CN112142675B - 一种作为jak激酶抑制剂的小分子化合物及其用途 - Google Patents
一种作为jak激酶抑制剂的小分子化合物及其用途 Download PDFInfo
- Publication number
- CN112142675B CN112142675B CN202011072703.7A CN202011072703A CN112142675B CN 112142675 B CN112142675 B CN 112142675B CN 202011072703 A CN202011072703 A CN 202011072703A CN 112142675 B CN112142675 B CN 112142675B
- Authority
- CN
- China
- Prior art keywords
- compound
- cycloalkyl
- small molecule
- alkyl
- molecule compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 Small molecule compound Chemical class 0.000 title claims abstract description 29
- 102000042838 JAK family Human genes 0.000 title claims abstract description 25
- 108091082332 JAK family Proteins 0.000 title claims abstract description 25
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 201000004624 Dermatitis Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 208000010668 atopic eczema Diseases 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 206010047642 Vitiligo Diseases 0.000 claims description 6
- 208000004631 alopecia areata Diseases 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 230000008506 pathogenesis Effects 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 241000896563 Glossus Species 0.000 claims description 3
- 206010024434 Lichen sclerosus Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 206010047115 Vasculitis Diseases 0.000 claims description 3
- 206010000496 acne Diseases 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 201000001981 dermatomyositis Diseases 0.000 claims description 3
- 208000002557 hidradenitis Diseases 0.000 claims description 3
- 201000007162 hidradenitis suppurativa Diseases 0.000 claims description 3
- 201000011486 lichen planus Diseases 0.000 claims description 3
- 206010033675 panniculitis Diseases 0.000 claims description 3
- 230000008482 dysregulation Effects 0.000 claims description 2
- 230000011664 signaling Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000036039 immunity Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 abstract description 14
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 abstract description 14
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract description 14
- 239000003112 inhibitor Substances 0.000 abstract description 14
- 125000003118 aryl group Chemical group 0.000 abstract description 11
- 229940125436 dual inhibitor Drugs 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- 239000012453 solvate Substances 0.000 abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- 239000000203 mixture Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 23
- 230000000694 effects Effects 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000001514 detection method Methods 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000004973 liquid crystal related substance Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- 102000020233 phosphotransferase Human genes 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 208000027866 inflammatory disease Diseases 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 239000011535 reaction buffer Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 3
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 3
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 3
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 3
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010024121 Janus Kinases Proteins 0.000 description 3
- 102000015617 Janus Kinases Human genes 0.000 description 3
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- SMRPWXYMAKMQOY-UHFFFAOYSA-N 3-o-tert-butyl 1-o-methyl 2-(5-nitropyridin-2-yl)propanedioate Chemical compound CC(C)(C)OC(=O)C(C(=O)OC)C1=CC=C([N+]([O-])=O)C=N1 SMRPWXYMAKMQOY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229940123371 Tyrosine kinase 2 inhibitor Drugs 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229940127108 compound 5g Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- RNRRNCPSXOTLIS-UHFFFAOYSA-N 4-(2-chloropyrimidin-4-yl)aniline Chemical compound C1=CC(N)=CC=C1C1=CC=NC(Cl)=N1 RNRRNCPSXOTLIS-UHFFFAOYSA-N 0.000 description 1
- JOFDSYLCZIHGGO-UHFFFAOYSA-N 4-[(4-cyclohexylphenyl)methyl-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetyl]amino]-2-hydroxybenzoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(=O)N(C=1C=C(O)C(C(O)=O)=CC=1)CC(C=C1)=CC=C1C1CCCCC1 JOFDSYLCZIHGGO-UHFFFAOYSA-N 0.000 description 1
- YREYESUNBGAGBP-UHFFFAOYSA-N 4-amino-n-ethyl-2-methylbenzamide Chemical compound CCNC(=O)C1=CC=C(N)C=C1C YREYESUNBGAGBP-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- MNVXDPSMAMMSMX-JTQLQIEISA-N ClC1=NC=CC(=N1)C1=CC=C(C=C1)NC(=O)[C@H]1C(C1)(F)F Chemical compound ClC1=NC=CC(=N1)C1=CC=C(C=C1)NC(=O)[C@H]1C(C1)(F)F MNVXDPSMAMMSMX-JTQLQIEISA-N 0.000 description 1
- ZIIOZMOOEVYLFA-UHFFFAOYSA-N ClC1=NC=CC(=N1)C=1C=CC(=NC1)N Chemical compound ClC1=NC=CC(=N1)C=1C=CC(=NC1)N ZIIOZMOOEVYLFA-UHFFFAOYSA-N 0.000 description 1
- UYLYAMQEARQZGB-QMMMGPOBSA-N ClC1=NC=CC(=N1)C=1C=CC(=NC1)NC(=O)[C@H]1C(C1)(F)F Chemical compound ClC1=NC=CC(=N1)C=1C=CC(=NC1)NC(=O)[C@H]1C(C1)(F)F UYLYAMQEARQZGB-QMMMGPOBSA-N 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- OXCJCFNGIGVZFM-KRWDZBQOSA-N FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC1=CC(=C(C(=O)NCC)C=C1)C)F Chemical compound FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC1=CC(=C(C(=O)NCC)C=C1)C)F OXCJCFNGIGVZFM-KRWDZBQOSA-N 0.000 description 1
- LNTSOZZRTWROQI-INIZCTEOSA-N FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC1=CC=C(C(=O)NCC)C=C1)F Chemical compound FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC1=CC=C(C(=O)NCC)C=C1)F LNTSOZZRTWROQI-INIZCTEOSA-N 0.000 description 1
- GVCPAUDLNYUZBY-ZDUSSCGKSA-N FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)N)C)F Chemical compound FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)N)C)F GVCPAUDLNYUZBY-ZDUSSCGKSA-N 0.000 description 1
- FEGSKVDYRNZOIW-AWEZNQCLSA-N FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)NC)C)F Chemical compound FC1([C@@H](C1)C(=O)NC1=CC=C(C=N1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)NC)C)F FEGSKVDYRNZOIW-AWEZNQCLSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- IDSJZIHADHJOSL-UHFFFAOYSA-N NC=1C=CC(=NC=1)C(CO)C Chemical compound NC=1C=CC(=NC=1)C(CO)C IDSJZIHADHJOSL-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 1
- 108010010057 TYK2 Kinase Proteins 0.000 description 1
- 102000015774 TYK2 Kinase Human genes 0.000 description 1
- 210000000447 Th1 cell Anatomy 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Chemical group 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
本发明提供了一种小分子化合物,所述小分子化合物为由下式表示的化合物,或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、以及药学上可接受的盐或前药,其中R1至R4各自独立地选自C或N;并且其中R选自环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基。本发明的小分子化合物能够抑制JAK激酶,更特别是作为JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂。
Description
技术领域
本发明属于小分子化合物领域,具体地,涉及一种能够用于预防或治疗缓解自身免疫性疾病如风湿性关节炎、溃疡性结肠炎和***性红斑狼疮等,或相关的炎症性皮肤病如银屑病、湿疹、白癜风和斑秃等的小分子化合物。
背景技术
JAK(Janus激酶,Janus Kinase)是细胞内非受体性酪氨酸蛋白激酶的一个家族,包括JAK1、JAK2、JAK3和Tyk2四个成员。JAK-STAT(转录蛋白的信号转导和激活剂,SignalTransducer and Activator of Transcription proteins)信号传导通路是炎症性细胞因子和受体相结合之后激发的信号在细胞内传导的主要通路。许多证据表明,JAK-STAT信号传导通路在很多疾病的发病机理中起到不可或缺的驱动作用,特别是自身免疫性疾病如风湿性关节炎、红斑狼疮、炎症性肠病、多发性硬化、干燥综合征、银屑病、斑秃和白癜风等;过敏性疾病如哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎和湿疹等等。因此,利用高效的小分子对JAK激酶活性,特别是JAK1、TYK2激酶活性进行抑制可以阻断参与炎症反应的细胞因子介导的信号通路,从而控制炎症,有效治疗自身免疫性疾病和/或过敏性炎症性疾病。
不同炎症性疾病发病过程中T细胞会根据不同的炎症诱发因素如病毒或细菌感染而向不同的方向分化,形成Th1,Th2,Th17等T细胞亚群,这些T细胞相应地产生不同的细胞因子,如与病毒感染引起的急性炎症相关的Th1细胞产生IFNγ,IL-2;与过敏有关的Th2细胞产生IL-4,IL-5,IL-13;与自身免疫有关的Th17细胞产生IL-17,IL-12,IL-21,IL-22,IL-23;这些细胞因子和细胞表面的受体结合后,通过细胞内的JAK传递炎症信号,驱动疾病的病理过程。更重要的是,很多病因不清楚的炎症性疾病发表机理复杂,在不同的阶段甚至同一阶段会涉及多种T细胞亚群,也就是会涉及多个JAK通路,这就对开发针对JAK的炎症性疾病治疗药物提出了新的要求。
虽然有研究报道JAK1抑制剂对Th2类过敏性炎症有特异性抑制,同时有效抑制JAK1和/或TYK2抑制剂的研究鲜有报道,尤其我们认为JAK1/Tyk2双抑制剂和Tyk2抑制剂在临床上有更广泛的前途,尤其发病机制涉及到自身免疫异常的炎症性疾病。此外,更多的炎症性疾病尤其是炎症性皮肤病的发病机理可能涉及多个JAK,因此开发强效JAK1和Tyk2的单抑制剂或双抑制剂具有重要意义,尤其用于皮肤病的外用治疗,强效抑制剂在带来很好的疗效的同时又能避免***用药造成的副作用,但是这将同时需要很强的抑制活性才能实现。
发明内容
本发明的目的旨在获得高效的JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂,为不同的炎症性疾病提供有针对性的靶向治疗,例如JAK1/Tyk2双抑制剂可能适合于SLE、白癜风、IBD和湿疹等疾病,Tyk2特异性抑制剂可能更适合于治疗类风湿性关节炎、银屑病和斑秃等,同时克服由于抑制JAK2带来的造血抑制和凝血异常。另外,选择适合用于外用给药途径如针对炎症性皮肤病外用与疾病病因和症状表现相关联的不同性质的JAK家族成员抑制剂对疾病进行干预和症状控制,能够获得好的治疗效应。
为了实现上述目的,在一方面,本发明提供了一种小分子化合物,所述小分子化合物为由如下所示的式I表示的化合物,或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、以及药学上可接受的盐或前药:
[式I]
其中,R1至R4各自独立地选自C或N;并且
其中,R选自环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基。
在一个实施方式中,R1至R4中的至多两个为N。
在另一个实施方式中,R具有如下所示的式II表示的结构:
[式II]
其中,R5选自C或N;
其中,R6选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R7选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在另一个实施方式中,R6和R7各自独立地选自氢、烷基或环烷基。
在另一个实施方式中,R具有如下所示的式III表示的结构:
[式III]
其中,R8选自C或N;
其中,R9选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R10选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在另一个实施方式中,R9和R10各自独立地选自氢、烷基或环烷基。
在另一个实施方式中,所述烷基为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
在另一方面,本发明还提供了如上所述的小分子化合物在抑制JAK激酶中的用途。
在另一方面,本发明还提供了如上所述的小分子化合物在制备用于预防或治疗JAK相关的自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药物中的用途。
在一个实施方式中,所述自身免疫性疾病选自类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、***性红斑狼疮、皮肌炎、多发性硬化、I型糖尿病、干燥综合症和血管炎中的至少一种。
在另一个实施方式中,所述与免疫有关的炎症性皮肤疾病选自特应性皮炎、湿疹、斑秃、银屑病、白癜风、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮和化脓性汗腺炎中的至少一种。
本发明的作用和效果:
本发明根据JAK激酶的蛋白结构,特别是Tyk2的蛋白结构,进行了小分子化合物有目的的合理设计,合成的化合物首先进行JAK的激酶生化活性检测,根据IC50建立SAR(structure-activity relationship),对IC50在200nM以下的强效抑制剂再进行细胞学的测试,并确定化合物的选择性。参见具体活性实验数据可以发现,本发明涉及的化合物具有良好的JAK激酶活性和细胞生物学活性的抑制能力。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
在详细描述本发明前,应了解,在此使用的术语只在于描述特定的实施方式,而不希望限制本发明的范围,本发明的范围仅由所附权利要求书限定。为了更完全地了解在此描述的本发明,采用以下术语,它们的定义如下所示。除非另外定义,在此使用的所有技术和科学术语具有与本发明所属领域的普通技术人员所理解的相同的含义。
在一方面,本发明提供了一种小分子化合物,所述小分子化合物为由如下所示的式I表示的化合物,或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、以及药学上可接受的盐或前药:
[式I]
其中,R1至R4各自独立地选自C或N;并且
其中,R选自环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基。
也就是说,R1、R2、R3和R4可以各自独立地选自C或N。在一个优选的实施方式中,R1至R4中的至多两个(即0、1或2个)可以为N。在另一个优选的实施方式中,R1至R4中的至多一个(即0或1个)可以为N。当R1至R4中的至多一个(即0或1个)为N时,它们将构成苯环或吡啶环。
根据本发明,在一个优选的实施方式中,R可以具有如下所示的式II表示的结构:
[式II]
其中,R5可以选自C或N;
其中,R6选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R7选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在一个更优选的实施方式中,R6和R7可以各自独立地选自氢、烷基或环烷基,进一步,所述烷基可以为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
例如,在一个具体的实施方式中,R5为N,R6为甲基,且R7为甲基。在这种情况下,R可以具有如下所示的结构:。
例如,在一个具体的实施方式中,R5为C,R6为甲基,且R7为乙基。在这种情况下,R可以具有如下所示的结构:。
例如,在一个具体的实施方式中,R5为N,R6为甲基,且R7为氢。在这种情况下,R可以具有如下所示的结构:。
根据本发明,在另一个优选的实施方式中,R可以具有如下所示的式III表示的结构:
[式III]
其中,R8可以选自C或N;
其中,R9选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R10选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在一个更优选的实施方式中,R9和R10可以各自独立地选自氢、烷基或环烷基,进一步,所述烷基可以为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
如本文所用,术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质,并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。在本发明中,“药学上可接受的盐”可以包括无机盐和有机盐,其中,所述有机盐可以包括但不限于铵、锂、钠、钾、铯、钙、镁、铜、铝、锌、钡或季铵盐,并且所述无机盐可以包括但不限于精氨酸、叔丁胺、二甲胺、二乙醇胺、乙醇胺、乙二胺、咪唑、赖氨酸、甲胺、吡啶、吡啶甲酸酯、哌嗪、三乙胺、三乙醇胺、三甲胺或脲盐。
在另一方面,本发明提供了上述小分子化合物在抑制JAK激酶中的用途,特别是作为JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂。
在另一方面,本发明还提供了上述小分子化合物在制备用于预防或治疗自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药物中的用途。研究表明,这些疾病的发病机理均与JAK信号传导的失调相关。
如本文所用,术语“治疗”是指根据治疗性方案的治疗性试剂的任何施用,所述治疗性方案达到所需效果,即部分或完全减轻、改善、缓解、抑制、延迟发作、降低严重程度和/或降低特定疾病、障碍和/或病症的一种或多种症状或特征的发生率;在一些实施方式中,根据治疗性方案的治疗性试剂的施用与所需效果的实现相关。这种治疗可以针对没有表现出相关疾病、障碍和/或病症的受试者和/或针对仅表现出疾病、障碍和/或病症的早期迹象的受试者。替代地或另外地,这种治疗可以针对表现出相关疾病、障碍和/或病症的一种或多种所确定迹象的受试者。在一些实施方式中,治疗可以针对已被诊断患有相关疾病、障碍和/或病症的受试者。在一些实施方式中,治疗可以针对已知具有一种或多种易感因素的受试者,所述易感因素在统计学上与相关疾病、障碍和/或病症发展的风险增加相关。
根据本发明,上述用途中制得的药物可以包含有效量的本发明的小分子化合物,以及药学上可接受的赋形剂、载体或稀释剂。
如本文所用,术语“有效量”、“治疗有效量”或“药学有效量”是指对于治疗的受试者以适用于任何药物治疗的合理受益/风险比赋予治疗效果的治疗性试剂的量。这样的治疗效果可以是客观的(即可以通过某种测试或标记测量)或主观的(即受试者给出指示或感觉到效果)。在一些实施方式中,“治疗有效量”是指诸如通过改善与疾病有关的症状、预防或延迟疾病发作和/或还减轻疾病症状的严重性或频率来有效治疗、改善或预防(例如延迟发作)相关疾病或病症和/或表现出可检测的治疗或预防效果的治疗性试剂或组合物的量。
本领域的技术人员将认识到,待施用的所述小分子化合物的治疗有效量将根据以下各项而变化:受试者和疾病的性质和严重程度、受试者的身体状况、治疗方案(例如是否使用第二治疗剂)、以及所选择的施用途径;合适的剂量可以由本领域的技术人员容易地确定。另外,该药物的个体剂量的最佳数量和间隔将通过所治疗的病状的性质和程度、施用的形式、途径和位置、以及所治疗的特定受试者的年龄和病状确定,并且医师将最终确定待施用的合适剂量。此剂量可以视需要重复多次。如果出现副作用,则可以根据正常临床实践改变或减少剂量的量和/或频率。
在本发明中,“药学上可接受的赋形剂、载体或稀释剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等。
根据本发明,进一步地,上述用途中制得的药物除了可以包含本发明的小分子化合物作为有效成分之外,还可以包含其他可用于预防或治疗自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药剂作为另一种有效成分。所述药剂的实例包括但不限于维生素D衍生物、维生素A衍生物、糖皮质激素、钙调神经磷酸酶抑制剂或非甾体类抗炎药等。当该药物包含多种有效成分时,各有效成分可以根据医师的判断同时、依次或分开施用。
另外,本发明的小分子化合物可以通过多种途径施用于患者,这些途径诸如口服、透皮、皮下、鼻内、静脉内、肌内、鞘内、区域或局部(例如粘膜)。在任何给定情况下最适合的施用途径将取决于受试者和疾病的性质和严重程度、以及受试者的身体状况等。在一个实施方式中,本发明的小分子化合物可以经静脉内施用。在另一个实施方式中,本发明的小分子化合物可以口服施用。相应地,根据不同的施用方式,本发明的药物可以制备为不同的剂型。例如,在一个实施方式中,所述药物可以制备为片剂、胶囊剂、丸剂、颗粒剂、雾化剂、喷雾剂或注射剂。
经发明人研究发现,本发明的小分子化合物或其制得的药物在用于预防或治疗JAK相关的自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病能够发挥优异的效果。具体地,所述自身免疫性疾病可以包括但不限于类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、***性红斑狼疮、皮肌炎、多发性硬化、I型糖尿病、干燥综合症和血管炎等;而所述与免疫有关的炎症性皮肤疾病可以包括但不限于特应性皮炎、湿疹、斑秃、银屑病或白癜风、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮和化脓性汗腺炎等。
以下,将通过实施例对本发明的特定小分子化合物的效果进行详细描述。
实施例
实施例1合成化合物1的一般方法(TDM-180972)
步骤1:化合物1c(4-(2-氯嘧啶-4-基)苯胺)的制备
向三口烧瓶加入化合物1a(2g,9.129mmol),化合物1b(1.36g,9.129mmol),四三苯基膦钯(527g,0.45mmol),碳酸钾(2.5g,18.258mmol),二氧六环(20mL)和水(20mL),用氮气置换数次,然后将混合物加热至80℃并搅拌45分钟。反应结束减压浓缩反应物,残余物通过硅胶色谱法进行纯化(石油醚/乙酸乙酯=0-60%),以得到淡黄色固体目标化合物(化合物1c,394mg,收率21%)。LCMS[M+1]+=206。
步骤2:化合物1e((S)-N-(4-(2-氯嘧啶-4-基)苯基)-2,2-二氟环丙烷-1-羧酰胺)的制备
向三口烧瓶中加入化合物1c(300mg,1.459mmol)和化合物1d(187mg,1.531mmol),将混合物用氮气置换几次,然后在0℃下加入吡啶(10mL)和三氯氧磷(335.6mg,2.189mmol)。将混合物在室温搅拌1h,然后减压浓缩,残余物用乙酸乙酯(30mL*3)萃取,合并有机层,并用水(50mL*3)和饱和盐水(50mL*2)洗涤,用硫酸钠干燥,将滤液减压浓缩,残余物通过硅胶色谱法进行纯化(石油醚/乙酸乙酯=0-12%),以得到黄色固体目标化合物(化合物1e,327.7mg,收率72.5%)。LCMS[M+H]+=310。
步骤3:化合物1((S)-4-((4-(4-(4-(2,2-二氟环丙烷-1-羧酰胺基)苯基)嘧啶-2-基)氨基)-N-乙基苯甲酰胺)的制备
向化合物1e(80mg,0.258mmol)的正丁醇(8mL)溶液加入化合物1f(85mg,0.517mmol)和对甲苯磺酸一水合物(98mg,0.517mmol)。将所得混合物加热至110℃并搅拌3小时。反应结束将混合物在减压下浓缩,残余物通过制备型HPLC(甲酸)纯化,以得到黄色固体目标化合物TDM-180972(化合物1,19.7mg,收率17.5%)。LCMS[M+H]+=438.2。
1H NMR(400MHz,DMSO)δ10.70(s,1H),9.91(s,1H),8.57(d,J=5.3Hz,1H),8.28(t,J=5.5Hz,1H),8.19(d,J=8.8Hz,2H),7.92(d,J=8.9Hz,2H),7.83(d,J=8.9Hz,2H),7.78(d,J=8.8Hz,2H),7.44(d,J=5.3Hz,1H),3.28(dt,J=12.7,6.4Hz,2H),2.86(ddd,J=13.6,10.8,8.0Hz,1H),2.12–1.94(m,2H),1.13(t,J=7.2Hz,3H)。
实施例2合成化合物2的一般方法(TDM-180974)
步骤1:化合物2((S)-5-((4-(4-(4-(2,2-二氟环丙烷-1-羧酰胺基)苯基)嘧啶-2-基)氨基)-3-甲基吡啶啉)的制备
向化合物2a(80mg,0.258mmol)的正丁醇(8mL)溶液加入化合物2b(78mg,0.517mmol)和对甲苯磺酸一水合物(98mg,0.517mmol),将混合物加热至115℃并搅拌过夜。反应结束将混合物在减压下浓缩,向残余物中加入甲醇,通过过滤收集固体,通过制备型HPLC(甲酸)纯化固体,以得到白色固体目标化合物TDM-180974(化合物2,18.9mg,收率10.6%)。LCMS[M+H]+=425.2。
1H NMR(400MHz,DMSO)δ10.73(s,1H),10.08(s,1H),8.89(d,J=2.2Hz,1H),8.60(d,J=5.3Hz,1H),8.23(d,J=2.0Hz,1H),8.18(d,J=8.8Hz,2H),7.90(s,1H),7.79(d,J=8.8Hz,2H),7.49(d,J=5.3Hz,1H),7.26(s,1H),2.87(ddd,J=13.6,10.8,8.1Hz,1H),2.61(s,3H),2.10–1.96(m,2H)。
实施例3合成化合物3的一般方法(TDM-180977)
步骤1:化合物3b(4-氨基-N-乙基-2-甲基苯甲酰胺)的制备
向化合物3a(1.8g,11.91mmol)的N,N-二甲基甲酰胺(80mL)溶液中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.4g,14.289mmol)和N,N-二异丙基乙胺(3.8g,29.775mmol),将混合物搅拌5分钟,然后加入乙胺的四氢呋喃(2M)(9mL,18mmol)溶液,将混合物在室温搅拌过夜。减压浓缩混合物除去一些溶剂,向残余物中加入水并用乙酸乙酯(100mL*3)萃取,合并有机相,用水(150mL*3)和饱和盐水(150mL)洗涤,用硫酸钠干燥,减压浓缩滤液,通过硅胶色谱法纯化(石油醚/乙酸乙酯=0%-50%),以得到黄色油状目标化合物(化合物3b,1.32g,收率62.2%)。LCMS[M+1]+=179。
步骤2:化合物3((S)-4-((4-(4-(4-(2,2-二氟环丙烷-1-羧酰胺基)苯基)嘧啶-2-基)氨基)-N-乙基-2-甲基苯甲酰胺)的制备
向化合物3c(80mg,0.258mmol)的正丁醇(8mL)溶液加入化合物3b(92mg,0.517mmol)和对甲苯磺酸一水合物(98mg,0.517mmol)。将所得混合物加热至110℃并搅拌3小时。反应结束将混合物在减压下浓缩,残余物通过制备型HPLC(甲酸)纯化,以得到白色固体目标化合物TDM-180977(化合物3,19.4mg,收率13.3%。LCMS[M+H]+=425.2。
1H NMR(400MHz,DMSO)δ10.70(s,1H),9.72(s,1H),8.54(d,J=5.3Hz,1H),8.18(d,J=8.8Hz,2H),8.08(d,J=5.6Hz,1H),7.81–7.67(m,4H),7.40(d,J=5.3Hz,1H),7.32(d,J=8.4Hz,1H),3.28–3.17(m,2H),2.86(ddd,J=13.6,10.8,8.1Hz,1H),2.37(s,3H),2.14–1.93(m,2H),1.11(t,J=7.2Hz,3H)。
实施例4合成化合物4的一般方法(TDM-180981)
步骤1:化合物4((S)-5-((4-(4-(4-(2,2-二氟环丙烷-1-羧酰胺基)苯基)嘧啶-2-基)氨基)-N,3-二甲基吡啶啉酰胺)的制备
以与实施例3相似的方法制备得到化合物4(白色固体,3.5mg,收率1.6%)。
1H NMR(400MHz,DMSO)δ10.74(s,1H),10.06(s,1H),8.92(d,J=2.2Hz,1H),8.60(d,J=5.3Hz,1H),8.48(d,J=4.8Hz,1H),8.22–8.18(m,2H),8.17(s,1H),7.78(d,J=8.8Hz,2H),7.49(d,J=5.3Hz,1H),2.87(ddd,J=13.6,10.8,8.0Hz,1H),2.78(d,J=4.8Hz,3H),2.61(s,3H),2.03(ddd,J=18.1,11.7,6.0Hz,2H)。LCMS[M+H]+=439.2。
实施例5合成化合物5的一般方法(TDM-180989)
步骤1:化合物5c(2-(5-硝基吡啶-2-基)丙二酸1-(叔丁基)3-甲基酯)的制备
在室温下向化合物5a(10g,63.076mmol)的N,N-二甲基甲酰胺(100mL)溶液中加入碳酸钾(17.435g,126.152mmol)和化合物5b(13.185g,75.691mmol),混合物用氮气置换几次。将混合物加热至100℃并搅拌过夜。反应结束将混合物冷却至室温,然后添加饱和氯化铵溶液(150mL),将混合物过滤,将滤液用乙酸乙酯(300mL*3)萃取,合并有机层,用饱和盐水(200mL*2)洗涤,用硫酸钠干燥,将滤液减压浓缩,残余物通过硅胶色谱法进行纯化(石油醚/乙酸乙酯=0%-6%),以得到黄色油状目标化合物(化合物5c,7.286g,收率39%)。LCMS[M-C4H9]+=241.1。
步骤2:化合物5d(1-(叔丁基)3-甲基-2-甲基-2-(5-硝基吡啶-2-基)丙二酸酯)的制备
在0℃下,向化合物5c(7g,23.626mmol)的N,N-二甲基甲酰胺(150mL)溶液中加入碳酸铯(15.4g,47.252mmol)。然后将混合物温热至室温并搅拌10分钟,添加碘甲烷(13.4g,94.505mmol),在室温搅拌3小时。反应结束在0℃下向混合物中加入水(150mL),并用乙酸乙酯(150mL*3)萃取,合并有机层,并用饱和盐水(250mL*2)洗涤,用硫酸钠干燥,将滤液减压浓缩,残留物通过硅胶色谱纯化(石油醚/乙酸乙酯=0%-3%),得到黄色油状目标化合物(化合物5d,6.026g,收率82.2%)。LCMS[M-C4H9]+=255.1。
步骤3:化合物5e(2-(5-硝基吡啶-2-基)丙酸丙酯)的制备
向化合物5d(6g,19.366mmol)的二氯甲烷(150mL)溶液中加入三氟乙酸(50mL)。将混合物在室温搅拌3小时。反应结束将混合物在减压下浓缩,残余物通过硅胶色谱法纯化(石油醚/乙酸乙酯=0%-6%),得到黄色油状目标化合物(化合物5e,3.671g,收率90.3%)。LCMS[M+1]+=211.1。
步骤4:化合物5f(2-(5-氨基吡啶-2-基)丙酸甲酯)的制备
在室温下向化合5e(3.67g,17.460mmol)的甲醇(120mL)溶液中加入合适的钯碳,混合物用氢气置换几次,然后在室温下搅拌2小时。反应结束将混合物过滤并将滤液减压浓缩,残余物通过硅胶色谱法纯化(石油醚/乙酸乙酯=0%-50%),以得到黄色油状目标化合物(化合物5f,2.6025g,收率82.7%)。LCMS[M+1]+=181。
步骤5:化合物5g(2-(5-氨基吡啶-2-基)丙-1-醇)的制备
在100mL三颈烧瓶中,用氮气置换瓶内空气,在冰浴下加入氢化铝锂(1.8g,47.26mmol),然后逐滴加入四氢呋喃(180mL),然后加入化合物5f(1.31g,7.27mmol)的四氢呋喃(20mL)溶液。将反应温热至室温并搅拌2小时。反应结束将反应液在冰浴中冷却,并依次滴加1.8mL水、1.8mL的15%氢氧化钠水溶液和5.4mL水。将混合物过滤以获得滤液,并将滤饼用乙酸乙酯洗涤。将滤液用无水硫酸钠干燥,过滤并浓缩,以获得黄色油状目标化合物(化合物5g,1.2g,收率95%)。LCMS[M+1]+=153。
步骤6:化合物5((1S)-2,2-二氟-N-(4-(2-((6-(1-(1-羟基丙烷-2-基)吡啶-3-基)氨基)嘧啶-4-基)苯基)环丙烷-1-羧酰胺)的制备
向化合物389h(100mg,0.323mmol),化合物389g(98mg,0.646mmol),醋酸钯(7.3mg,0.032mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(37.4mg,0.065mmol)和碳酸铯(316mg,0.969mmol)的混合物中加入二氧六环(25mL),将混合物用氩气置换几次,将混合物加热至100℃并搅拌1小时。反应结束向反应混合物中加入水(30mL),并用乙酸乙酯(30mL*3)萃取,合并有机层,然后用水(60mL)和饱和盐水(60mL)洗涤,用硫酸钠干燥,将滤液在减压下浓缩,残余物通过制备型HPLC(甲酸)进行纯化,以得到淡黄色固体目标化合物TDM-180989(化合物5,30.3mg,收率18.4%)。LCMS[M+H]+=426.1。
1H NMR(400MHz,DMSO)δ10.70(s,1H),9.71(s,1H),8.86(d,J=2.5Hz,1H),8.52(d,J=5.3Hz,1H),8.20–8.10(m,3H),7.77(d,J=8.8Hz,2H),7.39(d,J=5.3Hz,1H),7.22(d,J=8.5Hz,1H),4.60(s,1H),3.64(dd,J=10.3,6.6Hz,1H),3.50(dd,J=10.3,7.0Hz,1H),2.98–2.81(m,2H),2.13–1.94(m,2H),1.20(d,J=7.0Hz,3H)。
实施例6合成化合物6的一般方法(TDM-180971)
步骤1:化合物6c(5-(2-氯嘧啶-4-基)吡啶-2-胺)的制备
向250mL的三口烧瓶中加入化合物6a(1.5g,10mmol),化合物6b(2.21g,1.01mmol),四(三苯基膦)钯(1.16g,1mmol),碳酸钾(2.76g,20mmol),1,4-二氧六环(60mL)和水(60mL),反应液用氮气置换数次,升温至80℃搅拌45分钟,LCMS[M+H]+=227,检测反应完全。后处理:反应液浓缩拉干,得到的粗品过柱,[洗脱剂:(EA/PE)=0-70%]得到黄色固体目标化合物(化合物6c,1.47g,收率71.36%),LCMS[M+1]+=207。
步骤2:化合物6e((S)-N-(5-(2-氯嘧啶-4-基)吡啶-2-基)-2,2-二氟环丙烷-1-羧酰胺)的制备
向化合物6c(1.47g,7.11mmol)的无水吡啶(50ml)溶液加入化合物6d(910mg,7.47mmol)和三氯氧磷(1.64g,10.67mmol)。反应液在室温下搅拌1小时,LCMS[M+H]+=311,检测反应完全。后处理:反应液浓缩拉干,残余物加水和乙酸乙酯(3*100mL)萃取三次,合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩拉干,得到的粗品过柱,[洗脱剂:(EA/PE)=0-30%],粗品再重结晶,以得到黄色固体目标化合物(化合物6e,1.73g,收率78.6%),LCMS[M+H]+=311。
步骤3:化合物6((S)-4-((4-(6-(2,2-二氟环丙烷-1-甲酰胺基)吡啶-3-基)嘧啶-2-基)氨基)-N-乙基苯甲酰胺)的制备
向化合物6e(100mg,0.32mmol)的正丁醇(10ml)溶液中加入化合物6f(105.7mg,0.64mmol)和一水合对甲苯磺酸(122.5mg,0.64mmol)。反应液升温至110℃搅拌2小时,LCMS[M+H]+=439,检测反应完全。后处理:反应液浓缩拉干,制备得到黄色固体目标化合物(化合物6,12.3mg,收率8.7%),LCMS[M+H]+=439.2。
1H NMR(400MHz,DMSO)δ11.30(s,1H),9.99(s,1H),9.25–9.06(m,1H),8.62(d,J=5.2Hz,1H),8.57(dd,J=8.8,2.4Hz,1H),8.34–8.17(m,2H),7.90(d,J=8.9Hz,2H),7.82(d,J=8.9Hz,2H),7.53(d,J=5.2Hz,1H),3.28(dt,J=12.7,6.4Hz,2H),3.04(dd,J=8.8,5.7Hz,1H),2.12–1.98(m,2H),1.13(t,J=7.2Hz,3H)。
实施例7合成化合物7的一般方法(TDM-180979)
步骤1:化合物7((S)-5-((4-(6-(2,2-二氟环丙烷-1-羧酰胺基)吡啶-3-基)嘧啶-2-基)氨基)-N,3-二甲基吡啶啉酰胺)的制备
向化合物7a(100mg,0.32mmol)的二氧六环(25ml)溶液中加入化合物7b(106.3mg,0.64mmol),乙酸钯(3.6mg,0.02mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(18.6mg,0.03mmol)和碳酸铯(314.7mg,0.97mmol)。反应液用氩气置换数次,并升温至100℃搅拌2小时,LCMS[M+H]+=440,检测反应完全。后处理:将反应液浓缩至干,残留物用甲醇打浆,粗品制备得到黄色固体目标化合物(化合物7,6.4mg,收率3.2%),LCMS[M+1]+=440.0。
1H NMR(400MHz,DMSO)δ11.34(s,1H),10.15(s,1H),9.17(d,J=2.0Hz,1H),8.87(d,J=2.2Hz,1H),8.65(d,J=5.2Hz,1H),8.56(dd,J=8.8,2.4Hz,1H),8.50(d,J=4.8Hz,1H),8.30–8.18(m,2H),7.58(d,J=5.3Hz,1H),3.04(dd,J=8.9,3.5Hz,1H),2.77(d,J=4.8Hz,3H),2.61(s,3H),2.05(dt,J=10.7,5.2Hz,2H)。
实施例8合成化合物8的一般方法(TDM-180980)
步骤1:化合物8((S)-5-((4-(6-(2,2-二氟环丙烷-1-羧酰胺基)吡啶-3-基)嘧啶-2-基)氨基)-3-甲基吡啶啉酰胺)的制备
以相似的方法制备得到化合物8(2.3mg,黄色固体,收率1.2%)。
1H NMR(400MHz,DMSO)δ11.35(s,1H),10.16(s,1H),9.18(d,J=2.0Hz,1H),8.84(d,J=2.2Hz,1H),8.66(d,J=5.2Hz,1H),8.56(dd,J=8.8,2.4Hz,1H),8.25(dd,J=8.2,5.5Hz,2H),7.90(s,1H),7.58(d,J=5.3Hz,1H),7.25(s,1H),3.13–2.94(m,1H),2.61(s,3H),2.06(d,J=9.6Hz,2H)。LCMS[M+H]+=426.1。
实施例9合成化合物9的一般方法(TDM-180984)
步骤1:化合物9((S)-4-((4-(6-(2,2-二氟环丙烷-1-羧酰胺基)吡啶-3-基)嘧啶-2-基)氨基)-N-乙基-2-甲基苯甲酰胺)的制备
以相似的方法制备得到化合物9(26.6mg,黄色固体,收率13.04%)。
1H NMR(400MHz,DMSO)δ11.33(s,1H),9.80(s,1H),9.17(d,J=1.8Hz,1H),8.68–8.49(m,2H),8.22(d,J=8.7Hz,1H),8.09(t,J=5.6Hz,1H),7.80–7.61(m,2H),7.50(d,J=5.2Hz,1H),7.32(d,J=8.4Hz,1H),3.28–3.19(m,2H),3.04(dt,J=13.5,9.8Hz,1H),2.37(s,3H),2.12–2.00(m,2H),1.11(t,J=7.2Hz,3H)。LCMS[M+H]+=453.2。
实施例10合成化合物10的一般方法(TDM-180987)
步骤1:化合物10((1S)-2,2-二氟-N-(5-(2-((6-(1-(羟丙基-2-基)吡啶基-3-基)氨基)嘧啶基-4-基)吡啶基-2-基环丙烷-1-羧酰胺)的制备
以相似的方法制备得到化合物10(79mg,类白色固体,收率27.8%)。
1H NMR(400MHz,DMSO)δ11.30(s,1H),9.79(s,1H),9.13(d,J=2.1Hz,1H),8.84(d,J=2.5Hz,1H),8.65–8.46(m,2H),8.30–8.07(m,2H),7.48(d,J=5.2Hz,1H),7.22(d,J=8.5Hz,1H),4.59(t,J=5.3Hz,1H),3.71–3.43(m,2H),3.04(dt,J=13.5,9.9Hz,1H),2.91(dt,J=14.0,7.0Hz,1H),2.13–1.95(m,2H),1.20(d,J=6.9Hz,3H)。LCMS[M+H]+=427.1。
测试例1JAK激酶小分子抑制剂的酶活性抑制检测
实验方案
1、试剂准备
激酶反应缓冲液:配置激酶反应缓冲液,组分如下:50mM HEPES,pH 7.5,1mMEGTA,10mM MgCl2,2mM DTT,0.01%Tween20。1X检测缓冲液:配置检测缓冲液,去离子水9:1稀释10X检测缓冲液至1X。4X激酶溶液:激酶反应缓冲液稀释JAK激酶至4X终浓度(JAK1:80nM,JAK2/JAK3/Tyk2:4nM)。4X底物溶液:激酶反应缓冲液稀释ULightTM-JAK(Tyr1023)底物至200nM(终浓度:50nM)。4XATP溶液:激酶反应缓冲液稀释ATP至4X终浓度(JAK1:160μM,JAK2/JAK3/Tyk2:40μM)。4X测试化合物溶液:DMSO溶解测试用化合物至10mM储存液,3倍梯度稀释配置成所需浓度,每个化合物设置10个浓度点,测试化合物终浓度范围为:10μM-0.5nM。4X酶反应终止液:1X检测缓冲液溶解EDTA至40mM(EDTA终浓度:10mM)。4X检测抗体溶液:1X检测缓冲液稀释Eu标记检测抗体(抗磷酸酪氨酸(PT66))至8nM(抗体终浓度:2nM)。
2、实验过程
向384微孔板中依次加入2.5μL的4X激酶溶液和2.5μL已经稀释好的不同浓度的4X测试化合物溶液,每个浓度设置2个复孔,同时设置酶溶液空白对照组和阴性对照组(DMSO组)。震荡384多孔板,混匀酶和化合物,1000转,离心1分钟,在室温下孵育60分钟。向384多孔板中加入2.5μL,4X底物溶液,1000转离心1分钟。向384多孔板中加入2.5μL,4XATP溶液,1000转离心1分钟,起始酶反应。JAK1室温反应2小时,JAK2/JAK3/Tyk2室温反应1小时。JAK1反应的各组分终浓度分别为:JAK1:20nM,底物:50nM,ATP:40uM,测试化合物终浓度范围为:10μM-0.5nM。JAK2/JAK3/Tyk2反应的各组分终浓度分别为:JAK2:1nM,底物:50nM,ATP:10μM,测试化合物终浓度范围为:10μM-0.5nM。酶反应结束后,向384多孔板每孔中加入5μL,4X酶反应终止液,1000转,离心1分钟,在室温下孵育5分钟。向384多孔板每孔中加入5μL,4X检测抗体溶液,(检测抗体终浓度为2nM),1000转,离心1分钟,室温条件下孵育1小时。抗体孵育结束后,在Envision读板仪上测定各孔的信号值
3、数据分析
以酶溶液空白对照组为100%抑制率和阴性对照组(DMSO组)为0%抑制率,计算检测各个浓度对应的百分比抑制率。在GraphPad Prism软件中对检测化合物的浓度对数值和相对应的百分比抑制率进行非线性回归分析,得到检测化合物的半数抑制浓度(IC50),针对实施例1-10的化合物所测得的实验结果列在下表1中。
表1
编号 | Tyk2/μM | JAK1/μM | JAK2/μM | JAK3/μM |
TDM-180972 | 0.005 | 0.004 | 0.003 | 0.117 |
TDM-180974 | 0.008 | 0.007 | 0.007 | 0.346 |
TDM-180977 | 0.004 | 0.003 | 0.004 | 0.057 |
TDM-180981 | 0.008 | 0.008 | 0.008 | 0.183 |
TDM-180989 | 0.014 | 0.011 | 0.013 | 0.177 |
TDM-180971 | 0.005 | 0.006 | 0.007 | 0.219 |
TDM-180979 | 0.017 | 0.025 | 0.033 | 0.931 |
TDM-180980 | 0.018 | 0.028 | 0.030 | >5 |
TDM-180984 | 0.005 | 0.008 | 0.009 | 0.105 |
TDM-180987 | 0.017 | 0.025 | 0.022 | 0.310 |
从上表1的结果可以看出,本申请的化合物的酶活性数据非常优异,以上具体化合物测得的半数抑制浓度较低,特别是针对Tyk2、JAK1和JAK2时基本上达到小于0.03μM,尤其是化合物TDM-180972、TDM-180974、TDM-180977、TDM-180981、TDM-180971和TDM-180984,其半数抑制浓度均小于0.01μM。因此,通过以上实验已经证明了本申请的小分子化合物是一类针对JAK家族靶向性强、酶活性优异的化合物,能够作为JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (6)
1.一种小分子化合物,其特征在于,所述小分子化合物为由如下所示的式I表示的化合物,或其立体异构体、互变异构体、以及药学上可接受的盐:
[式I]
其中,R1和R3为C,R2和R4各自独立地选自C或N,且R1至R4中的至多一个为N;并且
其中,R具有如下所示的式II或式III表示的结构:
其中,R5选自C或N;
其中,R6选自氢、卤素、烷基、氨基、酰胺基或环烷基;并且
其中,R7选自氢、烷基或环烷基;
其中,R8选自C或N;
其中,R9选自氢、卤素、烷基、氨基、酰胺基或环烷基;并且
其中,R10选自氢、烷基或环烷基,
其中,所述烷基为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
2.根据权利要求1所述的小分子化合物,其特征在于,R6和R7各自独立地选自氢、烷基或环烷基。
3.根据权利要求1-2中任一项所述的小分子化合物在制备用于抑制JAK激酶的药物中的用途。
4.根据权利要求1-2中任一项所述的小分子化合物在制备用于预防或治疗自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药物中的用途,其中,这些疾病的发病机理均与JAK信号传导的失调相关。
5.根据权利要求4所述的用途,其中,所述自身免疫性疾病选自类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、***性红斑狼疮、皮肌炎、多发性硬化、I型糖尿病、干燥综合症和血管炎中的至少一种。
6.根据权利要求4所述的用途,其中,所述与免疫有关的炎症性皮肤疾病选自特应性皮炎、湿疹、斑秃、银屑病、白癜风、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮和化脓性汗腺炎中的至少一种。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011072703.7A CN112142675B (zh) | 2020-10-09 | 2020-10-09 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
PCT/CN2021/120119 WO2022073424A1 (zh) | 2020-10-09 | 2021-09-24 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
EP21876942.0A EP4227298A1 (en) | 2020-10-09 | 2021-09-24 | Small molecule compound serving as jak kinase inhibitor and use thereof |
KR1020237015632A KR20240004211A (ko) | 2020-10-09 | 2021-09-24 | Jak 키나아제 억제제인 저분자 화합물 및 이의 용도 |
US18/248,362 US20230373933A1 (en) | 2020-10-09 | 2021-09-24 | Small molecule compound serving as jak kinase inhibitor and use thereof |
JP2023521673A JP2023544431A (ja) | 2020-10-09 | 2021-09-24 | Jakキナーゼ阻害剤としての小分子化合物及びその用途 |
TW110137632A TWI780944B (zh) | 2020-10-09 | 2021-10-08 | 作為jak激酶抑制劑的小分子化合物及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011072703.7A CN112142675B (zh) | 2020-10-09 | 2020-10-09 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112142675A CN112142675A (zh) | 2020-12-29 |
CN112142675B true CN112142675B (zh) | 2021-11-30 |
Family
ID=73952716
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011072703.7A Active CN112142675B (zh) | 2020-10-09 | 2020-10-09 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20230373933A1 (zh) |
EP (1) | EP4227298A1 (zh) |
JP (1) | JP2023544431A (zh) |
KR (1) | KR20240004211A (zh) |
CN (1) | CN112142675B (zh) |
TW (1) | TWI780944B (zh) |
WO (1) | WO2022073424A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112142675B (zh) * | 2020-10-09 | 2021-11-30 | 嘉兴特科罗生物科技有限公司 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
CN113603677B (zh) * | 2021-08-06 | 2022-06-14 | 嘉兴特科罗生物科技有限公司 | 一种具有高口服生物利用度的jak抑制剂 |
AU2022350509A1 (en) * | 2021-09-23 | 2024-04-04 | Bristol-Myers Squibb Company | Methods of treating hair-loss disorders with tyk2 inhibitors |
WO2023076161A1 (en) | 2021-10-25 | 2023-05-04 | Kymera Therapeutics, Inc. | Tyk2 degraders and uses thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004041789A1 (en) * | 2002-11-01 | 2004-05-21 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of jak and other protein kinases |
CN101421250A (zh) * | 2006-01-30 | 2009-04-29 | 埃克塞里艾克西斯公司 | 作为jak-2调节剂的4-芳基-2-氨基-嘧啶或4-芳基-2-氨基烷基-嘧啶及包含它们的药物组合物 |
CN101861313A (zh) * | 2007-03-12 | 2010-10-13 | 西托匹亚研究有限公司 | 苯基氨基嘧啶化合物及其用途 |
CN102791697A (zh) * | 2009-10-12 | 2012-11-21 | 瑞科西有限公司 | 作为TBKL和/或IKKε抑制剂的氨基-嘧啶化合物 |
WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
CN110627775A (zh) * | 2019-10-24 | 2019-12-31 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2951911A1 (en) * | 2015-12-17 | 2017-06-17 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
CN112142675B (zh) * | 2020-10-09 | 2021-11-30 | 嘉兴特科罗生物科技有限公司 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
-
2020
- 2020-10-09 CN CN202011072703.7A patent/CN112142675B/zh active Active
-
2021
- 2021-09-24 JP JP2023521673A patent/JP2023544431A/ja active Pending
- 2021-09-24 KR KR1020237015632A patent/KR20240004211A/ko active Search and Examination
- 2021-09-24 WO PCT/CN2021/120119 patent/WO2022073424A1/zh unknown
- 2021-09-24 EP EP21876942.0A patent/EP4227298A1/en active Pending
- 2021-09-24 US US18/248,362 patent/US20230373933A1/en active Pending
- 2021-10-08 TW TW110137632A patent/TWI780944B/zh active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004041789A1 (en) * | 2002-11-01 | 2004-05-21 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of jak and other protein kinases |
CN101421250A (zh) * | 2006-01-30 | 2009-04-29 | 埃克塞里艾克西斯公司 | 作为jak-2调节剂的4-芳基-2-氨基-嘧啶或4-芳基-2-氨基烷基-嘧啶及包含它们的药物组合物 |
CN101861313A (zh) * | 2007-03-12 | 2010-10-13 | 西托匹亚研究有限公司 | 苯基氨基嘧啶化合物及其用途 |
CN102791697A (zh) * | 2009-10-12 | 2012-11-21 | 瑞科西有限公司 | 作为TBKL和/或IKKε抑制剂的氨基-嘧啶化合物 |
WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
CN110627775A (zh) * | 2019-10-24 | 2019-12-31 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
Also Published As
Publication number | Publication date |
---|---|
TWI780944B (zh) | 2022-10-11 |
JP2023544431A (ja) | 2023-10-23 |
WO2022073424A1 (zh) | 2022-04-14 |
EP4227298A1 (en) | 2023-08-16 |
CN112142675A (zh) | 2020-12-29 |
US20230373933A1 (en) | 2023-11-23 |
TW202214576A (zh) | 2022-04-16 |
KR20240004211A (ko) | 2024-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112142675B (zh) | 一种作为jak激酶抑制剂的小分子化合物及其用途 | |
CN111961037B (zh) | 一种作为jak激酶抑制剂的药物化合物 | |
CN105712998B (zh) | 氮杂吲哚类衍生物、其制备方法及其在医药上的应用 | |
WO2021193756A1 (ja) | 新規ベンズイミダゾール誘導体 | |
CN112159394B (zh) | 一种作为jak激酶抑制剂的小分子化合物及其用途 | |
TWI790024B (zh) | 三氮唑並吡嗪類化合物及其用途 | |
AU2015274285B2 (en) | Pyrimidine compounds and methods using the same | |
US11021479B2 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
CN113549065B (zh) | 作为JAK抑制剂的吡咯并[2,3-b]吡啶衍生物 | |
WO2023246858A1 (zh) | 一种硼酸酯衍生物的可药用盐、其结晶形式及用途 | |
WO2022199669A1 (zh) | 稠合吡啶酮类化合物盐型、晶型及其应用 | |
CN116947764A (zh) | 一种嘧啶胺类nuak抑制剂及其制备方法和用途 | |
EP4206196A1 (en) | Pyrimidine substituted derivatives as tyk2 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |