino-3,6-dimethyltrifluoromethyI-3,6-
dihydro—2H-[1,4]oxazinyI)-pyridinyl]-amide;
-Cyano—3-methyI-pyridinecarboxylic acid [6-((3R,6R)—5—amino-3,6-dimethyltrifluoro—
methyl-3,6-dihydro-2H-[1 ,4]oxazinyl)fluoro-pyridin—2-y|]-amide;
-Cyano—3-methyl-pyridine-2—carboxylic acid [6-((3S,6R)amino-3,6-dimethyl-6—
oromethyI-3,6-dihydro-2H-[1,4]oxaziny|)f|uoro-pyridinyl]-amide;
4,6-DideuterochIorotrideuteromethyl-pyridine-2—carboxylic acid [4-(5-amino
fluoromethyI-B,6-dihydro—2H-[1,4]oxazinyl)-pyridinyl]—amide;
-ChIoro-pyridinecarboxylic acid aminofluoromethyl-3,6-dihydro-2H-[1,4]oxazin
yl)-pyridinyI]-amide;
-Cyano—3-methyi-pyridinecarboxylic acid [4-((3R,6R)amino-3,6—dimethyl
trifluoromethyI-B,6-dihydro-2 H-[1,4]oxazinyl)f|uoro-pyridinyl]—amide;
—Cyano—3—methyl-pyridinecarboxylic acid [4-((3S,6R)amino-3,6—dimethyl-6—
oromethyl-3,6-dihydro-2H-[1,4]oxaziny|)f|uoro-pyridin-Z-yi]-amide;
o-pyridinecarboxylic acid [5-(5-amino—3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin—3-
yl)ch|oro-pyridinyl]-amide;
3-Aminocyano-pyridine—2—carboxylic acid [6-((3R,6R)amino-3,6—dimethyI
trifluoromethyI-3,6-dihydro-2H-[1,4]oxazinyI)-pyridinyl]—amide;
3-Chlorocyano—pyridinecarboxylic acid [6-((3R,6R)—5-amino-3,6—dimethyI
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)—pyridin—2—yl]—amide;
ro—4,6-dideuteriotrideuteriomethyl—pyridine—2—carboxylic acid [6-((3R,6R)amino-
3,6-dimethyltrifluoromethyl-3,6—dihydro-2H-[1,4]oxazinyi)-pyridinyl]—amide;
-Bromochloro—pyridinecarboxylic acid [6-((3R,6R)amino-3,6-dimethyl
trifluoromethyl-3,6-di hydro-2 H-[1,4]oxazinyl)-pyridin—2—yl]-amide;
3-Amino(2,2,2—trifluoro-ethoxy)-pyrazinecarboxylic acid [6-((3R,6R)-5—amino-3,6-
dimethyltrifluoromethyl-3,6—dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide;
rocyano-pyridinecarboxylic acid [6-((3R, amino—3,6—dimethyI
trifluoromethyI-3,6-dihydro-2H-[1 ,4]oxazinyl)fluoro-pyridinyl]-amide;
-Methoxymethyl-pyridine-Z-carboxylic acid [6-((3R,6R)—5-amino-3.6-dimethyl
trifluoromethyl-3,6—dihydro-2H—[1,4]oxaziny|)fluoro-pyridiny|]amide;
o(2,2,2—trifluoro-ethoxy)—pyrazine-2—carboxylic acid [6-((3R,6R)amino—3,6-
dimethyltrifluoromethyl-3,6-dihydro-2H—[1,4]oxazinyl)-5—fluoro-pyridin-Z-yl]amide;
3-Aminocyano-pyridinecarboxylic acid [6-((3R,6R)amino—3,6—dimethyl-6—
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridin-Z-yl]amide;
3-ChIorocyano-pyridine-2—carboxylic acid [6-((3S,6R)amino—3,6—dimethy|—6—
trifluoromethyI-S,6-dihydro—2H-[1,4]oxazinyl)fluoro-pyridin-2—y|]amide;
-Difluoromethoxymethyl-pyridine-Z-carboxylic acid [6-((3R,6R)—5—amino-3,6—dimethyl
trifluoromethyI-B,6-dihydro-2 H-[1,4]oxazin-3—yI)fluoro-pyridin-2—yl]amide;
3-Chlorodifluoromethoxy-pyridinecarboxylic acid [6-((3R,6R)amino-3,6—dimethyl-6—
trifluoromethyl-3,6-dihydro-2H—[1 ,4]oxazinyl)fluoro-pyridin-Z-yl]amide;
3,5-Dichloro—pyridine-2—carboxylic acid [6-((3R,6R)amino-3,6-dimethyltrifluoromethyl-
3,6-dihydro—2H-[1,4]oxazinyl)fluoro-pyridin-Z-yl]amide;
5-Fluoromethoxy—3-methyl-pyridine-2—carboxylic acid [6—((3R,6R)—5—amino—3,6—dimethyl-6—
trifluoromethyl-S,6-dihydro-2H-[1,4]oxazinyI)fluoro-pyridin-Z-yl]amide;
yl-pyrazine—2—carboxylic acid [6-((3R,6R)—5-amino—3,6—dimethyltrifluoromethyl-3,6-
dihydro—2H-[1,4]oxazinyI)fluoro-pyridin-2—yl]amide;
3-ChlorotrifluoromethyI-pyridine—2—carboxylic acid [6-((3R,6R)—5-amino-3,6-dimethyl
trifluoromethyI-3,6-dihydro-2H-[1,4]oxazinyl)—5-fluoro-pyridinyi]amide;
3-Chlorocyano—pyridine-2—carboxylic acid [4-((3R,6R)amino-3,6-dimethyl
trifluoromethyI-3,6-dihydro-2H-[1,4]oxazinyi)—5-fluoro-pyridin-2—yI]-amide;
3-Chlorodifluoromethoxy—pyridine-2—carboxylic acid [4-((3S,6R)amino-3,6-dimethyl-6—
trifluoromethyl-3,6-di hydro-2 ]oxazinyl)f|uoro-pyridiny|]-amide;
5-CyanomethyI-pyridine—2—carboxylic acid [4-((R)amino-6,6-bis-fluoromethyI-B-methyl-
3,6—dihydro—2H-[1,4]oxazinyl)—5-f|uoro-pyridin—2-yl]-amide;
WO 95469
-Cyano—3-methyl-pyridine-2—carboxylic acid [6-((R)amino-3—difluoromethyl-3,6—dihydro-
2H-[1,4] oxazinyl)fluoro-pyridin—2—yl]—amide;
-Cyano—3-methyl-pyridinecarboxylic acid [6-((S)aminodifluoromethyl-3,6-dihydro-
2H-[1,4] yl)fluoro-pyridiny|]-amide;
3-Chloro-5—cyano-pyridinecarboxylic acid [6-((R)amino-3—difluoromethyl-3,6—dihydro-2H-
[1,4] oxazinyl)fluoro-pyridin-Z-yl]—amide;
3,5-Dimethyl-pyrazinecarboxylic acid [6-((3R,6R)-5—amino-3,6—dimethyl-6—trifluoromethyl-
3,6-dihydro-2H—[1,4]oxazinyl)—5-fluoro-pyridiny|]amide;
3-Amino(3—fluoro—propoxy)-pyrazinecarboxylic acid [6-((3R,6R)—5-amino-3,6—dimethyI
trifluoromethyl-3,6-dihydro—2 H—[1,4]oxazin-3—yI)-5—fluoro—pyridin-2—yl]amide;
3-Amino(2—methoxy-ethyl)-5H-pyrrolo[2,3—b]pyrazinecarboxylic acid [6-((3R,6R)
amino-3,6-dimethyl-6—trifluoromethyl-3,6-dihydro-2H—[1 ,4]oxazinyI)fl uoro-pyridin
yl]amide;
3-Aminotrifluoromethyl-pyrazine—2—carboxylic acid [6—((3R,6R)amino-3,6-dimethyl—6-
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)f|uoro-pyridinyl]amide;
3-Amino(2,2—dif|uoro-ethyl)—5H-pyrrolo[2,3—b]pyrazine—2—carboxy|ic acid [6-((3R,6R)
amino-3,6-dimethy|—6—trifluoromethyI-3,6-dihydro-2H-[1 zinyI)fluoro-pyridinyl]-
amide;
4-Chlorodifluoromethyl-1H-pyrazoIecarboxylic acid [6-((3R,6R)amino-3,6—dimethyl
trifluoromethyI-3,6-dihydro-2 H-[1,4]oxazin—3-yl)fluoro-pyridin—2-yI]-amide;
6-Chloro(2,2-dif|uoro-ethyl)-1H—pyrro|o[3,2-b]pyridinecarboxy|ic acid [6-((3R,6R)—5-
amino-3,6-dimethyl-6—trifluoromethyl-3,6—dihydro-2H—[1,4]oxazinyl)-5—fluoro-pyridin—2-yl]—
amide; and
6-Chloro(2-methoxy—ethyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid [6-((3R,6R)—5-
amino-3,6-dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]-
amide;
and pharmaceutically acceptable salts thereof.
In a further aspect, the ion relates to a process for the preparation of a compound of
the formula I, in free form or in salt form, comprising
a) the reaction of a compound of the formula
51/ \E2
HN x A PG 2 /1 N N/
I R6 H (II),
XQX/xs
in free form or in salt form, in which X1, X3, X4, X5, R5, E1 and E2 are as defined for the
formula I and PG is a protecting group, with a compound of the formula
R‘\n/L (III).
in which R2 is as defined for the formula I and L is a leaving group, for example a hydroxy
group, in free form or in salt form,
b) the reaction of a compound of the formula
E1/ \E2
Hal x A PG
/ 17/’\N N/
| R, H (Ila),
x3§ /X5
in free form or in salt form, in which X1, X3, X4, X5, R6, E1 and E2 are as defined for the
formula I, Hal is halogen, for example bromine, and PG is a protecting group, with a
compound of the formula
R2\n/NH2 ,
in which R2 is as defined for the formula I, in free form or in salt form,
c) the reaction of a compound of the a
E1/\E2
R2 N X1 k
\n/YIRE s
a (V)l.
0 xQ/sx
in which X1, X3, X4, X5, R2, R6, E1 and E; are as defined for the a I, in free form or in
salt form, with ammonia,
d) the optional reduction, oxidation or other functionalisation of the resulting compound,
e) the cleavage of any protecting s) optionally present and
f) the recovery of the so obtainable compound of the formula I in free form or in salt form.
The reactions can be ed ing to conventional methods, for example as described
in the Examples.
The working-up of the reaction mixtures and the purification of the compounds thus
obtainable may be carried out in accordance with known procedures.
Salts may be ed from free compounds in known manner, and vice-versa.
In more detail, the reaction of a compound of formula (II) with a compound of formula (III) as
described in step a) may be d out in the ce of a suitable coupling agent, for
example 1-hydroxyazabenzotriazole, a le activating agent, for example 1-(3—
dimethylaminopropyl)—3-ethylcarbodiimide hydrochloride, a suitable base, for example
diisopropylethylamine, a suitable solvent, for example dimethylformamide, and at a suitable
temperature, for example 0 to 50 °C, more suitably 0 to 25 °C.
In more detail, the reaction of a compound of formula (Ila) with a compound of formula (Illa)
as described in step b) may be carried out in the presence of, a suitable catalyst, for example
tris(dibenzylidene-acetone) di palladium, a suitable ligand, for example Xanthphos, a suitable
base, for example cesium carbonate, a suitable solvent, for example 1,4—dioxane, and at a
suitable temperature, for example 10 to 100 °C, more suitably 30 to 85 °C.
In more detail, the reaction of a compound of formula (IV) with ammonia as described in step
c) may be carried out in the presence of a le solvent, for e methanol, and at a
suitable temperature, for example 0 to 50 °C, more suitably 0 to 30 °C.
Compounds of the formula I can also be ed by further processes, which processes are
further aspects of the invention, for example as bed in the Examples.
The starting materials of the formulae II, Ila, III, Illa and IV are known or may be prepared
according to conventional procedures starting from known compounds, may be prepared
from known compounds as described in the Examples or may be prepared using procedures
ous to those described in the Examples.
Compounds of the formula l, in free form, salt form, or in pharmaceutically acceptable salt
form, hereinafter often referred to as “agents of the invention”, exhibit valuable
pharmacological properties, when tested in vitro or in vivo, and may, therefore, be useful in
medicaments, in therapy or for use as research chemicals, for example as tool compounds.
For example, agents of the invention are inhibitors of BACE-1 and BACE—2 and may be used
for the treatment or prevention of a ion, disease or disorder involving processing by
such enzymes, particularly the tion of beta-amyloid and the subsequent aggregation
into oligomers and fibrils, and loss of B cell mass and/or on.
The inhibiting properties of an agent of the invention towards ses can be ted in
tests as described hereinafter.
Test 1: Inhibition of human BACE-1
Recombinant BACE—1 (extracellular domain, expressed in baculovirus and purified using
standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at
various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH
4.5, containing 0.1 % CHAPS. Synthetic fluorescence-quenched peptide substrate, derived
from the sequence of APP and containing a suitable hore-quencher pair, is added to a
final concentration of 1 to 5 uM, and the increase in fluorescence is recorded at a suitable
excitation / emission wavelength in a microplate o-fluorimeter for 5 to 30 s in 1-
minute intervals. leo values are calculated from percentage of inhibition of BACE-1 activity
as a function of the test compound concentration.
Test 2: Inhibition of human BACE-2
Recombinant BACE-2 (extracellular domain, sed in baculovirus and purified using
standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at va-
rious concentrations for 1 hour at room ature in 10 to 100 mM acetate buffer, pH 4.5,
containing 0.1 % CHAPS. Synthetic fluorescence-quenched peptide substrate, derived from
the sequence of APP and containing a suitable fluorophore—quencher pair, is added to a final
concentration of 1 to 5 uM, and the increase in fluorescence is recorded at a suitable
tion / emission ngth in a microplate spectro-fluorimeter for 5 to 30 minutes in 1-
minute intervals. IC50 values are ated from percentage of inhibition of BACE-2 activity
as a function of the test compound concentration.
Test 3: Inhibition of human cathepsin D
Recombinant cathepsin D (expressed as procathepsin D in baculovirus, purified using stan-
dard methods and activated by incubation in sodium formate buffer pH 3.7) is incubated with
the test compound at various concentrations for 1 hour at room temperature in sodium for-
mate or sodium acetate buffer at a suitable pH within the range of pH 3.0 to 5.0. Synthetic
peptide substrate Mca—Gly—Lys-Pro-lle-Leu-Phe—Phe—Arg-Leu-Lys(DNP)-D-Arg-NH2 is added
to a final concentration of 1 to 5 uM, and the increase in scence is recorded at excita-
tion of 325 nm and emission at 400 nm in a microplate o—fluorimeter for 5 to 30 minutes
in 1-minute intervals. IC50 values are calculated from the percentage of inhibition of cathepsin
D-activity as a function of the test compound concentration.
Test 4: Inhibition of cellular release of d peptide 1-40
Chinese hamster ovary cells are transfected with the human gene for amyloid precursor
protein. The cells are plated at a density of 8000 cells/well into 96-well microtiter plates and
cultivated for 24 hours in DMEM cell culture medium containing 10 °/o FCS. The test
compound is added to the cells at various concentrations, and the cells are cultivated for 24
hours in the presence of the test compound. The supernatants are collected, and the
concentration of amyloid peptide 1-40 is determined using state of the art assay
ques, for example sandwich ELISA, homogenous esolved fluorescence (HTRF)
immunoassay, or o-chemiluminescence immunoassay. The potency of the compound
is calculated from the percentage of inhibition of amyloid peptide release as a on of the
test compound concentration.
Agents of the invention were tested in at least one of the described tests.
The compounds of the Examples show the following mean |C5o values in Test 1 described
hereinbefore:
I_\ o 80'1
on m A o o oooco
A —\ o 0oA A N o A‘9
_\ 00 (A) \l A A 0) - _x
Xo _\ 0') _o8N
A \l .‘l O) A 00 0.14
_\ co poA00 N 0.01
N —\ o oon 4 N o o A 0:
Nco —‘ N N o oo0)
N01 0 otow N O A
\l o o AA. Ioo ...\ _\
CON(0—x 00 O) II(2903 00 ' OOhNU‘IU‘I
0000 0.82 IA IOO\l
0001 0.15 I00 IA_\
(A)\l 0.38 on
coco __\ 01 9.0.000MA:»mm
A _\ 0.23 4:.
00 _\ N 0.04
A01 V A O IO) 0.01
W0 2012/095469 2012/050395
The compounds of the Examples show the following mean lC5o values in Test 2 described
hereinbefore:
Table 2
Compounds of the es show the following mean leo values in Test 4 described
hereinbefore:
Table 3
Amyloid-B1-40
release |C50 [pM]
0.058
0.098
I O OA 0.063
IA Z_| IA 0.077
AA (ON 0.015
.00:5ACO0) NA 000 0.005
IN .0 \l IA 0.003
IN lONO) N0‘) 0.28
IN IOO01 N(I) Z_}
IN .0 oNA o: 0.024
0.13 34 0.003
0.14 36 0.41
I\l O OCO00 (A)CD 0.005
I(O 0.29 IO 0.012
NT = Not Tested
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents,
dispersion media, coatings, surfactants, idants, vatives (e.g., antibacterial
agents, antifungal ), isotonic agents, absorption delaying agents, salts, vatives,
drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening
agents, ing agents, dyes, and the like and combinations thereof, as would be known to
those d in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier
1O is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical
compositions is contemplated.
The term "a eutically effective amount" of a compound of the present invention refers
to an amount of the compound of the present invention that will elicit the biological or medical
response of a subject, for example, reduction or inhibition of an enzyme or a protein activity,
or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a
disease, etc. In one non-limiting embodiment, the term “a therapeutically ive amount”
refers to the amount of the compound of the present invention that, when administered to a
subject, is ive to (1) at least partially alleviating, inhibiting, preventing and/or
ameliorating a condition, or a disorder or a disease (i) mediated by BACE-1 or (ii) associated
with BACE-1 activity, or (iii) characterized by ty (normal or abnormal) of BACE-1; or (2)
reducing or inhibiting the activity of BACE—1. In another non-limiting embodiment, the term “a
therapeutically effective amount” refers to the amount of the compound of the present
invention that, when administered to a cell, or a tissue, or a non-cellular ical material,
or a medium, is effective to at least partially reduce or inhibit the activity of BACE-1. The
g of the term “a eutically effective amount” as illustrated in the above
embodiments for BACE-1 also applies by the same means to any other relevant
proteins/peptides/enzymes, such as BACE—2, or cathepsin D.
2012/050395
As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A
subject also refers to for e, primates (e.g., humans, male or female), cows, sheep,
goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain
embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term it”, "inhibition" or “inhibiting” refers to the reduction or
ssion of a given condition, symptom, or disorder, or disease, or a significant decrease
in the baseline ty of a biological activity or process.
As used herein, the term “treat”, “treating" or "treatment" of any disease or disorder refers in
one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the clinical symptoms thereof). In
yet another embodiment, “treat”, "treating" or "treatment" refers to modulating the disease or
disorder, either physically, (e.g., stabilization of a discernible symptom), logically, (e.g.,
stabilization of a physical parameter), or both.
As used herein, the term “prevention” of any particular disease or disorder refers to the
stration of a compound of the invention to a t before any symptoms of that
disease or disorder are apparent.
As used herein, a subject is “in need of” a treatment if such subject would benefit biologically,
medically or in quality of life from such treatment.
As used , the term an “agent” of the invention is used interchangeably with the term a
“compound” of the ion and has no difference in meaning therefrom.
As used herein, the term "a,” "an,” "the” and similar terms used in the context of the present
invention ially in the context of the claims) are to be construed to cover both the
singular and plural unless othenivise indicated herein or clearly dicted by the context.
The use of any and all examples, or exemplary language (9.9. "such as”) provided herein is
intended merely to better illuminate the invention and does not pose a limitation on the scope
of the invention otherwise claimed.
Due to their inhibiting properties s proteases, and BACE-1 in particular, agents of the
invention may be useful, e. g., in the ent or prevention of a variety of disabilitating
psychiatric, psychotic, neurological or vascular states, e. g. of a condition, disease or
disorder of the vascular system or of the nervous system, in which beta-amyloid generation
or aggregation plays a role. Based on the inhibition of BACE-2 (beta-site APP-cleaving
enzyme 2) or cathepsin D, which are close homologues of the pepsin-type aspartyl
proteases and beta-secretase, and the correlation of BACE-2 or cathepsin D expression with
a more tumorigenic or atic ial of tumor cells, the agents of the invention may
also be useful as anti-cancer medicaments, e. g. in the suppression of the metastasis
process associated with tumor cells. Furthermore, based on the inhibition of BACE-2 and
the correlation of BACE-2 activity with TME27 ge and B cell mass, the agents of the
invention may also be useful for treating or preventing loss of B cell mass and/or function,
e.g. in the treatment of diabetes.
The said condition, disease or disorder of the vascular system or of the nervous system is
exemplified by, and includes, without limitation, an anxiety disorder, such as panic disorder
with or without agoraphobia, agoraphobia without history of panic disorder, an animal or
other specific phobia, including a social phobia, social anxiety disorder, anxiety, obsessive-
compulsive disorder, a stress disorder, including post-traumatic or acute stress disorder, or a
generalized or nce-induced anxiety disorder; a neurosis; seizures; epilepsy, especially
partial es, simple, complex or partial seizures ng to secondarily generalized
seizures or generalized seizures [absence (typical or atypical), myoclonic, clonic, tonic, tonic-
clonic or atonic seizures]; convulsions; migraine; an affective disorder, including a depressive
or bipolar disorder, e. g. single—episode or ent major depressive disorder, major
depression, a dysthymic disorder, dysthymia, depressive er NOS, bipolar | or bipolar II
manic er or cyclothymic disorder; a psychotic disorder, including schizophrenia or
sion; egeneration, e. g. neurodegeneration g from cerebral ischemia; an
acute, traumatic or chronic degenerative process of the nervous system, such as Parkinson’s
disease, Down’s syndrome, dementia, e. g. senile ia, dementia with Lewy bodies or a
fronto—temporal dementia, a cognitive disorder, cognitive ment, e. 9. mild cognitive
impairment, memory impairment, an amyloid neuropathy, a peripheral neuropathy,
Alzheimer’s disease, Gerstmann-Straeussler—Scheinker syndrome, Niemann-Pick disease, e.
g. Niemann-Pick type C disease, brain inflammation, a brain, spinal cord or nerve injury, e. g.
traumatic brain injury (TBI), a nerve trauma or a brain trauma, vascular amyloidosis, al
haemorrhage with dosis, gton’s chorea, amyotrophic lateral sclerosis, multiple
sclerosis or fragile X syndrome; scrapie; cerebral amyloid angiopathy; an encephalopathy, e.
g. transmissible spongiform encephalopathy; stroke; an ion disorder, e. g. attention
deficit hyperactivity disorder; te's syndrome; a speech disorder, including stuttering; a
disorder of the circadian rhythm, e. g. in subjects suffering from the effects of jet lag or shift
work; pain; nociception; itch; emesis, including acute, d or anticipatory emesis, such
as emesis induced by chemotherapy or ion, motion sickness, or post-operative nausea
2012/050395
or vomiting; an eating disorder, including anorexia a or bulimia nervosa; premenstrual
syndrome; a muscle spasm or spasticity, e, g. in paraplegic patients; a hearing er, e. g.
tinnitus or age-related hearing impairment; urinary incontinence; glaucoma; ion-body
myositis; or a substance-related disorder, including substance abuse or dependency,
including a substance, such as alcohol, withdrawal disorder. Agents of the invention may
also be useful in enhancing cognition, e. g. in a t suffering from a dementing condition,
such as Alzheimer's disease; as dication prior to anaesthesia or a minor l
intervention, such as endoscopy, including gastric opy; or as ligands, e. g.
radioligands or positron emission tomography (PET) ligands.
Due to their inhibiting properties towards BACE—2, compounds of the invention may be useful
in the treatment or prevention a disease or disorder mediated by BACE-2. Diseases and
disorders associated with BACE-2 include: metabolic syndrome (such as dyslipidemia,
obesity, insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and
hypercoagulability), insulin resistance, glucose intolerance (also known as impaired glucose
tolerance or ed glucose nce, IGT), obesity, hypertension, or diabetic
complications (such as retinopathy, nephropathy, diabetic foot, ulcers, macroangiopathies,
metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia), glucose
metabolic disorder, dyslipidaemias of ent origins, atherosclerosis and d diseases,
high blood pressure, chronic heart failure, Syndrome X, diabetes, non-insulin-dependent
diabetes mellitus, Type 2 diabetes, Type ’I diabetes, body weight disorders, weight loss,
body mass index and leptin related es.
Compounds of the invention may be suitable for preventing beta-cell ration such as
apoptosis or necrosis of pancreatic beta cells, for improving or restoring the functionality of
pancreatic cells, and/or increasing the number and/or size of pancreatic beta cells.
As used herein a patient is suffering from “obesity” if the patient exhibits at least one of:
o a body mass index (BMI), i.e. the patient’s mass (in kg) divided by the square of the
patient’s height (in m), of 30 or more;
. an absolute waist circumference of >102 cm in men or >88 cm in women;
. a waist-to-hip ratio >0.9 in men or >0.85 in women; or
. a percent body fat >25% in men or >30% in women.
As used herein a patient is suffering from “Type 2 es” if they meet the World Health
Organisation criteria for Diabetes diagnosis (Definition and diagnosis of diabetes mellitus and
intermediate hyperglycaemia, WHO, 2006), i.e. the patient ts at least one of:
. a fasting plasma glucose 27.0 mmoI/l (126mg/dl); or
. a venous plasma glucose 211.1 mmol/l (200mg/dl) 2 hours after ingestion of 759 oral
glucose load.
As used herein a patient is suffering from “IGT” if they meet the World Health Organisation
criteria for IGT sis (Definition and diagnosis of diabetes mellitus and intermediate
hyperglycaemia, WHO, 2006), i.e. the patient exhibits both of:
. a fasting plasma e <7.0 mmol/l (126mg/dl); and
. a venous plasma glucose 27.8 and <11.1 mmol/l (200mg/dl) 2 hours after ingestion of
759 oral e load.
As used herein, the term "metabolic syndrome" is a ized clinical term used to describe
a condition sing combinations of Type II diabetes, impaired glucose tolerance, insulin
resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL,
hyperuricaernia, hypercoagulability and/or microalbuminemia. The American Heart
Association has published guidelines for the diagnosis of metabolic syndrome, Grundy, S.,
et. a/., (2006) Cardiol. Rev. Vol. 13, No. 6, pp. 322-327.
For the above-mentioned indications, the appropriate dosage will vary ing on, e. g.,
the nd employed as active pharmaceutical ingredient, the host, the mode of admini-
stration, the nature and severity of the condition, disease or disorder or the effect desired.
However, in general, satisfactory results in animals are ted to be obtained at a daily
dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal
body weight. In larger mammals, for example humans, an indicated daily dosage is in the
range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent
of the invention conveniently administered, for e, in divided doses up to four times a
day or in sustained release form.
An agent of the invention may be administered by any conventional route, in particular en-
terally, preferably orally, e. g. in the form of a tablet or capsule, or erally, e. g. in the
form of an injectable solution or suspension.
2012/050395
In a further aspect, the invention relates to a pharmaceutical composition comprising an
agent of the invention as active pharmaceutical ingredient in association with at least one
pharmaceutically acceptable carrier or diluent and optionally in association with other
auxiliary substances, such as inhibitors of cytochrome P450 enzymes, agents preventing the
degradation of active pharmaceutical ingredients by cytochrome P450, agents improving or
enhancing the cokinetics of active pharmaceutical ingredients, agents improving or
enhancing the bioavailability of active pharmaceutical ingredients, and so on, e. g. grapefruit
juice, ketoconazole or, preferably, ritonavir. Such a composition may be manufactured in
1O conventional manner, e. g. by mixing its ents. Unit dosage forms contain, e. g., from
about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the
invention.
In addition, the pharmaceutical compositions of the present invention can be made up in a
solid form ding without limitation es, tablets, pills, granules, powders or
suppositories), or in a liquid form (including without tion solutions, sions or
emulsions). The pharmaceutical compositions can be subjected to conventional
pharmaceutical ions such as sterilization and/or can n tional inert
diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the
active ingredient together with
a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or
glycine;
b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or m salt and/or
polyethyleneglycol; for tablets also
0) binders, e.g., magnesium um silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if
desired
d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent
mixtures; and/or
e) absorbents, nts, flavors and sweeteners.
_45-
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable itions for oral administration include an effective amount of a compound of
the invention in the form of tablets, es, s or oily suspensions, dispersible
powders or granules, on, hard or soft capsules, or syrups or elixirs. Compositions
intended for oral use are ed according to any method known in the art for the
manufacture of pharmaceutical compositions and such compositions can contain one or
more agents ed from the group consisting of sweetening agents, ng agents,
coloring agents and preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic
1O pharmaceutically able excipients which are suitable for the manufacture of tablets.
These excipients are, for example, inert ts, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn starch, or c acid; binding agents, for example, starch, gelatin
or acacia; and lubricating agents, for example magnesium te, stearic acid or talc. The
tablets are uncoated or coated by known techniques to delay disintegration and absorption in
the gastrointestinal tract and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or glyceryl distearate can be
employed. Formulations for oral use can be presented as hard gelatin capsules wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules n the active ingredient is mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic ons or suspensions, and
suppositories are advantageously prepared from fatty emulsions or suspensions. Said
compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing,
wetting or emulsifying , solution promoters, salts for regulating the osmotic pressure
and/or buffers. In addition, they may also contain other therapeutically valuable substances.
Said compositions are prepared according to conventional mixing, granulating or coating
methods, respectively, and contain about 01-75%, or contain about 1-50%, of the active
ient.
Suitable compositions for transdermal application include an effective amount of a nd
of the invention with a suitable carrier. Carriers suitable for transdermal ry include
absorbable cologically acceptable ts to assist passage through the skin of the
host. For example, transdermal devices are in the form of a e comprising a backing
member, a reservoir containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to secure the device to the
skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include s
solutions, suspensions, ointments, creams, gels or sprayable ations, e.g., for ry
by aerosol or the like. Such topical delivery systems will in particular be riate for
dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun
, lotions, sprays and the like. They are thus particularly suited for use in topical,
including cosmetic, formulations well-known in the art. Such may contain solubilizers,
izers, ty enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal
application. They may be conveniently delivered in the form of a dry powder (either alone, as
a mixture, for example a dry blend with lactose, or a mixed component particle, for example
with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a
pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a
suitable propellant.
The present invention further provides ous pharmaceutical compositions and dosage
forms comprising the compounds of the present invention as active ingredients, since water
may facilitate the ation of certain compounds.
Anhydrous pharmaceutical itions and dosage forms of the invention can be prepared
using anhydrous or low moisture containing ients and low moisture or low humidity
conditions. An anhydrous pharmaceutical composition may be prepared and stored such
that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged
using materials known to prevent exposure to water such that they can be included in
suitable formulary kits. Examples of suitable packaging include, but are not limited to,
ically sealed foils, plastics, unit dose containers (9. g., vials), r packs, and strip
packs.
The invention further provides pharmaceutical compositions and dosage forms that comprise
one or more agents that reduce the rate by which the compound of the present invention as
an active ingredient will decompose. Such agents, which are referred to herein as
"stabilizers,” include, but are not limited to, idants such as ascorbic acid, pH buffers, or
salt buffers, etc.
2012/050395
In accordance with the foregoing, in a further aspect, the invention relates to an agent of the
invention for use as a medicament, for example for the treatment or prevention of a
ogical or vascular condition, disease or disorder, in which beta—amyloid generation or
aggregation plays a role, or for the suppression of the metastasis process ated with
tumor cells, or for the treatment or tion of loss of B cell mass and/or function. In one
embodiment, the invention relates to an agent of the invention for use in the treatment of a
disease or disorder mediated by BACE-1, BACE-2 or cathepsin D activity. In another
embodiment, the ion relates to an agent of the invention for use in the treatment or
prevention of Alzheimer’s Disease or mild cognitive ment. In a further embodiment, the
invention relates to an agent of the invention for use in the ent or prevention of insulin
ance, glucose rance, type 2 diabetes, obesity, hypertension, or ic
complications. In yet another embodiment, the invention relates to a nd of the
invention for use in the treatment of impaired glucose tolerance or Type 2 diabetes.
In a r aspect, the invention relates to the use of an agent of the invention as an active
pharmaceutical ingredient in a medicament, for example for the treatment or prevention of a
neurological or vascular condition, disease or disorder, in which myloid generation or
aggregation plays a role, or for the suppression of the asis process associated with
tumor cells, or for the treatment or prevention of loss of B cell mass and/or on. In a
further embodiment, the invention relates to the use of an agent of the invention as an active
pharmaceutical ingredient in a medicament for the treatment or prevention of a disease or
disorder mediated by BACE-‘I, BACE—2 or cathepsin D activity. In one embodiment, the
invention relates to the use of an agent of the invention as an active pharmaceutical
ingredient in a medicament for the treatment or prevention of Alzheimer’s Disease or mild
cognitive impairment. In a further embodiment, the invention relates to the use of a
compound of the invention as an active pharmaceutical ingredient in a medicament for the
treatment or tion of insulin resistance, glucose intolerance, type 2 diabetes, obesity,
hypertension, or diabetic complications. In yet a further embodiment, the invention relates to
the use of a compound of the invention as an active pharmaceutical ingredient in a
medicament for the treatment or prevention of impaired e tolerance or Type 2
diabetes.
In a further aspect, the invention relates to the use of an agent of the invention for the manu-
facture of a medicament for the treatment or prevention of a ogical or vascular condi-
tion, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for
the suppression of the metastasis process associated with tumor cells, or for the treatment or
prevention of loss of B cell mass and/or function. In a further embodiment, the invention
relates to the use of an agent of the invention for the manufacture of a medicament for the
treatment or prevention of a e or er ed by BACE-1, BACE-2 or sin
D activity. In one embodiment, the invention relates to the use of an agent of the invention for
the manufacture of a medicament for the treatment or prevention of Alzheimer’s Disease or
mild cognitive impairment. In a further embodiment, the invention s to the use of a
compound of the invention as an active pharmaceutical ingredient in a medicament for the
treatment or prevention of insulin resistance, glucose intolerance, type 2 diabetes, obesity,
hypertension, or diabetic complications. In yet a further ment, the invention relates to
the use of a compound of the invention as an active pharmaceutical ingredient in a
medicament for the treatment or prevention of impaired glucose tolerance or Type 2
diabetes.
In a further aspect, the invention relates to a method for the treatment or prevention of a
ogical or vascular condition, disease or disorder, in which beta-amyloid generation or
aggregation plays a role, or for the suppression of the metastasis process associated with
tumor cells, or for the treatment or prevention of loss of [3 cell mass and/or function, in a
subject in need of such treatment, tion or suppression, which method comprises
administering to such subject an effective amount of an agent of the invention. In one
embodiment, the ion relates to a method of modulating , BACE-2 or cathepsin
D ty in a subject, wherein the method comprises administering to the subject a
therapeutically effective amount of an agent of the invention. In another embodiment, the
invention relates to a method for the treatment or prevention of a disease mediated by
, BACE-2 or cathepsin D ty, in a subject in need of such treatment or
prevention, which method comprises administering to such subject an effective amount of an
agent of the invention. In yet another embodiment, the invention relates to a method for the
treatment or prevention of Alzheimer’s Disease or mild cognitive impairment, in a subject in
need of such treatment or prevention, which method comprises administering to such t
an effective amount of an agent of the invention. In a further embodiment, the invention
relates to a method for the treatment or prevention of insulin resistance, glucose intolerance,
type 2 diabetes, obesity, hypertension, or diabetic cations, in a subject in need of such
treatment or prevention, which method comprises administering to such t a
therapeutically effective amount of a nd of the invention. In yet a further embodiment,
the invention relates to a method for the treatment or prevention of impaired glucose
tolerance or Type 2 diabetes, in a t in need of such treatment or prevention, which
method comprises administering to such subject a therapeutically effective amount of a
compound of the invention.
An agent of the invention can be administered as sole active pharmaceutical ingredient or as
a combination with at least one other active pharmaceutical ingredient effective, e. g., in the
treatment or prevention of a neurological or vascular condition, disease or disorder, in which
beta-amyloid generation or aggregation plays a role, or in the suppression of the metastasis
process associated with tumor cells, or in the treatment or prevention of loss of B cell mass
and/or function. Such a pharmaceutical combination may be in the form of a unit dosage
form, which unit dosage form comprises a predetermined quantity of each of the at least two
active ents in association with at least one pharmaceutically acceptable r or
diluent. Alternatively, the pharmaceutical combination may be in the form of a package
comprising the at least two active components separately, e. g. a pack or dispenser-device
adapted for the itant or separate administration of the at least two active
components, in which these active components are separately arranged. In a further aspect,
the invention relates to such ceutical combinations.
In a further aspect, the invention therefore s to a pharmaceutical combination
comprising a therapeutically effective amount of an agent of the invention and a second drug
substance, for aneous or sequential administration.
In one embodiment, the invention provides a product comprising an agent of the invention
and at least one other therapeutic agent as a combined preparation for simultaneous,
separate or tial use in therapy. In one embodiment, the therapy is the treatment of a
disease or condition ed by BACE-1, BACE—2 or cathepsin D activity, such as
Alzheimer’s Disease, mild cognitive impairment, impaired glucose tolerance or type 2
In one embodiment, the invention provides a pharmaceutical composition comprising an
so agent of the invention and r therapeutic agent(s). ally, the pharmaceutical
composition may comprise a pharmaceutically acceptable excipient, as bed above.
In one embodiment, the ion provides a kit comprising two or more separate
ceutical itions, at least one of which contains an agent of the invention. In one
embodiment, the kit comprises means for separately retaining said compositions, such as a
container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as
typically used for the packaging of tablets, capsules and the like. The kit of the invention may
be used for stering different dosage forms, for example, oral and parenteral, for
administering the separate compositions at different dosage intervals, or for titrating the
separate compositions against one another. To assist compliance, the kit of the invention
typically comprises directions for administration.
In the ation ies of the ion, the agent of the invention and the other
eutic agent may be manufactured and/or formulated by the same or different
manufacturers. Moreover, the compound of the invention and the other therapeutic may be
1O brought together into a combination therapy: (i) prior to release of the combination product to
physicians (e.g. in the case of a kit comprising the compound of the invention and the other
therapeutic ; (ii) by the ian themselves (or under the guidance of the physician)
shortly before administration; (iii) in the patient themselves, e.g. during sequential
administration of the compound of the invention and the other therapeutic agent. Accordingly,
the invention provides an agent of the invention for use in the treatment of a disease or
condition mediated by BACE-1, BACE—2 or cathepsin D activity, such as Alzheimer’s
Disease, impaired glucose tolerance or type 2 diabetes, wherein the medicament is prepared
for administration with another therapeutic agent. The invention also provides the use of
another therapeutic agent for treating a disease or condition mediated by BACE-1, BACE-2
or cathepsin D activity, such as Alzheimer’s e, impaired e nce or type 2
diabetes, wherein the medicament is administered with an agent of the invention.
The invention also provides an agent of the invention for use in a method of treating a
disease or condition mediated by BACE-1 or cathepsin D activity, such as
, BACE-2
Alzheimer’s Disease, impaired glucose tolerance or type 2 diabetes, wherein the agent of the
invention is ed for administration with another therapeutic agent. The invention also
provides another therapeutic agent for use in a method of treating a disease or condition
mediated by BACE-1, BACE-2 or cathepsin D activity, such as Alzheimer’s e,
ed glucose tolerance or type 2 diabetes, wherein the other therapeutic agent is
prepared for administration with an agent of the invention. The invention also provides an
agent of the invention for use in a method of treating a disease or condition mediated by
BACE-1, BACE-2 or cathepsin D activity, such as Alzheimer’s e, ed e
tolerance or type 2 diabetes, wherein the agent of the invention is administered with another
therapeutic agent. The invention also provides another therapeutic agent for use in a method
of treating a disease or condition mediated by BACE-1, BACE-2 or sin D activity, such
_51-
as Alzheimer’s Disease, impaired glucose tolerance or type 2 diabetes, wherein the other
eutic agent is administered with an agent of the invention.
The ion also provides the use of an agent of the invention for treating a e or
condition mediated by BACE-1, BACE-2 or cathepsin D activity, such as mer’s
Disease, impaired glucose tolerance or type 2 diabetes, wherein the patient has usly
(9.9. within 24 hours) been treated with another therapeutic agent. The invention also
provides the use of another therapeutic agent for treating a disease or condition mediated by
BACE-1, BACE-2 or cathepsin D activity, such as Alzheimer’s Disease, impaired glucose
1O tolerance or type 2 diabetes, wherein the patient has previously (e.g. within 24 hours) been
treated with an agent of the invention.
In one embodiment, the invention relates to a compound of the invention in ation with
r therapeutic agent wherein the other therapeutic agent is selected from:
(a) acetylcholinesterase inhibitors, such as donepezil (AriceptTM), rivastigmine (ExelonTM)
and galantamine (RazadyneTM);
(b) glutamate antagonists, such as memantine (NamendaTM);
(c) antidepressant medications for low mood and irritability, such as citalopram (CelexaTM),
fluoxetine (ProzacTM), paroxeine (PaxilTM), sertraline (ZoloftT'V') and trazodone (DesyrelTM);
(d) anxiolytics for anxiety, restlessness, verbally disruptive behavior and resistance, such as
lorazepam nT'V') and oxazepam (SeraxTM);
(e) antipsychotic tions for hallucinations, delusions, aggression, agitation, hostility and
uncooperativeness, such as aripiprazole (AbilifyTM), clozapine (ClozarilTM), ridol
lTM), olanzapine (ZyprexaTM), quetiapine (SeroquelTM), risperidone (RisperdalTM) and
ziprasidone (GeodonTM);
(f) mood stabilizers, such as carbamazepine (TegretoITM) and divalproex oteTM);
(g) nicotinic apha — 7 agonists;
(h) mGluR5 antagonists;
(i) H3 ts; and
(j) amyloid therapy vaccines.
Thus, in one embodiment, the invention provides a pharmaceutical composition comprising:
i) a compound of the invention, or a pharmaceutically acceptable salt thereof;
ii) at least one compound selected from:
a) acetylcholinesterase tors,
b) glutamate antagonists,
WO 95469
c) antidepressant tions,
d) anxiolytics,
e) antipsychotic medications,
f) mood stabilizers,
g) nicotinic apha — 7 agonists,
h) mGIuR5 antagonists,
i) H3 agonists, and
j) amyloid therapy vaccines; and
ii) one or more pharmaceutically acceptable carriers.
In r embodiment, the invention relates to a compound of the ion, or a
pharmaceutically able salt thereof, in combination with another therapeutic agent
wherein the other therapeutic agent is selected from:
a) antidiabetic agents, such as insulin, insulin derivatives and mimetics; insulin
agogues such as the sulfonylureas, e.g., Glipizide, ide and Amaryl; insulinotropic
sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; protein
tyrosine phosphatase-1B (PTP—1 B) inhibitors such as PTP-112; GSK3 (glycogen synthase
kinase-3) tors such as SB—517955, SB-4195052, SB—216763, NN-57—05441 and NN
05445; RXR ligands such as GW—0791 and AGN-194204; sodium-dependent glucose
cotransporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY
R3401; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-
1 (glucagon like peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; and
DPPIV (dipeptidyl peptidase IV) inhibitors such as vildagliptin;
b) hypolipidemic agents such as 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA)
reductase inhibitors, e.g., lovastatin, statin, simvastatin, pravastatin, cerivastatin,
mevastatin, velostatin, fluvastatin, tatin, atorvastatin, rosuvastatin and rivastatin;
squalene se inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) s;
cholestyramine; fibrates; nicotinic acid bile acid binding resins such as cholestyramine;
fibrates; nicotinic acid and other GPR109 agonists; cholesterol absorption inhibitors such as
ezetimibe; CETP inhibitors (cholesterol-ester-transfer—protein inhibitors), and n;
c) anti-obesity agents such as orlistat, sibutramine and Cannabinoid Receptor 1 (CB1)
antagonists e.g. rimonabant; and
d) anti-hypertensive , e.g., loop diuretics such as ethacrynic acid, furosemide and
torsemide; ensin converting enzyme (ACE) inhibitors such as benazepril, captopril,
enaiapril, fosinopril, pril, moexipril, perinodopril, quinapril, ramipril and trandolapril;
inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase
(NEP) inhibitors; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril;
angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan
and valsartan, in particular tan; renin inhibitors such as ditekiren, zankiren, terlakiren,
aliskiren, RO 66-1132 and RO1168; B-adrenergic receptor blockers such as acebutolol,
atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; pic
agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as
pine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, pine, nisoldipine and
verapamil; aldosterone or antagonists; and aldosterone se inhibitors.
e) agonists of peroxisome proliferator-activator receptors, such as fenofibrate, pioglitazone,
rosiglitazone, tesaglitazar, EMS-298585, 49, the compounds specifically described in
the patent application i.e. compounds of examples 1 to 35 or compounds
specifically listed in claim 21, or the compounds specifically described in the patent
application WO 03/043985 i.e. compounds of es 1 to 7 or compounds specifically
listed in claim 19 and especially (R)—1-{4—[5-methyl(4-trifluoromethyl-phenyl)-oxazol
ylmethoxy]-benzenesulfony|}-2,3-dihydro-1H-indole—2—carboxylic or a salt thereof.
Thus, in one embodiment, the invention provides a pharmaceutical composition comprising;
i) a compound of the invention, or a pharmaceutically acceptable salt thereof, and
ii) at least one compound selected from
a) antidiabetic agents,
b) hypolipidemic agents,
c) anti-obesity ,
d) anti-hypertensive agents,
e) agonists of peroxisome proliferator—activator receptors, and
ii) one or more ceutically acceptable carriers.
Other specific anti-diabetic compounds are described by Patel Mona in Expert Opin lnvestig
Drugs, 2003, 12(4), 3, in the figures 1 to 7.
The structure of the therapeutic agents identified by code numbers, generic or trade names
. may be taken from the actual edition of the standard compendium “The Merck Index” or from
databases, e.g., Patents International (e.g. IMS World Publications).
Examples
The following Examples illustrate the invention, but do not limit it.
iations
aq. aqueous
anhy. anhydrous
Boc tert-butoxycarbonyl
Boczo di-tent-butyl dicarbonate
t-Bu tert-butyl
t-BuOH tert-butanol
conc. concentrated
(1 —10-CSA (1 R)-(-)-10—Camphor sulphonic acid
DCM dichloromethane
DEA diethylamine
DIPEA diisopropylethylamine
DMAP 4-dimethyl amino pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EDC 1—(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride
eq. equivalent(s)
ESI electrospray ionisation
ETA ethanol / conc. aq. ammonia 95/5
Eth triethylamine
Et20 diethylether
EtOAc ethyl acetate
EtOH l
h hour(s)
HOAt 1-hydroxyazabenzotriazole
HPLC high performance liquid chromatography
LC liquid chromatography
MeOH methanol
min minute(s)
MS mass ometry
NEt3 triethyiamine
NMR nuclear magnetic resonance spectrometry
org organic
Rf retention factor
ROESY Rotating-frame user Effect SpectroscopY
Rt retention time (min)
rt room temperature
soln. solution
TBDMS tertiary butyl dimethyl silyl
TBM E tert—butyl-methyl-ether
TFAA trifluoroacetic acid anhydride
THF tetrahydrofuran
TLC thin layer chromatography
UPLC ultra performance liquid chromatography
Xantphos 4,5-bis(diphenylphosphino)—9,9-dimethylxanthene
NMR Methodology
Proton a are recorded on a Bruker 400 MHz ultrashield spectrometer unless otherwise
noted. Chemical shifts are ed in ppm relative to methanol (6 3.31), dimethyl sulfoxide
(6 2.50), or chloroform (6 7.29). A small amount of the dry sample (2-5 mg) is dissolved in an
appropriate deuterated solvent (0.7 mL). The shimming is ted and the spectra
obtained in ance with normal procedure.
General chromatography information
HPLC method H1 (Rtm):
HPLC-column dimensions: 3.0 x 30 mm
HPLC-column type: Zorbax SB-C18, 1.8 pm
HPLC-eluent: A) water + 0.05 Vol.-% TFA; B) ACN + 0.05 Vol.-% TFA
HPLC-gradient: 30-100 % B in 3.25 min, flow = 0.7 ml / min
_ 56 -
HPLC method H2 (RtHz):
HPLC-column dimensions: 3.0 x 30 mm
HPLC-column type: Zorbax SB—C18, 1.8 pm
HPLC-eluent: A) water + 0.05 VoI.-% TFA; B) ACN + 0.05 VoI.-% TFA
HPLC-gradient: 0-100 % B in 3.25 min, flow = 0.7 ml / min
LCMS method H3 (RtHa):
HPLC-column dimensions: 3.0 x 30 mm
HPLC-column type: Zorbax SB-C18, 1.8 pm
HPLC-eluent: A) water + 005 Vol.-% TFA, B) ACN + 0.05 Vol.-% TFA
HPLC-gradient: 10-100 % B in 3.25 min, flow = 0.7 ml / min
UPLCMS method H4 (RtH4):
olumn dimensions: 2.1 x 50 mm
HPLC-column type: Acquity UPLC HSS T3, 1.8 pm
HPLC-eluent: A) water + 0.05 VoI.-% formic acid + 3.75 mM ammonium
acetate B) ACN + 0.04 Vol.—% formic acid
radient: 2-98 % B in 1.4 min, 98% B 0.75 min, flow = 1.2 ml / min
HPLC-column temperature: 50 °C
UPLCMS method H5 (RtH5):
HPLC-column dimensions: 2.1 x 50 mm
HPLC-column type: Acquity UPLC HSS T3, 1.8 pm
HPLC-eluent: A) water + 0.1 VoI.—% formic acid, B) ACN + 0.1% formic acid
HPLC-gradient: 10-95% B in 1.5 min, 1.0 min 95% B, flow = 1.2 ml / min
HPLC-column temperature: 50 °C
LCMS method H6 (RtHG):
HPLC-column dimensions: 2.1 x 30 mm
HPLC-column type: is Express C18, 2.7 pm
HPLC-eluent: A) water + 0.05 Vol.-% formic acid + 0.05 ammonium acetate,
B) ACN + 0.04 Vo|.-% formic acid
radient: 2-98 % B in 1.4 min, 0.75 min 98% B, flow = 1.2 ml / min
HPLC-column temperature: 50 °C
2012/050395
LCMS method H7 (RtH7):
HPLC—column dimensions: 4.0 x 20 mm
HPLC-column type: Mercury MS Synergi, 2 pm
HPLC-eluent: A) water + 0.1 Vol.—% formic acid, B) ACN
HPLC-gradient: 0.5 min 30% B, 30-95% B in 1 min, 0.9 min 95% B,
flow = 2.0 ml / min
HPLC-column temperature: 30 °C
LCMS method H8 (RtHa):
HPLC-column dimensions: 4.0 x 20 mm
HPLC-column type: Mercury MS Synergi, 2 pm
HPLC-eluent: A) water + 0.1 Vol.-% formic acid, B) ACN
HPLC-gradient: 0.5 min 70% B, 70-100% B in 1 min, 0.9 min 100% B,
flow = 2.0 ml / min
olumn temperature: 30 °C
HPLC method H9 (RtHg):
HPLC-column dimensions: 4.6 x 150 mm
HPLC-column type: Zorbax XDB-C18, 5 pm
HPLC-eluent: A) water + 0.01 Vol.-% TFA; B) ACN / MeOH 1:1
HPLC-gradient: 1 min 30% B, 30—100% B in 5 min, % B in 4 min,
flow :10 ml / min
HPLC-column temperature: 40 °C
HPLC method H10 (Rtmo):
HPLC-column dimensions: 4.6 x 150 mm
HPLC-column type: Zorbax XDB—C18, 5 pm
luent: A) water + 0.01 Vol.-% TFA; B) ACN / MeOH 1:1
HPLC-gradient: 1 min 5% B, 5-100% B in 5 min, 100-5% B in 4 min,
flow = 1.0 ml / min
HPLC-column temperature: 40 °C
LCMS method H11 (RtH11):
HPLC-column dimensions: 3.0 x 30 mm
HPLC-column type: Zorbax SB—C18, 1.8 pm
HPLC-eluent: A) water + 0.05 Vol.-% TFA; B) ACN + 0.05 VoI.-% TFA
radient: 70 — 100 % B in 3.25 min, flow = 0.7 ml / min
LCMS method H12 (Rtmz):
HPLC-column dimensions: 3.0 x 30 mm
HPLC-column type: Zorbax SB-C18, 1.8 pm
HPLC-eluent: A) water + 0.05 VoI.-% TFA; B) ACN + 0.05 Vol.-% TFA
radient: 80 - 100 % B in 3.25 min, flow = 0.7 ml / min
LCMS method H13 (Rtm3):
HPLC-column dimensions: 3.0 x 30 mm
HPLC-column type: Zorbax SB—C18, 1.8 urn
HPLC-eluent: A) water + 0.05 Vo|.-% TFA; B) ACN + 0.05 Vol.-% TFA
HPLC-gradient: 40 - 100 % B in 3.25 min, flow = 0.7 ml / min
Example 1: 5-Bromo-pyridinecarboxylic acid [6-((R)aminomethyl-3,6-dihydro-
2H -[1,4]-oxaziny|)-pyridinyl]-amide
Br 0
l/ n N /
\\“‘ N NH2
0 /
a) 5-(6-Bromo-pyridinyl)methyI-imidazolidine-2,4-dione
To a on of 1-(6-bromo-pyridinyl)-ethanone (CA8 496698, 8.75 g, 43.7 mmol) and
potassium cyanide (4.27 g, 65.6 mmol) in ethanol/water (400/267 ml) was added
ammonium carbonate (21.02 9, 219.0 mmol). The reaction mixture was stirred in an
autoclave at 100 °C for 17 h, then diluted with H20, 1M aq. NaHC03 soln. and EtOAc. The
phases were separated and the aq. phase was acted with EtOAc, EtZO and DCM. The
combined org. phases were dried over Na2804, filtered and concentrated to leave the title
nd as a pale white solid that was used in the next step without further purification.
HPLC RtH4= 0.62 min; ESIMS: 270, 272 [(M + H)+]; 1H NMR (400 MHz, DMSO-da): 6 10.86
(br s, 1H), 8.48 (s, 1H), 7.81 (m, 1H), 7.64 (d, 1H), 7.57 (d, 1H), 1.68 (s, 3H).
b) 4-(6-Bromo-pyridinyl)methyl-2,5-dioxo-imidazolidine-1,3-dicarboxylic acid di-
tert-butyl ester
A solution of 5-(6—bromo-pyridinyl)-5—methyl-imidazolidine—2,4—dione (22.8 g, 84.4 mmol),
Boczo (58.8 ml, 55.3 g, 253.4 mmol) and DMAP (0.516 g, 4.22 mmol) in THF (600 ml) was
stirred at rt for 4 h. The reaction mixture was concentrated to dryness, then taken up with
EtOAc and filtered h silica. The silica cartridge was washed with EtOAc and THF, the
combined filtrates were trated to leave the title compound as a pale yellow solid that
was used in the next step without further purification.
HPLC RtH4= 1.23 min; ESIMS: 470, 472 [(M + H)+]; 1H NMR (400 MHz, CD30D): 6 7.82 (m,
1H), 7.65 (m, 2H), 2.11 (s, 3H), 1.60 (s, 9H), 1.30 (s, 9H).
c) 2-Amino(6-bromo-pyridinyl)-propionic acid
A solution of 4-(6-bromo-pyridinyl)methyI-2,5-dioxo-imidazolidine-1,3-dicarboxylic acid
di-tert-butyl ester (31.53 g, 67.0 mmol) in 2.5M aq. NaOH soln. (215 ml) was refluxed for 40
h. The reaction mixture was diluted with EtOAc (100ml) and filtered. The filtrates were
ted and the org. layer was washed with H20. The combined aq. layers were
evaporated to dryness to leave a solid that was suspended in MeOH (350 ml) and stirred for
min. The suspension was filtered and the white precipitate was washed with MeOH. The
filtrates were evaporated to leave a pale orange solid which was used for the next step
t further purification.
HPLC RtH4= 0.35-0.37 min; ESIMS: 245, 247 [(M + H)“]; 1H NMR (400 MHz, : 6 7.60-
7.51 (m, 2H), 7.36 (dd, 1H), 1.62 (s, 3H).
d) 2-Amino(6-bromo-pyridinyl)-propanol
To a sion of 2-amino(6-bromo—pyridinyl)-propionic acid (25.5 g, 72.8 mmol) and
Boczo (33.8 mi, 31.8 9, 145.7 mmol) in itrile (300 ml) and methanol (150 ml) was
added tetramethylammonium hydroxide (65.1 ml of a 25% aq. soln., 182 mmol). The reaction
was allowed to stir at rt for 6.5 h and was filtered. The filtrates were washed with MeOH and
CH3CN, then evaporated to leave an orange solid which was triturated with DCM and brine.
The phases were separated and the aq. phase was 3x extracted with DCM. The combined
org. phases were concentrated to leave crude 2-(6-bromo—pyridin—2—yl)—2—tert—
butoxycarbonylamino-propionic acid as a pale brown foam (H PLC RtH4= 0.96-0.97 min,
ESIMS: 345, 347 [(M + H)*]).
To a suspension of 2-(6—bromo-pyridinyl)tert-butoxycarbonylamino-propionic acid (14.1
g, 40.8 mmol) in THF (150 ml) was added portionwise NaBH4 (3.45 g, 90.0 mmol) at 0 °C.
BF3*Et20 soln. (11.39 ml, 12.75 g, 90.0 mmol) was added dropwise over a period of 15 min
and the reaction mixture was allowed to stir for 17 h at rt. In order to react remaining starting
material, NaBH4 (1.0 g, 26.43 mmol), and BF3*Et20 soln. (3.3 ml, 26.43 mmol) was added at
0 °C and the reaction mixture was stirred at rt for another 23 h. MeOH was added and the
reaction e was d at 80 °C for 30 min, then cooled to rt and filtered. The filtrates
were evaporated to leave a white foam which was taken up with EtOAc and 1N aq. NaOH
soln.. The phases were separated and the aq. phase was extracted three times with EtOAc.
The ed org. phases were dried over NaZSO4, filtered and concentrated to leave [1-(6—
bromo-pyridinyl)hydroxymethyl-ethyl]—carbamic acid tert—butyl ester in a mixture with
2-amino(6-bromo-pyridin-2—yl)—propanol. This mixture (7.5 g, 9.74 mmol) was
rebo'cylated using Boczo (5.65 ml, 5.31 g, 24.34 mmol) and tetramethylammonium ide
(65.1 ml of a 25% aq. soln., 182 mmol) in acetonitrile (100 ml). After stirring for 1.5 h at rt, the
reaction mixture was quenched with H20 and diluted with EtOAc. The phases were
separated and the aq. layer was twice reextracted with EtOAc. The combined org. layers
were dried over NaZSO4, filtered and the solvent was removed to leave a yellow solid that
was without further purification debocylated on a 8.1 g scale using 100 ml 4N aq. HCI. The
reaction mixture was stirred at rt for 17 h, concentrated and the residue was taken up with
H20 and EtOAc. The phases were separated and the org. phase was washed with H20. The
combined aq. phases were basified using 2N aq. NaOH soln. and then extracted with EtOAc.
The phases were separated and the aq. phase was reextracted twice with EtOAc. The
combined org. phases were dried over Na2804, ed and concentrated to leave 2-amino
(6-bromo-pyridinyl)-propanol as a colourless solid. HPLC RtH4= 0.35 min; ESlMS: 231,
233 [(M + H)"]; 1H NMR (400 MHz, DMSO—ds): 6 .63 (m, 2H), 7.45 (dd, 1H), .69
(m, 1H), 3.58 (dd, 1H), 3.40 (dd, 1H), 2.00 (br s, 2H), 1.26 (s, 3H).
e) N-[1-(6-Bromo-pyridinyl)hydroxymethyl-ethyl]chlore-acetamide
To a on of 2-amino—2-(6-bromo-pyridinyl)—propanol (4.9 g, 21.2 mmol) in DCM (50
ml) was added K2C03 (5.86 g, 42.4 mmol). The reaction mixture was cooled to 0 °C and 2—
chloroacetyl chloride (2.55 ml, 3.59 g, 31.8 mmol) was added dropwise. The reaction mixture
was allowed to warm to rt and to stir for 5 h. MeOH (20 ml) was added and stirring was
continued at rt for 1 h. The reaction mixture was diluted with H20 and DCM, the phases were
3O separated and the aq. phase was twice extracted with DCM. The combined org. phases were
dried over NaZSO4, filtered and the solvent was removed to leave N—[1-(6-bromo-pyridinyl)-
2-hydroxymethyl-ethyl]chloro-acetamide as an orange oil. HPLC RtH4= .77 min;
ESIMS: 307, 309 [(M + H)*]; 1H NMR (400 MHz, DMSO-de): 6 8.35 (s, 1H), 7.70-7.66 (m,
1H), 7.48 (dd, 1H), 7.38 (dd, 1H), 5.05-5.02 (m, 1H), 4.14 (s, 2H), 3.68-3.66 (m, 2H), 1.55 (s,
3H).
f) 5-(6-Bromo-pyridinyl)methyl-morpholinone
To a solution of N-[1-(6-bromo-pyridinyl)hydroxymethyl-ethyl]chloro-acetamide in
tert—butanol (90 ml) was added KOtBu and the reaction mixture was stirred at rt for 4 h. The
reaction e was quenched with H20 and diluted with EtOAc. The phases were
separated and the aq. phase was twice extracted with EtOAc. The combined org. phases
were washed with brine, dried over Na2804, d and the solvent was removed to leave
the title compound as a pale yellow solid. HPLC RtH4= 0.73 min; ESIMS: 271, 273 [(M + H)+];
1H NMR (400 MHz, DMSO—de): 6 8.72 (s, 1H), 7.82-7.78 (m, 1H), 7.57-7.51 (m, 2H), 4.10 (d,
2H), 4.00 (d, 1H), 3.65 (d, 1H), 1.42 (s, 3H).
9) 5—(6-Bromo-pyridinyl)—5-methyI-morpholinethione
A e of 5-(6-bromo-pyridin—2-yl)—5-methyl-morpholinone (4.65 g, 17.15 mmol) and
P285 (4.57 g, 20.58 mmol) in pyridine (60 ml) was stirred at 80 °C under N2 for 6 h. The
reaction mixture was cooled to rt and diluted with 0.5N aq. HCI and EtOAc. The phases were
separated and the aq. phase was twice extracted with EtOAc. The combined org. phases
were washed with brine, dried over Na2804, filtered and concentrated. The title compound
was obtained as a pale yellow solid after flash chromatography on silica gel (cyclohexane/
EtOAc 100:0 to 75:25). HPLC RtH4= 0.89 min; ESIMS: 287, 289 [(M + H)+]; 1H NMR (400
MHz, DMSO-de): 6 11.15 (s, 1H), .82 (m, 1H), 7.61 (dd, 1H), 7.39 (dd, 1H), 4.44-4.34
(d, 2H), 4.13 (d, 1H), 3.74 (d, 1H), 1.52 (s, 3H).
h) 5-(6-Bromo-pyridinyl)methyl-5,6-dihydro-2H-[1,4]oxazinylamine
A mixture of 5-(6-bromo-pyridinyl)methyl-morpholine-3—thione (1.4 g, 4.88 mmol) in 7N
NH3/MeOH (20.89 ml, 146 mmol) was stirred at 50 °C for 3 d in an autoclave. The reaction
mixture was ated to dryness and purified by FC (gradient cyclohexanezEtOAc 75:25 to
50:50, then +10% Et3N, finally MeOH +10% Et3N) to obtain the crude title compound that
was further purified by washing with DCM. HPLC RtH4= 0.54 min; ESIMS: 270, 272 [(M +
H)+]; 1H NMR (400 MHz, DMSO—ds): 6 8.51 (br s, 2H), 7.83-7.79 (m, 1H), .61 (m, 2H),
4.45 (s, 2H), 4.11 (d, 1H), 3.84 (d, 1H), 1.51 (s, 3H).
i) [5-(6-Bromo-pyridinyl)methy|-5,6-dihydro-2H-[1,4]oxazin-3—yl]-carbamic acid
tert-butyl ester
A suspension of 5-(6-bromo-pyridinyl)methyl-5,6—dihydro-2H-[1,4]oxazinylamine
(1.100 g, 4.07 mmol), Boczo (1.229 ml, 1.155 g, 5.29 mmol) and DIPEA (1.067 ml, 0.789 g,
6.11 mmol) in DCM (30 ml) was stirred at rt for 20 h. The reaction mixture was diluted with
H20 and DCM. The phases were separated and the aq. phase was twice reextracted with
DCM. The ed org. phases were washed with brine, dried over Na2804, filtered and
trated to yield the title compound as a colourless solid that was used in the next step
without further purification. HPLC RtH4= 0.92 min; ESIMS: 370, 372 [(M + H)+].
j) (+)- and (6-Amino-pyridinyl)methyl-5,6-dihydro-2H-[1,4]oxazinyl]-
carbamic acid tert-butyl ester
A mixture of [5-(6-Bromo-pyridinyl)methyl-5,6—dihydro-2H-[1,4]oxazinyl]—carbamic
acid tert—butyl ester (986 mg, 2.66 mmol), cyclohexanedimethyldiamine (0.420 ml, 379 mg,
2.66 mmol), sodium ascorbate (211 mg, 1.07 mmol), NaN3 (1385 mg, 21.31 mmol) and Cul
(203 mg, 1.07 mmol) in ethanol/water (22.0/8.8 ml) was degassed with N2 in a dry ice/EtOH
bath. The reaction mixture was then stirred at 45 °C for 4 h. The reaction mixture was
allowed to warm to rt and filtered through hyflo, rinsed with EtOAc and concentrated. Flash
chromatography on silica gel hexane / EtOAc gradient 0-3 min 100:0, 3-25 min 60:40,
40-52 min 50:50) yielded the title compound. HPLC RtH4= 0.60, 0.66 min; ESIMS: 305 [(M -
H)*]; 1H NMR (400 MHz, DMSO-ds): 6 7.77-7.73 (m, 1H), 6.81-6.76 (m, 2H), 4.71-4.63 (m,
1H), 4.70-4.56 (m, 2H), 4.06-3.96 (m, 2H), 1.69 (s, 3H), 1.51 (s, 9H).
Racemic 5-(6-amino-pyridiny|)methyl—5,6-dihydro-2H-[1,4]oxazin-3—yl]-carbamic acid
tert-butyl ester was ted into the pure omers by preparative chiral HPLC (column:
Chiralpak AS; solvent: n—heptane / ethanol / isopropylamine = 80 : 12 : 8; flow: 70 ml / min;
detection at 220 nm). Enantiomer 1: [0L]D = -138.5° (c=1.00, MeOH). Enantiomer 2: [orb =
+141.5° (c=1.03, MeOH). (-)-Enantiomer 1 was used for the following steps, its configuration
was assigned (R) in analogy to similar structures of which the configuration has been
determined by x-ray crystallography.
k) ((R){6-[(5-Bromo-pyridinecarbonyl)-amino]-pyridinyl}methyl-5,6-dihydro-
2H-[1,4]oxazinyl)-carbamic acid tert-butyl ester
To a solution of 5—bromopyridinecarboxylic acid (34.5 mg, 0.171 mmol) in DCM (2 ml) was
3O added 1-chloro-N,N,2-trimethylpropenylamine (0.045 ml, 45.7 mg, 0.342 mmol) and the
on mixture was stirred at 0 °C for 1 h. The reaction e was then added dropwise to
a dry solution of (6-amino-pyridinyl)—5—methyl-5,6—dihydro-2H-[1,4]oxazinyl]-
carbamic acid tert—butyl ester (enantiomer 1 from procedure step j) above, 47.6 mg, 0.155
mmol) and NEtg (0.048 mi, 34.6 mg, 0.342 mmol) in DCM (2 ml) at 0 °C. The reaction mixture
was allowed to warm to rt and to stir for 20 min at rt. The reaction mixture was diluted with
DCM and quenched with H20. The phases were ted and the aq. phase was extracted
with DCM. The combined org. phases were washed with brine, dried over , filtered
and twice purified by HPLC (Alltech Grom Saphir65 Si 10 uM column 150x30 mm, gradient 1
n-heptane:EtOAc O-1.2 min 85:15, 1.2-9 min 0:100, 9-12 min 0:100, gradient 2 n-
heptanezEtOAc2MeOH 04.2 min 47:50:3, 1.2-9min 0:60:40, 9-12min 0:60:40, flow 50 ml/min,
detection 254 nm]. HPLC RtH4= 1.10 min; ESIMS: 490, 492 [(M + H)+].
I) 5-Bromo-pyridinecarboxylic acid [6-((R)aminomethyl-3,6-dihydro-2H-[1,4]-
oxazinyl)-pyridinyl]-amide
To a on of 5-{6-[(5-bromo-pyridinecarbony|)-amino]—pyridin—2~yl}methyl-5,6-
dihydro-ZH-[1,4]oxazinyI)-carbamic acid utyl ester (43 mg, 0.088 mmol) in DCM (270
pl) was added TFA (270 pl, 400 mg, 3.51 mmol) and the reaction mixture was stirred at rt for
1 h. The reaction mixture was quenched with 1M aq. NaHCOa soln. and diluted with DCM.
The phases were ted and the aq. phase was twice reextracted with DCM. The
combined org. phases were dried over Na2804, filtered, concentrated and purified by manual
flash chromatography esactivated silica gel, hexane:DCM:MeOH 1021021 then
DCM:MeOH 10:1, then +0.1%NH3 and finally MeOH +1%NH3) to yield the title compound as
a colourless solid. To a solution of the free base in DCM was added 1 eq. 2N HCl/EtZO and
the resulting hydrochloride salt was collected. HPLC RtH4= 0.76 min; ESIMS: 390, 392 [(M +
H)"]; 1H NMR (400 MHz, CD30D): 6 8.88 (d, 1H), 8.38 (d, 1H), 8.33 (dd, 1H), .24 (m,
1H), 8.24-7.98 (m, 1H), 7.33 (d, 1H), 4.69 (d, 1H), 4.67 (d, 1H), 4.30 (d, 1H), 4.11 (d, 1H),
1.78 (s, 3H).
Example 2: 5—Bromo-pyridinecarboxylic acid [6—(5-amino-3—methyl-3,6-dihydro-2H-
[1,4]-oxazinyl)-pyridinyl]-amide
Br O
i ..
\ N N /l
N \ N
I NH2
0 /
The racemate of Example 1 can be ed by a procedure analogous to that used in
Example 1 completing the synthesis using the racemic mixture obtained in step j) of Example
1 and has the same analytical data.
Example 3: 5-{6-[(5-ChIoro-pyridinecarbonyl)-amino]-pyridinyl}fluoromethyl-
,6-dihydro-2H-[1,4]oxazinyl-ammonium trifluoro acetate
cI o
\ n N /
\ N NH;
O / F CFacOO-
a) 2-(6-Bromo-pyridin-Z-yl)—malonic acid diethyl ester
m diisopropylamide (2.0 M solution in heptane/THF/ethyl benzene, 581.3 ml) was taken
in dry THF (400 mL) and cooled to -78 °C. 2-Bromomethyl pyridine (50.0 9, 296.64 mmol)
was added slowly to the LDA solution at the same ature for 15 min., allowed to stir
constantly for 30 min. Ethylchloroformate (94.62 9, 871.94 mmol) in dry THF (50 ml) was
then added to the stirred contents drop wise and allowed the reaction mass to stir at -78 °C
for 2 h. Reaction mixture was quenched with saturated ammonium chloride solution and
product formed was extracted with ethyl e by g with water, brine and dried over
1O anhy. NaZSO4. Organic layer was concentrated under reduced pressure and the crude
t was purified by column chromatography using 10% ethyl acetate in hexane to h
title compound as a brown colored liquid. Yield = 65.0 g (71.4 %). TLC (10% ethyl acetate in
) R = 0.31; LCMS: RtH8 = 1.866; [M+1] = 315.8 and 317.9; HPLC: mm = 4.636 min
(48 %); 1H NMR (400 MHz, CDCI3): 6 7.587 (t, 1H), 7.47 (d, 1H), 7.27 (d, 1H), 3.91 (s, 1H),
4.25-4.09 (m, 4H), 1.24 (t, 6H).
b) (6-Bromo-pyridinyl)-acetic acid
2—(6—Bromo-pyridiny|)-ma|onic acid diethyl ester (64.0 9, 202.4 mmol) was added to a
solution of ium carbonate (279.8 g, 2024 mmol) in water (400 ml) at rt and the reaction
mixture was heated to reflux at 100 °C for 36 h. The reaction mixture was treated with sat.
um chloride solution and the product formed was extracted with ethyl acetate (3 x
800 ml), washed with brine (10 ml). Organic layer was concentrated under reduced pressure
to obtain title compound as a pale brown solid. Yield = 34.0 g (77.7 %). TLC (50% ethyl
acetate in hexane) Rf = 0.11; LCMS: RtHa = 0.45; [M+1] = 216.0 and 218.0.
c) (6-Bromo-pyridinyl)-acetic acid ethyl ester
To a solution of (6-bromo—pyridinyl)—acetic acid (34.0 g, 158.14 mmol) in ethanol (300 ml)
was added conc. H2804 (5.0 ml) and heated to reflux for 12 h. The reaction mixture was
cooled to rt and concentrated under reduced pressure to dryness. Water was added to the
residue and the product was extracted with ethyl acetate. Organic layer was washed with
brine, dried over anhy. NaZSO4 and concentrated under reduced pressure to furnish the
crude t. Column chromatography purification furnished the title compound as a brown
liquid. Yield = 31.2 g (82 %). TLC (20% ethyl acetate in hexane) R = 0.51; LCMS: mm =
0.996, [M+‘l]’r = 244.0 and 246.0; HPLC: RtHg = 3.87 min (97.2 %); 1H NMR (400 MHZ,
CDCIg): 6 7.53 (t, 1H), 7.39 (d, 1H), 7.28 (d, 1H),4.19 (q, 2H), 3.83 (s, 2H), 1.25 (t, 3H).
d) 2-(6-Bromo-pyridinyl)hydroxyhydroxymethyl-propionic acid ethyl ester
To the solution of para formaldehyde (9.6 9, 319.55 mmol) and sodium ethoxide (0.87 g,
12.784 mmol) in dry THF (250 ml) was added (6-bromo-pyridin-2—yl)-acetic acid ethyl ester
(31.2 9, 127.82 mmol) at 0 °C to -10 °C and allowed the on mixture to stir at same
temperature for 4 h. Solids formed in the reaction mixture were filtered and washed with ethyl
acetate and the filtrate was concentrated to obtain crude t as a brown liquid. Yield =
30.0 g (crude). TLC (30% ethyl acetate in hexane) R = 0.28; LCMS: RtHs = 0.702, M+1 =
304.0 and 306.0.
e) 2-(6-Bromo-pyridinyl)methoxymethoxy-Z-methoxymethoxymethyl-propionic
acid ethyl ester
To the solution of 2-(6-bromo-pyridiny|)hydroxy—2—hydroxymethyl-propionic acid ethyl
ester (30.0 9, 98.638 mmol) in dry THF (250 ml) was added tetrabutyl ammonium bromide
(15.8 9, 49.319 mmol) and di-isopropyl ethyl amine 7 9, 163.0 mi) followed by
methoxymethyl chloride was added drop wise at rt. Resultant reaction contents were refluxed
at 65 °C for 3 h and cooled to rt. ReactiOn mixture was concentrated under reduced pressure
and purified by column chromatography over silica gel using 10 % ethyl acetate in hexane to
furnish title compound as a brown liquid. Yield = 20.4 g (52 %). TLC (30% ethyl acetate in
hexane) R = 0.55; LCMS: Rtm = 1.639, [M+1]+ = 392.0 and 394.0; 1H NMR (400 MHz,
CDCls): 6 7.49 (t, 1H), 7.35 (d, 1H), 7.22 (d, 1H), 4.62-4.47 (m, 4H), .16 (m, 6H), 3.25
(s, 6H), 1.23 (t, 3H).
f) 2-(6-Bromo-pyridinyl)methoxymethoxy-Z-methoxymethoxymethyl-propionic
acid
Lithium hydroxide (10.69 9, 254.95 mmol) was added to a solution of romo-pyridin
y|)methoxymethoxy—Z-methoxymethoxymethyl-propionic acid ethyl ester (20.0 g, 50.99
mmol) in ethanol (100 ml) and water (100 ml) at rt and the on mixture was allowed to
stir ght. The reaction mass was concentrated under reduced pressure and acidified
with dilute HCl and at 0 °C. The product was extracted with ethyl acetate, washed with
minimum amount of brine. Organic layer was concentrated under reduced pressure to obtain
title nd as a brown liquid. Yield = 18.0 g. TLC (50% ethyl acetate in hexane) Rf =
0.05; LCMS: RtHs = 1.383, [M+1] = 364.0 and 366.0; HPLC: RtHg = 3.844 min (49 %) and
3.885 min. (22%).
g) 1-(6-Bromo-pyridinyl)methoxymethoxymethoxymethoxymethyl-ethylamine
To a sion of 2—(6-bromo—pyridinyl)—3—methoxymethoxymethoxymethoxymethyl-
propionic acid (18.0 g) in toluene (150 ml) diphenyl phosphoryl azide (4.08 9, 148.27 mmol)
and triethylamine (14.97 g [20.6 ml], 148.27 mmol) were added at rt and stirred at 100 °C for
h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The
residue obtained was dissolved in THF (600 ml) and 20% NaOH solution was added at rt and
1O stirred for 1 h. Solvent was removed under reduced pressure and the product formed was
extracted with ethyl acetate. Organic layer was washed with brine, ed by dried over
M9804. The organic portion was concentrated under reduced re and column
tographic purification of the crude product using 35% ethyl acetate in hexane
furnished title nd as a brown liquid. Yield = 15.0 g (88% [2 steps]). TLC (70% ethyl
acetate in hexane) Rf = 0.51; LCMS: mm = 0.28, [M+1]=335.0 and 337.0.
h) N-[1-(6-Bromo-pyridinyl)methoxymethoxymethoxymethoxymethyl-ethyl]
chloro-acetamide
To a on of 1-(6-bromo-pyridinyl)methoxymethoxymethoxymethoxymethyl-
ethylamine (15.0 g, 44.75 mmol) in DCM (150 ml) was added aqueous NaZCO3 on
(10.91 9, 102.925 mmmol in water, 30 ml) was added at 0 °C and stirred for 10 min.
Chloroacetylchloride (5.56 9, 49.225 mmol) was added to the resultant reaction mixture at 0
"C stirring continued for 1 h at ambient temperature. on mixture was diluted with DCM
(~1 l), and worked up the reaction mixture by washing with water, brine and dried over anhy.
Na2804. Organic layer was separated and concentrated under reduced pressure to obtain
title compound as a brown liquid. Yield = 9.0 g (48 %). TLC (50% ethyl acetate in ) Rf
= 0.54; LCMS: RtH7 = 1.341, [M+1]=411.0 and 413.0; HPLC: RtHg = 4.27 min (50.4 %); 1H
NMR (400 MHz, : 6 8.11 (d, 1H), 7.57-7.52 (m, 1H), 7.46-7.37 (m, 2H), 4.59-4.52 (m,
4H), 4.23-4.17 (m, 4H), 4.09-4.04 (m, 2H), 3.21 (s, 6H).
i) N-[1-(6-Bromo-pyridinyl)hydroxyhydroxymethyl-ethyl]chloro-acetamide
To a solution of N-[1-(6-bromo-pyridinyl)methoxymethoxymethoxymethoxymethyl-
ethyl]—2-chloro-acetamide (9.0 9, 21.861 mmol) in ethanethiol (30 ml) and BF3.Et20 (9.3 9,
141.93 mmol) was added at 0 °C and stirred for 10 min. Stirring was continued for 3 h at rt.
Reaction mixture was quenched with saturated NaHC03 solution and the product formed
—67-
was extracted with ethyl acetate. Organic layer was separated and washed with brine
on, followed by drying over anhydrous NaZSO4. Organic layer was concentrated under
reduced pressure and purified by column chromatography using 2% methanol in chloroform
to obtain title compound as a brown liquid. Yield = 5.5 g (77 %). TLC (10% methanol in
chloroform) Rf = 0.51; LCMS: RtHa = 0.916, [M+1] = 322.9 and 324.8; HPLC RtHg = 5.931 min
(89 %); 1H NMR (400 MHz, CDCI3): 6 8.27 (s, 1H), 7.56 (t, 1H), 7.42-7.39 (m, 2H), 4.38 (s,
2H), 4.09-4.07 (m, 4H), 3.95 (d, 2H).
j) 5-(6-Bromo-pyridinyl)hydroxymethyl-morpholinone
To the solution of N-[1-(6-bromo-pyridinyl)—2—hydroxyhydroxymethyl-ethyl]chloro-
acetamide (5.4 g, 16.69 mmol) in t-BuOH (80 ml) was added t-BuOK (2.06 g, 18.38 mmol) at
rt followed by sodium iodide (0.25 g, 1.669 mmol) and allowed the reaction mixture to stir at
90 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the
residue ed was treated with water. Compound present in the residue was extracted
with ethyl acetate (2 x 100 ml). Organic portion was washed with brine, dried over NaZSO4
and concentrated under reduced pressure to obtain gummy compound. Further ation of
the formed product with n-pentane (5.0 ml) and diethyl ether (5.0 ml) furnished title
nd as a pale yellow gummy compound. Yield = 3.3 g (68.8 %). TLC (50% ethyl
acetate in ) R, = 0.21; LCMS: RtHg = 0.155, [M+1] = 286.9 and 288.8; HPLC RtHg =
3.03 min (69.8 %); 1H NMR (400 MHz, : 6 8.40 (s, 1H), 7.79 (t, 1H), 7.57 (d, 2H), 5.11
(s, 1H), 4.15 (d, 1H), 3.99 (d, 2H), 3.88 (d, 1H), 3.71-3.60 (m, 2H).
k) 5-(6-Bromo-pyridinyl)—5—fluoromethyI-morpholinone
To a solution of 5-(6-bromo-pyridinyl)hydroxymethyl-morpholinone (2.8 g, 9.756
mmol) in dry THF (30 ml), diethylamino sulfur ride (4.72 9, 29.268 mmol) was added at
rt and stirring ued for 4 h. Nazcog was then added to the resultant on mixture and
stirred for further 30 min. The reaction mixture was concentrated under reduced pressure
and the product was extracted with ethyl acetate. Organic layer was washed with brine, dried
over anhy. NaZSO4 and concentrated under reduced pressure to obtain crude compound as
gummy residue. cation of the crude product with 45 % ethyl acetate in hexane solvent
system furnished the title compound as off—white solid. Yield = 1.15 g (40 %). TLC (70% ethyl
acetate in hexane) R = 0.49; LCMS: RtH7 = 0.383, [M+1]+ = 289 and 289; HPLC RtHg =
3.27min (84 %); 1H NMR (400 MHz, CDCI3): 6 7.62 (t, 1H), 7.49 (dd, 1H), 7.32 (d, 1H), 7.09
(br. s, 1H), 4.92 (dd, 1H), 4.52 (dd, 1H), 4.32-4.17 (m, 3H), 3.98-3.93 (dd, 1H);19F NMR
(376.2 MHz): 6 -255.65 (t, 1F).
WO 95469
I) 5-Chloro-pyridinecarboxylic acid [6-(3-fluoromethyloxo-morpholinyl)—pyridin-
2-yl]-amide
A mixture of 4,5-Bis(diphenyl phosphino)—9,9—dimethyl xanthene (0.04 g, 0.069 mmol),
tris(dibenzylidene-acetone) di palladium(0) (0.032 g, 0.035 mmol) and cesium carbonate
(0.678 g, 2.083 mmol) were taken in 1,4-dioxane and degassed with argon for 10 min. 5-(6-
Bromo-pyridinyl)f|uoromethyl-morpholinone (0.2 g, 0.694 mmol) followed by 5-
chloropicolinamide (0.119 g, 0.764 mmol) were added to the resultant reaction mixture and
degassed with argon for further 5 min. Reaction mixture was then heated at 80 °C for 16 h
and cooled to rt. Reaction contents were treated with water and t was extracted with
ethyl e, washed with brine and dried over anhy. . The c layer was
concentrated under reduced pressure to obtain liquid which was triturated with n-pentane to
furnish title compound as a off-white solid. Yield = 0.24 g (crude). TLC (50% ethyl acetate in
hexane) Rf = 0.45; LCMS: RtHe = 1.215, [M+1] = 365.1 and 366.9; HPLC mm = 4.367 min (53
m) 5-Chloro-pyridinecarboxylic acid [6-(3-fluoromethylthioxo-morpholinyl)-
pyridinyl]-amide
To a on of 5-chloro-pyridine-2—carboxylic acid [6-(3-fluoromethyloxo-morpholinyl)-
pyridinyl]-amide (0.24 g, 0.658 mmol) in THF (10.0 ml), Lawesson’s reagent (0.798 g,
1.974 mmol) was added at rt and heated at reflux temperature for 24 h. on mass was
concentrated under reduced pressure. The crude compound was directly purified by column
chromatography using 23 % ethyl acetate in hexane to furnish title compound as off-white
solid. Yield = 0.19 g (72 % [2 steps]). TLC (50% ethyl acetate in hexane) Rf = 0.71; LCMS:
RtHe = 1.578, [M+1]+ = 381.1 and 382.9.
n) 5-{6—[(5-Chloro-pyridinecarbonyl)-amino]-pyridin-2—yl}fluoromethyl-5,6-dihydro-
2H-[1,4]oxazinyl-ammonium trifluoro acetate
To a solution of 5-chloro-pyridine-2—carboxylic acid [6-(3-fluoromethylthioxo-morpholin-3—
yl)-pyridinyl]-amide (0.19 g, 0.499 mmol) in ol (2.0 ml), 10 % ammonia in methanol
(8.0 ml) was added at 0 °C in a sealed tube and stirred at rt for 24 h. Reaction mass was
concentrated under reduced pressure and directly purified by preparative HPLC. Conditions:
column: C18—ZORBAX 21.2 x 150mm; 5pm. mobile phase: 0.1 % TFA in water (A) /ACN;
flow: 20 ml/min. Yield: 86 mg (36 %). MP: 216-218°C. TLC (20% methanol in chloroform) R
= 0.45; LCMS: RtHa = 0.194 [M+1] = 364.0 and 366.1; HPLC RtHg = 3.222 min (98.7 %); 1H
NMR (400 MHz, DMSO-ds): 6 10.85 (s, 1H), 10.37 (s, 1H), 9.37 (s, 1H), 8.50-8.79 (m, 2H),
WO 95469
8.31-8.23 (m, 3H), 8.06 (t, 1H), 7.37 (d, 1H), 4.96 (dd, 1H), 4.85 (dd, 1H), 4.62 (dd, 2H),
4.25-4.16 (m, 2H). Product formation was also confirmed by 2D NM R-ROESY.
Examples 4 to 7: The compounds listed in Table 4 were prepared by a procedure
analogous to those used in Example 3.
1H-NMR
Compound
(8; DMSO-ds)
.74 (s, 1H), 10.34
Br o (s, 1H), 9.35 (s, 1H),
| H 8.92 (t, 1H), 8.69 (s,
\ N N /
\ N NHa 1H), 8.39 (dd, 1H),
0 / F 0Facoo- 8.29 (dd, 1H), 8.17
(dd, 1H), 8.05 (t, 1H),
-{6-[(5-Bromo-pyridine—2—carbonyl)-amino]- 7-36 (d1 1H): 4-96 (dd:
pyridin-2—yl}-5—fluoromethyl-5,6-dihydro-2H- 1H): 4-86 (dd, 1H),
[1,4]oxazinyl-ammonium trifluoro acetate 4-62 (dd! 2H)» 4-25'
4.15 (m, 2H).
9.01 (s, 1H), 8.43 (s,
1H), 8.11 (d, 1H),
7.874 (t, 1H), 7.40 (d,
1H), .45 (m,
-{6-[(5—Cyano—3—methyl-pyridine 2H), .85 (m,
carbonyl)—amino]-pyridin-2—yl}-5— 6H), 2-61 (S, 3H),
fluoromethyI-5,6-dihydro-2H-[1,4]oxazin-3— 1.89 (s, 3H).
yI-ammonium trifluoro acetate
.80 (s, 1H), 10.54
(s, 1H), 9.35 (s, 1H),
8.76 (s, 1H), 8.25 (d,
1H), 8.02 (t, 1H), 7.33
-{6-[(4,6-Dideutero-5—chl0rO (d 1H) 499'4.76 (m
trideuteromethyl—pyridinecarbonyl)- 2H) 4.61 (m 2H)
amino]-pyridin-2—y|}fluoromethyl-5,6- 4.18 (t 2H).
dihydro—2H-[1,4]oxazin-3—yl-ammonium
trifluoro acetate
1H-NMR
Compound
(5; DMSO-ds)
.82 (s, 1H), 10.46
0 (EDEO (5, 1H), 10.33 (s, 1H),
~ \ 9.96 (s, 1H), 9.36 (s,
\ N N /1
H N NH;
8 / 1H), 90.1-909 (m,
1H), 8.73 (s, 1H),
8.44 (dd, 1H), 8.28
-{6-[(5-Thiocarbamoyl-pyridine-Z- (dd, 2H), 8.06 (t, 1H),
yl)-amino]-pyridinyl} 7.37 (d, 1H), 5.03-
fluoromethyl-5,6-dihydro-2H-[1,4]oxazin 4.78 (m, 2H), 4.61
yI-ammonium trifluoro—acetate (dd, 2H), 4.26-4.16
(m, 2H).
Example 8: omethyl-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-
dimethyltrifluoro-methyl-3,6-dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide
\ o
/ '
N F
\ H N /
\ N
l NH2
0 /
a) 4-(6-Bromo-pyridinyl)methyloxo-2lambda*4*-[1,2,3]oxathiazolidine
carboxylic acid tert-butyl ester
To an at 0 °C precooled solution of thionyl chloride (3.42 ml, 5.57 g, 46.8 mmol) in pyridine
(9.46 ml, 9.25 g, 117.0 mmol) was added dropwise a solution of [1—(6-bromo-pyridin-2—yl)—2-
hydroxy—1-methyl-ethyl]-carbamic acid tert—butyl ester (see Example 1 step d), 7.75 g, 23.4
mmol) in DCM (230 ml). The reaction mixture was allowed to stir for 1 h at rt, then 0.5 N aq.
HCI and DCM were added, the phases were ted and the aq. phase was twice
acted with DCM. The combined org. phases were washed with brine, dried over
NaZSO4, filtered and concentrated to leave the title compound (mixture of diastereomers) as
an orange solid. HPLC RtH4= 1.16, 1.20 min (diastereomers); ESIMS: 377, 379 [(M + H)+].
b) 4-(6-Bromo-pyridinyl)methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-
3-carboxylic acid tert-butyl ester
To a solution of 4—(6-bromo-pyridinyl)methyloxo-2lambda*4*-[1 ,2,3]oxathiazolidine—3-
carboxylic acid utyl ester (8.83 g, 23.4 mmol) in acetonitrile (60 ml) and H20 (30.0 ml)
was added RuCls hydrate (0.971 g, 4.68 mmol) and NalO4 (10.01 g, 46.8 mmol). The
reaction mixture was stirred at 0 °C for 2 h. H20 and DCM were added, the phases were
separated and the aq. phase was twice reextracted with DCM. The combined org. phases
were washed with brine, dried over , d and concentrated. The residue was
dissolved in DCM and filtered through silica gel, the filtrate was evaporated and the residue
was triturated with TBME (10 ml) and n-hexane (100 ml). The resulting precipitate was
filtered and washed with n-hexane to yield the title nd as a less crystalline
solid. HPLC RtH4= 1.16 min; ESIMS: 393, 395 [(M + H)*]; 1H NMR (400 MHz, CDCI3): 6 7.63-
7.59 (m, 1H), 7.47-7.42 (m, 2H), 4.73 (d, 1H), 4.47 (d, 1H), 2.00 (s, 3H), 1.52 (s, 9H).
c) [(RS)(6-Bromo-pyridin-Z-yl)tert-butoxycarbonylamino-propoxy]-3,3,3-
trifluoromethyl-propionic acid ethyl ester
At 0 °C, NaH (0.508 g of a 60% dispersion in mineral oil, 12.69 mmol) was added to a
solution of 4-(6-bromo-pyridinyl)—4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine—3-
carboxylic acid tert—butyl ester (3.84 g, 9.76 mmol) and (R)—3,3,3—trifluorohydroxymethyl-
propionic acid ethyl ester (2.54 g, 13.67 mmol) in DMF (10 ml, soln. predried over 4A mol.
sieves). The reaction e was allowed to stir at rt for 30 min, then at 60 °C for 17 h. The
reaction mixture was quenched with H20 and diluted with 1N aq. HCI and EtOAc. The
phases were ted and the aq. phase was twice reextracted with EtOAc. The combined
org. phases were washed with brines, dried over N32804, filtered and concentrated. Flash
chromatography on silica gel (cyclohexane: EtOAc, gradient 0-5 min 100:0, 5-30 min 90:10,
30-40 min 90:10, 40-50 min 80:20, 50-55 min 80:20) yielded the title compound
(diastereomer mixture) as a clear oil. HPLC RtH4= 1.39 min; ESIMS: 499, 501 [(M + H)“].
d) [(RS)(6-Bromo-pyridinyl)((R)-1 -carbamoyl-2,2,2-trifluoro-1 -methyl-ethoxy)
methyl-ethyl]-carbamic acid tert-butyl ester
A solution of (R)-2—[(RS)-2—(6—bromo-pyridin—2—yl)tert—butoxycarbonylamino-propoxy]—3,3,3-
tri-fluoromethyl-propionic acid ethyl ester (3.0 g, 6.01 mmol) in 7N NH3/MeOH (6.5 ml) was
stirred in a sealed glass vial at 55 °C for 72 h. The reaction mixture was concentrated to
leave the title compound as a colourless solid that was used in the next step without further
purification. HPLC RtH4= 1.12, 1.14 min (diastereomers); ESIMS: 470, 472 [(M + H)+].
e) [(RS)(6-Bromo-pyridinyl)((R)cyano-2,2,2-trifluoromethyl-ethoxy)
methyl-ethyl]-carbamic acid tert-butyl ester
To an at 0 °C percooled solution of [(RS)(6—bromo-pyridinyl)—2-((R)carbamoyl-2,2,2-
trifluoromethy|—ethoxy)—1-methyl-ethyl]-carbamic acid tert—butyl ester (2.18 g, 4.64 mmol)
and NEt3 (1.615 ml, 1.173 g, 11.59 mmol) in DCM (30 ml) was added se TFAA (0.773
ml, 1.168 g, 5.56 mmol). After stirring for 5 min at 0 °C, then for 1 h at rt the reaction mixture
was diluted with sat. aq. Na2C03 soln. and with DCM. The phases were separated and the
aq. phase was twice reextracted with DCM. The combined org. phases were dried over
NaZSO4, filtered and concentrated to leave a pale yellow oil which was stirred with 7N
NH3/MeOH for 5 min. The mixture was evaporated to dryness and purified by flash
chromatography (cyclohexane: EtOAc 0-3 min 100:0, 3—35 min 65:35) to yield the title
nd as a clear oil.
HPLC RtH4= 1.30 min; ESIMS: 452, 454 [(M + H)*]; 1H NMR (400 MHz, CDCIg): 6 7.59-7.53
(m, 1H), 7.42-7.36 (m, 2H), 5.66 (br s, 1H), 4.41-4.31 (m, 1H), 4.25-4.18 (m, 1H), 1.71 (cl,
3H), 1.66 (d, 3H), 1.43 (s, 9H).
f) (R)[(RS)Amino(6-bromo-pyridinyl)-propoxy]-3,3,3-trifluoromethyl-
nitrile
A solution of [(RS)(6-bromo-pyridin-2—yl)—2-((R)cyano-2,2,2—trifluoro—1-methyI-ethoxy)
-ethyl]-carbamic acid tert—butyl ester (0.456 g, 1.008 mmol) and TFA (1.554 ml, 2.299
g, 20.17 mmol) in DCM (5 ml) was stirred at rt for 30 min, concentrated and triturated with 7N
NH3/MeOH at rt for 20 min and again concentrated to give the title compound that was used
for the next step without r purification. HPLC RtH4= 0.69, 0.73 min (diastereomers);
ESIMS: 352, 354 [(M + H)"].
g) (2R,5RS)(6-Bromo-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-dihydro-2H-
[1 ,4]oxazinylamine
A suspension of (R)[(RS)—2—amino(6-bromo-pyridinyl)—propoxy]-3,3,3-trifluoro-2—
methyl-propionitrile (0.688 g, 1.172 mmol), yl-L-cysteine (0.383 g, 2.344 mmol) and
K2C03 (0.356 g, 2.560 mmol) in abs. EtOH (4 ml) was stirred at 80 °C for 18 h. The reaction
mixture was quenched with 10% aq. K2C03 soln. and 3x extracted with TBM E. The combined
org. phases were washed with brine, dried over NaZSO4, filtered and concentrated to leave
the title compound as a colourless solid. HPLC RtH4= 0.68-0.70 min; ESIMS: 352, 354 [(M +
H)+].
WO 95469
h) [(2R,5R)(6-Bromo-pyridin-2—yl)—2,5-dimethyltrif|uoromethyl-5,6-dihydro-2H-
[1 ,4]oxazinyl]-carbamic acid tert-butyl ester and (2R,5$)-diastereomer
A mixture of (R)-5—(6-Bromo—pyridinyl)-2,5—dimethyltrifluoromethyl-5,6-dihydro-2H-
[1 ,4]oxazin-3—ylamine, Boczo and DIPEA in DCM (4 ml) was stirred at rt for 20 h. The
reaction mixture was ed with sat. aq. NaHCOa soln. and diluted with DCM. The
phases were separated and the aq. phase was twice reextracted with DCM. The combined
org. phases were washed with brine, dried over , filtered and concentrated. HPLC
purification (Alltech Grom Saphir 65 Si, 10pm, 250x50mm column, gradient HeptzEtOAc 0-
1.6 min 85:15, 16-16 min 0:100, 16-212 min 0:100, flow: 100 ml/min, detection: 254 nm)
yielded the desired (2R,5R) as well as the undesired (2R,58) diastereomer. HPLC RtH4= 1.28
min (2R, 58), 1.30 min (2R, 5R); ESIMS: 452, 454 [(M + H)*]; 1H NMR (2R, SR) (400 MHz,
: 6 10.98 (br s, 1H), 7.59 (t, 1H), 7.43 (d, 1H), 7.34 (d, 1H), 4.39 (d, 1H), 4.08 (d, 1H),
1.62 (s, 3H), 1.55 (s, 12H); 1H NMR (2R, 58) (400 MHz, CDCIS): 611.01 (br s, 1H), 7.57 (t,
1H), 7.42 (d, 1H), 7.37 (d, 1H), 4.45 (d, 1H), 3.91 (d, 1H), 1.74 (s, 3H), 1.65 (s, 3H), 1.55 (s,
19H).
i) ((2R,5R){6-[(5-Cyano-3—methyl-pyridine—2—carbonyl)-amino]-pyridiny|}-2,5-
dimethyltrifluoromethyl-5,6-dihydro-2H-[1,4]oxazinyl)-carbamic acid tert-butyl
ester
A mixture of [(2R,5R)(6-Bromo—pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-dihydro-2H-
[1,4]oxazinyl]-carbamic acid tert-butyl ester (60.00 mg, 0.133 mmol), 5-cyano
methylpicolinamide (23.52 mg, 0.146 mmol), Xantphos (6.91 mg, 0.012 mmol) and 052C03
(60.50 mg, 0.186 mmol) in dioxane (0.611 ml) was degassed with argon for 5 min, then
szdba3 (3.64 mg, 3.98 meI) was added and the reaction mixture was d at 40°C for 18
h. The reaction mixture was diluted with H20 and TBM E. The phases were separated and
the aq. phase was reextracted with TBM E. The combined org. phases were washed with
brine, dried over NaZSO4, d and concentrated. HPLC purification (Alltech Grom Saphir
65 Si 10 uM column, 150x30 mm, gradient n-heptanezEtOAc 0-1.2 min 75:25, 1.2-9 min
0:100, 9-12 min 0:100, flow: 50 ml/min, detection: 254 nm) yielded the title compound as a
less solid. HPLC RtH4= 1.37 min; ESIMS: 533 [(M + H)+]; 1H NMR (400 MHz, CDCI3): 6
11.22 (s, 1 H), 10.47 (s, 1 H), 8.78 (d, 1H), 8.33 (d, 1 H), 7.98 (d, 1H), 7.84-7.80 (m, 1 H), 7.13
(d, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 2.88 (s, 3H), 1.64 (s, 3H), 1.57 (br s, 12H).
j) 5-Cyanomethyl-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-dimethyl
trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide
To a solution of ((2R,5R)—5—{6-[(5-cyano-3—methyl-pyridinecarbonyl)-amino]-pyridin-2—y|}-
2,5—dimethyl-2—trifluoromethyl-5,6—dihydro-2H-[1,4]oxazin-3—yl)-carbamic acid tert—butyl ester
(50.0 mg, 0.094 mmol) in DCM (0.3 ml) was added TFA (0.289 ml, 428.0 mg, 3.760 mmol)
and the reaction e was stirred at rt for 2 h. The solvent was evaporated off, sat. aq.
NaHCO3 soln. and TBME was added, the phases were separated and the aq. phase was
reextracted twice with TBM E. The combined org. phases were dried over Na2804, ed
and concentrated and the residue was washed with MeOH to leave the title compound as a
colourless lline solid. HPLC RtH4= 0.84 min; ESIMS: 433 [(M + H)"]; 1H NMR (400 MHz,
CD30D): 6 8.85 (s, 1H), 8.21-8.18 (m, 2H), 7.82-7.78 (m, 1H), 7.23 (d, 1H), 4.18 (d, 1H), 3.80
(d, 1H), 2.76 (s, 3H), 1.46—1.45 (28, 6H).
Examples 9 and 10: The compounds listed in Table 5 can be prepared by a procedure
analogous to that used in Example 8.
Hydrochloride salts were obtained from solutions of the corresponding free base by addition
of hloric acid in dioxane or hydrochloric acid in diethylether and evaporation of the
solvents.
Table 5
”—n(5;CDCIS):1026
(br s, 1H), 8.97 (br
s, 1H), 8.45 (d,
UPLCMSI
1H), 8.29-8.12 (m,
RtH4 =
2H), 7.78-7.76 (m,
0.77
1H), 7.38 (d, 1H),
-Cyano-pyridinecarboxylic acid [6- [M+1] =
4.14 (d, 1H), 3.94
((38,6R)—5-amino—3,6—dimethyl-6— 419.3
(d, 1H), 1.69 (brs,
trifluoromethyl-3,6-dihydro-2H-[1 ,4]oxazin
3H), 1.55 (br s,
yl)-pyridin—2-yl]—amide hydrochloride
3H).
WO 95469
N\\ O
/ N\‘\“‘FN/- N (5; CDgOD): 9.07
\ H (d,1H),8.45—8.39 UPLCMS:
O U (m, 2H), 8.22 (d, RtH4=
1H), 7.83 (t, 1H), 0.79
-Cyano-pyridine—2-carboxylic acid [6- 7.27 (d, 1H), 4.19 [M+1] =
((3R,6R)—5—aminc-3,6-dimethyl (d, 1H), 3.83 (d, 4193
trifluoromethyl-3,6—dihydro—2H—[1,4]oxazin 1H), 1.47 (s, 6H).
ridin—2-yl]—amide
Example 11: 5-Cyanomethyl-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-
dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)f|uoro-pyridin-Z-yl]-amide
a) 2-(6-Bromofluoro-pyridinyl)-propanol
To a solution of 2-bromo—5-fluoropyridine (25 g, 142 mmol) in diethylether (600 ml) was
slowly added n-butyllithium (2.5 M in hexane, 56.8 ml, 142 mmol) at ~78 °C under a nitrogen
atmosphere. The resulting yellow reaction mixture was stirred at -78 °C for 2 hours and dry
acetone (11.47 mi, 156 mmol) was added over 30 minutes. Stirring was continued at -78 °C
for 1 hour. HCI (2N, 50 ml) was added and the reaction mixture was warmed to 0 °C. The pH
of the mixture was ajusted to ~7 with 2N HCl solution. The reaction mixture was diluted with
ethyl acetate and washed with brine, dried over sodium e, filtered and concentrated in
vacuo. The crude product (29.36 g) was chromatographed over silica gel (cyclohexane: ethyl
acetate 9:1): 22.3 g (67.1 % . TLC (cyclohexane/ethyl acetate 9:1) Rf=0.33; LCMS
RtH5=O.89 min (ES+ 234, 236). 1H-NMR (360 MHz, DMSO-ds): 7.72-7.62 (m, 2H), 5.27 (s,
1H, OH), 1.50 (s, 6H, 2xCH3).
b) 6-Bromofluoroisopropenyl-pyridine
To a solution of 2-(6-bromofluoro—pyridinyl)-propano| (22.3 g, 95 mmol) and
esulfonic acid anhydride (49.8 g, 286 mmol) in dichloromethane was added dropwise
ylamine (53.1 ml, 381 mmol) at 0° C. The reaction mixture was stirred at room
temperature for 20 hours. The on mixture was quenched with aq. sodium carbonate
solution and diluted with dichloromethane. The aqueous phase was extracted with
dichloromethane. The combined organic layers were washed with brine, dried over sodium
sulfate, filtered and evaporated in vacuo (volatile). The crude brown oil was
chromatographed over silica (cyclohexanezethyl acetate 9:1) to give the title compound as a
1O clear liquid. 17.35 g (84 % yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.58; 1H-NMR (360
MHz, : 7.26-7.15 (m, 2H), 5.72 (s, 1H), 5.47 (s, 1H), 2.12 (s, 3H, CH3).
c) 2-(6-Bromofluoro-pyridinyl)-propane-1,2-diol
To a solution of 6-bromofluoro—2-isopropenyl-pyridine (17.35 g, 80 mmol) in acetone (45
ml) and water (90 ml) was added N-methylmorpholine-N-oxide hydrate (11.4 g, 84 mmol) and
osmium tetroxide (5.04 ml, 0.402 mmol). The resulting reaction mixture was stirred at room
temperature for 44 hours, Sodium dithionite (2 g) in water (70 ml) was added and the
reaction mixture was d for 15 minutes and was then filtered and concentrated in vacuo.
Ethyl acetate was added and the organic layer was washed with brine, dried over sodium
sulfate, filtered and evaporated. 18.29 g slightly yellow solid (91 % yield). LCMS RtH5=0.64
min (ES+ 250, 252); 1H-NMR (360 MHz, CDCI3): 7.46 (dd, 1H), 7.35 (dd, 1H), 5.09 (s, 1H,
OH), 3.96 (d, 1H), 3.78 (d, 1H), 2.45 (broad, 1H, OH), 1.53 (s, 3H, CH3).
d) Methanesulfonic acid 2-(6-bromofluoro-pyridin-Z-yl)hydroxy-propyl ester
To a solution of 2-(6-bromo—3-fluoro-pyridinyl)rpropane—1,2-diol (18.29 g, 73.1 mmol) in
dichloromethane (350 ml) was added triethylamine (20.39 ml, 146 mmol). Methanesulfonyl
chloride (6.27 ml, 80 mmol) was added se at 0° C over 10 minutes. Stirring was
continued at 0 °C for 30 minutes. The reaction mixture was washed with sat. sodium
bicarbonate solution, water and brine. The organic layer was dried over sodium e,
filtered and evaporated. 31.46 g , used without r purification in the next step).
LCMS RtH5= 0.81 min. ( ES+ 328, 330); 1H-NMR (360 MHz, CDCI3): 7.52 (dd, 1H), 7.41 (dd,
1H), 5.13 (s, 1H, OH), 4.61 (d, 1H), 4.45 (d, 1H), 3.05 (s, 3H, CH3802), 1.61 (s, 3H, CH3).
e) 1-Azido(6-bromofluoro-pyridinyI)-propanol
A mixture of esulfonic acid 2-(6-bromo—3-fluoro-pyridinyl)hydroxy-propyl ester
(5g, 15.24 mmol), ammonium chloride (4.08 g, 76 mmol) and sodium azide (2.476 g, 38.1
mmol) in ethanol (100 ml) was stirred at 80 °C for 20 hours. The on mixture was diluted
with ethyl acetate and washed with water and brine. The organic layer was dried over sodium
sulfate, filtered and evaporated. 3.1 g (74 % yield). TLC (cyclohexane/ethyl acetate 9:1)
Rf=0.35; LCMS RtH5= 0.97 min. ( ES+ 275, 277); 1H-NMR (360 MHz, CDCI3): 7.51 (dd, 1H),
7.36 (dd, 1H), 5.18 (s broad, 1H, CH), 3.68-3.60 (AB system, 2H), 1.59 (s, 3H, CH3).
f) ofluoro(2-methyl-aziridinyI)-pyridine
To a solution of 1-azido(6-bromofluoro-pyridinyl)-propan—2—ol (11.2 g, 40.7 mmol) in
THF (60 ml) was added triphenylphosphine (10.68 g, 40.7 mmol) and the reaction mixture
was stirred for 18 hours at room temperature. The t was removed in vacuo and the
residue obtained was dissolved in diethylether and filtered through a cotton plug to remove
triphenylphosphine oxide. The filtrate was washed with citric acid (9.6 g in 20 ml of water)
and the organic phase was separated. The aqueous layer was made basic with 2N NaOH
and extracted with diethylether. The organic layer was dried over sodium sulfate, filtered and
evaporated to yield the title compound with some TPPO present: 8.1 g yellow oil (69 %
yield). TLC (cyclohexane/ethyl e 2:1) Rf=0.28; LCMS RtHe= 0.46 ( ES+ 231, 233);
1H-NMR (400 MHz, CDCI3): 7.34 (dd, 1H), 7.24 (dd, 1H), 1.99 (s, 1H), 1.89 (s, 1H), 1.65 (s,
3H, CH3).
9) ofluoro[2-methyl(2-nitro-benzenesulfonyl)-aziridinyl]-pyridine
To a on of 6-bromo-3—fluoro(2-methyl-aziridinyl)—pyridine (8 g, 27.7 mmol) in THF
(48 ml) and water (16 ml) was added N-methylmorpholine (3.5 ml, 27.7 mmol) and o-
nosylchloride. The reaction mixture was stirred for 4 hours at room temperature. 3 g neutral
Alox was added and the reaction e was filtered.The filtrate was diluted with
dichloromethane, washed with sat. sodium hydrogencarbonate solution and water. The
organic phase was dried over sodium sulfate, filtered and evaporated. 11.2 g of the crude
t was purified over silica gel (cyclohexanezethyl acetate 60:40) to afford the title
compound. 8.69 g (75 % yield). LCMS RtH5= 1.09 min. (ES+ 416, 418). 1H-NMR (400 MHz,
CDCI3): 8.27 (m, 1H), 7.80-7.73 (m, 3H), 7.46 (dd, 1H), 7.34 (dd, 1H), 3.32 (s, 1H), 3.20 (s,
1H), 2.10 (s, 3H, CH3).
h) (R)[2-(6-Bromofluoro-pyridinyl)(2-nitro-benzenesulfonylamino)-
propoxy]3,3,3-trifluoromethyl-propionic acid ethyl ester
WO 95469
To a solution of (R)-3,3,3—trifluoro—2-hydroxy—2-methyl-propionic acid ethyl ester (715 mg,
3.84 mmol) in DMF (4 ml) was added NaH (55%) (154 mg, 3.84 mmol) at room temperature
and the reaction mixture was d for 30 minutes at room temperature. A solution of 6-
bromo-3—fluoro[2-methyl(2-nitro-benzenesulfonyl)-aziridin—2—yl]—pyridine (800 mg, 1.922
mmol) in DMF (9 ml) was added and the reaction mixture was stirred at room temperature for
48 hours. The reaction mixture was poured onto a mixture of ice/2N HCI/t-butyl-methylether.
The organic layer was washed with sat. sodium bicarbonate solution and brine, dried over
sodium sulfate, filtered and evaporated. Silica gel chromatography (cyclohexane/ethyl
acetate) afforded the title compound as a e of 2 reoisomers. 300 mg (26 %
1O yield). TLC (cyclohexane/ethyl e 2:1) Rf=0.42; LCMS RtH5= 1.25 min (100%, TIC ES+
602, 604).
i) (R)[2-(6-Bromofluoro-pyridinyl)(2-nitro-benzenesulfonylamino)-propoxy]-
3,3,3-trifluoromethyl-propionamide
A solution of (R)[2-(6-bromo-3—fluoro-pyridin-2—yl)—2-(2-nitro-benzenesulfonylamino)-
propoxy]3,3,3-trifluoro-2—methyl-propionic acid ethyl ester (720 mg, 1.195 mmol) in NH3 7N
in methanol (19ml, 133 mmol) was stirred at at 50 °C for 2 days in a sealed 25 ml microwave
vial. The t was removed in vacuo and the residue (987 mg) was chromatographed
over silica gel (cyclohexane/ethyl acetate) affording the title compound as a mixture of two
diastereoisomers (500 mg, 73 % yield). TLC (cyclohexane/ethyl acetate 1:1) Rf=0.30; LC-MS
RtH5=1.05 min (ES+ 573, 575).
j) N-[1-(6-Bromofluoro-pyridinyl)((R)cyano-2,2,2-trifluoromethyl-ethoxy)-
1-methyl-ethyl]nitro-benzenesulfonamide
To a on of (R)[2-(6-bromofluoro-pyridinyI)(2—nitro-benzenesulfonylamino)-
propoxy]—3,3,3—trifluoromethyl-propionamide (200 mg, 0.349 mmol) and triethylamine
(0.121 ml, 0.872 mmol) in dichloromethane (3 ml) was added TFAA (0.059 ml, 0.419 mmol)
at O-5° C and the reaction mixture was stirred for 18 hours at room temperature. Further
addition of TFFA and triethylamine (0.6 and 1.2 aequivalent, respectively) brought the
reaction to tion after 24 hours. The reaction mixture was added to a cold sat. sodium
onate solution and the product was extracted with dichloromethane. The organic layer
was washed with cold 0.1 N HCI solution, water and sat. sodium bicarbonate solution, dried
over sodium sulfate, filtered and evaporated in vacuo. 190 mg (98 % yield) crude product as
a mixture of 2 diastereiosomers. TLC (cyclohexane/ethyl acetate 3:1) Rf=0.24; LCMS RtH5=
1.20 min (ES|+ 555, 557).
2012/050395
k) )(6-Bromofluoro-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-dihydro-
2H-[1,4]oxazinylamine and (2R,5R)(6-Bromofluoro-pyridinyl)-2,5-dimethyl
trifluoromethyl-5,6-dihydro-2H-[1,4]oxazinylamine
A solution of 6-bromofluoro—pyridinyl)((R)cyano-2,2,2-trifluoromethyl-
ethoxy)—1-methyl—ethyl]nitro-benzenesulfonamide (1000 mg, 1.801 mmol), potassium
carbonate (548 mg, 3.96 mmol) and N-acetylcysteine (588 mg, 3.6 mmol) in l (17 ml)
was stirred at 80 °C for 3 days until all starting material was consumed. The reaction mixture
was concentrated in vacuo and the yellow foam redissolved in ethyl acetate and 20%
aqueous potassium carbonate solution. The organic phase was washed with sat. sodium
bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated. 660
mg yellow oil. The 2 diastereOisomers were separated via normal phase preparative HPLC
tography ohexane/ethyl acete/MeOH).
(2R,58)(6-Bromofluoro-pyridinyl)-2,5-dimethyItrifluoromethyI-5,6-dihydro-2H-
[1,4]oxazinylamine (cis derivative): 76 mg. TLC (toluene/ethyl acetate 8:2 + 5% ETA)
6; LCMS RtH4= 0.73 min (100 % purity, El+ 370, 372); 1H-NMR (600 MHz, DMSO-De):
7.69-7.61 (m, 2H), 6.0 (broad s, 2H, NH2, amidine), 4.15 (d, 1H, AB—system), 3.71 (s, 1H,
AB-system), 1.59 (s, 3H, CH3), 1.47 (s, 3H, CH3).
(2R, 5R)(6-Bromofluoro-pyridinyl)-2, 5-dimethyltrifluoromethyl-5, 6-dihydro—2H-
[1,4]oxazinylamine (trans derivative): 89 mg. TLC ne/ethyl acetate 8:2 + 5% ETA)
Rf=0.31; LCMS RtH4= 0.73 min (100 % purity, El+ 370, 372); 1H-NMR (600 MHz, DMSO-De):
7.73-7.61 (m, 2H), 6.0 (broad s, 2H, NH2, amidine), 4.04 (d, 1H, AB—system), 3.72 (d, 1H,
AB-system), 1.52 (s, 3H, CH3), 1.48 (s, 3H, CH3).
I) 5-Cyanomethyl-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-dimethyl
trifluoromethyl-3,6-dihydro-2H-[1,4]oxaziny|)fluoro-pyridinyl]-amide
A mixture of (2R,5R)(6-bromofluoro-pyn'din-2—yl)-2,5-dimethyl-2—trifluoromethyl-5,6-
dihydro-2H-[1,4]oxazin-3—y/amine (80 mg, 0.216 mmol), 5-cyanomethyl-pyridine
carboxylic acid amide (34.8 mg, 0.216 mmol, see Intermediates Amide 1), os (11.26
mg, 0.019 mmol) and cesium carbonate (99 mg, 0.303 mmol) in dioxane (2 ml) was
degassed for 5 minutes with argon. Pd2(dba)3 (5.94 mg, 6.48 umol) was added, the
microwave vial was sealed and stirred at 80° C for 18 hours. The reaction mixture was
diluted with water and TBME. The organic phase was washed with brine, dried over sodium
sulfate, filtered and evaporated. 173 mg orange solid. Silica gel chromatography (applied on
two 20x20 cm plate, 1mm, dichloromethane : methanol 9:1, rechromatographed with
dichloromethane:methanol 95:5 with double evolution of the plates) ed the titel
compound: 15 mg and 21 mg. Combined amount: 36 mg (37 % . TLC
(dichloromethane/methanol 9:1) Rf=0.53; API ES+ MS 451. LCMS RtH4= 0.87 min. (100%,
ES+ 451), 1H-NMR (400 MHz, CDCI3): 10.80 (br s, 1H), 8.83 (br s, 1H), 8.41 (dd, 1H), 7.93
(br s, 1H), 7.55 (t, 1H), 5.8 — 4.6 (very broad 4.23 (br s, 2H), 2.83 (s, 3H), 1.75 (s, 3H),
, 2H),
1.66 (s, 3H).
Example 12: o-3—methyl-pyridinecarboxylic acid [6-((3S,6R)amino-3,6-
dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxaziny|)f|uoro-pyridin-Z-yl]-amide
-Cyanomethyl-pyridine—2-carboxylic acid [6-((3S,6R)—5—amino-3,6—dimethyI
trifluoromethyl-3,6-dihydro—2H-[1,4]oxazin-3—yl)-5—fluoro-pyridinyl]-amide can be prepared
by a procedure analogous to that used in Example 11.
TLC (dichloromethane/methanol 9:1) 7; API ES+ MS 451. LCMS RtH4= 0.86 min.
(100%, ES+ 451); 1H-NMR (400 MHz, CDCIg): 10.65 (br s, 1H), 8.83 (d, 1H), 8.37 (dd, 1H),
7.96 (d, 1H), 7.51 (dd, 1H), 6.0 — 5.0 (very broad 4.38 (d, 1H), 4.09 (d, 1H), 2.85 (s,
, 2H),
3H), 1.78 (s, 3H), 1.71 (s, 3H).
Example 13: 5-{2—[(5-Chloro-4,6-dideutero-3—trideuteromethyl-pyridinecarbonyl)-
amino]-pyridiny|}fluoromethyl-5,6—dihydro-2H-[1,4]oxazinyl-ammonium acetate
a) 2-(2-Bromo-pyridin-4—yl)—malonic acid diethyl ester
2-Bromo-4—methyl pyridine (70.0 g, 407 mmol) was added drop wise to a cooled (-78 °C)
solution of LDA (2.0 M in toluene/THF/ethyl benzene, 610.4 ml, 1.22 mol) in dry THF (600
ml) for 30 min. ethylchloroformate (132.3 g, 1.22 mol) was added to the resultant reaction
mixture with addition funnel at -78 °C and stirring continued for 90 min. Reaction mixture was
treated with saturated NH4C| on and worked up with ethyl acetate by washing with
_32-
water, brine followed by drying over anhy. Na2804. Organic layer ws concentrated under
reduced pressure to obtain crude product which was purified by column chromatography with
% ethyl acetate in Hexane to furnish title compound as a brown color oily liquid. Yield:
115.0 g (89 %). TLC (10% ethyl e in hexane) Rf = 0.15; LCMS: RtH8 = 1.475 [M + 1]+ =
315.8 and 317.8; HPLC RtHg = 7.30 min (86.7 %); 1H NMR (400 MHz, CDCI3) 6 8.38 (d, 1H),
7.56 (t, 1H), 7.34 (dd, 1H), 4.55 (s, 1H), 4.29-4.18 (m, 4H), 1.28 (t, 6H).
b) (2-Bromo-pyridin-4—yl)-acetic acid
A suspension of 2-(2—bromo-pyridinyl)-malonic acid diethyl ester (115 g, 316 mmol) and
1O K2CO3 (125.23 9, 907.5 mmol) in water (500 ml) was heated at 100 0C for 8 h under
constant stirring. on mixture was cooled to rt and concentrated under reduced
pressure to remove solvent completely. The solid residue was dissolved in minimum quantity
of water (25 ml) and washed with 20% ethyl acetate in hexane to remove non polar
impurities. The aqueous layer was seperated and cooled to 0 °C followed by adjusting pH ~
6 to 7 using aq. 6 N HCI. The precipitated solid was filtered using Buchner funnel, washed
with ice cold water and dried under vacuum to h title compound as an off white solid.
with sufficient purity. Yield: 60.0 g (76.3 %). TLC (70% ethyl e in hexane) Rf = 0.05;
LCMS: RtH8 = 0.193; [M + 11* = 215.9 and 217.9; HPLC RtHg = 3.025 min (98 %); 1H NMR
(400 MHz, CDCI3): 6 12.71 (s, 1H), 8.33 (d, 1H), 7.61 (s, 1H), 7.37 (d, 1H), 3.71 (s, 3H).
c) (2-Bromo-pyridinyl)-acetic acid ethyl ester
To a solution of (2-bromo-pyridin—4—yl)-acetic acid (60.0 9, 277.7 mmol) in ethanol (600 ml),
conc: sulfuric acid (5.0 ml) was added at rt and the reaction mixture was heated at 90 °C for
9 h. on mixture was cooled to rt and concentrated under reduced pressure to remove
solvent completely. The residue obtained was cooled to 0 °C and pH was adjusted to 8 using
% aqueous NaHCOs solution. The resultant contents were worked up with ethyl acetate by
washing with water, brine and dried over anhy. . Organic layer was concentrated
under reduced pressure to obtain crude compound. Column chromtography cation of
the crude nd using 15% ethyl acetate in hexane as eluent furnished title compound
as a brown oil. Yield: 65.0 g (88.5 %). TLC (30% ethyl e in hexane) R = 0.39; LCMS:
RtH7 = 0.824 [M + 1]+ = 243.8 and 245.8; HPLC RtHg = 3.759 min (69 %); 1H NMR (300 MHz,
CDCIS): 6 8.32 (t, 1H), 7.43 (s, 1H), 7.21-7.15 (M, 1H), 4.18 (q, 2H), 1.27 (t, 3H).
d) 2-(2-Bromo-pyridinyl)hydroxyhydroxymethyl-propionic acid ethyl ester
To an ice cooled stirred mixture of (2-bromo-pyridin-4—yl)—acetic acid ethyl ester (40.0 9,
163.93 mmol) and paraformaldehyde (9.84 9, 327.8 mmol) in dry DCM was added 1,8-
-33_
diazabicyclo[5.4.0]undecene (1.49 g, 1.49 ml, 9.83 mmol) and stirred for 2 h. Reaction
mixture was treated with (1 R)-(-)camphor sulphonic acid (2.283 g, 9.83 mmol) at 0 °C
and the organic layer was washed with brine and dried over anhydrous NaZSO4.
Concentration of c layer afforded gummy oily material. The crude compound was
purified over triethyl amine treated silicagel using 5 - 8% methanol in DCM as eluent
furnished title compound as a brown liquid. Yield = 20.0 g (40 %). TLC (30% ethyl acetate in
hexane) R = 0.06; LCMS: RtH7 = 0.191; [M + 1]+ = 303.9,and 305.8; HPLC RtHg = 6.019 min
(43%); 1H NMR (400 MHz, CDClg): 6 8.36-8.31 (m, 1H), 7.34-7.25 (m, 1H), 6.37-6.33 (m,
1H), 4.6 (d, 1H), 4.14—4.08 (m, 2H), 4.04-3.91 (m, 4H), 1.13 (t, 3H).
e) 5-(2-Bromo-pyridinyl)-2,2-dimethyI-[1,3]dioxanecarboxylic acid ethyl ester
A mixture of 2-(2-bromo-pyridin—4-yl)-3—hydroxyhydroxymethyl-propionic acid ethyl ester
(30.0 g, 98.6 mmol) 2,2-dimethoxy propane (51.11 g, [60.5 ml], 493.1 mmol) and (1 R)-(-)
camphor sulphonic acid (5.72 g, 24.65 mmol) in DMF (100 ml) was heated at 80 0C for 10 h.
Reaction mixture was cooled to it and concentrated under reduced pressure. The residue
was ved in ethyl acetate and worked up by washing with water, brine, followed by
drying over anhy. NaZSO4. Organic layer was concentrated under reduced re and the
crude product was d by column chromatography using 10% ethyl e in Hexane to
obtain title compound as a yellow solid. Yield = 18.15 g (53%). TLC (30% ethyl acetate in
hexane) Rf = 0.52; LCMS: RtH7 = 1.487; [M + 1]+ = 344.0 and 346.0; HPLC RtHg = 7.6 min (74
%); 1H NMR (300 MHz, CDCI3): 6 .34 (t, 1H), 7.54 (s, 1H), 7.32-7.28 (m, 1H), 4.51 (dd,
2H), 4.27-4.21 (q, 4H), 1.45 (s, 3H), 1.39 (s, 3H), 1.23 (t, 3H).
f) romo-pyridinyl)-2,2-dimethyl-[1,3]dioxanecarboxylic acid ethyl ester
A solution of LiOH.H20 (11.1 9, 263.5 mmol) in water (10 ml) was added to a solution of 5-(2—
pyridin-4—yl)-2,2-dimethyl-[1,3]dioxanecarboxylic acid ethyl ester (18.1 g, 52.7
mmol) in ethanol (60 ml) at 0 °C and the resultant reaction mixture was stirred at rt for 3 h.
Reaction mixture was concentrated under reduced pressure to remove solvent completely.
The wet mass obtained was cooled to 0 °C, acidified with glacial acetic acid (to maintain pH
~6) and the product was ted with ethyl acetate (2 x 100 ml). Organic layer was washed
with brine and concentrated to afford brown solid which was used in the next step without
further purification. Yield = 14.1 g (85 %). TLC (50% ethyl acetate in hexane) R = 0.03;
LCMS: RtH8 = 0.343 [M + 1]+ = 316.0, 318.0; 1H NMR (300 MHz, CDCI3): 6 8.28-8.21 (t, 1H),
7.7 (s, 1H), 7.58-7.54 (m, 1H), .95 (dd, 4H), 1.36 (s, 3H), 1.14 (s, 3H).
9) 5-(2-Bromo-pyridinyl)-2,2-dimethyl-[1,3]dioxanylamine
y phosphoryl azide (14.3 mL, 66.45 mmol) was added to a solution of 5-(2-bromo—
pyridin-4—yl)—2,2-dimethyl-[1,3]dioxanecarboxylic acid ethyl ester (14.0 g, 44.3 mmol) and
triethyl amine (17.24 ml, 133.0 mmol) in toluene (100 ml) at 0 °C. The resultant reaction
mixture was heated to 80 °C under constant stirring for 7 h. on mixture was
concentrated under reduced pressure to remove solvent completely. The residue obtained
after concentration was dissolved in THF (100 ml) and cooled to 0 °C. 2 N aq. NaOH solution
was added drop wise and stirred for 30 min at rt. Reaction mixture was concentrated under
reduced pressure to remove THF and the residue obtained was extracted with cetate.
Organic layer was washed with water, brine and dried over anhy. NaZSO4. Organic layer was
concentrated under reduced pressure to obtain furnished brownish oily material which was
solidified at low temperature (< 10 °C). Yield = 9.5 g (75%). TLC (50% ethyl acetate in
hexane) R = 0.15; LCMS: Rtm = 0.083; [M + 1]+ = 287.0 and 289.0.
h) N-[5-(2-Bromo-pyridinyl)-2,2-dimethyl-[1,3]dioxanyl]chloro-acetamide
To a solution of 5-(2-bromo-pyridinyl)—2,2—dimethyl-[1 ,3]dioxan-5—ylamine (9.5 g, 33.1
mmol) in DCM (100 ml) was added aq. Na2003 (8.7 g in 50 ml) at 0 °C and stirring continued
for 5 min. Chloroacetyl chloride (2.9 ml, 36.41 mmol) was added to the resultant reaction
mixture drop wise and stirred for 30 min at 0 °C. Reaction mass was diluted with DCM (200
ml) and organic layer was washed successively washed with water, brine, dried over
anhydrous NaZSO4 and concentrated under reduced pressure to obtain brown solid. The
t was directly used in the next step with r ation. Yield = 10.2 g (85%). TLC
(50% ethyl acetate in hexane) R = 0.15; LCMS: RtHe = 0.55 [M + 1]+ = 363.0 and 364.9.
i) N-[1-(2-Bromo-pyridinyl)hydroxyhydroxymethy|-ethyl]chloro-acetamide
A solution of N-[5-(2-bromo-pyridin—4-yl)-2,2-dimethyl-[1 ,3]dioxanyl]chloro-acetamide
(10.0 g, 27.6 mmol) in DCM (150 ml) was cooled to 0 °C for 10 min. and trifluoromethyl acetic
acid (15.0 ml) was added. Stirring ued for 2 h and the resultant contents were
concentrated under reduced pressure. The residue formed was basified with aq. NH4OH
solution and the product was ted with ethyl acetate (3 x 200 ml) by washing organic
layer with brine (5.0 ml) and dried over anhy. N32804. Organic layer was concentrated under
reduced pressure to obtain title nd as a brown liquid which was carried to next step
without any purification. Yield = 8.1 g (91 %). TLC (70% ethyl acetate in ) Rf = 0.15;
LCMS: RtHs = 0.12 [M + 1]+ = 322.9 and 324.9; HPLC RtHg = 5.266 min (61 %), 5.104 (25 %).
j) 5-(2-Bromo-pyridinyl)hydroxymethyl-morpholinone
To a solution of N-[1-(2-bromo-pyridinyl)hydroxyhydroxymethyl-ethyl]chIoro-
acetamide (8.0 g, 24. 8 mmol) in t—BuOH (50 ml) was added t-BuOK (5.5 g, 49.6 mmol) and
Nal (0.375 g, 2.48 mmol) and heated to 90 °C for 1 h. Reaction mass was concentrated
under reduced pressure and diluted the residue with EtOAc. c layer was separated
and washed with ammonium chloride solution, brine followed by drying over anhy. NaZSO4.
The crude product was purified by column chromatography using 5% methanol in DCM to
obtain title nd as a pale brown gum. Yield = 3.25 g (46 %). TLC (ethyl acetate) Rf =
0.17; LCMS: RtH8 = 0.12; [M + 1]+ = 286.7 and 289.
k) 5-(2-Bromo-pyridinyl)fluoromethyI-morpholinone
To a suspension of 5-(2-bromo-pyridinyl)hydroxymethyl-morpholinone (3.25 g, 11.0
mmol), Na2C03 (3.5 g, 13.06 mmol) in dry THF (15 ml) was added diethylaminosulfur
trifluoride (2.25 ml, 17.0 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and
stirred for 2 h. Solid Na2C03 (3.5 g) was again added to the reaction mixture and stirred for 4
h at rt. Solids present in the reaction mixture filtered through Buchner funnel. Filtrate was
concentrated under reduced pressure and the crude product was purified by column
chromatography using 5 % methanol in DCM to obtain title compound as a pale yellow solid.
Yield = 2.1 g (66 %). TLC (50% ethyl acetate in ) R = 0.17; LCMS: RtH7 = 0.201; [M +
1]+ = 289 and 291; HPLC: RtH9= 5.171 min. (50 %) and 5.063 (21 %).
I) ro-4,6-dideuterotrideuteromethyl-pyridinecarboxylic acid [4-(3-
fluoromethyloxo-morpholinyI)-pyridinyl]-amide
A stirred solution of 5—(2-bromo-pyridinyl)f|uoromethyl-morpholinone (0.2 g, 0.695
mmol), 5-ch|oro-4,6-dideuterotrideuteromethyl-pyridinecarboxylic acid (Acid 2) (0.135 g,
0.763 mmol) and cesium carbonate (0.678 g, 2.085 mmol) in 1,4-dioxane (5.0 ml) was
degassed with argon for 10 min. 4,5-Bis(dipheny| phosphino)-9,9-dimethyl xanthenes (0.041
g, 0.035 mmol) was added to the resultant mixture and degassed again for 10 min.
Tris(dibenzylidene-acetone) di ium(0) (0.032 g, 0.07 mmol) was then added finally and
degassed with argon for further 5 min. on mixture was heated to 80 °C for 20 h and
cooled to rt. Water was added to the reaction e and product was extracted with ethyl
acetate by g with brine followed by drying over anhy. Na2804. The organic layer was
concentrated under reduced pressure to obtain title compound as a sticky solid which was
used for the next step without purification. Yield = 0.14 g (52%). TLC (50% ethyl acetate in
hexane) Rf = 0.45; LCMS: RtHe = 0.868 [M + 1]+ = 384.0; 1H NMR (300 MHz, CDCI3): 6 10.7
(s, 1H), 8.51-8.41 (m, H) .46 (d, 1H), 7.34-7.16 (m, 1H), 4.99—4.60 (m, 2H), 4.34-3.79
(m, 4H).
-86—
m) 5-Chloro—4,6-dideuterotrideuteromethyl-pyridinecarboxylic acid [4-(3-
methylthioxo-morpholinyl)-pyridinyl]-amide
Lawesson’s t (0.46 g, 1.135 mmol) was added to a stirred solution of 5-chloro-4,6-
ero—3—trideuteromethyl-pyridine—2—carboxylic acid [4-(3-fluoromethyl-5—oxo-morpholin-3—
yl)-pyridinyl]-amide (0.14 g, 0.378 mmol) in THF (4.0 ml) and heated to reflux for 2 h. The
reaction e was concentrated under reduced re to obtain crude product as a
sticky solid which was purified by column chromatography using 25% ethyl acetate in hexane
as eluent to obtain title compound as a sticky solid. Yield = 0.095 g (65%). TLC (30% ethyl
acetate in hexane) Rf: 0.61; LCMS: RtH8 = 1.489 [M + 1]+ = 399.8.
n) 5-{2-[(5-Chloro-4,6-dideuterotrideuteromethyl-pyridinecarbonyl)—amino]-
pyridinyl}fluoromethyl-5,6-dihydro-2H-[1,4]oxazinyl-ammonium acetate
A solution of ro-4,6-dideutero-3—trideuteromethyl-pyridinecarboxylic acid [4-(3-
fluoromethyl-5—thioxo-morpholinyl)—pyridin—2-yl]-amide (0.095 g, 0.238 mmol) in 10%
methanolic ammonia (5.0 ml) was stirred in a sealed tube for 16 h at rt. Reaction mixture was
concentrated under reduced pressure to obtain semi-solid. Product was purified by
preparative HPLC method to obtain title compound as a semi solid. Conditions for
preparative HPLC: Column: Agilent Zorbax XDB C18. Mobile phase: A: 10 mm; ammonium
acetate; B: ACN, 60 ml; Flow: 20ml/min.; Gradient: 0-30, 2-40, 10-80. Yield = 28 mg (31 %).
LCMS: Rtm = 0.191 [M + 11" = 383.1; HPLC: RtHg 3.208 min (97 %); 1H NMR (300 MHz,
DMSO—ds): 610.52(s, 1H), 8.35 (dd, 2H), 7.28 (d, 1H), 6.15 (br. s, 1H), 4.51-4.28 (m, 2H),
4.07-3.94 (m, 3H), ), 3.69 (d, 2H), 1.89 (s, 3H); 19F NMR (376.1): 6 -218.9.
Examples 14 and 15: The compounds listed in Table 6 were prepared by a procedure
analogous to those used in Example 13.
Table 6
1H-NMR
Compound
(5; DMSO-de)
a-1H-NMR (8; DMSO-ds)
.3 (br. s, 1H), 8.83
CI o (d, 1H, J: 2.0 Hz),
I H 8.45 (s, 1H), 8.33 (d,
\ /
\ N NH;
i 1H, J: 5.2 Hz),
O N /
F CFSCOO- 8.28-8.18 (m, 2H),
7.31 (d, 1H, J= 5.8
-{2-[(5-Chloro-pyridine—2-carbonyI)-amino]- Hz), 6.07 (brs, 2H),
pyridinyl}fluoromethyl-5,6-dihydro-2H- 4.51-4.28 (m, 2H),
[1 ,4]oxazinyI-ammonium trifluoro—acetate 4.06-3.93 (m, 4H),
3.7-3.6? (m, 2H).
8.96 (d, 1H), 8.51 (s,
2H), 8.45 (d, 2H),
8.19 (s, 1H), 7.32 (d,
2H), 5.11-4.99 (m,
-Fluoromethyl-5—{2-[(3-methyI 2H), 4.72 (s, 3H),
thiocarbamoyl-pyridine—2-carbonyl)-amino]— 4.27-4.19 (m, 2H),
pyridinyl}-5,6—dihydro-2H-[1,4]oxaziny|— 4.16-4.08 (m, 2H).
ammonium trifluoro-acetate
Example 16: omethyl-pyridine-Z-carboxylic acid [4-((3R,6R)amino-3,6-
dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxaziny|)fluoro-pyridinyl]-amide
a) 2-(2-Bromofluoro-pyridinyl)-propanol
To a solution of ofluoro—pyridine (CAS 414044, 25.0 g, 139 mmol) in THF (300
ml) was added dropwise LDA (100 ml of a 2M soln. in THF/heptane/ethylbenzene, 200
mmol) at -78 °C under a N2 atmosphere. Stirring was continued for 1 h at -78 °C, then
acetone (20.44 ml, 16.17 g, 278 mmol) was added dropwise and stirring was continued at -
78 °C for another 1 h. The reaction mixture was quenched with aq. 1M NH4C| soln. and
diluted with EtOAc. The phases were separated and the aq. phase was twice reextracted
with EtOAc. The combined org. phases were washed with brine, dried over NaZSO4, filtered,
concentrated. Flash chromatography on silica gel (gradient exanezEtOAc 100:0 to
90:10) followed by crystallization from pentane yielded the title compound as a less
solid. HPLC RtH4= 0.81 min; ESIMS: 234, 236 [(M + H)"]; 1H NMR (400 MHz, DMSO-ds): 6
8.32 (br s, 1H), 7.71 (d, 1H), 5.57 (s, 1H), 4.90 (t, 1H), 3.65-3.57 (m, 1H), 3.53-3.44 (m, 1H),
1.39 (s, 3H).
b) 2-Bromofluoroisopropenyl-pyridine
To a solution of 2-(2-bromofluoro—pyridin-4—yl)—propanol (24.7 g, 106 mmol) and
methanesulfonic ide (55.1 g, 317 mmol) in DCM (250 ml) was added triethylamine
(58.8 ml, 42.7 g, 422 mmol). The reaction mixture was stirred at rt for 20 h. Another 1 eq. (18
g) of methanesulfonic anhydride and 1.2 eq. (17ml) of ylamine were added and the
reaction mixture was stirred an additional 20 h at rt. The on mixture was quenched with
1M aq. Na2C03 sol. and diluted with DCM. The phases were ted and the aq. phase
was acted twice with DCM. The combined org. phases were washed with brine, dried
over Na2804, filtered and concentrated. Flash tography on silica gel (hexanezEtOAc
8:1) yielded the title compound as a clear colourless liquid. HPLC RtH4= 1.12 min; ESIMS:
216, 218 [(M + H)+]; 1H NMR (400 MHz, CDCI3): 6 8.20 (d, 1H), 7.40 (d, 1H), 5.48-5.44 (m,
2H), 2.14 (s, 3H).
0) 2-(2-Bromofluoro-pyridinyl)-propane-1,2-diol
To a solution of 2-bromofluoroisopropenyl-pyridine (17.1 g, 79 mmol) in acetone (50
mL) and H20 (100 mL) was added N-methylmorpholine oxide (10.51 g, 87 mmol) and 0304
(4.97 mL, 4.02 g, 0.396 mmol). The biphasic mixture was stirred at rt for 17 h. The reaction
mixture was quenched with sodium hydrosulfite (1.516 g, 8.71 mmol) in H20 (50 ml) and
stirred at rt for 20 min. The reaction mixture was filtered h celite and the celite pad was
washed three times with acetone. The combined filtrates were evaporated and the residue
was taken up with EtOAc and 1N aq. NaOH soln. The phases were separated and the aq.
phase was reextracted with EtOAc. The combined org. phases were dried over NaZSO4,
filtered and concentrated to yield the title compound as a light purple solid. HPLC RtH4= 0.60
min; ESIMS: 250, 252 [(M + H)+]; 1H NMR (400 MHz, DMSO-ds): 6 8.32 (d, 1H), 7.71 (d, 1H),
5.57 (s, 1H), 4.89 (t, 1H), 3.65-3.57 (m, 1H), 3.53-3.45 (m, 1H), 1.39 (s, 3H).
2012/050395
_39-
d) Methanesulfonic acid 2-(2-bromofluoro-pyridinyl)hydroxy-propyl ester
To a suspension of 2—(2—bromo-5—fluoro-pyridin—4-yl)-propane—1 ,2—diol (17.45 g, 69.8 mmol)
and triethylamine (19.45 ml, 14.12 g, 140 mmol) in DCM (350 ml) at 0 °C was added
dropwise methanesulfonyl chloride (5.71 ml, 8.39 g, 73.3 mmol) over a period of 10 min. The
reaction mixture was stirred at 0 °C for 30 min, then quenched with 1M aq. NaHCOs soln..
The phases were separated, the aq. phase was twice reextracted with DCM and the
combined org. phases were washed with brine, dried over NaZSO4, filtered and concentrated.
Flash chromatography on silica gel (gradient heptane: EtOAc 0—5 min 88:12, 5-37.5 min
24:76) yielded the title nd as a clear oil. HPLC RtH4= 0.76 min; ESIMS: 328, 330 [(M
+ H)”’]; 1H NMR (400 MHz, DMSO—ds): 6 8.22 (d, 1H), 7.82 (d, 1H), 4.58-4.47 (m, 2H), 3.04
(s, 3H), 3.00 (s, 1H), 1.64 (s, 3H).
e) 1-Azido(2-bromofluoro-pyridinyI)-propanol
To a solution of methanesulfonic acid 2-(2-bromofluoro—pyridinyl)hydroxy-propy|
ester (10.36 g, 31.6 mmol) in ethanol (160 ml) was added NaN3 (5.13 g, 79.0 mmol) and
NH4C| (8.44 9, 158.0 mmol). The reaction mixture was d at 80 °C for 20 h. The reaction
mixture was d with H20 and TBME and the phases were separated. The aq. phase was
twice reextracted with TBM E, the combined org. phases were washed with brine, dried over
NaZSO4, filtered and concentrated. HPLC RtH4= 0.89 min; ESIMS: 275, 277 [(M + H)*]; 1H
NMR (400 MHz, : 6 8.20 (d, 1H), 7.80 (d, 1H), 3.81 (d, 1H), 3.65 (d, 1H), 1.61 (s, 3H).
f) Methanesulfonic acid 2-azido(2-bromof|uoro-pyridinyl)methyl-ethyl ester
At 0 °C, methanesulfonyl chloride (2.04 ml, 3.00 g, 26.20 mmol) was dropwise added to a
solution of 1-azido(2-bromofluoro—pyridinyl)-propanol (6.00 g, 21.81 mmol) and
N33 (3.65 ml, 2.65 g, 26.2 mmol) in DCM (200 ml). The reaction mixture was stirred at 0 °C
for 1 h, then for another 1 h at 0 °C to rt. The reaction mixture was quenched with 1M aq.
NaHCO3 soln. and d with DCM. The phases were separated and the aq. phase was
twice reextracted with DCM. The combined org. phases were dried over Na2804, filtered and
concentrated. HPLC purification (Alltech Grorn Saphir 65 Si 10 uM column, 250x50 mm,
nt n-heptane2EtOAc 0-1.6 min 85:15, 16-16 min 0:100, 16-212 min 0:100, flow
100ml/min, detection 254 nm) yielded the title compound as well as recovered ng
material that could be reacted again according to the above procedure. HPLC RtH4= 0.96
min; ESIMS: 353, 355 [(M + H)*]; 1H NMR (400 MHz, CDCI3): 6 8.28 (d, 1H), 7.56 (d, 1H),
4.08 (d, 1H), 3.82 (d, 1H), 3.22 (s, 3H), 2.13 (s, 3H).
g) 2-Bromofluoro[2-methyl(2-nitro-benzenesulfonyl)-aziridinyl]-pyridine
A mixture of methanesulfonic acid 2-azido(2-bromofluoro—pyridin—4—yl)methyl-ethyl
ester (2.1 g, 6.09 mmol) and PPh3 (1.597 g, 6.09 mmol) in THF (20 mL) was stirred at rt for
min. The reaction mixture was evaporated to dryness, the residue was taken up with
TBME and 10% aq. citric acid soln. The aq. phase was reextracted with TBME, the combined
org. phases were washed with H20. The combined aq. phases were basified using 2N aq.
NaOH soln. and three times extracted with TBME. The combined org. phases were dried
over Na2804, filtered and concentrated to yield 2-bromo—5—fluoro(2-methyl-aziridinyl)-
pyridine in a mixture with thO that was used for the next step without further purification,
HPLC RtH4= 0.96 min; ESIMS: 231, 233 [(M + H)”].
To a solution of crude o-5—fluoro(2—methyl-aziridinyI)-pyridine (3.17 g as a 45%
mixture with PthO, 6.17 mmol) and 2-nitrobenzenesulfonyl chloride (1.368 g, 6.17 mmol)
in THF (23.15 mL) and H20 (7.72 mL) was added N-methylmorpholine and the reaction
mixture was stirred at rt for 1.5 h. Alox neutral (2-3 spatula) was added and the reaction
mixture was filtered through celite, washed with DCM and the filtrates were diluted with DCM
and 1M aq. NaHCOs scln. The phases were separated and the aq. phase was reextracted
twice with DCM. The combined org. phases were dried over NaZSO4 and concentrated. Flash
chromatography on silica gel (heptanezEtOAc 4:1 to 3:1) followed by tallization from
EtOAc/hexaneyielded the title compound as a colourless solid. HPLC RtH4= 1.11 min;
ESIMS: 416, 418 [(M + H)"]; 1H NMR (400 MHz, CDCl;;): 6 8.31-8.30 (m, 1H), 8.23 (d, 1H),
7.86-7.77 (m, 3H), 7.68 (d, 1H), 3.28 (s, 1H), 2.78 (s, 1H), 2.09 (s, 3H).
h) [(RS)(2-Bromofluoro-pyridinyl)-2—(2—nitro-benzenesulfonylaminc)-
propoxy]-3,3,3-trifluoromethyl-propionic acid ethyl ester
To a on of ofluoro[2-methyl(2-nitro-benzenesulfonyl)—aziridin-2—yl]-
ne (795 mg, 1.91 mmol) and (R)-3,3,3-trifluorohydroxymethyl-propionic acid ethyl
ester (498 mg, 2.67 mmol) in DMF (8 ml, soln. predried over mol. sieves) was added NaH
(99 mg of a 60% sion in mineral oil, 2.48 mmol) and the reaction mixture was stirred at
rt for 3 h. The reaction mixture was quenched with aq. 1N HCl and diluted with H20 and
TBM E. The phases were separated and the aq. phase was twice ted with TBM E. The
combined org. phases were washed with H20, dried over Na2804, filtered and concentrated.
Flash chromatography on silica gel (heptanezEtOAc 1:1) yielded the title compound
(diastereomer mixture) as a colourless solid. HPLC RtH4= 1.26 min; ESIMS: 602, 604 [(M +
H)*]; 1H NMR (400 MHz, CDCI3): 5 7.99 (m, 1H), 7.95-7.93 (m, 1H), 7.79-7.61 (m, 4H), 6.94
(m, 1H), 4.45-4.33 (m, 2H), 3.94-3.81 (m, 2H), 1.85 (m, 3H), 1.61 (m, 3H), 1.40-1.34 (m, 3H).
i) (R)[(RS)(2-Bromofluoro-pyridinyl)(2-nitro-benzenesulfonylamino)-
propoxy]-3,3,3-trifluoromethyl-propionamide
A solution of (R)-2—[(RS)(2-Bromofluoro-pyridin-4—yl)—2-(2-nitro-benzenesulfonylamino)-
propoxy]-3,3,3-trifluoromethyl-propionic acid ethyl ester (920 mg, 1.527 mmol) in 7N
NH3/MeOH (11 ml) was stirred in a sealed glass vial at 55 °C for 44 h. The reaction mixture
was ated to dryness to leave a yellow solid that was used for the next step without
further purification (diastereomer mixture). RtH4= 1.03 min; ESIMS: 573, 575 [(M + H)+]; 1H
NMR (400 MHz, CDCI3): 6 8.00 (m, 1H), 7.97-7.91 (m, 1H), 7.80—7.63 (m, 3H), 7.55 (m, 1H),
6.63 (m, 1H), 6.41 (m, 1H), 5.74 (m, 1H), 4.15 (m, 1H), 3.97 (m, 1H), 1.84 (23, 3H), 1.69 (23,
3H).
j) N-[(RS)(2-Bromofluoro-pyridiny|)((R)cyano-2,2,2-trifluoromethyl-
ethoxy)methyl-ethyl]nitro-benzenesulfonamide
To a dry solution of (R)[(RS)(2-bromofluoro-pyridinyl)(2-nitro-benzenesulfonyl-
amino)—propoxy]-3,3,3-trifluoromethyl-propionamide (860 mg, 1.35 mmol) in DCM (9 ml)
was added at rt NEt3 (0.470 ml, 342 mg, 3.38 mmol). At 0 °C, trifluoroacetic ide (0.229
ml, 340 mg, 1.62 ml) was added dropwise. The on mixture was allowed to warm to rt
and to stir for 1.5 h. The reaction mixture was diluted with 1M aq. Na2C03 soln. and DCM.
The phases were separated and the aq. phase was twice reextracted with DCM. The
combined org. phases were dried over Na2804, filtered and concentrated to yield the crude
title compound as an orange solid that was used in the next step without further purification
(diastereomer mixture). RtH4= 1.19 min; ESIMS: 555, 557 [(M + H)+]; 1H NMR (400 MHz,
CDCI3): 5 8.01-7.93 (m, 2H), 7.79-7.63 (m, 3H), 7.59 (m, 1H), 4.26-4.16 (m, 2H), 1.85-1.84
(2d, 3H), 1.78-1.76 (2d, 3H).
k) (2R,5R)- and )(2-Bromofluoro-pyridinyl)-2,5-dimethyl-2—trifluoro-
methyl-5,6-dihydro-2H-[1,4]oxazinylamine
A mixture of 2-bromofluoro-pyridin—4—yl)—2-((R)cyano-2,2,2-trifluoromethyl-
ethoxy)methyl-ethyl]nitro-benzenesulfonamide (585 mg, 1.053 mmol), N-acetylcysteine
(344 mg, 2.107 mmol) and KZCO3 (291 mg, 2.107 mmol) in EtOH (7 ml) was stirred at 85 °C
for 68 h under N2. The reaction mixture was trated to 1/3 of its volume and diluted
with cold 10% aq. KZCOS soln. and TBME. The phases were separated and the aq. phase
was twice reextracted with TBME. The combined org. phases were washed with 1M aq.
NaHCO3 soln. and brine, was dried over Na2804, ed and concentrated. HPLC
purification (Alltech Grom Saphir 65 Si 10 uM column, 150x30 mm, gradient nheptanezEtOAczMeOH
0-1.2 min 2, 1.2—9 min 0:80:20, 9—12 min 0:65:35, flow: 50
ml/min, detection: 254 nm) separated the )- from the (2R,58)-diastereomer of the title
compound. RtH4= 0.70 min; ESIMS: 370, 372 [(M + H)+]; 1H NMR (400 MHz, DMSO-de):
(2R,5R)- diastereomer 6 8.39 (br s, 1H), 7.81 (d, 1H), 6.28 (br s, 2H), 3.94 (d, 1H), 3.75 (d,
1H), 1.49 (s, 3H), 1.41 (s, 3H);
(2R,5S)-diastereomer 5 8.37 (d, 1H), 7.68 (d, 1H), 6.34 (br s, 2H), 3.91 (d, 1H), 3.83 (d, 1H),
1.59 (s, 3H), 1.40 (s, 3H).
l) 5-Cyanomethyl-pyridine—2-carboxylic acid [4-((3R,6R)amino-3,6-dimethyI
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]-amide
A mixture of omethyl-pyridine—2—carboxylic acid amide (43.5 mg, 0.270 mmol),
(2R,5R)(2-bromofluoro-pyridin-4—yl)—2, 5-dimethyltrifluoromethyl-5,6-dihydro-2H-[1 ,4]—
oxazinylamine (100.0 mg, 0.270 mmol), Xantphos (14.1 mg, 0.024 mmol) and C52003
(123.0 mg, 0.378 mmol) in dioxane (2.5 ml) was degassed with argon for 5 min, then
Pd2(dba)3 (7.42 mg, 8.11 umol) was added and the reaction mixture was stirred at 60 °C for
24 h. The reaction mixture was diluted with H20 and TBME. The phases were ted and
the aq. phase was twice reextracted with TBM E. The combined org. phases were washed
with brine, dried over NaZSO4, filtered and concentrated. Prep HPLC (Alltech Grom Saphir 65
Si 10 pM column, 150x30 mm, gradient n-heptanezEtOAczMeOH 0-1.2 min 68:30:2, 1.2-9
min 0:80:20, 9 -12 min 0:65:35, flow: 50 , detection: 254 nm) yielded the parent
compound as a colourless solid. RtH4= 0.83 min; ESIMS: 451 [(M + H)+]; 1H NMR (400 MHz,
DMSO-de): 6 10.80 (br s, 1H), 8.98 (br s, 1H), 8.42 (s, 1H), 8.36 (dd, 1H), 8.30 (dd, 1H), 6.24
(br s, 2H), 3.97 (d, 1H), 3.82 (d, 1H), 2.58 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H).
The nd in Table 7 can be prepared by a procedure analogous to that used in
Example 16.
Table 7
1H-NMR
Compound
(5; DMSO-ds)
1H-NMR
Compound
(6; DMSO-ds)
.75 (s, 1H),
N\\ 8.97 (s, 1H),
8.42 (s, 2H),
UPLCMS:
8.27 (d, 1H),
RtH4 =
6.21 (br s,
0'79
2H), 3.91 (s,
-Cyanomethyl-pyridinecarboxylic acid [4- [MM] =
2H), 2.58 (s,
((38,6R)—5—amino-3,6-dimethyltrifluoromethyl-3,6— 451
3H), 1.61 (s,
o-2H-[1,4]oxazinyl)-5—fluoro-pyridin-2—y|]- -3H), 1_44 (s,
amide
3H).
Example 18: 5-Bromo-pyridinecarboxylic acid aminofluoromethyl-3,6-
dihydro-2H-[1,4]oxazinyl)chloro-pyridinyl]-amide hydrochloride
\ o 0
HM l
\ N
I NH2
/ F
N CI .HCI
a) 5-Bromochloronitromethyl—pyridine
To a solution of 5-bromobromomethylchloro-pyridine (4.10 g, 14.37 mmol) in TBME
. (50.3 ml) in a tin-foil wrapped flask was added silver nitrite (2.65 g, 17.24 mmol) and the
reaction mixture was stirred at room temperature for 15 h. The solid was filtered off, rinsed
with TBME and the filtrate was evaporated. The residue was ed by chromatography on
silica gel (cyclohexane to cyclohexane/EtOAc 3:2) to provide the title compound as pale
brown oil.
HPLC: RtH4= 0.91 min; ESIMS [M-H]'= 248.9, 251.0; 1H-NMR (600 MHz, DMSO-de): 8.71 (d,
1H), 8.40 (d, 1H), 5.92 (s, 2H).
b) 2-(5-Bromochloro-pyridinyl)nitropropane-1,3-diol
To a solution of 5-bromo-2—chloronitromethyl-pyridine (286 mg, 1.14 mmol) in dioxane
(2.3 ml) was added 35% aq. formaldehyde (215 mg, 2.50 mmol), triethylamine (0.079 ml,
0.57 mmol) and the on mixture was stirred at room temperature for 2 h, to the mixture
was added a mixture of saturated aq. NaCl and 12N HCl (0.05 ml, 0.6 mmol). Then the
e was extracted with TBME the combined organic layers were washed with saturated
aq. NaCl, dried with NaZSO4 and evaporated. The residue was purified by tography
on silica gel (cyclohexane to cyclohexane/EtOAc 1:1) to provide the title compound as
colorless solid. M.p. 162-163 °C. HPLC: RtH4= 0.69 min; ESIMS [M+H]*= 311.0, 313.0; 1H
NMR (600 MHz, DMSO—de): 8.64 (d, 1H), 8.11 (d, 1H), 5.60 (t, 2H), 4.34 (dd, 2H), 4.19 (dd,
1O 2H).
c) 2-(5-Bromochloro-pyridinyl)-2—nitropropane-1,3-diol
To a suspension of zinc dust (2.03 g, 31 mmol) in acetic acid (8.6 ml) was added dropwise
within 1 h a solution of 2-(5-bromochloro-pyridinyl)nitropropane—1,3-diol (1.61 g, 5.17
mmol) in acetic acid (17.3 ml) and DMF (5.2 ml), while maintaining the temperature between
and 40 °C (ice cooling), the reaction mixture was stirred at 40 °C for 1.5 h. The mixture
was filtered, the residue rinsed with methanol and at 0 °C the filtrate poured on a 1:1 mixture
of EtOAc and saturated aq. NaHCOa. The pH was adjusted to 12 by addition of 1N NaOH,
the layers separated and the aq. phase extracted with EtOAc. The combined organic layers
were washed with saturated aq. NaCl, dried with Na2804 and evaporated to provide the title
compound as yellow solid.
HPLC: RtH5= 0.22 min; ESIMS = 281.0, 283.0; 1H NMR (400 MHz, DMSO—de): 8.43 (d,
1H), 8.38 (d, 1H), 4.80 (t, 2H), 3.93 (dd, 2H), 3.67 (dd, 2H), 2.18 (br. s, 2H).
d) N-[1-(5-Bromochloro-pyridinyl)hydroxyhydroxymethy|-ethyl]chloro-
acetamide
To a suspension of 2-(5—bromo—2—ch|oro-pyridinyl)nitropropane—1,3—diol (904 mg, 3.21
mmol) in DCM (64 ml) was added pyridine (2.6 ml, 32.1 mmol), after g to —30 °C a
solution of chloro—acetylchloride (1.022 ml, 12.84 mmol) in DCM (32 ml) was added within 10
min., the reaction e was stirred at -30 °C for 1.5 h. At -30 °C 1M HCI and DCM was
added, the layers were separated, the aq. phase extracted with DCM and the combined
c layers washed with halfsaturated aq. NaHCO3 and halfsaturated aq. NaCl, dried with
NaZSO4 and evaporated. The obtained per-acetylated product was dissolved in methanol
(19.3 ml) and K2003 powder (222 mg, 1.6 mmol) added, the mixture was stirred at room
temperature for 30 min. After on of 1M HCI and TBME the layers were separated, the
aq. layer was extracted with TBME, the combined organic layers were washed with
2012/050395
halfsaturated aq. NaCl, dried with NaZSO4 and evaporated. The residue was purified by
chromatography on silica gel (cyclohexane/EtOAc 1:0 to cyclohexane/EtOAc 0:1) to provide
the title compound as colorless solid.
HPLC: RtH5= 0.51 min; ESIMS = 356.9, 358.9; 1H NMR (600 MHz, DMSO-de): 8.44 (d,
1H), 8.27 (s, 1H), 7.99 (s, 1H), 5.08 (t, 2H), 4.11 (s, 2H), 4.00 - 3.95 (m, 2H), 3.94 - 3.89 (m,
2H).
e) 5-(5-Bromochloro-pyridinyl)hydroxymethyl-morpholinone
To a suspension of N—[1-(5-bromo—2-chloro-pyridinyl)—2-hydroxyhydroxymethyl-ethyl]
chloro-acetamide (622 mg, 1.74 mmol) in tert.-butanol (10.2 ml) was added at 0 °C
potassium tert.-butoxide (292 mg, 2.61 mmol), the reaction mixture was stirred at room
temperature for 1 h. Water was added and the tert.-butano| evaporated, the mixture was
ted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl,
dried with NaZSO4 and evaporated to provide the title compound as beige foam.
HPLC: RtH4= 0.58 min; ESIMS [M+H]+= 320.9, 322.9; 1H NMR (600 MHz, DMSO-ds): 8.56 (d,
1H), 8.39 (s, 1H), 8.21 (d, 1H), 5.44 (t, 1H), 4.42 (d, 1H), 4.04 (s, 2H), 3.94 (dd, 1H), 3.90 (d,
1H), 3.86 (d, 1H).
f) 5-(5-Bromochloro-pyridinyl)f|uorom'ethyl-morpholinone
To a suspension of 5-(5-bromochloro-pyridin-3—yI)hydroxymethyl-morpholinone (547
mg, 1.70 mmol) in THF (13.6 ml) was added at 0 °C within 5 min a on of DAST (1.01
ml, 7.65 mmol) in THF (7.2 ml), the reaction mixture was stirred at room temperature for 6 h.
The mixture was cooled to 0 °C, halfsaturated aq. Na2C03 was added and the mixture was
extracted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl,
dried with Na2804 and evaporated. The residue was purified by chromatography on silica gel
(cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as colorless solid.
HPLC: RtH5= 0.66 min; ESIMS [M-H]'= 320.8, 322.8; 1H NMR (600 MHz, DMSO-de): 8.80 (s,
1H), 8.63 (d, 1H), 8.12 (d, 1H), 5.01 - 4.93 (m, 1H), 4.92 - 4.85 (m, 1H), 4.37 (dd, 1H), 4.10
(s, 2H), 3.95 (d, 1H).
9) 5-[5-(Benzhydrylidene-amino)ch|oro-pyridin-3—yl)fluoromethyl-morpholinone
To a solution of romochloro-pyridin-3—yl)—5-fluoromethyl-morpholinone (199 mg,
0.615 mmol), benzophenone imine (86 mg, 0.473) and C52C03 (620 mg, 1.89 mmol) in
toluene (4.6 ml) and e (4.6 ml) was added Pd2(dba)3 (22 mg, 0.024 mmol) and
Xantphos (41 mg, 0.071 mmol) and the mixture was purged with nitrogen, the reaction
mixture was heated to 100 °C for 4 h. After cooling to 0 °C water was added and the mixture
—96-
was extracted with EtOAc, the combined organic layers were washed with water, dried with
NaZSO4 and evaporated. The residue was purified by chromatography on silica gel
(cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as yellowish foam.
HPLC: RtH5= 1.11 min; ESIMS = 424.1; 1H NMR (600 MHz, DMSO—de): 8.71 (s, 1H),
7.80 (s, 1H), 7.70 (d, 2H), 7.58 (t, 1H), 7.50 (t, 2H), 7.36 (d, 4H), 7.16 (d, 2H), 4.87 - 4.70 (m,
2H), 4.28 (d, 1H), 4.04 (d, 1H), 3.93 (d, 1H), 3.80 (d, 1H).
h) 5-(5-Aminochloro-pyridinyl)fluoromethyl-morpholinethione
To a solution of 5—[5-(benzhydrylidene-amino)chloro-pyridinyl)—5—fluoromethyl-
morpholin—3-one (206 mg, 0.467 mmol) in THF (2.4 ml) was added Lawessons’s reagent
(189 mg, 0.467 mmol), the reaction mixture was heated to reflux for 1 h. The solvent was
evaporated and the crude product ved in THF (12 ml), 2M HCI (6.3 ml) were added and
the mixture stirred at room temperature for 17 h. After cooling to 0 °C aq. 2M K2C03 was
added and the basic mixture was ted with EtOAc, the combined organic layers were
washed with halfsaturated aq. NaCl, dried with NaZSO4 and evaporated. The residue was
ed by chromatography on silica gel (cyclohexane/EtOAc 1:0 to exane/EtOAc 0:1)
to provide the title compound as beige foam.
HPLC: RtH5= 0.59 min; ESIMS [M+H]+= 276.0; 1H NMR (600 MHz, DMSO—de): 10.99 (s, 1H),
7.70 (d, 1H), 7.08 (d, 1H), 5.76 (s, 2H), 4.99 (dd, 1H), 4.82 (dd, 1H), 4.46 - 4.35 (m, 3H), 3.96
(d, 1H).
i) 5-Bromo-pyridinecarboxylic acid oro(3-fluoromethylthioxo-morpholin-
3-yl)-pyridinyl]-amide
A on of 5—(5-amino—2-chloro—pyridinyl)fluoromethyl-morpholine—3—thione (33 mg,
0.12 mmol), 5-bromo-pyridinecarboxylic acid (36 mg, 0.18 mmol) and HOAt (29 mg, 0.215
mmol) in DMF (0.4 ml) was cooled to 0 °C and DIPEA (0.042 ml, 0.24 mmol) and EDC (34
mg, 0.18 mmol) were added, the reaction mixture was stirred at 0 °C for 10 min, then allowed
to warm to room temperature over night. At 0 °C aq. 1M KHC03 was added and the mixture
extracted with toluene. The combined organic layers were washed with water, dried with
Na2804 and evaporated. The residue was taken up in DCM/MeOH 65/35 from which the
product started to crystallize. Filtration, rinsing of the crystallized material with DCM and
drying provide the title compound as yellow crystals.
TLC (cyclohexane / EtOAc 1:1) R, = 0.45; HPLC: RtH5= 1.08 min; ESIMS [M+H]*= 458.9,
461.0.
j) 5-Bromo-pyridinecarboxylic acid [5-(5-aminofluoromethyl-3,6-dihydro-2H-
[1 ,4]oxazinyl)chloro-pyridinyl]-amide hydrochloride
To a suspension of 5—bromo-pyridinecarboxylic acid [6-chloro(3-fluoromethylthioxo-
morpholinyl)-pyridin-3—yl]-amide (26 mg, 0.057 mmol) in 7M NH3 in MeOH (0.23 ml) was
added at -20 °C, tert.—butylhydroperoxide (0.055 ml, 0.566 mmol) and aq. 25% NH3 (0.15 ml,
0.99 mmol), the reaction mixture was stirred at room temperature for 80 min, 7M NH3 in
MeOH (0.69 ml) were added and stirring continued for 20 h. At 0 °C halfsaturated aq.
3 was added and the mixture extracted with EtOAc. The combined organic layers
were washed with halfsaturated aq. NaCl, dried with NaZSO4 and evaporated. The residue
was purified by preparative TLC OH 9:1 toyield the d compound as colorless
foam. The product was dissolved in DCM/MeOH, 5 equivalents of 5M HCI in EtZO were
added and the solvents evaporated to provide the title compound as beige solid.
TLC (DCM / MeOH 9:1) Rf: 0.22; HPLC: RtH5= 0.71 min; ESIMS [M+H]+= 442.0, 443.9; 1H
NMR (600 MHz, DMSO-de): 11.12 (s, 1H), 8.88 (d, 1H), 8.86 (s, 1H), 8.65 (d, 1H), 8.35 (dd,
1H), 8.09 (d, 1H), 6.02 (br. s, 2H), 4.80 - 4.66 (m, 2H), 4.13 - 3.93 (m, 4H).
Example 19: 3-Aminocyano-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-
dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide
\ o&F
/ _
' H F
\ N
\v‘“ N/
I NH2
NH2 0 /
a) (2R,5R)(6-Amino-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-dihydro-2H-
[1,4]oxazinylamine
To a suspension of (2R,5R)(6-bromo-pyridin-Z-yl)-2,5-dimethyI-Z-trifluoromethyl-5,6-
dihydro—2H—[1,4]oxazinylamine (6.0 g, 17.04 mmol, Example 8 step h) , CuZO (0.122 g,
0.852 mmol), K2C03 (0.471 g, 3.41 mmol) and N,N'-dimethylethylenediamine (0.15 g, 1.704
mmol) were suspended in ethylene glycol (34 ml) were added 53 ml aq. NH3 (25% w). The
flask was sealed and the suspension was stirred to 60 °C for 20 h. A green on was
obtained. It was occasionally necessary to shake the flask to make sure that all insoluble
parts went in solution. The e was partitioned between water and EtOAc. The aq. phase
was extracted with EtOAc, the combined org layers were washed with brine, dried with
Na2804 and ated to give 5.11 g of a green resin, which was purified by
chromatography on silica gel -4% (EtOH 25%aq NH3 9:1)) to give 2.77 g of the title
compound as a colorless foam.
HPLC: RtHz = 2.480 min; ESIMS: 289 +]; 1H-NMR (600 MHz, DMSO-de): 7.31 (t, 1H),
6.63 (d, 1H), 6.27 (d, 1H), 5.89 (br s, 2H), 5.77 (br s, 2H), 3.90 (d, 1H), 3.65 (d, 1H), 1.40 (s,
3H), 1.28 (s, 3H).
b) [(2R,5R)(6-Amino-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-dihydro-2H-
[1 ,4]oxazinyl]-carbamic acid tert-butyl ester
A solution of (2R,5R)—5—(6-amino-pyridinyl)-2,5-dimethyl-2—trifluoromethyl-5,6-dihydro-2H-
xazinylamine (2.77 g, 9.61 mmol), Boc20 (2.31 g, 10.57 mmol) and DIPEA (2.2 mi,
12.5 mmol) in DCM (28 ml) and THF (2 ml) was stirred for 3 days. The mixture was
’IO ated and purified by chromatography on silica gel (hexanes/10-20% EtOAc) to give
3.34 g of the title compound as a colorless solid. HPLC: RtHs = 3.048 min; ESIMS: 389
[(M+H)"]; 1H-NMR (600 MHz, DMSO-de): 10.88 (s, 1H), 7.43 (t, 1H), 6.48 (d, 1H), 6.41 (d,
1H), 6.01 (br s, 2H), 4.16 (d, 1H), 4.11 (d, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.45 (s, 9H).
c) ((2R,5R)—5-{6-[(3-Amino-5—cyano-pyridinecarbonyl)-amino]-pyridinyl}-2,5-
dimethyl-Z-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazinyl)—carbamic acid tert-butyl
ester
A e of [(2R,5R)(6-amino-pyridin-2—yl)—2,5-dimethyltrifluoromethyl-5,6-dihydro-2H-
[1,4]oxazinyl]-carbamic acid utyl ester (80 mg, 0.206 mmol), 3-aminocyano-
pyridinecarboxylic acid (40.3 mg, 0.247 mmol, Acid-4, HOAt (50.5 mg, 0.371 mmol) in
DMF (1 ml) and EDC.HCI (59.2 mg, 0,309 mmol) was stirred overnight. The reaction mixture
was diluted with EtOAc, washed with aq. NaHC03 and brine, and dried with M9804.H20. The
title compound was obtained after chromatography on silica gel (toluene/1-3% EtOAc) to give
71 mg of the title compound as a pale yellow solid slightly contaminated with some starting
material. HPLC: Rtm = 3.608 min; ESIMS: 534 *]; 1H-NMR (600 MHz, CDCI3): 10.92
(s, 1H), 8.29 (d, 1H), 8.18 (s, 1H), 7.82 (t, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 6.33 (br, 1H), 4.39
(d, 1H), 4.12 (d, 1H), 1.66 (s, 3H), 1.60 (s, 9H), 1.59 (s, 3H).
d) 3-Aminocyano-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-dimethyl
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide
To a solution of ((2R,5R)—5-{6-[(3-amino-5—cyano-pyridine—2—carbonyl)—amino]—pyridin—2—yl}-
2,5-dimethyl-2—trifluoromethyl-5,6—dihydro-2H-[1,4]oxazin-3—yl)-carbamic acid tert—butyl ester
(71 mg, 0.133 mmol) in DCM (3 ml) was added TFA (1 ml). After stirring for 1.5 h the mixture
was poured onto 10% aq. Na2C03 and extracted three times with DCM. The combined
organic layers were dried with K2CO3, filtered and evaporated. The title compound (46 mg)
was obtained after chromatography on silica gel (hexanes/15-25% /EtOH 9:1)) as a
yellow solid. HPLC: mm = 3.027 min; ESIMS: 434 [(M+H)"]; 1H-NMR (600 MHz, e):
.23 (s, 1H), 8.25 (s, 1H), 8.06 (d, 1H), 7.85 (t, 1H), 7.69 (s, 1H), 7.36 — 7.27 (m, broad,
3H), 6.12 —6.00, (s, broad, 2H), 3.94 (d, 1H), 3.76 (d, 1H), 1.42 (s, 3H), 1.34 (s, 3H).
Examples 20 to 23: The compounds listed in Table 8 can be prepared by a procedure
analogous to that used in Example 19.
Hydrochloride salts were obtained from solutions of the ponding free base by addition
of hydrochloric acid in dioxane or hydrochloric acid in diethylether and evaporation of the
solvents.
Table 8
0 (6;DMSO-d5):11.04
/ N '
| H (br s, 1H), 9.07 (s,
\ N N
w / UPLCMSZ
U“ N NHZ 1H),8.78(s,1H),8.02
RtH4 =
0' 0 / (d, 1H), 7.86-7.82 (m,
0.78
3-ChIorocyano-pyridinecarboxylic acid 1H), 7-34 (d. 1H), 5-02
[M+1] =
[6-((3R,6R)amino-3,6-dimethyl (br 5, 2H): 3-92 (d:
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin 1H), 3.73 (d, 1H). 1.41
yl)-pyridinyl]-amide (s, 3H), 1.32 (s, 3H)
(8; DMSOd6; 600
MHz): 10.41 (s, 1H),
LCMS:
8.08 (d, 1H), 7.83 (t,
RtHS =
1H), 7.30 (d, 1H), 6.10
-Chloro-4,6-dideuterio—3—trideuteriomethyl- 3.367
— 5.98, (s, broad, 2H),
pyridinecarboxylic acid [6-((3R,6R) [M+1] =
3.94 (d, 1H), 3.74 (d,
amino-3,6-dimethyItrifluoromethyI-3,8- 447, 449
1H), 1.42 (s, 3H), 1.33
o-2H-[1 ,4]oxazin-3—yl)—pyridinyl]- (s, 3H).
(5; DMSO—de; 600
MHz): 10.86 (s, 1H),
LCMSI
8.78 (s, 1H), 8.53 (s,
RtH3 =
1H), 8.02 (d, 1H), 7.84
3.180
(t, 1H), 7.28 (d, 1H),
—Bromochloro-pyridine-2—carboxylic acid [M+1] =
6 10 _ 6 01 (s broad
trifluoromethyi-3,6-dihydro-2H-[1,4]oxazin 510
(d 1H) 1 41 (5 3H)
y|)-pyridinyI]-amide 1.32 (S, 3H).
(5; DMSO—de; 600
MHz): 9.88 (s, 1H),
8.05 — 7.72 (s, broad,
2H), 8.03 (d, 1H), 7.82
(t, 1H), 7.72 (s, 1H),
7.28 (d, 1H), 6.08 —
3-Amino(2,2,2-trifluoro-ethoxy)—pyrazine-
6.01, (s, broad, 2H),
2-carboxyiic acid [8-((3R,6R)amino-3,6-
.03 (q, 2H), 3.92 (d,
dimethyltrifluoromethyI-S,6—dihydro—2H-
1H), 3.74 (d, 1H), 1.41
[1 ,4]oxazinyl)-pyridinyl]-amide
(s, 3H), 1.33 (s, 3H).
Example 24: 3-Chlorocyano-pyridine-Z-carboxylic acid [6-((3R, 6R)amino-3,6-
dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridin-Z-yl]-amide
mugs
a) (2R, 5R)(6-Aminofluoro-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-
dihydro-2H-[1,4]oxazinyl amine and (2R, 58)—5-(6-Aminofluoro-pyridinyl)-2,5-
dimethyltrifluoromethyl-5,6-dihydro-2H-[1,4]oxazin—3-y| amine
A glass/stainless steel autoclave was purged with nitrogen and then a mixture of )—5-
(6-bromo-3—fl uoro-pyridin-Z-yl)-2,5-dimethyl-2—trifluoromethyl—5,6—dihydro—2H-[1,4]oxazin-3—
ylamine and (2R,5R)(6-Bromofluoro-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-
dihydro-2H-[1,4]oxazinylamine (13.3 g, 35.9 mmol, ca. 1:3 mixture, Example 11 (step k) or
see alternative procedure below), CuZO (1.271 g, 8.88 mmol) and a (150 ml, 25%,
aq., 1078 mmol, 30 equivalents) in ne glycol (215 ml) was added. The autoclave was
closed and the suspension heated up to 60 °C and the solution was d for about 48
hours (max. Pressure 0.9 bar, inside temperature 58-60 °C). The reaction mixture was
diluted with ethyl acetate and water. The organic phase was washed with water and brine,
dried over sodium sulfate, filtered and evaporated. The dark green crude product (13.64 g,
containing some ethylen glycol, quantitative yield) was used in the next step without further
pufificafion.
LCMS: RtH4 = 0.62 min (23%, ES+ 307) and mm = 0.65 min (74%, ES+ 307)
b) [(2R, 5R)(6-Aminofluoro-pyridinyl)-2,5-dimethyltrifluoromethyl-5,6-
o-2H-[1,4]oxazinyl] -carbamic acid tert-butyl ester and [(2R, 58)(6-Amino-
fluoro-pyridin-Z-yl)-2,5-dimethyl~2-trifluoromethyI-5,6-dihydro-2H-[1,4]oxazinyl] —
carbamic acid tert-butyl ester
A sclution of (2R, (6—aminofluoro—pyridinyl)—2,5-dimethyltrifluoromethyl-5,6-
dihydro—2H-[1,4]oxazinyl amine and (2R, 5S)(6-Aminofluoro-pyridinyl)—2,5-
dimethyl-2—trifluoromethyI-5,6-dihydro-2H-[1,4]oxazinyl amine (10.99 g, 35.9 mmol, ca.
3:1 mixture), Boczo (7.05 g, 32.3 mmol) and HiJnig’s base (7.52 ml, 43.1 mmol) in
dichloromethane (120 ml) was stirred at 0 °C for 4 hours and then at rt over night. The
reaction mixture was evaporated and the residue was diluted with ethyl acetate. Crushed ice
was added and the mixture was washed with water and brine, dried over sodium sulfate,
filtered and evaporated. The crude product (14.23 g) was ated with toluene / cyclo-
hexane lethyl acetate 4:4:2, cooled and filtered. 5.14 g colorless solid. The filtrate was
evaporated and the ing mixture was filtered over silica (TBME) to give the 2 isomers as
an 8:2 mixture (6.31 g). The colorless solid (5.14 g) was dissolved in romethane and
chromatographed over silicagel (toluene/cyclohexane/ethyl acetate 4:4:2) to afford the two
isomers.
[(2R, 5R)(6-Aminofluoro-pyn‘din—2—yl)-2,5-dimethyItn'fluoromethy/-5,6-dihydro-2H-
[1,4]oxazinyl]-carbamic acid tert-buty/ ester: 1.38 g, TLC Rf=0.16 (toluene:cyclohexane
:ethyl acetate 4:422), [01] -86.4°, c=0.975 (19.5 mg in 2 ml CHCI3), LC/MS .17 min
(100%, ES+ 407/408), HPLC chiral (CHIRACEL oj-h, heptane/ethanol/methanol 80:10:10 +
0.1 % dea) Rt=3.937 min (99.16%),% ee 98.3%. 1H-NMR (400 MHz, CDCI3): 11.50 (s, 1H,
NH), 7.24 (t, 1 H), 6.47 (br. d, 1H), 4.55 - 4.40 (br. s, 2H, NH2), 4.35 (d, 1H, AB), 4.10 (d, 1H,
AB—system), 1.71 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.55 (s, 9H).
[(2R, 5S)(6-Aminofluoro-pyridinyl)-2,5-dimethyltn'fluoromethyI-5, 6-dihydro-2H-
[1,4]oxazin-3—yI]-carbamic acid tert-butyl ester: 1.12 g, TLC Rf=0. 19 (toluene:cyclohexane
:ethyl acetate 424:2), [or] +72.9°, c=1.01 (20.2 mg in 2 ml , LC/MS .16 min
(100%, ES+ 407/408), HPLC chiral (CHIRACEL oj-h, heptane/ethanol/methanol 80:10:10 +
0.1 % dea) Rt=5.36 min (99.44%),% ee 98.9%. 1H-NMR (400 MHz, CDCI3): 11.65 (s, 1H,
NH), 7.23 (t, 1H), 6.47 (br. d, 1H), 4.55 — 4.40 (br. s, 2H, NH2), 4.35 (dd, 1H, AB), 4.24(d, 1H,
AB—system), 1.78 (s, 3H, CH3), 1.70 (s, 3H, CH3), 1.58 (s, 9H).
Mixed fractions (2.53 g) and recovered material from the filtrate (6.31 g) were purified
separately affording additional 4.13 g of [(2R, 5R)(6-aminofluoro—pyridin-2—yl)—2,5-
dimethyl-2—trifluoromethyl-5,6-dihydro-2H-[1,4]oxazinyl]-carbamic acid tert—butyl ester and
1.07 g of [(2R, 58)—5—(6—aminofluoro-pyridin-2—yI)—2,5—dimethyl—2-trifluoromethyl—5,6-
dihydro-2H-[1,4]oxazinyl]-carbamic acid tert-butyl ester.
c) ((2R, 5R){6-[3-ChIorocyano-pyridinecarbony|)-amino]f|uoro-pyridin-Z-yl}-
2,5-dimethyltrifluoromethyl-5,6-dihydro-2H-[1,4]oxazinyl)-carbamic acid tert-butyl
ester
A e of [(2R, 5R)(6—aminofluoro-pyridin—2—yI)-2,5-dimethyltrifluoromethyI-5,6-
o—2H-[1,4]oxaziny|]-carbamic acid tert—butyl ester (406 mg, 0.999 mmol), 3-chloro-5—
cyanopicolinic acid (201 mg, 1.099 mmol), HOAt (245 mg, 1.798 mmol) and EDC
hydrochloride (287 mg, 1.499 mmol) was stirred in DMF (10.2 ml) at rt for 44 hours. The
reaction mixture was diluted with toluene and washed with sat. aq. sodium onate
solution, water and brine, dried over sodium sulfate, filtered and evaporated. The crude
product (595 mg) was chromatographed over silicagel (toluene: ethyl e 9:1) to yield the
title compound: 455 mg (76% yield).
TLC (silica, toluenezethyl acetate 9:1) Rf=0.28; ESIMS [M+H]+ 571, 573;
1H-NMR (400 MHz, CDCI3): 11.7 (s, 1H, NH), 10.33 (s, 1H), 8.80 (s, 1H), 8.45 (br. d, 1H),
8.24 (s, 1H), 7.60 (br. t, 1H), 4.40 (d, 1H, AB), 4.20 (d, 1H, AB), 1.75 (s, 3H), 1.68 (s, 3H),
1.62 (s, 9H).
d) rocyano-pyridinecarboxylic acid [6-((3R,6R)amino-3,6-dimethyl
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]-amide
1O A mixture of ((2R, 5R)-5—{6—[3-chlorocyano-pyridinecarbonyl)-amino]—3-fluoro-pyridin ‘
yl}-2,5-dimethyltrifluoromethyl-5,6-dihydro—2H-[1,4]oxazinyl)-carbamic acid tert-butyl
ester (450 mg, 0.788 mmol) and TFA (0.90 ml, 11.68 mmol) in dichloromethane (9 ml) was
stirred at rt for 5 hours. The solvent was evaporated and the e diluted with ethyl
acetate and aq. ammonia. Ice was added and the organic phase was washed with water and
brine, dried over sodium sulfate, filtered and evaporated. ess solid: 360 mg (96%
yield).
LC-MS: RtH4= 0.79 min (99 %, ES|+ 471, 473);
1H—NMR (400 MHz, CDCI3): 10.2 (br. s, 1H, NH), 8.85 (d, 1H), 8.35 (dd, 1H), 8.20 (d, 1H),
7.50 (dd, 1H), 4.32 (d, 1H, AB), 3.93 (d, 1H, AB), 1.64 (s, 3H), 1.54 (s, 3H).
Alternative stereoselective procedure for the preparation of (2R,5R)—5-(6-bromo
fluoro- 2- I -2 5-dimeth ifluorometh l-5 6-dih dro-2H- 1 4 oxazin lamine
a) 2-Bromofluorotriethylsilanyl-pyridine
A solution of diisopropylamine (25.3 g, 250 mmol) in 370 ml THF was cooled with a dry-ice
acetone bath at -75 °C. BuLi (100 ml, 250 mmol, 2.5 M in hexanes) was added dropwise
while maintaining the temperature below —50 °C. After the temperature of the mixture had
reached -75 °C again, a solution of o-5—fluoropyridine (36.7 g, 208 mmol) in 45 ml
THF was added dropwise. The mixture was stirred for 1 h at -75 °C. Triethylchlorosilane
(39.2 g, 260 mmol) was added quickly. The temperature stayed below -50 °C. The g
bath was removed and the reaction mixture was allowed to warm to -15 °C, poured onto aq.
NH4CI (10%). TBME was added and the layers were separated. The organic layer was
washed with brine, dried with M9804.H20, filtered and evaporated to give a brown liquid
which was distilled at 0.5 mm Hg to yield the title compound as a slightly yellow liquid (b.p.
-1o4-
105-111 °C). HPLC: RtH11 = 2.284 min; ESIMS: 290, 292 [(M+H)+, 1Br];1H-NMR (400 MHZ,
CDCIg): 8.14 (s, 1H), 7.40 (d, 1H), 1.00-0.82 (m, 15H).
b) 1-(6-Bromofluorotriethylsilanyl-pyridinyl)-ethanone
A solution of diisopropylamine (25.4 g, 250 mmol) in 500 ml THF was cooled to -75 °C. BuLi
(100 ml, 250 mmol, 2.5 M in hexanes) was added se while maintaining the
temperature below -50 °C. After the reaction temperature had reached -75 °C again, a
solution of 2-bromofluorotriethylsilanyl-pyridine (56.04 g, 193 mmol) in 60 ml THF was
added dropwise. The mixture was d in a dry ice bath for 70 minutes. N,N—
dimethylacetamide (21.87 g, 250 mmol) was added quickly, the reaction temperature rose to
-57 °C. The reaction mixture was stirred in a dry ice bath for 15 min and then allowed to
warm to -40 °C. ltwas poured on a mixture of 2M aq. HCI (250 ml, 500 mmol), 250 ml water
and 100 ml brine. The mixture was extracted with TBME, washed with brine, dried over
H20, filtered and evaporated to give a yellow oil which was purified on a silica gel
column by eluting with hexane/0—5% TBME to yield 58.5 g of the title compound as a yellow
liquid. TLC (Hex/TBME 99/1): Rf: 0.25; HPLC: RtH11 = 1.921 min; ESIMS: 332, 334 [(M+H)",
1Br]; 1H-NMR (400 MHz, CDCI3): 7.57 (d, 1H), 2.68 (s, 3H), 1.00-0.84 (m, 15H).
c) (S)(6-Bromofluorotriethylsilanyl-pyridin-Z-yl)trimethylsilanyloxy-
propionitrile
At first, the catalyst solution was prepared by dissolving water (54 mg, 3.00 mmol) in 100 ml
dry DCM ( $0.001 % . This wet DCM (44 ml, 1.32 mmol water content) was added to a
well d solution of titanium(lV) butoxide (500 mg, 1.47 mmol) in 20 ml dry DCM. The
resulting clear solution was refluxed for 1 h. This solution was then cooled to rt and 2,4—di-
tert-butyl{[(E)—(S)hydroxymethylmethyl-propylimino]-methy|}-pheno| [CAS
6] (469 mg, 1.47 mmol) was added. The resulting yellow solution was d at rt for 1 h.
This catalyst solution (0.023 M, 46.6 ml, 1.07 mmol) was added to a solution of 1-(6-bromo-
3—fluorotriethylsilanyl-pyridinyl)-ethanone (35.53 g, 107 mmol) and trimethylsilyl cyanide
(12.73 g, 128 mmol) in 223 ml dry DCM. The mixture was d for 2 days and evaporated
to give 47 g of the crude title compound as an orange oil. HPLC: Rtmz = 2.773 min; ESIMS:
431, 433 [(M+H)*, 1Br]; 1H-NMR (400 MHz, CDCla): 7.46 (d, 1H), 2.04 (s, 3H), 1.00 (t, 9H),
1.03-0.87 (m, 15H), 0.20 (s, 9H).
d) (R)Amino(6-bromofluorotriethylsiIanyl-pyridin-2—yl)-propano|
hydrochloride
—105-
Borane yl sulfide complex (16.55 g, 218 mmol) was added to a solution of crude (S)—2-
(6-bromo—3-fluoro—4—triethylsilanyI-pyridinyl)-2—trimethylsilanyloxy—propionitrile (47 g, 109
mmol) in 470 ml THF. The mixture was d for 2 h. The heating bath was removed and
the reaction mixture was ed by careful and dropwise addition of MeOH. After the
evolution of gas had ceased, aq. 6M HCl (23.6 ml, 142 mmol) was added slowly. The
resulting solution was evaporated and the residue was dissolved in MeOH and evaporated
(twice) to yield 44.5 g of a yellow foam, pure enough for further reactions. HPLC: Rtm =
2.617 min; ESIMS: 363, 365 [(M+H)*, 1Br]; 1H-NMR (400 MHz, CDCI3): 7.93 (3, br, 3H), 7.53
(d, 1H), 6.11 (3, br, 1H), 3.36-3.27 (m, 1H), 3.18-3.09 (m, 1H), 1.53 (s, 3H), 0.99-0.81 (m,
15H).
e) (R)-N-(2-(6-bromofluoro(triethylsilyl)pyridinyl)hydroxypropyl)
nitrobenzenesulfonamide
To a solution of crude (R)amino—2-(6-bromo—3-fluoro—4—triethylsilanyl-pyridinyl)-propan-
2-ol hydrochloride (43.5 g, 109 mmol) in 335 ml THF was added a solution of NaHC03 (21.02
g, 250 mmol) in 500 ml water. The mixture was cooled to 0-5 °C and a solution of 4-
nitrobenzenesulfonyl de (26.5 g, 120 mmol) in 100 ml THF was added in a dropwise.
The resulting emulsion was stirred overnight while allowing the temperature to reach rt. The
mixture was extracted with TBME. The organic layer was dried with MgSO4.HZO, filtered and
evaporated to give an orange resin which was d on a silca gel column by g with
Hexanes/10-20% EtOAc to yield 37.56 g of the title compound as a yellow resin. TLC
(Hex/EtOAc 3/1) Rf: 0.34; HPLC: RtH11 = 1.678 min; ESIMS: 548, 550 [(M+H)+, 1Br]; 1H-
NMR (400 MHz, DMSO-de): 8.40 (d, 2H), 8.06 (t, 1H), 7.97 (d, 2H), 7.45 (d, 1H), 5.42 (s, 1H),
3.23 (d, 2H), 1.44 (s, 3H) 0.97-0.81 (m, 15H); Chiral HPLC (Chiralpak AD-H 1213, UV 210
nm): 90% ee.
f) 6-Bromofluoro[(S)—2-methy|(4-nitro-benzenesulfonyl)—aziridinyl]
triethylsilanyl-pyridine
A on of triphenylphosphine (21.55 g, 82 mmol) and (R)—N-(2-(6-bromo—3—fluoro—4-
(triethylsilyl)pyridinyl)hydroxypropyl)nitrobenzenesulfonamide (37.56 g, 69 mmol) in
510 ml THF was cooled to 4 °C. A solution of diethyl azodicarboxylate in toluene (40% by
weight, 38.8 g, 89 mmol) was added in a dropwise while maintaining the temperature below
°C. The cooling bath was removed and the rm was stirred at rt for 1 h. The reaction
mixture was diluted with . 1000 ml toluene and THF was removed by evaporation at
the rotavap. The resulting toluene solution of crude t was pre-purified on a silca gel
column by eluting with s/5-17% EtOAc. Purest fractions were combined, evaporated
and crystallized from TBME/hexane to yield 29.2 g of the title compound as white crystals.
HPLC: RtH11 = 2.546 min; ESIMS: 530, 532 [(M+H)“, 1Br]; 1H-NMR (400 MHz, CDCI3): 8.40
(d, 2H), 8.19 (d, 2H), 7.39 (d, 1H), 3.14 (s, 1H), 3.02 (s, 1H), 2.01 (s, 3H) 1.03— 0.83 (m,
15H); a[D] -35.7° (c = 0.97, DCM).
g) 6-Bromofluoro[(S)methyl(4-nitro-benzenesulfonyl)-aziridinyl]-pyridine
Potassium fluoride (1.1 g, 18.85 mmol) was added to a solution of 6-bromo-3—fluoro-2—[(S)
methyl(4-nitro-benzenesulfonyl)—aziridinyl]—4-triethylsiIanyl-pyridine (5 g, 9.43 mmol)
and AcOH (1.13 g, 9.43 mmol) in 25 ml TH F. DMF (35 ml) was added and the sion
was d for 1 h at rt. The reaction mixture was poured onto a mixture of sat. aq. NaHCOs
and TBME. The layers were separated and washed with brine and TBME. The combined
organic layers were dried over MgSO4H20, filtered and evaporated to give a yellow oil which
was crystallized from TBM E/hexane to yield 3.45 g of the title compound as white crystals.
HPLC: RtH13 = 2.612 min; ESIMS: 416, 418 +, 1Br]; 1H-NMR (400 MHz, CDCl3): 8.41
(d, 2H), 8.19 (d, 2H), 7.48 (dd, 1H), 7.35 (t, 1H), 3.14 (s, 1H), 3.03 (s, 1H), 2.04 (s, 3H); o[D] -
.7° (c = 0.89, DCM).
h) (R)[(R)(6-Bromofluoro-pyridinyl)(4-nitro-benzenesulfonylaminc)-
propoxy]-3,3,3-trifluoromethyl-propionic acid ethyl ester
A solution of (R)-3,3,3-trifluorohydroxymethyl-propionic acid ethyl ester (11.93 g, 64.1
mmol) in DMF (158 ml) was ted/flushed with nitrogen twice. A solution of KOtBu (6.21
g, 55.5 mmol) in DMF (17 ml) was added in a se while maintaining a reaction
temperature of ca 25 °C using cooling with a water bath. After 15 min solid 6-bromo—3—fluoro-
2-[(S)methyl(4-nitro-benzenesulfonyl)—aziridinyI]-pyridine (17.78 g, 42.7 mmol) was
added and stirring was continued for 3 h. The reaction mixture was poured onto a mixture of
1M HCI (56 ml), brine and TBME. The layers were separated, washed with brine and TBME.
The combined organic layers were dried over MgSO4HZO, filtered and evaporated. The
crude reaction product was purified via chromatography on silica gel (hexanes/25-33% TBME)
to yield 16.93 g of the title compound as a yellow resin that was contaminated with an
isomeric side-product (ratio 70:30 by 1H—NMR).
HPLC: Rtms = 2.380 min; ESIMS: 602, 604 [(M+H)*, 1Br]; 1H-NMR (400 MHz, CDCI3): 8.32
(d, 2H), 8.07 (d, 2H), 7.46 — 7.41 (m, 1H), 7.30 — 7.23 (m, 1H), 6.92 (s, 1H), 3.39 — 4.30 (m,
2H), 3.95 (d, 1H), 3.84 (d, 1H), 1.68 (s, 3H), 1.56 (s, 3H), 1.40-1.34 (m, 3H) + ic side-
product.
i) (R)[(R)(6-Bromofluoro-pyridinyl)(4-nitro-benzenesulfonylamino)-
y]-3,3,3-trifluoromethyl-propionamide
A solution of (R)[(R)(6-bromo-3—fluoro—pyridin—2-yl)(4-nitro-benzenesulfonylamino)-
propoxy]-3,3,3-trifluoromethyl-propionic acid ethyl ester (16.93 g, 28.1 mmol) in a
NH3/MeOH (7M, 482 ml) was stirred at 50 °C in a sealed vessel for 26 h. The reaction
e was evaporated and the residue was crystallized from DCM to yield 9.11 g of the title
compound as colorless crystals.
HPLC: Rtms = 2.422 min; ESIMS: 573, 575 [(M+H)*, 1Br]; 1H-NMR (400 MHz, CDCI3): 8.33
(d, 2H), 8.06 (d, 2H), 7.42 (dd, 1H), 7.30—7.26 (m, 1H), 7.17 (5, br, 1H), 6.41 (s, 1H), 5.57
.10 (8, br, 1H), 4.15 (m, 2H), 1.68 (s, 3H), 1.65 (s, 3H).
j) N-[(R)(6-BrOmofluoro-pyridinyl)((R)cyano-2,2,2—trifluoromethyl-
)methyl-ethyl]nitro-benzenesulfonamide
A suspension of (R)—2-[(R)(6-bromofluoro-pyridin—2—yI)(4-nitro-
benzenesulfonylamino)-propoxy]-3,3,3—trifluor042-methyl—propionamide (8.43 g, 14.70 mmol)
and triethylamine (5.12 ml, 36.8 mmol) in 85 ml DCM was cooled to 0-5 °C. Trifluoroacetic
anhydride (2.49 ml, 17.64 mmol) was added dropwise over 30 min. Additional triethylamine
(1.54 ml, 11.07 mmol) and trifluoroacetic anhydride (0.75 ml, 5.29 mmol) were added to
complete the reaction. The reaction mixture was quenched by addition of 14 ml aqueous
ammonia (25%) and 14 ml water. The emulsion was stirred for 15 min, more water and DCM
were added and the layers were ted. The c layer was dried with MgSO4 H20,
filtered and evaporated. Purification by column chromatography on a silica gel (hexanes/10-
% EtOAc) gave 8.09 g of the title compound as a yellow resin.
HPLC: RtH13 = 3.120 min; ESIMS: 555, 557 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCI3): 8.35
(d, 2H), 8.11 (d, 2H), 7.50 (dd, 1H), 7.32 (dd, 1H), 6.78 (s, 1H), 4.39 (d 1H), 4.22 (d, 1H),
1.68 (s, 6H).
k) (2R,5R)(6-Bromofluoro-pyridinyl)-2,5-dimethyl-Z-trifluoromethyl-5,6-dihydro-
2H-[1,4]oxazinylamine
A solution of N-[(R)(6-bromo-3—fluoro-pyridinyl)((R)cyano—2,2,2-trifluoromethyl-
ethoxy)methyl-ethyl]nitro-benzenesulfonamide (9.18 g, 16.53 mmol) and N-
acetylcysteine (5.40 g, 33.10 mmol) in 92 ml ethanol was evacuated and d with
nitrogen. K2C03 (4.57 g, 33.1 mmol) was added and the mixture was stirred at 80 °C for 3
days. The reaction mixture was trated in vacuo to about 1/4 of the original volume and
partitioned between water and TBM E. The organic layer was washed with 10% aq. K2003
—108-
solution, dried over , filtered and evaporated to give a yellow oil. Column
chromatography on silica (hexanes/14—50% (EtOAc:MeOH 9525)) gave 4.55 g of the title
compound as an off-white solid.
HPLC: RtHa = 2.741 min; ESIMS: 370, 372 *, 1Br]; 1H-NMR (400 MHz, DMSO-ds):
7.71 —7.62 (m, 2H), 5.97 (5, br, 2H), 4.02 (d 1H), 3.70 (d, 1H), 1.51 (s, 3H), 1.47 (s, 3H).
Examples 25 to 34: The compounds in Table 9 were prepared by similar procedures as for
Example 11 or Example 24; Example 28 required intermediate [(2R, 5S)(6-Amino-3—fluoro-
pyridinyl)—2,5-dimethyltrifluoro-methyl-5,6-dihydro-2H-[1,4]oxazinyl]—carbamic acid
tert-butyl ester from e 24 (step b, second isomer).
Table 9
F F (5; DMSO-de, 600 MHz):
.40 (br. s, 1H, NH),
H 8.28 (d, 1H), 8.18 (br. d,
/ N N
,8 /
N UN NH2
1H), 7.72 (t, 1H), 7.44 (d,
0 /
F 1H), 6.00 (br. s, 2H,
-Methoxy—3-methyI-pyridinecarboxylic NH2), 4.11 (d, 1H, AB),
acid [6-((3R,6R)—5-amino-3,6-dimethyI 3.91 (s, 3H), 3.75 (d, 1H,
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin- AB), 2.70 (s, 3H), 1.50
3-yl)fluoro-pyridinyl]amide (s, 3H), 1.49 (s, 3H).
(6; e + 1 drop
F F TFA, 600 MHz):
FSVOF N\ NH2 0
\II an 10.10 (br. s, 1H, NH),
N F / 9.68 (s, 1H, NH-
N \\ N
0 UL, amidine), 9.50 (s, 1H,
NH-amidine), 8.26 (dd,
3-Amino(2,2,2-trifluoro-ethoxy)- 1H), 8.20-7.70 (broad,
pyrazine—2-carboxylic acid [6-((3R,6R) 2H, NHz-pyrazine), 7.92
amino-3,6-dimethyltrifluoromethyI-3,6- (t, 1H), 7.67 (s, 1H), 5.02
dihydro-2H-[1 ,4]oxazin—3—yl)—5—fl uoro- (q, 2H), 4.40 (d, 1H, AB),
pyridinyl]amide 4.25 (d, 1H, AB), 1.70 (s,
3H), 1.68 (s, 3H).
(6; DMSO-ds, 600 MHz):
N\\ (if: 10.30 (br. s, 1H, NH),
m”\NHZ ""” 8.23 (d, 1H), 8.12 (br. d,
N\ ““PN/
MHZ 1H), 7.75 (t, 1H), 7.69 (d,
0 UP 1H), 7.31 (br. s, 2H, NH2
-pyridine), 5.95 (br.
3—Amino-5—cyano-pyridinecarboxylic s,
2H, NHg-amidine), 4.11
acid [6-((3R,6R)amino-3,6-dimethyI
(d, 1H, AB), 3.72 (d, 1H,
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-
AB), 1.50 (s, 3H), 1.49
3-y|)f|uoro-pyridinyllamide
(s, 3H).
(6; DMSO-de, 600 MHz):
11.10 (s, 1H, NH), 9.10
(s, 1H), 8.79 (s, 1H),
8.10 (br. d, 1H), 7.72 (br.
t, 1H), 5.90 (br. s, 2H,
3-Ch|orocyano-pyridine—2-carboxylic NH2 -amidine), 4.20 (br.
acid [6-((38,6R)—5-amino-3,6-dimethyl s, 1H, AB), 3.70 (br. s,
oromethyI-3,6-dihydro—2H—[1,4]oxazin- 1H, AB), 1.60 (s, 3H),
3-yl)—5-fluoro-pyridinyl]amide 1.50 (s, 3H).
Compound
(8; DMSO-de, 600 MHz):
.45 (br. s, 1H, NH),
8.44 (s, 1H), 8.18 (d,
1H), 7.76 (s, 1H), 7.72 (t,
1H), 7.45 (t, 1H), 5.90
-Difluoromethoxymethyl—pyridine
(br. s, 2H, NH2), 4.11 (d,
carboxylic acid [6-((3R,6R)amino-3,6-
1H, AB), 3.72 (d, 1H,
dimethyltrifluoromethyl-3,6-dihydro-2H-
AB), 2.68 (s, 3H), 1.50
[1 ,4]oxazin—3-yl)—5—f|uoro—pyridin
(s, 3H), 1.49 (s, 3H).
yl]amide
(5; DMSO-ds, 600 MHz):
.90 (br. s, 1H, NH),
8.59 (s, 1H), 8.11 (d,
1H), 8.10 (s, 1H), 7.72 (t,
1H), 7.49 (t, 1H), 5.88
3-Chloro—5-difluoromethoxy—pyridine-Z-
(br. s, 2H, NH2), 4.11 (d,
carboxylic acid [6-((3R,6R)-5—amino-3,6-
1H, AB), 3.72 (d, 1H,
dimethyl—6—trifluoromethyI-S,6-dihydro-2H-
AB), 1.50 (s, 3H), 1.49
[1 ,4]oxazinyl)fluoro—pyridin
(s, 3H).
yl]amide
(8; e, 400 MHz):
.92 (br. s, 1H, NH),
8.73 (br. s, 1H), 8.44 (d,
1H), 8.12 (dd, 1H), 7.73
(dd, 1H), 5.88 (br. s, 2H,
3,5-Dichloro-pyridine—2—carboxylic acid [6-
NH2), 4.11 (d, 1H, AB),
((3R,6R)—5-amino-3,6—dimethyl
3.72 (d, 1H, AB), 1.51 (s,
trifluoromethyI-B,6-dihydro-2H-[1,4]oxazin-
3H), 1.48 (s, 3H).
3-yl)fluoro-pyridinyl]amide
F F
F (5; DMSO-de, 400 MHz):
Fvo 0
/l UFN 10.42(br.s,1H, NH),
.,,u,
\ H N / 8.43 (d, 1H), 8.16 (dd,
N NH2
0 1H), 7.73 (dd, 1H), 7.66
F (d, 1H), 6.04 (d, 2H,
CHZF), 5.91 (br. s, 2H,
-Fluoromethoxy—3-methyl-pyridine
NH2), 4.13 (d, 1H, AB),
ylic acid [6-((3R,6R)amino-3,6-
3.74 (d, 1H, AB), 2.70 (s,
yltrifluoromethyl-3,6-dihydro—2H-
3H), 1.51 (s, 3H), 1.49
[1 ,4]oxazin-3—yl)fluoro-pyridin
(s, 3H).
yl]amide
F (5; DMSO-ds, 400 MHz):
N o F 10.19 (br. s, 1H, NH),
\ III|||
I H 9.22 (d, 1H), 8.73 (d,
/ N N /
N mN NH2
1H), 8.18 (dd, 1H), 7.79
0 /
F (dd, 1H), 5.92 (br. s, 2H,
-Methyl-pyrazinecarboxylic acid [6— NH2), 4.15 (d, 1H, AB),
((3R,6R)amino-3,6-dimethyI 3.76 (d, 1H, AB), 2.66 (s,
trifiuoromethyl-3,6-dihydro-2 H-[1,4]oxazin- 3H), 1.52 (s, 3H), 1.50
3—yl)fluoro-pyridinyl]amide (s, 3H).
(5; DMSO-de, 400 MHz):
11.15 (br. s, 1H, NH),
9.06 (s, 1H), 8.69 (s,
1H), 8.13 (dd,1H), 7.75
3-Chloro—5-trifiuoromethyl-pyridine—2— (dd, 1H), 5.88 (br. s, 2H,
carboxylic acid [6-((3R,6R)amino—3,6- NH2), 4.13 (d, 1H, AB),
dimethyltrifluoromethyI-3,6-dihydro-2H- 3.73 (d, 1H, AB), 1.52 (s,
[1 ,4]oxazinyI)fiuoro—pyridin-Z— 3H), 1.49 (s, 3H).
yl]amide
Examples 35 to 36: The compounds in Table 10 can be ed by a procedure analogous
to that used in Example 16.
Table 10
M-1H-NMR (8; DMSO-ds)
\ F 11.23 (br s, 1H),
' F 9.08 (d, 1H), 8.79
H UPLCMSI
(d, 1H), 8.33-8.30
Cl 0 RtH4 =
N / (m, 2H), 6.23 (br s,
0.78
2H), 3.97 (d, 1H),
3-ChIorocyano-pyridinecarboxylic acid [M+1] =
3.82 (d, 1H), 1.49
[4-((3R,6R)—5-amino-3,6-dimethyl 471.2
(s, 3H), 1.44 (s, 3H)
trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin
yl)—5-fluoro-pyridinyl]—amide
.95 (s, 1H), 8.56
F O
Y O
/ N - (d, 1H), 8.37-8.25
F \ mii N/ (m, 2H), 8.09 (d, UPLCMSI
1H), 7.48 (t, 1H),
CI 0 N / RtH4 =
F 5.23 (br s, 2H), 3.97 0.89
3-Chlorodifluoromethoxy—pyridine-Z- (d, 1H), 3.82 (d, [M+1] =
carboxylic acid [4-((3R,6R)-5—amino-3,6- 1H), 1.49 (s, 3H), 512.2
1.44 (s, 3H)
dimethyl—6—trifluoromethyl-3,6-dihydro-2H-
[1,4]oxaziny|)f|uoro-pyridin-Z-yfl-amide
Example 37: 5-Cyanomethyl-pyridinecarboxylic acid [4-((R)amino-6,6-bis-
fl thyImethyl-3,6-dihydro-2H-[1 ,4]oxazinyl)fluoro-pyridin-Z-yl]-amide
—113-
F F
I HN\£/N NH2
a) 2-[2-(2-Bromofluoro-pyridinyl)(2-nitro-benzenesulfonylamino)-
propoxy]fluorofluoromethyl-propionic acid ethyl ester
A solution of 3-fluoro—2-fluoromethylhydroxy-propionic acid ethyl ester (see Intermediates
Hydroxyester 1, 0.606 g, 3.60 mmol) in DMF (7 ml) was ed over activated 4 A
molecular sieves, then a suspension of NaH (0.135 g of a 60% dispersion in mineral oil, 3.36
mmol) was added and the reaction mixture was stirred at rt for 10 min. A solution of 2-bromo-
-fluoro—4-[2-methyl(2-nitro-benzenesulfonyl)—aziridinyl]-pyridine (see Example 16, step
9, 1.0 g, 2.403 mmol) in DMF (7 ml, soln. predried over activated 4 A molecular sieves) was
1O slowly added. The reaction mixture was stirred at rt for 3.5 h, then quenched with aq. 1N HCI
soln. and diluted with H20 and TBME. The phases were separated and the aq. layer was
twice reextracted with TBME. The combined organic layers were washed with H20, dried
over Na2804, filtered and concentrated. The resulting crude title compound was purified by
NP-HPLC (Alltech Grom 65 Si 10 um column, 250x50mm, gradient ane:EtOAc
75:25 to .
HPLC: RtH4= 1.18 min; ESIMS [M+H]+= 584, 586 (1Br);
1H-NMR (400 MHz, DMSO-ds): 6 8.76 (s, 1H), 8.21 (d, 1H), 7.94-7.92 (m, 2H), .75 (m,
2H), 7.70 (d, 1H), 4.85-4.46 (m, 4H), 4.20 (q, 2H), 4.04 (d, 1H), 3.83 (d, 1H),1.62 (s, 3H),
1.21 (t, 3H).
b) 2-[2-(2-Bromofluoro-pyridiny|)(2—nitro—benzenesulfonylamino)-propoxy]-3—
fluorofluoromethyl-propionamide
A solution of 2-[2-(2-bromo—5—fluoro—pyridinyl)~2-(2-nitro-benzenesulfonylamino)—propoxy]—
3—fluorofluoromethyl-propionic acid ethyl ester (970 mg, 1.660 mmol) amd 7M NH3 in
MeOH (10 ml) was stirred in a in a sealed glass vial at 55 °C for 20 h. Another 3 ml of 7N
NH3/MeOH were added and stirring was continued for 16 h at 55 °C. The reaction mixture
was concentrated and yielded the title compound as a yellow solid that was used in the next
step without further cation.
HPLC: RtH4= 0.95 min; ESIMS = 555, 557 (1Br);
1H-NMR (400 MHz, DMSO-de): 6 9.01 (s, 1H), 8.25 (d, 1H), 7.99-7.90 (m, 2H), 7.85-7.58 (m,
5H), 4.73-4.51 (m, 4H), 3.96 (d, 1H), 3.90 (d, 1H), 1.58 (s, 3H).
c) N-[1-(2-Bromofluoro-pyridinyl)(cyano-bis-fluoromethyl-methoxy)—1—methylethyl
]nitro-benzenesulfonamide
To a solution of 2-[2-(2-bromofluoro-pyridinyl)(2-nitro-benzenesulfonylamino)
propoxy]—3—fluorofluoromethyl-propionic acid ethyl ester (900 mg, 1.621 mmol) in DCM (11
ml) was added NEL», (0.565 ml, 410 mg, 4.050 mmol). The reaction mixture was cooled to 0
°C, then TFA anhydride (0.275 ml, 408 mg, 1.945 mmol) was added dropwise. The reaction
mixture was allowed to warm to rt and to stir for 18 h. In order to obtain complete conversion,
the reaction mixture was cooled again to 0 °C and more TFA anhydride (0.450 ml, 670 mg,
3.190 mmol) followed by NEta (0.230 ml, 168 mg, 1.659 mmol) was added and the reaction
mixture was allowed to warm to rt and to stir for another 30 min.
The reaction mixture was diluted with sat. aq. Na2C03 soln. and DCM. The phases were
separated and the aq. phase was twice acted with DCM. The combined organic phases
were washed with brine, dried over NaZSO4, filtered and trated. The resulting crude
title compound was purified by NP-HPLC (Alltech Grom Saphir65 Si 10 um column,
150x30mm, gradient n-heptanezEtOAc 85:15 to 0:100).
HPLC: RtH4= 1.09 min; ESIMS [M+H]*= 537, 339 (1Br);?
1H—NMR (400 MHz, s): 6 9.02 (s, 1H), 8.24 (d, 1H), .90 (m, 2H), 7.87-7.75 (m,
2H), 7.61 (d, 1H), 4.95-4.48 (m, 4H), 4.14-4.02 (m, 2H), 1.60 (s, 3H).
d) romofluoro-pyridinyl)-2,2-bis-fluoromethylmethy|-5,6-dihydro-2H-
[1 ,4]oxaziny|amine
A on of N-[1-(2-bromofluoro-pyridiny|)(cyano-bis-fluoromethyl-methoxy)
methyI-ethyI]nitro-benzenesulfonamide (840 mg, 1.563 mmol), N-acetyI-L-cysteine (510
mg, 3.13 mmol) and K2C03 (432 mg, 3.130 mmol) in abs. EtOH (10 ml) was stirred at 85 °C
for 18 h. N-acetyI-L-cysteine (250 mg, 1.533 mmol) and K2003 (210 mg, 1.519 mmol) was
added and stirring at 85 °C was ued for 18 h. The reactiOn mixture was concentrated to
1/3 of its volume, quenched with 10% aq. K2C03 soln. and 3x extracted with TBME. The
combined org. phases were washed with sat. aq. NaHCOs soln, brine, dried over NaZSO4,
filtered and concentrated to leave the crude title compound that was purified by NP—HPLC
(Alltech Grom Saphir65 Si 10 um column, 150x30mm, gradient n-heptane:EtOAc:MeOH
682302 to 0:65:35),
HPLC: RtH4= 0.57 min; ESIMS [M+H]+= 352, 354 (1Br);
1H-NMR (400 MHz, DMSO-de): 6 8.35 (d, 1H), 7.76 (d, 1H), 6.32 (br s, 2H), .71 (m,
2H), 4.66-4.39 (m, 2H), 3.94 (dd, 1H), 3.82 (d, 1H), 1.40 (s, 3H).
e) 5-Cyano-3—methyl-pyridinecarboxylic acid [4-(5-amino-6,6-bis-fluoromethyl
methyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]-amide
A mixture of 5-cyano—3-methyl-pyridinecarboxylic acid amide (see Intermediates Amide 1,
96 mg, 0.596 mmol), 5-(2-bromofluoro-pyridin—4-y|)-2,2-bis-fluoromethyl-5—methyl-5,6-
dihydro-2H-[1,4]oxazin-3—ylamine (210 mg, 0.596 mmol), Xantphos (31.1 mg, 0.054 mmol)
and C52003 (272 mg, 0.835 mmol) in dioxane (6 ml) was degassed with argon, a)3
(16.38 mg, 0.018 mmol) was added and the reaction mixture was stirred at 60 °C for 16 h.
More Pd2(dba)3 (8.19 mg, 0.009 mmol) and Xantphos (15.60 mg, 0.027 mmol) was added
and stirring was continued at 60 °C for 4 h. The reaction mixture was filtered through celite
and the celite pad rinsed with DCM. The combined filtrates were concentrated and the
ing crude title compound was purified by NP-HPLC (Alltech Grom Saphir65 Si 10 um
column, 150x30mm, gradient ane:EtOAc:MeOH 68:30:2 to 0:65:35), then by RP—HPLC
(Waters SunFire C18 column, 5 pM, 30x100 mm, gradient 10 to 30% ACN+0.1% TFA) and
obtained as a free base after filtration over an SCX cartridge.
HPLC: RtH4= 0.72 min; ESIMS [M+H]+= 433;
1H-NMR (400 MHz, DMSO-de): 5 10.75 (s, 1H), 8.98 (s, 1H), 8.42 (s, 2H), 8.28 (s, 1H), 6.20
(br s, 2H), 5.05-4.45 (m, 4H), 4.02-3.84 (m, 2H), 2.58 (s, 3H), 1.45 (s, 3H)
f) 5-Cyano-3—methyl-pyridinecarboxylic acid [4-((R)amino-6,6-bis-fluoromethyl
methyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]-amide
Racemic (5-cyanomethyl—pyridinecarboxylic acid amino-6,6-bis—fluoromethyI
methyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro-pyridinyl]—amide was separated into the
pure enantiomers by preparative chiral HPLC (column: Chiralpak AD-H 20 x 250 mm, 5 uM;
solvent: n-heptane / ethanol 75 : 25; flow: 12 ml / min; detection at 220 nm). Enantiomer 1: Rt
8.964 min. Enantiomer 2: Rt 16.220 min mined by analytical HPLC using Chiralpak AD-
H 250 x 4.6 mm, 5 uM column; solvent: n-heptane / l / MeOH 70 : 25 : 5 + DEA; flow:
1.600 ml / min; detection at 220 nm).The absolute configuration of enantiomer 2 was
assigned (R) in analogy to similar structures of which the ration has been determined
by X-ray crystallography.
1H-NMR (400 MHz, DMSO-de): 6 10.76 (s, 1H), 8.98 (s, 1H), 8.42 (s, 2H), 8.28 (s, 1H), 6.21
(br s, 2H), 5.02-4.45 (m, 4H), 3.95 (d, 1H), 3.89 (d, 1H), 2.58 (s, 3H), 1.44 (s, 3H).
Example 38: 5-Cyanomethyl-pyridinecarboxylic acid [6-((R)amino-3—
difluoromethyl-3,6-dihydro-2H-[1,4] oxazinyl)—5-fluoro-pyridin-Z-yl]-amide
a) 2-Bromofluorotriethylsilanylpyridine
To a solution of diisopropylamine (25.3 g, 250 mmol) in THF (400 ml) was added n-BuLi (100
ml, 2.5 mol/L in hexanes) below -50 °C. A solution of 2-bromo—5-fluoropyridine (41.9 g, 238
mmol) in THF (60 ml) was added to the LDA-solution at -78 °C in a dropwise manner below -
63 °C. After 60 minutes at -78 °C triethylchlorosilane (44 ml, 262 mmol) was added in a fast
manner keeping the temperature below -50 °C. The cooling bath was removed and the
reaction mixture was allowed to reach -20 °C. The on e was poured on a mixture
of 1M aq. HCl (250 ml) and aq. NH4C| (10%). butyl methyl ether was added and the
1O layers were separated. The organic phase was washed with brine, dried over magnesium
sulfate, filtered and evaporated to give a yellow liquid. Distillation (bp. 99-101 °C, 0.5 mm
Hg). afforded the title compound as a slightly yellow liquid: 66.26 g (96% yield)
1H-NMR (400 MHz, CDCI3): 8.17 (s, 1H), 7.42 (d, 1H), 1.01-0.97 (m, 9H), 0.92-0.87 (m, 6H).
b) 1-(6-Bromofluorotriethylsilanyl-pyridin-Z-yl)-2,2-difluoro-ethanone
To a freshly prepared solution of LDA (6.25 mmol) in THF (5 ml) was added se a
solution of ofluoro-4—triethylsilanylpyridine (1.6 g, 5.51 mmol) in THF (12 ml) at -78
°C. Stirring was continued at -78 °C for 3 hours. Ethyl 2,2-difluoroacetate (0.58 ml, 5.51
mmol) was added dropwise and the solution was stirred at -78 °C for 3 hours. The on
mixture was quenched with sat. um chloride solution (20 ml) and ethyl acetate was
added. The organic phase was washed with brine, dried over sodium sulfate, filtered and
evaporated. The crude brown oil (2.11 g) was chromatographed over silica gel (cyclohexane
/ ethyl acetate) to give the title nd. 1.53 g (75% yield, mixture of ketone and hydrate
form).
TLC (cyclohexane/ethyl acetate 10:1) Rf=0.26; 1H-NMR (400 M Hz, CDCI3): 7.70 (d, 1H), 6.96
(t, 1H, CHF2)), 1.02-0.98 (m, 9H), 0.96-0.92 (m, 6H).
c) (S)Methyl-propane-Z-sulfinic acid[1-(6-bromofluorotriethylsilanyl-pyridin
yl)-2,2-difluoro-ethylidene]-amide
A mixture of 1-(6-bromofluoro—4-triethylsilanyl-pyridiny|)-2,2-difluoro-ethanone (9.8 g,
26.6 mmol), (S)methylpropanesulfinamide (3.23 g, 26.6 mmol) and tetraethoxytitanium
(13.81 ml, 53.2 mmol) in THF (66.5 ml) was stirred at 80 °C in 3 capped microwave vials
(3x25 ml) for 3 hours. The cold reaction mixture was poured into ice cold water and the
precipitate was d h a pad of hyflo and washed thoroughly with ethyl acetate. The
organic phase was washed with brine, dried over sodium sulfate, ed and evaporated.
The crude product (12.5 g) was chromatographed over silica gel (cyclohexane:ethyl acetate
:1) to afford the title compound. 7.96 g (63% yield).
TLC (cyclohexane/ethyl acetate 5:1) Rf=0.65; LCMS RtH4= 1.53 min. (100 % pure, ESl+ 471,
473); 1H-NMR (400 MHz, CDCI3): 7.50 (d, 1H), 6.49 (t,1H, CHFZ), 1.33 (s, 9H), 1.03-0.98 (m,
9H), 0.93-0.89 (m, 6H).
d) (S)Methyl-propane-Z-sulfinic acid[(S)(6-bromofluorotriethylsilanyl-pyridin-
1-difluoromethyl-allyI]-amide and (S)Methyl-propane-Z-sulfinic acid[(R)(6-
bromofluorotriethylsilanyl-pyridin-2—yl)—1-difluoromethyl-allyl]-amide
Vinylmagnesium bromide 1M in THF (2.3 ml, 2.3 mmol) was added to dichloromethane (5ml)
and the solution was cooled down to -78 °C. (S)Methyl-propane-Z-sulfinic acid[1-(6-
bromofluorotriethylsilanyl-pyridinyl)-2,2-difluoro-ethylidene]-amide (500 mg, 1.06
mmol) in dichloromethane (5 ml) was added dropwise to the above solution keeping the
temperature below -65 °C. After 30 s the reaction was ed at -78 °C with
ammonium chloride solution (10%) and the reaction mixture was extracted with TBME. The
organic layer was washed with brine, dried over sodium sulfate, filtered and ated. 620
mg (quant. yield) as a 4:1 mixture of diastereoisomers used without purification in the next
step.
TLC (cyclohexane/ethyl acetate 10:1) Rf=0.15 and (cyclohexane/ethyl acetate 10:1);
R,~=0.10; LCMS RtH4= 1.50 min. (ESI+ 499, 501); 1H—NMR (400 MHz, CDCI3): 8.56 (s, 1H,
NH), 7.47 and 7.45 (d,1H), 6.60-6.30 (t, 1H, CHFz), 6.25-6.16 (m, 1H), 5.65-5.30 (m, 2H),
1.34 and 1.31 (s, 9H), 0.99-0.96 (m, 9H), 0.90-0.84 (m, 6H).
e) (S)—2-Methyl-propane-Z-sulfinic acid [(R)(6-bromofluorotriethylsilylanyl-
pyridinyl)-2,2-difluorohydroxymethyl-ethyIJ-amide and (S)Methyl-propane
sulfinic acid [(S)—1 -(6-bromofluorotriethylsilylanyl-pyridinyl)-2,2-difluoro
hydroxymethyl-ethyl]-amide
A mixture of methyl-propane-2—sulfinic acid[(S)(6—bromofluoro-4—triethylsilanyl-
pyridinyl)—1-difluoromethyl-a|lyl]-amide and (S)—2-Methy|-propanesulfinic acid[(R)—1-(6-
3-fluorotriethylsi|anyl-pyridinyI)—1-dif|uoromethyl-allyl]-amide from step d)
(5.1379, 10.28 mmol) was dissolved in dichloromethane (77 ml) and methanol (25.7ml) ,
sodium bicarbonate (1.296 g, 15.43 mmol) was added and the reaction mixture was cooled
to -78 °C. Ozone was bubbled through the on until a blue coloration appeared (4 hr).
Excess ozone was blown outwith en until the blue color has eared. Sodium
borohydride (1.945 g, 51.4 mmol) was added to the on and the reaction mixture was
stirred at -78 °C for 3 hours. The reaction mixture was diluted with TBME and 2N HCI to
destroy excess sodium dride. The organic layer was washed carefully with 1N HCI
solution and brine, dried over sodium sulfate, filtered and evaporated. 6.15 9 yellow oil. The
crude product was chromatographed over silica gel (120 g, cyclohexane/ethyl acetate 3:1) to
give the title compounds:
(S)Methyl-propanesulfinic acid [(R)(6-bromofluoroz‘riethylsilylanyl-pyn'dinyl)-
2, 2-difluorohydroxymethy/-ethyl]-amide: 2.36 g (45.6 % yield).
TLC (cyclohexane/ethyl acetate 3:1) Rf=0.24; LCMS RtH4= 1.36 min. (93% pure, ESI+ 503,
505);
1H-NMR (400 MHz, CDCI3): 7.46 (d,1H), 6.24 (t, 1H, CHFZ), 4.60 (br. s, 1H, NH), 4.47 (br. s,
2H, AB), 3.48 (br. s, 1H, OH), 1.32 (s, 9H), 0.99 (t, 9H), 0.89 (q, 6H).
(S)Methyl—propanesulfinic acid [(S)(6-bromof/uorotriethylsilylanyl-pyridinyl)-
2,2-difluorohydroxymethyl-ethyl]-amide: 1.72 g (33.2 % yield).
TLC (cyclohexane/ethyl acetate 3:1) R,=0.31;
LCMS RtH4= 1.43 min. (100% pure, ESI+ 503, 505);
1H-NMR (400 MHz, CDCI3): 7.47 , 6.62 (br. s, 1H), 6.23 (t, 1H, CHFZ), 4.51-4.48 (d,
1H, AB), 4.36-4.32 (d, 1H, AB), 1.42 (s, 9H), 0.99 (t, 9H), 0.89 (q, 6H).
f) (R)-2—Amino(6-bromofluorotriethylsilanyl-pyridin-Z-yl)-3,3-difluoro-propan
To a solution of (S)methyl-propane-2—sulfinic acid [(R)(6-bromofluoro-4—
triethylsilylanyI-pyridinyl)-2,2-difluorohydroxymethyl-ethyI]-amide (2.3 g, 4.57 mmol) in
dichloromethane (45 ml) was added HCl (5.48 ml, 16.45 mmol, 3 molar in methanol) and the
reaction mixture was stirred for 5 hours at room temperature. The solvent was removed in
vacuo and the residue diluted with ethyl acetate and poured onto a mixture of a
. The layers were separated and the organic phase was washed with water and brine,
dried over sodium sulfate, filtered and evaporated. 2.15 9. Used in next step without further
purification.
LCMS RtH4= 1.18 min. (94% purity, ESI+ 399, 401); 1H-NMR (400 MHz, CDCIg): 7.43 (d,1H),
6.16 (t, 1H, CHFZ), 4.13-4.10 (d, 1H, AB), 3.99-3.93 (d, 1H, AB), 2.52 (br. s, 3H, OH, NHZ),
0.99 (t, 9H), 0.89 (q, 6H).
2012/050395
g) N-[(R)(6-BromofluorotriethylsiIanyl-pyridinyl)-2,2-difluoro
hydroxymethyl-ethyI]chloro-acetamide
To a solution of (R)amino—2-(6-bromo-3—fluorotriethylsilanyl-pyridinyl)-3,3-difluoro-
propanol (2.15 g, 5.38 mmol) in dichloromethane (14.55 ml) was added an aq. sodium
carbonate solution (14.55 ml, 10% aq. solution) at 0 °C. 2-Chloroacetyl chloride (0.518 ml,
6.46 mmol) was added dropwise at 0 °C and the ice bath was removed after the addition.
The reaction mixture was stirred at rt for 15 min. Methanol was added and the on
mixture was stirred at 50 °C for 10 min. The reaction e was diluted with
romethane and water. The mixture was extracted with dichloromethane, dried over
sodium e, filtered and evaporated. The crude light yellow oil (2.91 g) was
chromatographed over silica gel (40 g redisep column, cyclohexane / ethyl acetate 10-70%)
to give the title compound. 2.32 g (91% yield).
TLC (cyclohexane/ethyl acetate 2:1) 3; LCMS RtH4= 1.30 min. (ESI+ 475, 477, 479);
1H-NMR (400 MHz, CDCls): 8.17 (br. s, 1H, NH), 7.47 (d,1H), 6.58 (t, 1H, CHFZ), 4.64-4.55
(m, 1H, AB), 4.20-4.12 (m, 3H, AB), 0.98 (t, 9H), 0.89 (q, 6H).
h) (R)(6-Bromofluoro-pyridinyl)—5—difluoromethyl-morpholinone
To a solution of N-[(R)(6-bromofluoro—4—triethylsilanyl-pyridinyl)-2,2-difluoro
hydroxymethyl-ethyl]chloro-acetamide (2.32 g, 4.88 mmol) in nol (50 ml) was added
potassium tert—butoxide (7.31 ml, 7.31 mmol, 1M in THF) and the solution was stirred in a
closed vial for 18 h at 100 °C. The reaction mixture was diluted with ethyl acetate, washed
with water, sat. NaHSO4 solution and brine, dried over sodium sulfate, filtered and
evaporated. The crude product (2.36 g) was chromatographed over silica gel (24 g redisep
column, cyclohexane / ethyl acetate 10-80%) to give the title compound. 1.13 g (71% yield).
Triethylsilylated lactam (640 mg) was recovered.
TLC (cyclohexane/ethyl acetate 1:1) Rf=0.25;
LCMS RtH4= 0.79 min. (ESI+ 325, 327); 1H-NMR (400 MHz, : 7.59—7.57 (m, 1H), 7.51
(br. s, 1H, NH), 7.45-7.42 (m,1H), 6.23 (t, 1H, CHFZ), 4.86 (d, 1H, AB), 4.38 (d, 1H, AB), 4.16
(d, 1H, AB), 3.97 (d, 1H, AB).
i) (R)(6-Bromofluoro-pyridinyl)difluoromethyl-morpholinthione
To a solution of (R)(6-bromofluoro-pyridin-2—yl)—5—difluoromethyl-morpholin-3—one
(1.13 g, 3.48 mmol) in pyridine (34.8 ml) was added phosphorous pentasulfide, the vial was
sealed and the reaction mixture was stirred at 100 “C for 2 h. The reaction mixture was
diluted with 2M HCI solution and ethyl acetate. The organic layer was washed with brine,
dried over sodium sulfate, filtered and evaporated. The crude product (1.4 g) was used in the
next step without purification.
LCMS RtH4= 0.98 min. ( ESI+ 341, 343); 1H-NMR (400 MHz, CDCI3): 9.40 (br. s, 1H, NH),
7.62 (dd, 1H), 7.45 (dd, 1H), 6.25 (t, 1H, CHFZ), 4.93 (dd, 1H, AB), 4.79 (d, 1H, AB), 4.44 (d,
1H, AB), 4.00 (dd, 1H, AB).
j) (R)(6-Bromofluoro-pyridin-Z-yl)difluoromethyl-5,6-dihydro-2H-[1,4]oxazin
ylamine
To a solution of (R)(6-bromofluoro-pyridinyl)-5—difluoromethyl—morpholinthione
(611 mg, 1.79 mmol) in methanol (15 ml) was added ammonia (5.12 ml, 35.8 mmol, 7M in
methanol), the vial was sealed and the reaction mixture was stirred at rt for 20 h. The
reaction e was diluted with ethyl acetate. The organic layer was washed with aq.
sodium thiosulfate solution (10%), water and brine, dried over sodium sulfate, d and
evaporated. The crude t (640 mg) was chromatographed over silica gel (14 g,
dichloromethane/methanol 95/5 + 0.5% NH3) to give the title compound. 180 mg (31% yield).
LCMS RtH4= 0.55 min. ( ESI+ 325, 327); 1H-NMR (400 MHz, CDCI3): 7.45 (dd, 1H), 7.32 (dd,
1H), 6.31 (t, 1H, CHFZ), 4.38 (d, 1H, AB), 4.22 (d, 1H, AB), 4.15 (d, 1H, AB), 4.10 (d, 1H,
AB), 3.0 — 1.5 (very br. s, 2H, NH2).
k) [(R)-5—(6—Bromofluoro-pyridinyl)difluoromethyl-5,6-dihydro-2H-[1,4]oxazin
yl]-carbamic acid utyl ester
A solution of (6-bromofluoro-pyridinyl)—5-difluoromethyl-5,6—dihydro—2H-
[1,4]oxazinylamine (180 mg, 0.555 mmol), BOC-anhydride (121 mg, 0.555 mmol) and
’s base (108 mg, 0.833 mmol) in dichloromethane (5.5 ml) was stirred at rt for 18 h.
The reaction mixture was diluted dichloromethane and washed with aq. saturated
onate solution and brine, dried over sodium sulfate, filtered and evaporated. The crude
product (352 mg light yellow solid) was chromatographed over silica gel (4 g, cyclohexane/
ethyl acetate 5—40%) to give the title compound. 190 mg (81% yield).
TLC (cyclohexane/ethyl acetate 3:1) Rf=0.30;
LCMS RtH4= 1.11 min. (93% purity, ESI+ 424, 426); 1H-NMR (400 MHz, DMSO-ds): 9.97 (s,
1H, NH), 7.77-7.75 (m, 2H), 6.40 (t, 1H, CHFZ), 4.51 (br. s, 2H, AB), 4.21 (d, 1H, AB), 3.88
(d, 1H, AB), 1.41 (s, 9H).
l) ((R){6-[(5-Cyanomethyl-pyridinecarbonyl)-amino]fluoro-pyridinyl}
difluoromethyl-4,6-dihydro-2H-[1,4]oxazinyl) -carbamic acid tert-butyl ester
A mixture of [(R)—5-(6-bromofluoro-pyridin-2—yl)—5-difluoromethyl-5,6-dihydro-2H-
[1,4]oxazinyl]-carbamic acid tert—butyl ester (90 mg, 0.212 mmol), 4-cyanomethyl-
pyridinecarboxylic acid amide (41 mg, 0.255 mmol), OS (11.05 mg, 0.019 mmol)
and cesium carbonate (97 mg, 0.297 mmol) in dioxane (3 ml) was degassed with argon for 5
minutes. Pd2(dba)3 (5.83 mg, 6.36 pmol) was added and the sealed vial was heated at 60
°C for 18 h. The reaction mixture was diluted with water and TBME . The phases were
separated and the aq. phase was extracted with TBM E. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product
was chromatographed over silica gel (12 g redisep column, cyclohexane / ethyl acetate 5-
40%) to give the title compound. 76 mg (71% .
TLC hexane/ethyl acetate 3:1) Rf=0.15; LCMS RtH4= 1.16 min. (100% purity, ESl+
505).
m) 5-Cyanomethyl-pyridinecarboxylic acid )aminodifluoromethyl-3,6-
dihydro-2H-[1,4]oxaziny|)fluoro-pyridin-Z-yl1-amide
A on of ((R)-5—{6—[(5-cyanomethyl-pyridinecarbonyl)—amino]fluoro-pyridinyl}-
—difluoromethyl-4,6-dihydro-2H-[1,4]oxazin—3-yl) mic acid utyl ester (75 mg,
0.149 mmol) and TFA (115 pl, 1.48 mmol) in dichloromethane was stirred at rt for 2 h. The
reaction mixture was diluted with ethyl acetate and poured into an ice/ammonia 2M mixture.
The organic layer was washed with water and brine, dried over sodium sulfate, filtered and
evaporated. 62 mg solid (quantitative yield).
TLC (dichloromethane/methanol 95/5 + 0.5% ammonia) Rf=0.21;
LCMS RtH4= 0.75 min. (ESl+ 405); 1H-NMR (400 MHz, DMSO—ds): 10.75 (br. s, 1H, NH),
902 (s, 1H), 8.44 (s, 1H), 8.20 (d, 1H), 7.78 (t, 1H), 6.36 (t, 1H, CHFZ), 6.06 (br. s, 2H, NH2),
4.27 (d, 1H, AB), 4.04-3.86 (m, 3H, AB), 2.61 (s, 3H).
Example 39: 5-Cyanomethyl-pyridine—2—carboxylic acid [6-((S)amino
difluoromethyl-3,6-dihydro-2H-[1,4] oxazinyI)f|uoro-pyridin-Z-yl]-amide
Example 39 (enantiomer of Example 38) was prepared in analogy to Example 38 with
intermediate (S)—2-Methyl-propanesulfinic acid [(8)(6-bromo-3—fluorotriethylsilylanyl-
pyridinyl)—2,2-difluorohydroxymethyl-ethyl]-amide from step e).
—122-
LCMS RtH4= 0.75 min. (ESI+ 405); 1H-NMR (400 MHZ, DMSO-de): 10.75 (br. s, 1H, NH),
9.02 (s, 1H), 8.44 (s, 1H), 8.20 (d, 1H), 7.78 (t, 1H), 6.36 (t, 1H, CHFZ), 6.06 (br. s, 2H, NH2),
4.27 (d, 1H, AB), 4.04-3.86 (m, 3H, AB), 2.61 (s, 3H).
Example 40: 3-Chlorocyano-pyridinecarboxylic acid [6-((R)amino
difluoromethyl-3,6-dihydro-2H-[1,4] yl)fluoro-pyridinyl]-amide
N\ O
/ mp, N . /
N NH2
Cl 0 /
Example 40 was prepared in analogy to Example 38 using Amide-2 in step m).
LCMS RtH12= 0.66 min. (ESI+ 424); 1H-NMR (400 MHz, DMSO-ds): 5 11.22 (br. s, 1H, NH),
9.11 (s, 1H), 8.81 (s, 1H), 8.16 (dd, 1H), 7.79 (dd, 1H), 6.31 (t, 1H), 6.04 (br. s, 2H, NHZ),
4.29 (d, 1H, AB), 3.96 (dd, 2H), 3.87 (d, 1H, AB).
Examples 41 to 48: The compounds in Table 11 were ed by similar procedures as
described for Example 11 or Example 24 and using Acids 5, 6, 7, 8 and 9 for Examples 42,
43, 45, 47 and 48 respectively.
Table 11
F F
WAN 0:6? (5; DMSO—ds, 400 MHz):
Nlfl“ 10.44 (br.
N\ 8““:N/ s, 1H, NH), 8.52
| 2 (s, 1H), 8.15 (br. d, 1H),
7.74 (dd, 1H), 5.90 (br. s,
3,5-Dimethyl-pyrazinecarboxylic acid 2H, NH;), 4.12 (d, 1H, AB),
[6-((3R,6R)amino-3,6-dimethyl 3.73 (d, 1H, AB), 2.80 (s,
trifluoromethyl-3,6—dihydro—2H- 3H), 2.57 (s, 3H), 1.50 (s,
[1 ,4]oxazinyI)f|uoro—pyridin-Z- 3H), 1.48 (s, 3H).
yl]amide
(6; DMSO-de, 400 MHz):
9.88 (br. s, 1H, NH), 8.12
(dd, 1H), 7.72 (dd, 1H), 7.57
(s, 1H), 5.90 (br s, 2H,
3-Amino(3-fluoro-propoxy)-pyrazine- NHZ), 4.68 (t, 1H), 4.56 (t,
2-carboxyiic acid R,6R)amino- 1H), 4.42 (t, 2H), 4.12 (d,
3,6-dimethyltrifluoromethyI-3,6- 1H, AB), 3.73 (d, 1H, AB),
o-2H-[1,4]oxazinyI)fluoro— 2.20 - 2.11 (m, 2H), 1.51 (s,
pyridin-2—yl]amide 3H), 1.48 (s, 3H).
(6; DMSO-de, 400 MHz):
.26 (br. s, 1H, NH), 8.18
(dd, 1H), 7.74 (dd, 1H), 7.63
(d, 1H), 7.51 (br. s, 2H,
3-Amino(2-methoxy—ethyI)-5H- NH;), 6.58 (d, 1H), 5.92 (br.
pyrrolo[2,3-b]pyrazinecarboxylic acid s, 2H, NHZ), 4.26 (t, 2H),
[6-((3R,6R)amino—3,6-dimethyl 4.15 (d, 1H, AB), 3.78 (d,
trifluoromethyl-3,6—dihydro-2H— 1H, AB), 3.70 (t, 2H), 3.32
[1,4]oxazinyI)fluoro-pyridin (s, 3H), 1.53 (s, 3H), 1.51
yl]amide (s, 3H).
F F
FPM” F
F0 .,.... (8; DMSO-de, 400 MHz):
/ 10.24 (br. s, 1H, NH), 8.37
(s, 1H), 8.12 (dd, 1H), 7.78
(dd, 1H), 5.91 (br. s, 2H,
3—Aminotrifluoromethyl-pyrazine-Z-
NH;), 4.15 (d, 1H, AB), 3.75
ylic acid [6-((3R,6R)-5—amino-
(d, 1H, AB), 1.52 (s, 3H),
3,6-dimethyl-6—trifluoromethyl-3,6-
1.51 (s, 3H).
dihydro—2H-[1,4]oxazinyl)—5-fluoro-
pyridinyl]amide
(8; DMSO-de, 400 MHz):
.23 (s broad, 1H, NH),
8.14 (dd, 1H), 7.78 (dd, 1H),
7.80 (d, 1H), 7.55 (s broad,
3—Amino(2,2-difluoro-ethyl)—5H- 2H, NH;), 8.84 (d, 1H), 8.41 0.87;
pyrrolo[2,3-b]pyrazine—2-carboxylic acid (tt, 1H), 5.90 (s broad, 2H, [M + 1]+
[6-((3R,6R)—5-amino—3,6-dimethyI NHZ), 4.54 (td, 2H), 4.12 (d, = 531.1
trifluoromethyl-S,6-dihydro-2H- 1H, AB), 3.75 (d, 1H, AB),
[1 ,4]oxazin-3—yl)f|uoro-pyridin-Z- 1.50 (s, 3H), 1.48 (s, 3H).
y|]amide
(8; DMSO—de, 400 MHz):
.15 (br. s, 1H, NH), 8.80
(s, 1H), 8.03 (dd, 1H), 7.92
(t, 1H), 7.75 (dd, 1H), 5.88
4-ChlorodifluoromethyI-1H-pyrazole—
(br. s, 2H, NHZ), 4.14 (d,
3-carboxylic acid R,6R)amino-
1H, AB), 3.73 (d, 1H, AB),
3,6-dimethyltrifluoromethyl-3,6-
1.52 (s, 3H), 1.48 (s, 3H).
dihydro-2H-[1 ,4]oxazinyl)fluoro-
pyridinyI]-amide
2012/050395
F’K’N ‘* (’6'DMSO—d6’ 400MHZ):
o CF3
\N ....1
I 10.77 (br.
H s, 1H, NH), 8.37
/ N N /
\ N NH (s,1H),8.17(dd,1H),7.88
(d, 1H), 7.72 (dd, 1H), 6.81
6-Chloro-1—(2,2—difluoro-ethyl)-1 H- (d, 1H), 6.44 (tt, 1H), 5.87
pyrrolo[3,2-b]pyridinecarboxylic acid (br. s, 2H, NH;), 4.84 (td,
[6-((3R,6R)—5-amino—3,6-dimethyl 2H), 4.14 (d, 1H, AB), 3.73
trifluoromethyl-3,6-dihydro-2H- (d, 1H, AB), 1.52 (s, 3H),
[1 zlnyl)fluoro—pyridiny|]- 1.49(s,3H).
(8; DMSO-ds, 400 MHz):
.72 (br. s, 1H, NH), 8.30
(s, 1H), 8.17 (dd, 1H), 7.87
(d, 1H), 7.72 (dd, 1H), 6.73
6-Chloro-1—(2-methoxy-ethyl)-1H-
(d, 1H), 5.88 (br. s, 2H,
pyrrolo[3,2-b]pyridine—5—carboxylic acid
NH2), 4.44 (t, 2H), 4.15 (d,
[6-((3R,6R)—5-amino-3,6-dimethyl
1H, AB), 3.74 (d, 1H, AB),
trifluoromethyl-3,6-dihydro-2H-
3.67 (t, 2H), 3.22 (s, 3H),
[1 ,4]oxaziny|)f|uoro-pyridin—2-yl]—
1.52 (s, 3H), 1.49 (s, 3H).
amide
Preparation of Intermediates
The substituted acid building blocks were either commercially available or can be prepared
as described in the literature e.g. DE19725802A1, edron: Asymmetry 1999, 10(4),
679-687, or in an analogous manner, or can be prepared as described hereafter or in an
analogous manner.
Acid 1: 5-Cyanomethyl-pyridinecarboxy|ic acid
a) 5-Bromomethyl-pyridine-Z-carboxylic acid tert-butyl ester
—126-
To a solution of 5-bromo-3—methyl-pyridine-2—carboxylic acid (10.20 g, 47.2 mmol) and di-
tert-butyldicarbonate (20.61 g, 94 mmol) in 100 ml THF were added DMAP (0.577 g).
Evolution of C02 started immediately and the mixture was d for 2 h at rt. TBME and sat
aq NaHCOs were added. The layers were separated and the organic layer washed with sat
aq NaHCOs and brine, and dried with MgSO4.H20. tography on silica gel (hexanes/
EtOAc 1-7%) provided the title compound as a yellow liquid.
HPLC: RtH3= 3.018 min; ESlMS [M+H]"= 272, 274 (1 Br); 1H-NMR (360 MHz, CDCIg): 6 8.59
s, 1H), 7.77 (s, 1H), 2.52 (s, 3H), 1.65 (s, 9H).
b) 5-Bromo-3—methyl-pyridinecarboxylic acid tert-butyl ester
A mixture of 5-bromomethyl-pyridinecarboxylic acid tert-butyl ester (6.0 g, 22.05
mmol), Zn(CN)2 (1.813 g, 15.43 mmol), Zn powder (0.144 g, 2.205 mmol) and Pd2(dba)
3 (0.571 g, 0.551 mmol) were suspended in 10 ml DMF under nitrogen atmosphere.
tBu3P (0.321 ml, 1.323 mmol) was added and the mixture was stirred for 5 h at 60 °C. After
being cooled down the mixture was diluted with TBME, filtered over celite and washed with
brine three times. The crude product was purified by column chromatography on silica gel
(hexanes/ EtOAc 5-15%) to give the title compound as an off white solid. TLC (hexanes/
EtOAc 3:1): R = 0.31; HPLC: RtH3= 2.431 min; ESIMS [M+Na]“= 241; 1H-NMR (360 MHz,
CDCI3): 6 8.78 (s, 1H), 7.88 (s, 1H), 2.56 (s, 3H), 1.67 (s, 9H); Ft-IR: 2231 cm"1 (CN).
0) 5-cyanomethyl-pyridinecarbo'xylic acid
To a solution of omethyl—pyridinecarboxylic acid tert-butyl ester (8.50 g, 38.9
mmol) in 1,3-dimethoxybenzene (51 ml, 389 mmol) was added TFA (85 ml) and stirred for
6.5 h. The reaction mixture was diluted with toluene and evaporated. The residue was taken
up in toluene and evaporated (2x). The product was crystallized from TBME/hexanes to give
the title nd as a white . HPLC: Rtm= 2.314 min; ESIMS [M+Na]+ = 163; 1H-
NMR (360 MHz, CDCIS): 6 8.77 (s, 1H), 8.07 (s, 1H), 2.87 (s, 3H).
Mi 5-Ch|oro-4,6-dideuterotrideuteromethyl-pyridinecarboxylic acid
A suspension of 500 mg (2.91 mmol) 5-chloromethyI-pyridinecarboxylic acid (CA8 Nr.:
886365-46—4) in 9 ml of D20 % D) was treated with 1 ml of a 40% solution of NaOD in
D20. The homogeneous solution was heated in a 100 ml Teflon vessel with a s 3000
Microwave tus. The mixture was heated at 160 °C for 5 h and cooled down. 1H-NMR
and MS analyses of the product showed'that deuteration had progressed to a high degree.
Only minor amounts of tetradeutero derivatives were present. The reaction mixture was
acidified to pH3 with 2N HCl and extracted with EtOAc. The org. phase was dried with
2012/050395
MgSO.«,.HZO and evaporated to give the title compound as a white solid, pure enough for
further transformations.
HPLC: RtH1= 2.820 min; ESIMS [M+H]+= 177 (5D); 1H-NMR (360 MHz, D20): 6 non
deuterated impurities.
Acid-3: 3-Amino(2,2,2-trifluoro-ethoxy)-pyrazinecarboxylic acid
a) 3-Amino(2,2,2-trifluoro-ethoxy)-pyrazinecarboxylic acid methyl ester
A mixture of 2,2,2-trifluorethanol (6.9 ml, 96 mmol) and cesium carbonate (1.56 g, 4.8 mmol)
was stirred for 20 min, 3-aminochloro-pyrazine—2—carboxylic acid methyl ester (600 mg, 3.2
mmol; GB 1248146) was added and the mixture was stirred at rt for 42 h. To complete the
reaction the mixture was heated to reflux for another 3 h. Saturated aq. NH4CI was added
and the mixture was extracted with EtOAc, the combined organic layers were washed with
saturated aq. sodium chloride, dried with NaZSO4 and evaporated. The residue was purified
by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 3:7) to provide the title
compound as ess solid.
HPLC: RtH4= 0.83 min; E‘SIMS [M+H]+= 252.2; 1H-NMR (400 MHz, DMSO-de): 6 7.66 (s, 1H),
7.60 (br s, 2H), 5.03 (q, 2H), 3.81 (s, 3H).
b) 3-Amino(2,2,2-trifluoro-ethoxy)-pyrazinecarboxylic acid
To a solution of 3-amino(2,2,2-trifluoro-ethoxy)-pyrazinecarboxylic acid methyl ester
(400 mg, 1.59 mmol) in 20 ml THF was added 2.5 ml (2.5 mmol) 1N sodium hydroxide and
the mixture was stirred at room temperature over night. To the mixture were added (2.39 ml,
2.39 mmol) 1N HCI after stirring for 5 min e was added and the solvents were
evaporated to e the title compound together with sodium chloride as an off-white solid.
The mixture was used for coupling reactions without r purification.
HPLC: RtH4= 0.71 min; ESlMS [M+H]*= 238.2; 1H NMR (400 MHz, DMSO-de): 6 7.46 (s, 1H),
4.97 (q, 2H).
A_ci_d;4_: 3-Aminocyano-pyridinecarboxylic acid
a) 5-Bromonitro-pyridinecarboxylic acid tert-butyl ester
To an ice cooled on of 5-bromonitro—pyridine-2—carboxylic acid (4.84 g, 19.59 mmol,
CAS 9542402) in THF (59 ml) was added DMAP (239 mg, 1.96 mmol) and Boczo (5.56
g, 25.5 mmol) and the reaction mixture was heated to 60 °C for 3 h. After cooling to 0 °C half
saturated aq. sodium bicarbonate was added and the mixture extracted with EtOAc. The
ed organic layers were washed with water and half saturated aq. NaCl, dried with
NaZSO4 and ated. The residue was purified by chromatography on silica gel
(cyclohexane to cyclohexane/EtOAc 3:2) to provide the title nd as pale beige solid.
HPLC: RtH5= 1.17 min; ESIMS [M+H]+= 304.1; 1H-NMR (600 MHz, DMSO-de): 6 9.11 (s, 1H),
8.92 (s, 1H), 1.53 (s, 9H).
b) 5-Cyanonitro-pyridinecarboxylic acid utyl ester
To a on of 5-bromo-3—nitro-pyridinecarboxylic acid tert—butyl ester (888 mg, 2.93
mmol) in DMF (8.8 ml) was added zinc cyanide (206 mg, 1.76 mmol) and zinc dust (2 mg,
0.03 mmol). The mixture was purged with nitrogen (3 times) bis(tri-tert-
1O butylphosphine)palladium(0) (150 mg, 0.293 mmol) was added and the mixture was heated
to 80 °C for 4 h. After cooling to 0 °C water was added and the mixture extracted with EtOAc,
the combined organic layers were washed with half saturated aq. NaCl, dried with NaZSO4
and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to
cyclohexane/EtOAc 1:4) to provide the title compound as beige solid.
HPLC: RtH5= 1.04 min; ESIMS [M+H]+= 248.0; 1H-NMR (600 MHz, DMSO-de): 6 9.39 (s, 1H),
9.29 (s, 1H), 1.55 (s, 9H).
c) ocyano-pyridinecarboxylic acid tert-butyl ester
To a mixture of 5-cyanonitro—pyridinecarboxylic acid tert—butyl ester (130 mg, 0.522
mmol) in water (3 ml) was added acetic acid (0.149 ml, 2.61 mmol), the e was stirred at
room temperature for 20 min, sodium dithionite (454 mg, 2.61 mmol) was added and stirring
was continued for 23 h. Additional sodium dithionite (182 mg, 1.043 mmol) was added and
the reaction mixture stirred for another 48 h. The mixture was extracted with DCM, the
combined organic layers were washed with water and saturated aq. NaCI, dried with Na2804
and evaporated to provide the title compound as yellow solid. The product was used for the
next step without further cation.
HPLC: RtH4= 0.86 min; ESIMS [M+H]+= 220.2; 1H-NMR (400 MHz, DMSO-de): 6 8.15 (d, 1H),
7.61 (d, 1H), 6.95 (br. s, 2H), 1.55 (s, 9H).
d) ocyano-pyridinecarboxylic acid
To a mixture of 3—amino—5—cyano-pyridinecarboxylic acid tert—butyl ester (60 mg, 0.274
mmol) and 1,3-dimethoxybenzene (0.358 ml, 2.74 mmol) was added dropwise within 10 min
TFA (0.59 ml, 7.66 mmol) and the reaction mixture was stirred for 6 h. Toluene was added
and the solvents were evaporated to provide the title compound as yellow solid. The product
was used for the next step without further purification.
HPLC: RtH4= 0.38 min; ESIMS [M+H]+= 164.1; 1H-NMR (400 MHz, DMSO-de): 6 13.05 (br. s,
1H), 8.16 (d, 1H), 7.64 (d, 1H), 7.08 (br. s, 2H).
Acid-5: 3—(Di-tert-butoxycarbonyl-amino)(3-fluoro-propoxy)-pyrazinecarboxylic
acid
a) 3-(Di-tert-butoxycarbonyl-amino)(3-fluoro-propoxy)-pyrazinecarboxylic acid 3-
fluoro-propyl ester
About a 1:1 mixture of 3-(di-tert—butoxycarbonyl-amino)(3-fluoro-propoxy)—pyrazine
carboxylic acid methyl ester and 3-(di-tert—butoxycarbonyl-amino)(3-fluoro-propoxy)-
ne—Z-carboxylic acid 3-fluoro-propyl ester was obtained following the procedure
described for acid-3 step a).
To an ice coolded solution of this mixture (245 mg, 0.89 mmol), DIPEA (1.31 ml, 7.48 mmol)
and DMAP (13 mg, 0.11 mmol) in DCM (10 ml) was added a solution of Boczo (1.05 g, 4.81
mmol) in DCM (10 ml) and the mixture was stirred and allowed to warm to r.t. overnight. After
addition of water the mixture was extraced with EtOAc (3x) and the combined organic layers
were washed with 0.5N HCI, saturated aq. sodium chloride, dried with NaZSO4 and
evaporated. The residue was purified by chromatography on silica gel (cyclohexane + 5%
NEt3 to cyclohexane + 0.5% NEt3/ EtOAc + 0.5% NELQ, 3:7) to provide the title compound
together with the 3-(di-tert—butoxycarbonyI-amino)(3-fluoro-propoxy)-pyrazinecarboxylic
acid methyl ester as yellow viscous oil. This mixture was used for the next step.
HPLC: RtH4= 1.19 min; ESIMS [M+H]*= 476.3; (Me-Ester: HPLC: RtH4= 1.15 min; ESIMS
[M+H]+ = 430.3).
b) 3-(Di-tert-butoxycarbonyl-amino)(3-fluoro-propoxy)-pyrazinecarboxylic acid
To a solution of 3-(di-tert-butoxycarbonyl-amino)(3-fluoro-propoxy)-pyrazinecarboxylic
acid 3-fluoro-propyl ester and tert—butoxycarbonyI-amino)(3-fluoro—propoxy)-pyrazine-
2-carboxylic acid methyl ester (395 mg, 0.92 mmol) in THF (10 ml) was added 0.5N LiOH
(2.02 ml, 1.01 mmol) and the mixture was d for 5.5 h. To the reaction mixture was
added 1N HCI (0.92 ml, 0.92 mmol) after stirring for 5 min e was added and the
solvents were evaporated to provide the title compound together with lithium chloride as a
light yellow solid. The mixture was used for coupling ons without further purification.
HPLC: RtH4= 0.98 min; ESIMS +H]“= 316.2; 1H NMR (400 MHz, DMSO-ds): 6 8.26 (s,
1 H), 4.67 (t, 1 H), 4.55 (t, 1 H), 4.41 (t, 2 H), 2.22 - 2.07 (m, 2 H), 1.32 (s, 18 H).
Acid-6: 3-Amino(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazinecarboxylic acid
WO 95469
a) obromo(2-methoxy-ethylamino)-pyrazinecarboxy|ic acid methyl ester
To a mixture of 3-amino-5,6-dichloro-pyrazinecarboxylic acid methyl ester [CAS 1458
0] and 3-aminobromo—5-chloro-pyrazinecarboxylic acid methyl ester [CAS 25—1]
(799 mg, 3 mmol) in DMF was added 2-methoxy-ethylamine (0.31 ml, 3.6 mmol) and NEt3
(2.09 ml, 15 mmol) and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was
poured into water (150 ml) and extracted with toluene (2x150 ml). The organic layers were
washed with half-saturated aq. sodium chloride, combined, dried with NaZSO4 and
evaporated. The residue was purified by chromatography on silica gel (cyclohexane/ EtOAc
100:0 to 0:100 %) to provide the title compound together with 3-amino—6-chloro-5—(2-
methoxy—ethylamino)-pyrazine-2—carboxylic acid methyl ester (about 1:1) as colorless solid.
This mixture was used for the next step.
HPLC: RtH4= 0.77 min; ESIMS [M+H]+ = 305.1; (Ci-pyrazine: HPLC: RtH4= 0.73 min; ESIMS
[M+H]+ = 261.1).
b) 3-Amino(2-methoxy-ethylamino)trimethylsilanylethynyl-pyrazinecarboxylic
acid methyl ester
To a solution of ethynyI-trimethyi-silane (1.05 g, 10.7 mmol),
ipheny|phosphine)pa|ladium(lI) de (150 mg, 0.214 mmol), Copper(l) iodide (41 mg,
0.214 mmol) and NEt3 (2.09 ml, 14.98 mmol) in THF (17 ml) was added under an argon
atmosphere a mixture (about 1:1) of 3—aminobromo(2-methoxy-ethylamino)-pyrazine-2—
carboxylic acid methyl ester and 3—aminochloro(2-methoxy—ethylamino)—pyrazine—2-
carboxylic acid methyl ester (651 mg, 2.14 mmol) and the mixture was heated to 80 °C for 17
h. The reaction mixture was filtered through Hyflo and the solvent evaporated. The residue
was purified by chromatography on silica gel (cyclohexane to exane/ EtOAc 60:40) to
provide the title compound as brown solid.
HPLC: RtH4= 1.12 min; ESIMS [M+H]+= 323.3; 1H NMR (400 MHz, DMSO—ds): 6 7.46 (br, 2
H), 6.65 (t, 1 H), 3.73 (s, 3 H), 3.59 - 3.45 (m, 4 H), 3.28 (s, 3 H), 0.25 (s, 9 H).
c) o(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazine-Z-carboxylic acid
To a solution of 3—amino(2-methoxy-ethylamino)—6-trimethylsilanylethynyl-pyrazine—2-
carboxylic acid methyl ester (487 mg, 1.51 mmol) in THF (7.6 ml) was added a suspension of
KOtBu (356 mg, 3.17 mmol) in THF (7.6 ml) and the reaction mixture was stirred at r.t. for 2
h. At 0 °C solid NH4C| (848 mg) was added and the mixture stirred for 30 min. After addition
of half-saturated NH4CI solution (15 ml) the mixture was extracted with EtOAc (2x 15 ml), the
pH of the aq. phase was adjusted the pH to 4 by addition of 1N HCI. The aq. phase was
extracted with DCM/EtOH 9:1 (2x100 ml), the combined organic layers were dried with
Na2804 and evaporated. The residue was filtered through a plug of silica gel (DCM / EtOH
90:10) to provide the title compound as brown powder. This material was used for coupling
reactions without further purification.
HPLC: RtH4= 0.53 min; ESIMS [M+H]*= 237.1; 1H NMR (600 MHz, DMSO—ds): 6 12.59 (br s,
1 H), 7.55 (d, 1 H), 7.26 (br s, 2 H), 6.46 (d, 1 H), 4.21 (t, 2 H), 3.66 (t, 2 H), 3.22 (s, 3 H).
Mi3-Amino(2,2—difluor-ethyl)-5H-pyrrolo[2,3-b]pyrazine-2—carboxylic acid
3-Amino(2,2-difluoro-ethylamino)trimethylsilanylethynyI-pyrazinecarboxylic acid
1O methyl ester was prepared by r ures as for Acid-6 (steps a and b) applying 80 °C
in step a) instead of room temperature.
a) 3-Amino(2,2-difluoro-ethyl)—6 H-pyrrolo[2,3-b]pyrazinecarboxylic acid methyl
ester
To a solution of 3—amino(2,2-difluoro—ethylamino)trimethylsilanylethynyl-pyrazine-2—
carboxylic acid methyl ester (624 mg, 1.9 mmol) in DMF (19 ml) was added Copper(l) iodide
(181 mg, 0.95 mmol) and the mixture was heated to 120 °C for 2 h. The reaction mixture was
filtered h Hyflo, the residue washed with toluene. The combined organic phases were
extracted with water, dried with Na2804 and evaporated. The e was purified by
chromatography on silica gel (cyclohexane to exane / EtOAc 40:60) to provide the title
compound as yellow solid.
HPLC: RtH4= 0.67 min; ESIMS [M+H]*= 257.1; 1H NMR (400 MHz, DMSO-de): 6 7.64 - 7.51
(m, 1 H), 7.27 (br s, 2 H), 6.56 (m, 1 H), 6.43 (t, 1H), 4.62 - 4.46 (m, 2 H), 3.86 (s, 3 H).
b) 3-Amino(2,2-difluor-ethyl)-5H-pyrrolo[2,3-b]pyrazinecarboxylic acid
To a solution of 3-amino(2,2-difluoro-ethyI)-6 H-pyrrolo[2,3-b]pyrazinecarboxylic acid
methyl ester (192 mg, 0.749 mmol) in THF (3.8 ml) was added a solution of 1M LiOH (0.824
ml, 0.824 mmol) and the reaction mixture was stirred at r.t. for 20 h. At 0 °C 1M HCl (0.749
ml) was added and the mixture diluted with toluene (7.5 ml). The solvents were ated
to provide the title nd together with LiCl as brown powder. This material was used for
coupling reactions without further purification.
HPLC: RtH4= 0.57 min; ESlMS [M+H]"= 243.1; 1H NMR (600 MHz, DMSO-de): 6 1271 (br s,
1 H), 7.56 (d, 1 H), 7.35 (br s, 2 H), 6.55 (d, 1 H), 6.41 (t, 1H), 4.61 - 4.43 (m, 2 H).
: 6-Chloro(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid
a) 6-Chloro(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid ethyl ester
To a solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-5—carboxylic acid ethyl ester (210 mg,
0.935 mmol) in DMF (10 ml) was added cesium ate (457 mg, 1.402 mmol), after 15
min stirring at room temperature 1,1-difluoro—2-iodoethane (538 mg, 2.8 mmol) was added
and stirring was continued over night. Tetrabutylammonium iodide (34.5 mg, 0.093 mmol)
was added and ng was continued for another 48 h. To the reaction mixture was added
saturated aq. NH4C| and the mixture was extracted with MTBE (2x). The combined organic
layers were washed with half-saturated aq. NaCl, dried with NaZSO4 and evaporated. The
residue was purified by chromatography on silica gel (cyclohexane to cyclohexane / EtOAc
:80) to provide the title compound as yellow solid.
HPLC: RtH4= 0.88 min; ESIMS [M+H]*= 289.4 / 291.1; 1H NMR (400 MHz, DMSO-ds): 6 8.34
(s, 1 H), 7.83 (d, 1 H), 6.74 (d, 1 H), 6.40 (t, 1 H), 4.78 (td, 2 H), 4.35 (q, 2 H), 1.31 (t, 3 H).
b) 6-Chloro(2,2-difluoro-ethyI)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid
To a solution of 6-chloro(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid
ethyl ester (150 mg, 0.520 mmol) in THF (10 ml) was added 1N aq. sodium ide (0.624
ml, 0.624 mmol) and mixture was stirred at 65 °C for 4.5 h. The solvents were evaporated,
the residue was dissolved in water, acidified with 2N aq. HCI and the e extracted with
EtOAc. The combined organic layers were dried with NaZSO4 and evaporated to e the -
title compound as light orange solid.
HPLC: RtH4= 0.50 min; ESIMS [M+H]+= 261.0 / 263.1; 1H NMR (400 MHZ, DMSO-ds): 6
13.36 (s, 1H), 8.31 (s, 1 H), 7.81 (d, 1 H), 6.72 (d, 1 H), 6.39 (t, 1 H), 4.87 - 4.67 (m, 2 H).
Aid-g 6-Chloro(2-methoxy-ethyl)-1H-pyrro|o[3,2-b]pyridinecarboxylic acid
6-Chloro(2—methoxy—ethyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid was prepared by
similar ures as for Acid-9 [steps a) and b)] using 1-bromo—2-methoxy-ethane in step a)
instead of 1,1-difluoroiodo-ethane without addition of tetrabutylammonium iodide and
stiring only once over night.
HPLC: RtH4= 0.47 min; ESIMS [M+H]*= 255.1 /257.1; 1H NMR (400 MHz, DMSO-ds): 6
13.26 (br. s, 1 H), 8.22 (s, 1 H), 7.79 (d, 1 H), 6.63 (d, 1 H), 4.38 (t, 2 H), 3.62 (t, 2 H), 3.17
(s, 3 H).
Amide 1: 5-CyanomethyI-pyridinecarboxylic acid amide
To a white suspension of 5—oyanomethyl-pyridinecarboxylic acid (84 mg, 0.518 mmol)
in DCM (1.5 ml) was added oxalyl chloride (0.068 ml, 99 mg, 0.777 mmol) and a catalytic
amount of DM F. The reaction mixture was stirred at rt for 1 h and was then added dropwise
to a 25% aq. NH4OH soln. (0.300 ml) at 0 °C. The reaction mixture was stirred for 10 min at
—133-
rt, H20 and TBME were added, the phases were separated and the aq. phase was twice
reextracted with TBME. The combined org. phases were dried over Na2804, d and
concentrated to leave a white powder that was used in the next step without further
purification. RtH4= 0.47 min; ESIMS: 162 [(M + H)+]; 1H NMR (400 MHz, DMSO-ds):l6 8.68 (d,
1H), 7.91 (d, 1H), 7.80 (br s, 1H), 5.57 (br s, 1H), 2.80 (s, 3H).
Amide 2: 3-Chlorocyano-pyridinecarboxylic acid amide was prepared from 3-
chloro—5-cyano-pyridinecarboxylic acid (CAS 1200497—81-9) in analogy to the procedure
described for Amide 1.
1O RtH4= 0.45 min;
1H NMR (400 MHz, DMSO-de): 6 9.01 (d, 1H), 8.70 (d, 1H), 8.17 (br s, 1H), 7.94 (br s, 1H).
Amide 3: 3-Chlorodifluoromethoxy-pyridine-Z-carboxylic acid amide was prepared
from rodifluoromethoxy-pyridine—2-carboxylic acid (CA8 12628609) in analogy to
above procedure. RtH4= 0.62 min; ESIMS: 223 [(M + H)+];
1H NMR (400 MHz, s): 6 8.49 (d, 1H), 8.08-7.97 (m, 2H), 7.73 (br s, 1H), 7.45 (t, 1H).
Hydroxyester 1: 3-Fluorofluoromethylhydroxy-propionic acid ethyl ester
a) rofluoromethyl-Z-trimethylsiIanyloxy-propionitrile
To 1,3-difluoro—propan—2-one (8.5 g, 90 mmol) was added drop wise over 30 min TMS-
Cyanide (8.97 g, 90 mmol). The reaction mixture was stirred for 16 h at ambient temperature.
Yield = 17.4 g (100%).
1H-NMR (400 MHz, CDCI3) 6 4.55 (d, 2 H), 4.44 (d, 2 H), 0.28 (s, 9H).
19F-NMR (376 MHz, CDCIg) 6 - 226 (t).
b) 3-Fluorofluoromethylhydroxy-propionic acid
3-Fluorofluoromethyltrimethylsilanyloxy—propionitrile (17.4 g, 90 mmol) was d with
37% HCI (300 ml) and heated to gentle reflux for 3 h. The reaction mixture was cooled to
ambient temperature and concentrated in vacuo. The solid thus obtained was redisolved in
300 ml ethanol and concentrated in vacuo and dried in high vaccum.
The solid thus ed (17 9) contained significant amount of ammonium-chloride and was
used without further purification.
1H-NMR (400 MHz, DMSO—ds) 6 7.0 — 7.3 (m, 4H), 5.6 — 6.5 (s, 1H), 4.43 — 4.58 (m, 4 H).
13C-NMR (150 MHz, DMSO—de) 6 171 (t), 85 (d), 83 (d), 75 (t).
-134—
c) 3-Fluorofluoromethylhydroxy-propionic acid ethyl ester
Crude 3-fluoro—2-fluoromethylhydroxy-propionic acid (17 g) was dissolved in ethanol (400
ml) and H2804 (98%, 30 g) was added. The reaction mixture was refluxed for 16 h.
The reaction mixture was cooled to ambient ature and filtered. The solution was
carefully treated with 30 9 solid Nazcog and the ing mixture was stirred for 30 min at
room temperature. 400 ml DCM were added and the mixture was ed. The solution was
concentrated (50 °C, 150 mbar) and further purified by distillation (82 “C, 20 mbar) to give a
colorless liquid.
Yield = 9.8 g (97%).
1H-NMR (400 MHz, DMSO—de) 6 4.43 - 4.65 (m, 4 H), 4.30 (q, 2 H), 3.63 - 3.88 (s,‘|H), 1.30
(t, 3 H).
Claims (28)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, , E/O\E \WNXst (I), in which either X1 is CR1 or N; X3 is CR3 or N; X4 is CR4 or N; X5 is CR5 or N; n'at least one of X1, X3, X4 and X5 is N and not more than 2 of X1, X3, X4 and X5 are N; R1 is en, cyano, halogen, (01.8)alkyl, halogen-(C1-8)alkyl, (01-8)alkoxy, halogen- (C1_8)alkoxy, (01-8)alkylthio, halogen-(01-3)alkylthio, (C1-3)alkoxy-(C1_8)alkyl, (C1-g)alkoxy-(C1. 3)alkoxy, (C1-a)alkoxy-(C1-g)alkylthio, (C1-8)alkylthio-(C1-g)alkyl, (C1-8)alkylthio-(C1-3)alkoxy, (C1- 8)a|ky|thio-(C1_8)alkylthio, (C2_8)alkenyl, or (C2_3)alkyny|; R2 is an aryl, heteroaryl or non-aromatic heterocyclyl group G1, which group G1 is optionally tuted by 1, 2, 3 or 4 substituents ndently selected from the group, consisting of cyano, amino, amino-(C1_8)alkyl, N-(C1-4)alkyl-amino-(C1_8)a|kyl, N,N-di(C1_ 4)a|kyl-amino-(C1_8)alkyl, aminocarbonyl, thiocarbamoyl, halogen, (C1_8)alkyl, halogen-(C1- 3)alkyl, hydroxy, oxo, (01.8)alkoxy, halogen-(C1.8)a|koxy, (C1.B)alkylthio, halogen-(C1. 8)alkylthio, (C1_g)a|koxy-(C1-3)alky|, (C3_8)cycloalky|-(C1-3)aIkoxy, (C1.g)alkoxy-(C1.8)alkoxy, (C1. 3)alkoxy—(C1-8)alkylthio, (C1-8)alkylthio-(C1-3)alkyl, (C1_8)a|kylthio-(C1_g)alkoxy, (C1_8)a|kylthio- (C1-g)alkylthio, alkenyl, (C2_8)alkynyl, (C2_3)alkenoxy, (02-5)alkynoxy and a (C3- 8)cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclyl group G2, which group G2 is ally substituted by 1, 2, 3, or 4 substituents independently selected _from the group, consisting of cyano, aminocarbonyl, halogen, (C1-3)3lle, halogen-(C1.g)alkyl, hydroxy, (C1- 3)alkoxy, halogen-(01-3)alkoxy, (01-8)alkylthio, halogen-(01-8)alkylthio, (01-8)alkoxy-(C1-s)alkyl, (C1.8)alkoxy-(C1-8)alkoxy, alkoxy-(C1_8)alkylthio, (C1-3)a|ky|thio-(C1-s)a|kyl, (C1-8)alky|thio- (C1_3)alkoxy, (C1-8)alkylthio-(C1-3)alkylthio, alkenyl and (C2_8)alkynyl; R3 is en, cyano, halogen, (C1_3)alkyl, halogen-(C1-8)alkyl, (C1_3)alkoxy; halogen- (C1_8)alkoxy, (01-8)alkylthio, halogen-(C1_8)alkylthio, (C1_3)alkoxy-(C1_8)alkyl, (C1-s)alkoxy-(C1- 3)alkoxy, (C1.8)alkoxy-(C1-8)alkylthio, (C1-8)alkylthio-(C1-3)alky|, (C1-8)alkylthio-(C1-8)alkoxy, (C1- g)alkylthio-(C1_8)alkylthio, (Cg.g)alkenyl, or (02.3)alkynyl; R4 is hydrogen, cyano, halogen, (C1_g)alkyl, halogen-(C1_g)alkyl, (01-8)alkoxy, halogen- (C1-3)alkoxy, (C1-g)alkylthio, halogen-(C1_8)alkylthio, (C1_8)alkoxy-(C1_8)alkyl, (C1_g)alkoxy-(C1_ 8)alkoxy, (C1-8)alkoxy-(C1-8)alkylthio, (C1-8)alkylthio-(C1-3)alkyl, alkylthio—(C1-3)alkoxy, (C1- lthio-(C1_a)alkylthio, (02-5)alkenyl, or (02.8)alkynyl; R5 is hydrogen, cyano, halogen, (C1_8)alkyl, halogen-(01-8)alkyl, (C1_g)alkoxy, halogen- (C1.8)alkoxy, (C1-8)alkylthio, halogen-(01.8)alkylthio, (C1.e)a|koxy-(C1-3)alkyl, (01-8)alkoxy-(C1- 3)alkoxy, (C1.8)alkoxy-(C1-3)alkylthio, (01-3)alkylthio-(C1.3)alkyl, (C1.B)alkylthio-(C1_g)alkoxy, (C1. 3)alkylthio-(C1_8)alkylthio, (C2-a)alkenyl, or (C2.3)alkynyl; R4 and R5, taken together, are -C(H)=C(H)-C(H)=C(H)— or a (01-8)alkylene group, in which (C1_8)alkylene group 1 or 2 -CH2- ring s are optionally replaced with hetero ring members independently selected from the group, consisting of -N(H)—, -N[(C1_8)alkyl]-, -O-, -S-, -S(=O)- or -S(=O)2-; R6 is (C1-g)a|kyl, halogen-(C1-a)alkyl, hydroxy-(C1_8)alkyl, (C1-8)alkoxy-(C1_8)alkyl, mercapto-(C1-8)alkyl, (C1-g)alkylthio-(C1-8)alky|, amino-(C1_8)alkyl, N-(C1_4)alkyl-amino-(C1_ l, N,N-di(C1.4)alkyl-amino-(C1.3)alky|, alkenyl, or (02-8)alkynyl; R5 and R6, taken er, are a (C1_4)a|kylene group, in which (01-4)alkylene group 1 -CH2- ring member is optionally replaced with a hetero ring member independently selected from the group, consisting of -N(H)-, -4)alkyl]-, -O-, -S—, -S(=O)- or -S(=O)2—; E1 is (R8)'§ E2 is 'C(R11)(R12)': 0" )(R12)‘C(R13)(R14)‘i each of R7 and R5 is en eflher each of R11 and R12 is independently selected from the group, consisting of hydrogen, cyano, halogen, (C1-g)alky|, halogen-(C1-g)alkyl, (C1-B)alkoxy-(C1_8)alkyl and (C1.8)alkylthio-(C1_ a)a|ky|; R11 and R12, taken together, are 0x0 or —CR15R16-CR17R18- wherein R15, R15, R17 and R18 are independently selected from hydrogen and fluoro; ~137- eflher each of R13 and R14 is ndently selected from the group, consisting of hydrogen, cyano, halogen, alkyl, halogen-(C1_3)alkyl. (C1_g)alkoxy-(C1_3)alkyl and (C1_g)alkylthio-(C1- s)a|ky|; R13 and R14, taken together, are oxo or -CH2-CH2-.
2. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein X1 is N; X3 is CR3; X4 is CR4; and X5 is CR5.
3. A compound according to Claim 1 or Claim 2, or a pharmaceutically acceptable salt thereof, wherein E2 is )(R12)-.
4. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, of formula (lo) 0 R11 1' R R2 N / T x1 / N | NH2 Rs (lo), 0 x3\\x4 in which X1 is CR1 or N; X3 is CR3 or N; X4 is CR4 or N; wherein at least one of X1, X3 and X4 is N and not more than 2 of X1, X3 and X4 are N; R1 is hydrogen, cyano, halogen, (C1_4)alkyl, n-(01-4)alkyl, (01-4)alkoxy, or halogen-(01-4)alkoxy; R2 is a 5- or ered heteroaryl group in which structure 1, 2, 3, or 4 ring members are hetero ring members independently selected from the group consisiting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, which group is optionally substituted by 1, 2, 3 or 4 substituents ndently selected from the group, consisting of cyano, amino, aminocarbonyl, thiocarbamoyl, halogen, (C1_4)alkyl, halogen-(C1- 4)alkyl, hydroxy, oxo, alkoxy, halogen-(01-4)alkoxy, (C1_4)alkylthio, halogen-(C1- 4)alkylthio, (C1-4)alkoxy-(C1-4)alkyl, (C1-4)alkoxy-(C1-4)alkoxy, (C1-4)alkoxy-(C1-4)alkylthio, (C1- 4)alkylthio-(C1-4)alkyl, (C1-4)alkylthio-(C1-4)alkoxy, (01-4)alkylthio-(C1-4)alky|thio, (C2_4)alkenyl, (C2-4)alkyny|, (CM)alkenoxy, and (C24)alkynoxy; R3, R4 and R5 are independently selected from the group ting of hydrogen, cyano, halogen, alkyl, halogen-(01-4)alkyl, (01-4)alkoxy, or halogen-(C1-4)alkoxy; R6 is (C1_3)alky| or fluoro-(C1_3)alkyl; and each of R11 and R12 is independently ed from the group, consisting of hydrogen, (C1_3)alkyl and halogen-(01-3)alkyl.
5. A compound according to any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
6. A compound according to Claim 1, or a ceutically acceptable salt thereof, of formula (lc) 0 R11 T R R2 N / Y x1 / N l NH2 R; (lo), 0 x3§ x4 R5 in which X1 is CH or N; X3 is CH or N; X4 is CR4 or N; wherein one and not more than one of X1, X3 and X4 is N; 10 R2 is a pyridyl or pyrazinyl group which is optionally substituted by 1, 2 or 3 substituents ndently ed from the group, consisting of cyano, amino, aminocarbonyl, thiocarbamoyl, halogen, (01.4)alkyl, halogen-(01-4)alkyl, hydroxy, oxo, (C1- 4)alkoxy, halogen-(01-4)alkoxy, (C1-4)alkylthio, halogen-(01-4)alkylthio, (C1-4)a|koxy—(C1_4)alkyl, (C1-4)alkoxy-(C1-4)a|koxy, (C1-4)alkoxy-(C1-4)alky|thio, (C1-4)a|kylthio-(C1-4)a|kyl, (C1_4)alkylthio- 15 (01.4)alkoxy, (C1.4)alkylthio-(C1-4)a|kylthio, (02-4)alkenyl, (C2_4)alkynyl, (C2_4)alkenoxy, and (Cg- 4)alkynoxy; R4 and R5 are independently hydrogen, or halogen; R5 is (01-3)alkyl or fluoro-(C1.3)alkyl; and each of R11 and R12 is independently ed from the group, consisting of hydrogen, 20 (01-3)alkyl and fluoro-(C1_3)alkyl. -139—
7. A compound according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R6 is methyl, fluoromethyl, difluoromethyl or trifluoromethyl.
8. A compound ing to any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each of R11 and R12 is independently selected from the group, consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and trifluoromethyl.
9. A compound according to Claim 1, or a ceutically acceptable salt thereof, of formula (Id) 0 R11 T R R2 N Y x1 / / “ N l NH2 Ra (Id). 0 X3§ x4 R5 in which X1 is CH or N; X3 is CH or N; X4 iS CR4 or N, n one and not more than one of X1, X3 and X4 is N; R2 is a pyridyl or pyrazinyl group which is substituted by 2 or 3 substituents and 10 n one of the substituents is located at the para on and one of the substituents is located at the ortho position of the pyridyl or pyrazinyl group relative to the amide linker and wherein the substituents are independently selected from the group, consisting of cyano, amino, halogen, (C1_4)alkyl, halogen-(01-4)alkyl, hydroxy, oxo, (01.4)alkoxy and halogen-(C1- 4)a|koxy; 15 R4 and R5 are independently hydrogen, or halogen; R6 is methyl, fluoromethyl, difluoromethyl or trifluoromethyl; and each of R11 and R12 is independently selected from the group, consisting of hydrogen, methyl, fluoromethyl, romethyl and trifluoromethyl.
10. A compound according to any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R2 is a pyridin-2—yl or pyrazinyl group which is substituted by 2 substituents and wherein one of the substituents is d at the para on and one of the substituents is located at the ortho position of the pyridinyl or pyrazinyl group relative to the amide linker and wherein the tuents are independently selected from the group, consisting of cyano, amino, fluoro, bromo, , hydroxyl, oxo, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, romethoxy and trifluromethoxy.
11. A compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X1 is N; X3 is CH; and X4 is CR4.
12. A compound ing to any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
13. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, of 5 formula (le) 0 R11 H R R2 N N i‘2 \H/ / “ N l NH2 R; (le). 0 \ in which R2 is a n-2—yl or pyrazin-Z-yl group which is substituted by 2 substituents and wherein one of the substituents is located at the para position and one of the substituents is 10 located at the ortho position of the pyridin-2—yl or nyl group relative to the amide linker and n the tuents are independently selected ’from the group, consisting of cyano, amino, fluoro, bromo, chloro, hydroxyl, oxo, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluromethoxy; R5 is hydrogen or fluoro; 15 R6 is methyl, fluoromethyl or difluoromethyl; and each of R11 and R12 is independently selected from the group, consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and trifluoromethyl.
14. A compound according to any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, n R5 is .
15. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 5-Bromo-pyridinecarboxylic acid [6-(5-aminomethyl-3,6-dihydro-2H-[1,4]-oxazin-3—yl)- pyridinyl]-amide; 5-Chloro-pyridinecarboxylic acid [6-(5—aminofluoromethyI-3,6-dihydro-2H-[1,4]oxazin y|)-pyridinyl]-amide; 5—Bromo-pyridinecarboxylic acid [6-(5-amino—3-fluoromethyI-3,6-dihydro-2H-[1,4]oxazin yI)-pyridiny|]-amide; 5—Cyanomethyl-pyridinecarboxylic acid [6-(5-aminofluoromethyI—3,6-dihydro-2H- [1 ,4]oxazinyl)-pyridin-2—yl]-amide; 4,6-Dideuterochlorotrideuteromethyl-pyridinecarboxylic acid [6-(5-amino fluoromethyI-3,6-dihydro-2H-[1,4]oxazinyi)-pyridinyl]-amide; 5—Thiocarbamoyl-pyridinecarboxylic acid aminofluoromethyI-3,6-dihydro-2H- [1 zinyl)-pyridin-2—yI]—amide; 5-CyanomethyI-pyridinecarboxyiic acid [6-(5-amino-3,6-dimethyl-G-trifluoro-methyl—3,6- dihydro-2H-[1,4]oxazinyi)—pyridin-2—yi]—amide; 5-Cyano-pyridinecarboxylic acid [6-(5-amino-3,6-dimethyl-B-trifluoromethyl-3,6-dihydro- 2H-[1 ,4]oxaziny|)-pyridinyl]—amide; 5—CyanomethyI—pyridinecarboxylic acid [6—(5-amino-3,6—dimethyl-6—trifiuoromethyl-3,6- dihydro-2H-[1 ,4]oxazinyl)f|uoro-pyridiny|]-amide; 4,6-DideuterochIorotrideuteromethyI-pyridinecarboxylic acid [4—(5-amino fluoromethyI-3,6-dihydro-2H-[1 zin—3-yI)-pyridinyI]—amide; 5-Chloro-pyridinecarboxylic acid [4-(5-amino-3—fluoromethyl-3,6-dihydro-2H-[1,4]oxazin yI)-pyridiny|]-amide; 5—CyanomethyI-pyridine-2—carboxyiic acid [4-(5-amino-3,6-dimethyltrifluoromethyI-3,6- dihydro-2H-[1,4]oxazinyi)—5-f|uoro-pyridinyi]-amide; 5-Bromo-pyridinecarboxylic acid [5-(5-amino-3—fluoromethyI-3,6-dihydro-2H-[1,4]oxazin yl)chIoro-pyridiny|]-amide; 3—Aminocyano-pyridinecarboxylic acid [6-(5-aminc-3,6-dimethyltrifluoromethyl-3,6- dihydro-2H—[1 ,4]oxazin—3—yI)-pyridinyl]-amide; 3-Chlorocyano-pyridinecarboxylic acid [6—(5-amino-3,6—dimethyltrifluoromethyl-3,6- dihydro-2H-[1 ,4]oxazinyl)—pyridiny|]-amide; 5-ChIoro-4,6-dideuteriotrideuteriomethyl-pyridine-2—carboxylic acid [6-(5-amino-3,6- yl-G-trifluoromethyI-3,6-dihydro-2H-[1,4]oxaziny|)-pyridinyl]-amide; 5-Bromochloro-pyridine—Z-carboxylic acid [6—(5—amino-3,6-dimethyltrifluoromethyI-3,6- dihydro-2H-[1,4]oxazinyl)-pyridinyl]-amide; 3—Amino(2,2,2-trifluoro-ethoxy)-pyrazine-2—carboxylic acid [6-(5-amino—3,6-dimethyI—6- trifluoromethyi-3,6-dihydro-2H—[1 ,4]oxaziny|)-pyridiny|]-amide; _3-Chiorocyano-pyridine—2—carboxyiic acid [6-(5-amino-3,6-dimethyltrifluoromethyI-3,6- dihydro-2H-[1,4]oxaziny|)f|uoro-pyridin-2—yI]-amide; 5-MethoxymethyI-pyridine—2—carboxyiic acid [6-(5-aminc—3,6-dimethyltrifluoromethyl- hyd ro-2H-[1 ,4]oxazinyl)—5-f|uoro-pyridin-Z-yl]amide; o(2,2,2-trifluoro-ethoxy)—pyrazinecarboxylic acid [6-(5-amino-3,6-dimethyI trifluoromethyI-3,6-dihydro-2H-[1,4]oxazin-3—yl)fluoro-pyridin-2—yl]amide; 3-Aminocyano-pyridine-Z-carboxylic acid [6-(5-amino-3,6-dimethyltrifluoromethyl-3,6- dihydro-2H-[1 ,4]oxazinyI)f|uoro-pyridinyl]amide; 5-Difiuoromethoxy—3-methyl-pyridinecarboxylic acid [6—(5-amino—3,6-dimethyl trifluoromethyI-3,6-dihydro-2H—[1 ,4]oxazin-3—yl)fiuoro-pyridin—2—yl]amide; rodifluoromethoxy-pyridinecarboxylic acid [6-(5-aminc-3,6-dimethyI trifluoromethyI-3,6-dihydro-2H-[1,4]oxazin-3—yl)f|uoro-pyridin-2—yl]amide; 3,5-Dichloro-pyridinecarboxyiic acid [6-(5-amino-3,6-dimethyltrifluoromethyI-3,6- dihydro—2H-[1,4]oxazin-3—y|)f|uoro-pyridin-2—yl]amide; 5-Fluoromethoxymethyl-pyridinecarboxylic acid [6-(5-aminc-3,6-dimethyl—6- trifluoromethyI—3,6-dihyd ro-2H-[1 ,4]oxazinyl)f|uoro-pyridin-Z-yl]amide; 5-Methyl-pyrazine—2—carboxylic acid [6—(5-amino—3,6-dimethyltrifluoromethyI-3,6-dihydro- 2H-[1 ,4]oxaziny|)f|uoro-pyridin-2—yl]amide; 3-ChIorotrifluoromethyl-pyridinecarboxylic acid [6-(5-amino-3,6—dimethyl trifluoromethyl-3,6-dihydro-2H-[1,4]oxaziny|)f|uoro-pyridinyl]amide; 3-ChIorocyano-pyridine—Z-carboxylic acid amino-3,6-dimethyltrifluoromethyl-3,6- dihydro-2H-[1 ,4]oxazin—3-y|)f|uoro-pyridinyI]-amide; 3-Chlorodifluoromethoxy-pyridinecarboxylic acid [4-(5-aminc-3,6—dimethyi trifluoromethyI-3,6-dihydro-2H-[1,4]oxazinyl)—5-f|uoro-pyridiny|]-amide; 5-Cyanomethyl-pyridinecarboxylic acid [4-(5-aminc-6,6-bis-fluoromethyImethyI-3,6- dihydro—2H-[1,4]oxazinyl)fluoro-pyridin-2—yI]-amide; 5-CyanomethyI-pyridinecarboxylic acid [6-( 5-amino-3—difluoromethyi-3,6-dihydro-2H- [1,4] yl)—5-fluoro-pyridinyl]—amide; 3-ChIoro-5—cyano-pyridinecarboxylic acid aminodifluoromethyl-3,6-dihydro-2H- [1,4] oxazinyl)fluoro-pyridin-Z-yI]-amide; 3,5—Dimethyl-pyrazinecarboxylic acid [6-(5-aminc-3,6-dimethyltrifluoromethyl-3,6— dihydro-2H-[1,4]oxazin-3—yl)fluoro-pyridin-2—yl]amide; 3-Amino-5—(3-fluoro-propoxy)—pyrazinecarboxylic acid [6-(5-amino-3,6-dimethyl trifluoromethyI-3,6-dihyd ro-2H-[1 ,4]oxaziny|)fluoro-pyridiny|]amide; 3-Amino(2-methoxy-ethyl)-5H-pyrrolo[2,3-b]pyrazinecarboxylic acid [6-((5-amino-3,6- dimethyltrifluoromethyl-3,6—dihydro-2H-[1,4]oxazinyl)—5-fluoro-pyridinyl]amide; 3-Aminotrifluoromethyl-pyrazine-2—carboxylic acid [6-(5-amino-3,6-dimethyI trifluoromethyl-3,6—dihydro-2H-[1,4]oxazin-3—yl)fluoro-pyridin-2—yl]amide; o(2,2-difluoro—ethyl)-5H-pyrrolo[2,3-b]pyrazinecarboxylic acid [6-(5-amino-3,6- dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)fluoro—pyridinyl]-amide; 4-Chlorodifluoromethyl-1H-pyrazoIecarboxylic acid [6-(5-amino-3,6—dimethyl trifluoromethyl-3,6-dihydro-2H-[1,4]oxazinyl)f|uoro-pyridin—Z-yl]—amide; 6—Chloro(2,2—difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid [6-(5—amino-3,6- 10 dimethyltrifluoromethyl-3,6-dihydro-2H-[1,4]oxazin—3—y|)—5-f|uoro-pyridin-2—yl]-amide; and 6-Chloro(2-methoxy-ethyl)-1H-pyrrolo[3,2—b]pyridinecarboxylic acid [6-(5-amino-3,6- dimethyltrifluoromethyl-3,6—dihydro-2H-[1,4]oxazin-3—y|)f|uoro-pyridinyl]-amide.
16. A compound according to Claim 1 which is 5-cyano—3-methyl-pyridinecarboxylic acid [6-((3R,6R)—5-amino-3,6-dimethyltrifluoromethyl—B,6-dihydro-2H-[1,4]oxazinyl)—5-fluoro- 15 pyridin-2—yl]-amide, or a pharmaceutically acceptable salt thereof, having the following formula
17. A compound according to Claim 1 which is 3-chlorotrifluoromethyl-pyridine-Z- carboxylic acid [6-((3R,6R)—5-amino-3,6—dimethyl-B—trifluoromethyl-3,6-dihydro-2H- [1 ,4]oxazinyl)fluoro-pyridinyl]amide, or a pharmaceutically able salt f, having the following formula
18. A compound ing to Claim 1which is 3-aminotrifluoromethyl-pyrazine-Z- carboxylic acid [6-((3R,6R)—5—amino-3,6—dimethyltrifluoromethyl-3,6-dihydro-2H- [1 ,4]oxazlnyl)fluoro-pyridinyl]amide, or a pharmaceutically acceptable salt thereof, having the following formula
19. A compound according to any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use as a medicament.
20. A compound according to any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Alzheimer’s disease or mild cognitive impairment.
21. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 18, or a pharmaceutically acceptable salt f, as active pharmaceutical ient in ation with at least one pharmaceutically able carrier or diluent.
22. The use of a compound according to any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the cture of a medicament for the treatment or prevention of Alzheimer’s disease or mild cognitive impairment.
23. A pharmaceutical ation comprising a therapeutically effective amount of a compound according to any one of Claims 1 to 18, or a pharmaceutically acceptable salt f, and a second drug substance, for simultaneous or sequential administration.
24. The compound according to Claim 1, substantially as herein described in any one of the Examples thereof.
25. The compound according to any one of Claims 1 to 20, substantially as herein described.
26. The pharmaceutical composition according to Claim 21, ntially as herein descnbed.
27. The use according to Claim 22, substantially as herein described.
28. The ceutical combination according to Claim 23, substantially as herein described.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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IN77/DEL/2011 | 2011-01-13 | ||
IN77DE2011 | 2011-01-13 | ||
US201161534591P | 2011-09-14 | 2011-09-14 | |
US61/534,591 | 2011-09-14 | ||
PCT/EP2012/050395 WO2012095469A1 (en) | 2011-01-13 | 2012-01-11 | Novel heterocyclic derivatives and their use in the treatment of neurological disorders |
Publications (2)
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NZ612990A NZ612990A (en) | 2014-11-28 |
NZ612990B2 true NZ612990B2 (en) | 2015-03-03 |
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