HRP20240521T1 - Spojevi i pripravci za liječenje stanja povezanih s aktivnošću nlrp - Google Patents
Spojevi i pripravci za liječenje stanja povezanih s aktivnošću nlrp Download PDFInfo
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- HRP20240521T1 HRP20240521T1 HRP20240521TT HRP20240521T HRP20240521T1 HR P20240521 T1 HRP20240521 T1 HR P20240521T1 HR P20240521T T HRP20240521T T HR P20240521TT HR P20240521 T HRP20240521 T HR P20240521T HR P20240521 T1 HRP20240521 T1 HR P20240521T1
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- 150000001875 compounds Chemical class 0.000 title claims 23
- 239000000203 mixture Substances 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 24
- -1 C 1 -C 6 lkoxy Chemical group 0.000 claims 22
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 19
- 125000005843 halogen group Chemical group 0.000 claims 17
- 125000003118 aryl group Chemical group 0.000 claims 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 12
- 125000004043 oxo group Chemical group O=* 0.000 claims 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 10
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 10
- 150000003839 salts Chemical class 0.000 claims 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 8
- 125000001424 substituent group Chemical group 0.000 claims 6
- 125000002837 carbocyclic group Chemical group 0.000 claims 5
- 208000035475 disorder Diseases 0.000 claims 5
- 239000001257 hydrogen Substances 0.000 claims 5
- 229910052739 hydrogen Inorganic materials 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 229910052717 sulfur Inorganic materials 0.000 claims 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims 4
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 claims 4
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims 4
- 125000004429 atom Chemical group 0.000 claims 4
- 125000005842 heteroatom Chemical group 0.000 claims 4
- 125000002950 monocyclic group Chemical group 0.000 claims 4
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 claims 4
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 claims 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 3
- 239000005557 antagonist Substances 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 125000000623 heterocyclic group Chemical group 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 239000011593 sulfur Chemical group 0.000 claims 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 2
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims 2
- 208000023275 Autoimmune disease Diseases 0.000 claims 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 2
- 208000020084 Bone disease Diseases 0.000 claims 2
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 2
- 206010016654 Fibrosis Diseases 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 claims 2
- 208000019693 Lung disease Diseases 0.000 claims 2
- 208000023178 Musculoskeletal disease Diseases 0.000 claims 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 2
- 101150020251 NR13 gene Proteins 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 208000016222 Pancreatic disease Diseases 0.000 claims 2
- 208000036142 Viral infection Diseases 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 2
- 210000004204 blood vessel Anatomy 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 208000015114 central nervous system disease Diseases 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 208000030533 eye disease Diseases 0.000 claims 2
- 239000011737 fluorine Substances 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- 208000028774 intestinal disease Diseases 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 208000017169 kidney disease Diseases 0.000 claims 2
- 208000019423 liver disease Diseases 0.000 claims 2
- 208000030159 metabolic disease Diseases 0.000 claims 2
- 208000017445 musculoskeletal system disease Diseases 0.000 claims 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 2
- 208000017520 skin disease Diseases 0.000 claims 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 2
- 230000009385 viral infection Effects 0.000 claims 2
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 208000030507 AIDS Diseases 0.000 claims 1
- 208000009304 Acute Kidney Injury Diseases 0.000 claims 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 208000011231 Crohn disease Diseases 0.000 claims 1
- 208000007465 Giant cell arteritis Diseases 0.000 claims 1
- 208000010412 Glaucoma Diseases 0.000 claims 1
- 201000005569 Gout Diseases 0.000 claims 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims 1
- 206010019799 Hepatitis viral Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010027476 Metastases Diseases 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 claims 1
- 208000008589 Obesity Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 206010033645 Pancreatitis Diseases 0.000 claims 1
- 206010033647 Pancreatitis acute Diseases 0.000 claims 1
- 206010033649 Pancreatitis chronic Diseases 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 208000033626 Renal failure acute Diseases 0.000 claims 1
- 206010061481 Renal injury Diseases 0.000 claims 1
- 206010039710 Scleroderma Diseases 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
- 201000011040 acute kidney failure Diseases 0.000 claims 1
- 201000003229 acute pancreatitis Diseases 0.000 claims 1
- 230000032683 aging Effects 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- 125000004104 aryloxy group Chemical group 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 230000007882 cirrhosis Effects 0.000 claims 1
- 208000019425 cirrhosis of liver Diseases 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 230000004761 fibrosis Effects 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 239000003862 glucocorticoid Substances 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 208000037806 kidney injury Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000002780 macular degeneration Diseases 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 230000035772 mutation Effects 0.000 claims 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims 1
- 235000020824 obesity Nutrition 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 230000002018 overexpression Effects 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 230000002685 pulmonary effect Effects 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 1
- 206010043207 temporal arteritis Diseases 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
- 201000001862 viral hepatitis Diseases 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Claims (21)
1. Spoj, naznačen time, što je predstavljen formulom AA:
[image]
pri čemu:
m = 0, 1 ili 2,
n = 0, 1 ili 2;
o = 2;
p = 0, 1, 2 ili 3;
gdje:
A je 5- do 10-člani monociklički ili biciklički heteroaril ili C6-C10 monociklički ili biciklički aril;
B je bilo koji od:
[image]
pri čemu:
R1 i R2 su svaki neovisno odabrani iz niza koji sadrži C1-C6 alkil, C1-C6 haloalkil, C1-C6 alkoksi, Ci-C6 haloalkoksi, halo, CN, NO2, COC1-C6 alkil, CO-C6-C10 aril; CO(5- do 10-člani heteroaril); CO2C1-C6 alkil, CO2C3-C8 cikloalkil, OCOC1-C6 alkil, OCOC6-C10 aril, OCO(5-to 10-člani heteroaril), OCO(3- do 7-člani heterocikloalkil), C6-C10 aril, 5- do 10-člani heteroaril, NH2, NHC1-C6 alkil, N(C1-C6 alkil)2, NHCOC1-C6 alkil, NHCOC6-C10 aril, NHCO(5- do 10-člani heteroaril), NHCO(3- do 7-člani heterocikloalkil), NHCOC2-C6 alkinil, NHCOOCC1-C6 alkil, NH-(C=NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkil, S(O2)C1-C6 alkil, S(O)C1-C6 alkil, S(O2)NR11R12, C3-C7 cikloalkil i 3- do 7-člani heterocikloalkil,
pri čemu je C1-C6 alkil, C1-C6 haloalkil, C3-C7 cikloalkil i 3- do 7-člani heterocikloalkil izborno supstituiran s jednim ili više supstituenata od kojih je svaki neovisno odabran iz niza koji sadrži hidroksi, halo, CN, okso, C1-C6 alkil, C1-C6 alkoksi, NR8R9, =NR10, COOC1-C6 alkil, CONR8R9, 3- do 7-člani heterocikloalkil, C6-C10 aril, 5- do 10-člani heteroaril, OCOC1-C6 alkil, OCOC6-C10 aril, OCO(5- do 10-člani heteroaril), OCO(3- do 7-člani heterocikloalkil), NHCOC1-C6 alkil, NHCOC6-C10 aril, NHCO(5- do 10-člani heteroaril), NHCO(3- do 7-člani heterocikloalkil), i NHCOC2-C6 alkinil;
pri čemu je svaki C1-C6 alkilni supstituent i svaki C1-C6 alkoksi supstituent od R1 ili R2 C3-C7 cikloalkil ili R1 ili R2 3- do 7-člani heterocikloalkil je dalje izborno neovisno supstituiran s jednim do tri hidroksi, halo, NR8R9, ili okso; pri čemu su 3- do 7-člani heterocikloalkil, C6-C10 aril, 5- do 10-člani heteroaril, NHCOC6-C10 aril, NHCO(5- do 10-člani heteroaril) i NHCO(3- do 7-člani heterocikloalkil) izborno supstituirani s jednim ili više supstituenata neovisno odabranih od halo, C1-C6 alkila, i OC1-C6 alkila;
ili najmanje jedan par R1 i R2 na susjednim atomima, uzeti zajedno s atomima koji ih povezuju, neovisno tvore najmanje jedan C4-C8 karbociklički prsten ili najmanje jedan 5- do 8-člani heterociklički prsten koji sadrži 1 ili 2 heteroatoma neovisno odabrana od O, N i S, pri čemu je karbociklički prsten ili heterociklički prsten izborno neovisno supstituiran s jednim ili više supstituenata neovisno odabranih iz niza koji sadrži hidroksi, halo, okso, C1-C6 alkil, C1-C6 alkoksi, NR8R9, =NR10, COOC1-C6 alkil, C6-C10 aril, i CONR8R9 pri čemu su C1-C6 alkil i C1-C6 alkoksi izborno supstituirani s hidroksi, halo, okso, NR8R9, =NR10, COOC1-C6 alkil, C6-C10 aril, i CONR8R9;
R6 i R7 su svaki neovisno odabrani iz niza koji sadrži C1-C6 alkil, C1-C6 haloalkil, C1-C6 alkoksi, Ci-C6 haloalkoksi, halo, CN, NO2, COC1-C6 alkil, CO2C1-C6 alkil, CO2C3-C8 cikloalkil, OCOCi-C6 alkil, OCOC6-C10 aril, OCO(5- do 10-člani heteroaril), OCO(3- do 7-člani heterocikloalkil), C6-C10 aril, 5- do 10-člani heteroaril, NH2, NHC1-C6 alkil, N(C1-C6 alkil)2, CONR8R9, SF5, S(O2)C1-C6 alkil, C3-C10 cikloalkil i 3- do 10-člani heterocikloalkil, i C2-C6 alkenil,
pri čemu su R6 i R7 svaki izborno supstituirani s jednim ili više supstituenata neovisno odabranih iz niza koji sadrži hidroksi, halo, CN, okso, C1-C6 alkil, C1-C6 alkoksi, NR8R9, =NR10, COOC1-C6 alkil, CONR8R9, 3- do 7-člani heterocikloalkil, C6-C10 aril, 5- do 10-člani heteroaril, OCOC1-C6 alkil, OCOC6-C10 aril, OCO(5- do 10-člani heteroaril), OCO(3- do 7-člani heterocikloalkil), NHCOC1-C6 alkil, NHCOC6-C10 aril, NHCO(5- do 10-člani heteroaril), NHCO(3- do 7-člani heterocikloalkil), NHCOC2-C6 alkinil, C6-C10 ariloksi, i S(O2)C1-C6 alkil; i pri čemu je C1-C6 alkil ili C1-C6 alkoksi s kojima je supstituiran R6 ili R7 izborno supstituiran s jednim ili više hidroksilom, C6-C10 arilom ili NR8R9, ili pri čemu je R6 ili R7 izborno kondenziran na petero- do sedmeročlani karbociklički prsten ili heterociklički prsten koji sadrži jedan ili dva heteroatoma neovisno odabrana od kisika, sumpora i dušika;
pri čemu je 3- do 7-člani heterocikloalkil, C6-C10 aril, 5- do 10-člani heteroaril, NHCOC6-C10 aril, NHCO(5- do 10-člani heteroaril) i NHCO(3- do 7-člani heterocikloalkil) su izborno supstituirani s jednim ili više supstituenata neovisno odabranih između halo, C1-C6 alkila, i OC1-C6 alkila;
ili najmanje jedan par R6 i R7 na susjednim atomima, uzet zajedno s atomima koji ih povezuju, neovisno tvori najmanje jedan C4-C8 karbociklički prsten ili najmanje jedan 5- do 8-člani heterociklički prsten koji sadrži 1 ili 2 heteroatoma neovisno odabrana između O, N i S, pri čemu je karbociklički prsten ili heterociklički prsten izborno neovisno supstituiran s jednim ili više supstituenata neovisno odabranih između hidroksi, hidroksimetila, halo, okso, C1-C6 alkila, C1-C6 alkoksi, NR8R9, CH2NR8R9, =NR10, COOC1-C6 alkila, C6-C10 arila, i CONR8R9;
svaki od R4 i R5 je neovisno odabran između vodika i C1-C6 alkila;
R10 je C1-C6 alkil;
svaki od R8 i R9 pri svakom pojavljivanju je neovisno odabran između vodika, C1-C6 alkila, (C=NR13)NR11R12, S(O2)C1-C6 alkila, S(O2)NR11R12, COR13, CO2R13 i CONR11R12, pri čemu je C1-C6 alkil izborno supstituiran s jednim ili više hidroksi, halo, C1-C6 alkoksi, C6-C10 arilom, 5- do 10-članim heteroarilom, C3-C7 cikloalkilom ili 3- do 7-članim heterocikloalkilom; ili R8 i R9 uzeti zajedno s dušikom na koji su vezani tvore 3- do 7-člani prsten koji izborno sadrži jedan ili više heteroatoma pored dušika na koji su vezani; R13 je C1-C6 alkil, C6-C10 aril, ili 5- do 10-člani heteroaril;
svaki Rp1 je neovisno odabran između vodika C1-C6-alkila;
R3 je vodik; i
R14 je vodik, C1-C6 alkil, 5- do 10-člani monociklički ili biciklički heteroaril ili C6-C10 monociklički ili biciklički aril, pri čemu svaki C1-C6 alkil, aril ili heteroaril je izborno neovisno supstituiran s 1 ili 2 R6,
ili njegova farmaceutski prihvatljiva sol.
2. Spoj prema patentnom zahtjevu 1, naznačen time, što A je 5- do 6-člani monociklički heteroaril izborno supstituiran s 1 ili 2 R1 i izborno supstituiran s 1 ili 2 R2; izborno pri čemu A je bilo koji od:
furanil izborno supstituiran s 1 ili 2 R1 i izborno supstituiran s 1 ili 2 R2;
tiofenil izborno supstituiran s 1 ili 2 R1 i izborno supstituiran s 1 ili 2 R2;
oksazolil izborno supstituiran s 1 ili 2 R1 i izborno supstituiran s 1 ili 2 R2;
tiazolil izborno supstituiran s 1 ili 2 R1 i izborno supstituiran s 1 ili 2 R2;
fenil izborno supstituiran s 1 ili 2 R1 i izborno supstituiran s 1 ili 2 R2.
3. Spoj prema patentnom zahtjevu 1 ili 2, naznačen time, što m=1 i n=0;
izborno pri čemu A je bilo koji od:
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ili
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4. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, što m=1 i n=1; izborno pri čemu je A bilo koji od:
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5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, što m=2 i n=1;
izborno pri čemu A je bilo koji od:
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6. Spoj prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, što je svaki od R1 i R2, kada je prisutan, neovisno odabran iz skupine koja sadrži C1-C6 alkil izborno supstituiran s jednim ili više hidroksi, halo, okso, C1-C6 alkoksi, ili NR8R9; C3-C7 cikloalkil izborno supstituiran s jednim ili više hidroksi, halo, okso, C1-C6 alkoksi, C1-C6 alkil, ili NR8R9 pri čemu je C1-C6 alkoksi ili C1-C6 alkil dalje izborno supstituiran s jednim do tri hidroksi, halo, NR8R9, ili okso; 3- do 7-člani heterocikloalkil izborno supstituiran s jednim ili više hidroksi, halo, okso, C1-C6 alkil, ili NR8R9 pri čemu je Ci-C6 alkoksi ili C1-C6 alkil dalje izborno supstituiran s jednim do tri hidroksi, halo, NR8R9, ili okso; C1-C6 haloalkil; C1-C6 alkoksi; C1-C6 haloalkoksi; halo; CN; CO-C1-C6 alkil; CO-C6-C10 aril; CO(5- do 10-člani heteroaril); CO2C1-C6 alkil; CO2C3-C8 cikloalkil; OCOC1-C6 alkil; OCOC6-C10 aril; OCO(5- do 10-člani heteroaril); OCO(3- do 7-člani heterocikloalkil); C6-C10 aril; 5- do 10-člani heteroaril; NH2; NHC1-C6 alkil; N(C1-C6 alkil)2; CONR8R9; SF5; S(Oa)NR11R12, S(O)C1-C6 alkil; i S(O2)C1-C6 alkil.
7. Spoj prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, što je R1 odabran iz skupine koja sadrži 1-hidroksi-2-metilpropan-2-il; metil; izopropil; 2-hidroksi-2-propil; hidroksimetil; 1-hidroksietil; 2-hidroksietil; 1-hidroksi-2-propil; 1-hidroksi-1-ciklopropil; 1-hidroksi-1-ciklobutil; 1-hidroksi-1-ciklopentil; 1-hidroksi-1-cikloheksil; morfolinil; 1,3-dioksolan-2-il; COCH3; COCH2CH3; 2-metoksi-2-propil; (dimetilamino)metil; 1-(dimetilamino)etil; fluor; klor; fenil; piridil; pirazolil; S(O2)CH3; i S(O2)NR11R12.
8. Spoj prema patentnom zahtjevu 6 ili 7, naznačen time, što je R2 odabran iz skupine koja sadrži fluor, klor, cijano, metil; metoksi; etoksi; izopropil; 1-hidroksi-2-metilpropan-2-il; 2-hidroksi-2-propil; hidroksimetil; 1-hidroksietil; 2-hidroksietil; 1-hidroksi-2-propil; 1-hidroksi-1-ciklopropil; COCH3; COPh; 2-metoksi-2-propil; (dimetilamino)metil; S(O2)CH3; i S(O2)NR11R12.
9. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što je B fenil supstituiran s 2 R6 i izborno supstituiran s 1, 2, ili 3 R7.
10. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja se sastoji od dolje navedenih spojeva:
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ili njegova farmaceutski prihvatljiva sol.
11. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja sadrži:
[image]
ili njegova farmaceutski prihvatljiva sol.
12. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja sadrži:
[image]
ili njegova farmaceutski prihvatljiva sol.
13. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja sadrži:
[image]
ili njegova farmaceutski prihvatljiva sol.
14. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja sadrži:
[image]
ili njegova farmaceutski prihvatljiva sol.
15. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja sadrži:
[image]
ili njegova farmaceutski prihvatljiva sol.
16. Spoj prema patentnom zahtjevu 1, naznačen time, što je odabran iz skupine koja sadrži:
[image]
ili njegova farmaceutski prihvatljiva sol.
17. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što sumpor u ostatku S(=O)(NHR3)=N- ima (S) stereokemiju.
18. Spoj prema bilo kojem od patentnih zahtjeva 1 do 16, naznačen time, što sumpor u ostatku S(=O)(NHR3)=N- ima (R) stereokemiju.
19. Farmaceutski pripravak, naznačen time, što sadrži spoj ili sol prema bilo kojem od patentnih zahtjeva 1 do 18 i jednu ili više farmaceutski prihvatljivih pomoćnih tvari.
20. Spoj prema bilo kojem od patentnih zahtjeva 1 do 18, naznačen time, što je za upotrebu u liječenju bolesti, poremećaja ili stanja koje je bilo koje od sljedećih:
metabolički poremećaj, izborno pri čemu je metabolički poremećaj dijabetes tipa 2, ateroskleroza, pretilost ili giht;
bolest središnjeg živčanog sustava, izborno pri čemu je bolest središnjeg živčanog sustava Alzheimerova bolest, multipla skleroza, amiotrofična lateralna skleroza ili Parkinsonova bolest;
bolest pluća, po izboru gdje je bolest pluća astma, KOPB ili plućna idiopatska fibroza;
bolest jetre, izborno pri čemu je bolest jetre NASH sindrom, virusni hepatitis ili ciroza;
bolest gušterače, izborno pri čemu je bolest gušterače akutni pankreatitis ili kronični pankreatitis;
bolest bubrega, izborno pri čemu je bolest bubrega akutna ozljeda bubrega ili kronična ozljeda bubrega;
crijevna bolest, izborno pri čemu je crijevna bolest Crohnova bolest ili ulcerozni kolitis;
kožna bolest, izborno pri čemu je kožna bolest psorijaza;
mišićno-koštana bolest, izborno pri čemu je mišićno-koštana bolest sklerodermija;
poremećaj krvnih žila, izborno pri čemu je poremećaj krvnih žila arteritis divovskih stanica;
poremećaj kostiju, izborno gdje je poremećaj kostiju osteoartritis, osteoporoza ili osteopetrozni poremećaji;
bolest oka, izborno gdje je bolest oka glaukom ili makularna degeneracija bolest uzrokovana virusnom infekcijom, po izboru gdje je bolest uzrokovana virusnom infekcijom HIV ili AIDS;
autoimuna bolest, izborno pri čemu je autoimuna bolest reumatoidni artritis, sistemski eritematozni lupus, autoimuni tiroiditis, rak ili starenje, izborno pri čemu je poremećaj ili stanje koje je rak odabrano između: mijelodisplastičnih sindroma (MDS); raka pluća nemalih stanica, kao što je rak pluća nemalih stanica kod pacijenata koji nose mutaciju ili prekomjernu ekspresiju NLRP3; akutna limfoblastična leukemija (ALL), kao što je ALL kod bolesnika otpornih na liječenje glukokortikoidima; histiocitoza Langerhansovih stanica (LCH); multipli mijelom; promijelocitna leukemija; akutna mijeloična leukemija (AML); kronična mijeloična leukemija (CML); rak želuca; i metastaze raka pluća.
21. Spoj za upotrebu prema patentnom zahtjevu 20, naznačen time, što nadalje uključuje davanje terapeutski učinkovite količine anti-TNFα sredstva pojedincu; izborno
pri čemu:
NLRP3 antagonist se daje pojedincu prije davanja anti-TNFα sredstva pojedincu; ili
pri čemu se anti-TNFα sredstvo daje pojedincu prije davanja NLRP3 antagonista pojedincu; ili
pri čemu se NLRP3 antagonist i anti-TNFα sredstvo daju pojedincu uglavnom u isto vrijeme.
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