TWI765906B - 經取代吡咯化合物及其用途 - Google Patents

Info

Publication number

TWI765906B

TWI765906B TW106128937A TW106128937A TWI765906B TW I765906 B TWI765906 B TW I765906B TW 106128937 A TW106128937 A TW 106128937A TW 106128937 A TW106128937 A TW 106128937A TW I765906 B TWI765906 B TW I765906B

Authority

TW

Taiwan

Prior art keywords

compound

pharmaceutically acceptable

acceptable salt

optionally substituted

alkyl

Prior art date

2016-08-26

Links

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• 125000002152 1H-pyrrolizinyl group Chemical class C1(C=CN2C=CC=C12)* 0.000 title abstract 2
• 239000008194 pharmaceutical composition Chemical class 0.000 claims abstract description 20
• 230000010076 replication Effects 0.000 claims abstract description 13
• 150000001875 compounds Chemical class 0.000 claims description 379
• 239000003112 inhibitor Substances 0.000 claims description 204
• 125000000217 alkyl group Chemical group 0.000 claims description 180
• 150000003839 salts Chemical class 0.000 claims description 161
• 241000700721 Hepatitis B virus Species 0.000 claims description 158
• -1 2-oxa-6-azaspiro[3.3]heptyl Chemical group 0.000 claims description 130
• 125000005842 heteroatom Chemical group 0.000 claims description 124
• 229910052760 oxygen Inorganic materials 0.000 claims description 121
• 229910052717 sulfur Inorganic materials 0.000 claims description 115
• 239000003814 drug Substances 0.000 claims description 100
• 229910052736 halogen Inorganic materials 0.000 claims description 86
• 150000002367 halogens Chemical class 0.000 claims description 86
• 229940124597 therapeutic agent Drugs 0.000 claims description 79
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 73
• 125000002950 monocyclic group Chemical group 0.000 claims description 69
• 125000001072 heteroaryl group Chemical group 0.000 claims description 62
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 51
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 50
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 39
• 125000001188 haloalkyl group Chemical group 0.000 claims description 39
• 229910052739 hydrogen Inorganic materials 0.000 claims description 39
• 125000003118 aryl group Chemical group 0.000 claims description 38
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 37
• 229910052799 carbon Inorganic materials 0.000 claims description 35
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 33
• 108090000623 proteins and genes Proteins 0.000 claims description 33
• 229960001355 tenofovir disoproxil Drugs 0.000 claims description 33
• 239000000427 antigen Substances 0.000 claims description 32
• 102000036639 antigens Human genes 0.000 claims description 32
• 108091007433 antigens Proteins 0.000 claims description 32
• SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 claims description 32
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
• VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 30
• 208000015181 infectious disease Diseases 0.000 claims description 28
• 229910052731 fluorine Inorganic materials 0.000 claims description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
• 230000008685 targeting Effects 0.000 claims description 25
• JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
• 208000002672 hepatitis B Diseases 0.000 claims description 22
• 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 claims description 21
• 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 claims description 21
• JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 21
• 239000003446 ligand Substances 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 20
• 108020004459 Small interfering RNA Proteins 0.000 claims description 19
• WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 19
• 229960004946 tenofovir alafenamide Drugs 0.000 claims description 19
• LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 claims description 19
• 239000000556 agonist Substances 0.000 claims description 18
• 229910052801 chlorine Inorganic materials 0.000 claims description 18
• IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 17
• 229960005486 vaccine Drugs 0.000 claims description 17
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
• 108010050904 Interferons Proteins 0.000 claims description 16
• 239000012270 PD-1 inhibitor Substances 0.000 claims description 16
• 239000012668 PD-1-inhibitor Substances 0.000 claims description 16
• 239000012271 PD-L1 inhibitor Substances 0.000 claims description 16
• 229940121655 pd-1 inhibitor Drugs 0.000 claims description 16
• 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 16
• 229960003560 tenofovir alafenamide fumarate Drugs 0.000 claims description 16
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
• 239000000134 cyclophilin inhibitor Substances 0.000 claims description 15
• 235000019000 fluorine Nutrition 0.000 claims description 15
• 229940076155 protein modulator Drugs 0.000 claims description 15
• 229960004556 tenofovir Drugs 0.000 claims description 15
• 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 claims description 14
• 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 claims description 14
• 101001125026 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 2 Proteins 0.000 claims description 14
• 102000014150 Interferons Human genes 0.000 claims description 14
• 102100029441 Nucleotide-binding oligomerization domain-containing protein 2 Human genes 0.000 claims description 14
• 108010078233 Thymalfasin Proteins 0.000 claims description 14
• 239000002955 immunomodulating agent Substances 0.000 claims description 14
• 229940121354 immunomodulator Drugs 0.000 claims description 14
• NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 claims description 14
• 229960004231 thymalfasin Drugs 0.000 claims description 14
• 102400000800 Thymosin alpha-1 Human genes 0.000 claims description 13
• 125000001153 fluoro group Chemical group F* 0.000 claims description 13
• 229960001627 lamivudine Drugs 0.000 claims description 13
• 125000001425 triazolyl group Chemical group 0.000 claims description 13
• 230000003612 virological effect Effects 0.000 claims description 13
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
• 102000004452 Arginase Human genes 0.000 claims description 12
• 108700024123 Arginases Proteins 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 12
• 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims description 12
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
• 229960001997 adefovir Drugs 0.000 claims description 11
• 239000011737 fluorine Substances 0.000 claims description 11
• 230000002265 prevention Effects 0.000 claims description 11
• 102100031151 C-C chemokine receptor type 2 Human genes 0.000 claims description 10
• 101710149815 C-C chemokine receptor type 2 Proteins 0.000 claims description 10
• 102100031780 Endonuclease Human genes 0.000 claims description 10
• 108010042407 Endonucleases Proteins 0.000 claims description 10
• 108010046075 Thymosin Proteins 0.000 claims description 10
• 102000007501 Thymosin Human genes 0.000 claims description 10
• IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 229940079593 drug Drugs 0.000 claims description 10
• 229960000980 entecavir Drugs 0.000 claims description 10
• YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims description 10
• 229960005311 telbivudine Drugs 0.000 claims description 10
• LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 claims description 10
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• 102000007999 Nuclear Proteins Human genes 0.000 claims description 9
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• 108020004999 messenger RNA Proteins 0.000 claims description 9
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• 108020000948 Antisense Oligonucleotides Proteins 0.000 claims description 8
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• 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 claims description 8
• 125000000304 alkynyl group Chemical group 0.000 claims description 8
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 claims description 8
• 125000000623 heterocyclic group Chemical group 0.000 claims description 8
• 229960004693 tenofovir disoproxil fumarate Drugs 0.000 claims description 8
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
• 229940045513 CTLA4 antagonist Drugs 0.000 claims description 7
• 108020004638 Circular DNA Proteins 0.000 claims description 7
• 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 7
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• 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
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• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 6
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• 102000001974 Hyaluronidases Human genes 0.000 claims description 5
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
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• 230000037361 pathway Effects 0.000 claims description 5
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• SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 4
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• 238000006467 substitution reaction Methods 0.000 claims description 4
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• 125000002393 azetidinyl group Chemical group 0.000 claims description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
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• 238000000034 method Methods 0.000 abstract description 34
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• 239000000203 mixture Substances 0.000 description 118
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• 239000000243 solution Substances 0.000 description 94
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• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 79
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