TWI729047B - 布魯頓氏（ｂｒｕｔｏｎ）酪胺酸激酶抑制劑及其使用方法 - Google Patents

Info

Publication number

TWI729047B

TWI729047B TW105140760A TW105140760A TWI729047B TW I729047 B TWI729047 B TW I729047B TW 105140760 A TW105140760 A TW 105140760A TW 105140760 A TW105140760 A TW 105140760A TW I729047 B TWI729047 B TW I729047B

Authority

TW

Taiwan

Prior art keywords

dihydro

thio

carboxamide

triazanthene

methyl

Prior art date

2015-12-10

Links

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• 238000000034 method Methods 0.000 title claims abstract description 43
• 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title claims description 6
• 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title claims description 6
• 239000003112 inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 578
• 125000000217 alkyl group Chemical group 0.000 claims description 969
• 125000001424 substituent group Chemical group 0.000 claims description 221
• 229910052799 carbon Inorganic materials 0.000 claims description 135
• 125000001188 haloalkyl group Chemical group 0.000 claims description 121
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 96
• 125000004076 pyridyl group Chemical group 0.000 claims description 92
• -1 2 -cyclohexyl Chemical group 0.000 claims description 88
• 229910052736 halogen Inorganic materials 0.000 claims description 81
• 150000002367 halogens Chemical class 0.000 claims description 81
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 72
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 69
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 65
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 57
• 229910052739 hydrogen Inorganic materials 0.000 claims description 57
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 55
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 50
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 50
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 48
• 150000003839 salts Chemical class 0.000 claims description 48
• 229910052801 chlorine Inorganic materials 0.000 claims description 38
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 37
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 34
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 31
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 31
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
• 230000000155 isotopic effect Effects 0.000 claims description 31
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
• 150000001335 aliphatic alkanes Chemical group 0.000 claims description 30
• RHEZVSHTUUQVIZ-UHFFFAOYSA-N 1,2-dihydroacenaphthylene-1-carboxamide Chemical compound C1=CC(C(C(=O)N)C2)=C3C2=CC=CC3=C1 RHEZVSHTUUQVIZ-UHFFFAOYSA-N 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 18
• QEXMUDIBEKFQDA-UHFFFAOYSA-N acridine-2-carboxamide Chemical compound C1=CC=CC2=CC3=CC(C(=O)N)=CC=C3N=C21 QEXMUDIBEKFQDA-UHFFFAOYSA-N 0.000 claims description 17
• 201000010099 disease Diseases 0.000 claims description 17
• 208000035475 disorder Diseases 0.000 claims description 14
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 13
• 229960002685 biotin Drugs 0.000 claims description 13
• 239000011616 biotin Substances 0.000 claims description 13
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 10
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
• 229940055764 triaz Drugs 0.000 claims description 10
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
• GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 6
• 101150065749 Churc1 gene Proteins 0.000 claims description 6
• 102100038239 Protein Churchill Human genes 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 150000001413 amino acids Chemical class 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 101150032584 oxy-4 gene Proteins 0.000 claims description 5
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
• ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
• AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 2
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Natural products C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 2
• 230000000694 effects Effects 0.000 claims description 2
• 230000001404 mediated effect Effects 0.000 claims description 2
• RCCYSVYHULFYHE-UHFFFAOYSA-N pentanediamide Chemical compound NC(=O)CCCC(N)=O RCCYSVYHULFYHE-UHFFFAOYSA-N 0.000 claims description 2
• 239000001294 propane Substances 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims 2
• 230000002757 inflammatory effect Effects 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 94
• 238000002360 preparation method Methods 0.000 abstract description 12
• 238000000132 electrospray ionisation Methods 0.000 description 259
• 239000000543 intermediate Substances 0.000 description 252
• 238000001819 mass spectrum Methods 0.000 description 249
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 219
• 238000005481 NMR spectroscopy Methods 0.000 description 193
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
• 125000000753 cycloalkyl group Chemical group 0.000 description 135
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 122
• 239000000243 solution Substances 0.000 description 98
• 150000001721 carbon Chemical group 0.000 description 85
• 238000006243 chemical reaction Methods 0.000 description 71
• 238000003818 flash chromatography Methods 0.000 description 67
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
• 239000000460 chlorine Substances 0.000 description 52
• 239000007787 solid Substances 0.000 description 49
• 238000000926 separation method Methods 0.000 description 48
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
• 239000011541 reaction mixture Substances 0.000 description 45
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 43
• 239000002585 base Substances 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 36
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• 229940086542 triethylamine Drugs 0.000 description 36
• 238000000746 purification Methods 0.000 description 34
• 239000002904 solvent Substances 0.000 description 32
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 31
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
• 229910052731 fluorine Inorganic materials 0.000 description 29
• 239000000047 product Substances 0.000 description 29
• 239000011734 sodium Substances 0.000 description 29
• 239000012044 organic layer Substances 0.000 description 27
• 239000002253 acid Substances 0.000 description 26
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 26
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
• 125000004432 carbon atom Chemical group C* 0.000 description 25
• 239000012071 phase Substances 0.000 description 25
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 235000019439 ethyl acetate Nutrition 0.000 description 24
• 125000001544 thienyl group Chemical group 0.000 description 24
• 238000012746 preparative thin layer chromatography Methods 0.000 description 22
• 238000006467 substitution reaction Methods 0.000 description 22
• 238000011282 treatment Methods 0.000 description 22
• 239000003795 chemical substances by application Substances 0.000 description 21
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 20
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 20
• FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 20
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 20
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 20
• 125000001624 naphthyl group Chemical group 0.000 description 20
• 230000005526 G1 to G0 transition Effects 0.000 description 19
• 125000005605 benzo group Chemical group 0.000 description 19
• 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 125000006239 protecting group Chemical group 0.000 description 18
• 229910002091 carbon monoxide Inorganic materials 0.000 description 17
• 238000003756 stirring Methods 0.000 description 17
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
• 125000003118 aryl group Chemical group 0.000 description 16
• 125000004093 cyano group Chemical group *C#N 0.000 description 16
• 125000003226 pyrazolyl group Chemical group 0.000 description 16
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
• 239000007821 HATU Substances 0.000 description 14
• 208000006673 asthma Diseases 0.000 description 13
• 125000004429 atom Chemical group 0.000 description 13
• 230000002829 reductive effect Effects 0.000 description 13
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
• 125000001072 heteroaryl group Chemical group 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
• 239000007864 aqueous solution Substances 0.000 description 11
• 239000012267 brine Substances 0.000 description 11
• 239000002244 precipitate Substances 0.000 description 11
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 10
• BQFOSZGLMPGGLY-UHFFFAOYSA-N 2-chloro-4-iodopyridine-3-carbonitrile Chemical compound ClC1=NC=CC(I)=C1C#N BQFOSZGLMPGGLY-UHFFFAOYSA-N 0.000 description 10
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• 125000003386 piperidinyl group Chemical group 0.000 description 10
• PAXDIBGWURAVIH-SFYZADRCSA-N tert-butyl n-[(1s,2r)-2-aminocyclopentyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1N PAXDIBGWURAVIH-SFYZADRCSA-N 0.000 description 10
• SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 9
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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• ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 9
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 9
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• 125000002877 alkyl aryl group Chemical group 0.000 description 9
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• 239000012074 organic phase Substances 0.000 description 9
• WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 9
• AKVIZYGPJIWKOS-BDAKNGLRSA-N tert-butyl n-[(1s,2r)-2-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N AKVIZYGPJIWKOS-BDAKNGLRSA-N 0.000 description 9
• PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 8
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
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• 239000012346 acetyl chloride Substances 0.000 description 8
• 150000001412 amines Chemical class 0.000 description 8
• 210000003719 b-lymphocyte Anatomy 0.000 description 8
• PAXDIBGWURAVIH-HTQZYQBOSA-N tert-butyl n-[(1r,2r)-2-aminocyclopentyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1N PAXDIBGWURAVIH-HTQZYQBOSA-N 0.000 description 8
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• VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 6
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• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 6
• 125000003342 alkenyl group Chemical group 0.000 description 6
• 125000000304 alkynyl group Chemical group 0.000 description 6
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• IKTHLTNWRLDEKR-SFYZADRCSA-N n-[(1s,2r)-2-aminocyclohexyl]prop-2-enamide Chemical compound N[C@@H]1CCCC[C@@H]1NC(=O)C=C IKTHLTNWRLDEKR-SFYZADRCSA-N 0.000 description 6
• 239000012299 nitrogen atmosphere Substances 0.000 description 6
• 208000023504 respiratory system disease Diseases 0.000 description 6
• FEYLUKDSKVSMSZ-UHFFFAOYSA-N tert-butyl n-(4-aminocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(N)CC1 FEYLUKDSKVSMSZ-UHFFFAOYSA-N 0.000 description 6
• PAXDIBGWURAVIH-JGVFFNPUSA-N tert-butyl n-[(1r,2s)-2-aminocyclopentyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1N PAXDIBGWURAVIH-JGVFFNPUSA-N 0.000 description 6
• DSDCDMKASWVZHI-UHFFFAOYSA-M zinc;2-methanidylpropane;bromide Chemical compound Br[Zn+].CC(C)[CH2-] DSDCDMKASWVZHI-UHFFFAOYSA-M 0.000 description 6
• AKVIZYGPJIWKOS-RKDXNWHRSA-N (1R,2R)-trans-N-Boc-1,2-cyclohexanediamine Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N AKVIZYGPJIWKOS-RKDXNWHRSA-N 0.000 description 5
• OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 5
• 208000023275 Autoimmune disease Diseases 0.000 description 5
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