HRP20210228T1 - Amidi pirola kao inhibitori alfa v integrina - Google Patents
Amidi pirola kao inhibitori alfa v integrina Download PDFInfo
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- HRP20210228T1 HRP20210228T1 HRP20210228TT HRP20210228T HRP20210228T1 HR P20210228 T1 HRP20210228 T1 HR P20210228T1 HR P20210228T T HRP20210228T T HR P20210228TT HR P20210228 T HRP20210228 T HR P20210228T HR P20210228 T1 HRP20210228 T1 HR P20210228T1
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- alkyl
- membered
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- carbocyclyl
- heterocyclyl
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- -1 Pyrrole amides Chemical class 0.000 title claims 13
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 102000006495 integrins Human genes 0.000 title 1
- 108010044426 integrins Proteins 0.000 title 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 23
- 125000004452 carbocyclyl group Chemical group 0.000 claims 21
- 125000000217 alkyl group Chemical group 0.000 claims 17
- 150000001875 compounds Chemical class 0.000 claims 16
- 125000003118 aryl group Chemical group 0.000 claims 15
- 125000005843 halogen group Chemical group 0.000 claims 14
- 125000003545 alkoxy group Chemical group 0.000 claims 13
- 229910052739 hydrogen Inorganic materials 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 12
- 229940124530 sulfonamide Drugs 0.000 claims 12
- 150000003456 sulfonamides Chemical class 0.000 claims 12
- 125000004438 haloalkoxy group Chemical group 0.000 claims 11
- 125000001188 haloalkyl group Chemical group 0.000 claims 11
- 229910003827 NRaRb Inorganic materials 0.000 claims 10
- 125000004103 aminoalkyl group Chemical group 0.000 claims 10
- 125000001072 heteroaryl group Chemical group 0.000 claims 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 9
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 8
- 125000003368 amide group Chemical group 0.000 claims 8
- 150000003839 salts Chemical class 0.000 claims 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 5
- 125000004429 atom Chemical group 0.000 claims 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 5
- 125000004043 oxo group Chemical group O=* 0.000 claims 5
- 206010016654 Fibrosis Diseases 0.000 claims 4
- 125000002947 alkylene group Chemical group 0.000 claims 4
- 230000004761 fibrosis Effects 0.000 claims 4
- 150000002431 hydrogen Chemical group 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 125000003282 alkyl amino group Chemical group 0.000 claims 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 230000001575 pathological effect Effects 0.000 claims 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 239000004475 Arginine Substances 0.000 claims 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 125000005884 carbocyclylalkyl group Chemical group 0.000 claims 2
- 210000001072 colon Anatomy 0.000 claims 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims 2
- 210000004185 liver Anatomy 0.000 claims 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- WAZDNDYXKHYGNI-UHFFFAOYSA-N 1,1-diaminourea Chemical compound NN(N)C(N)=O WAZDNDYXKHYGNI-UHFFFAOYSA-N 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 201000009594 Systemic Scleroderma Diseases 0.000 claims 1
- 206010042953 Systemic sclerosis Diseases 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- 210000003169 central nervous system Anatomy 0.000 claims 1
- 210000003679 cervix uteri Anatomy 0.000 claims 1
- 208000020832 chronic kidney disease Diseases 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 208000033679 diabetic kidney disease Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 210000004696 endometrium Anatomy 0.000 claims 1
- 210000003238 esophagus Anatomy 0.000 claims 1
- 210000000232 gallbladder Anatomy 0.000 claims 1
- 210000004392 genitalia Anatomy 0.000 claims 1
- 210000003128 head Anatomy 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 210000000867 larynx Anatomy 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 210000002200 mouth mucosa Anatomy 0.000 claims 1
- 210000003205 muscle Anatomy 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 210000002850 nasal mucosa Anatomy 0.000 claims 1
- 210000003739 neck Anatomy 0.000 claims 1
- 210000001672 ovary Anatomy 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 230000002685 pulmonary effect Effects 0.000 claims 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 claims 1
- 210000003491 skin Anatomy 0.000 claims 1
- 210000000813 small intestine Anatomy 0.000 claims 1
- 210000000952 spleen Anatomy 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 210000001550 testis Anatomy 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P35/00—Antineoplastic agents
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- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (16)
1. Spoj formule (I):
[image]
pri čemu:
A je kovalentna veza, O, S, NH, -O-(C1-3 alkilen)-, -S-(C1-3 alkilen)-, ili -NH-(C1-3 alkilen)-, gdje je svaki C1-3 alkilen nezavisno supstituiran sa 0, 1, ili 2 R7a;
X je odsutan ili je C1-5 linearni alkilen supstituiran sa 0, 1, 2, ili 3 R7b;
Y je C(O) ili C(R6aR6b);
L1 i L2 su svaki nezavisno C1-4 alkilen;
n je cijeli broj 1 ili 2;
r je cijeli broj 0, 1, 2, ili 3;
R1 je segment mimetika arginina odabran iz grupe koja se sastoji od
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jedna od zvjezdica u svakom segmentu mimetika arginina je točka vezivanja za X i druge dvije zvjezdice su vodik;
R2 je vodik ili C1-6 alkil;
R3 je vodik, C1-6 alkil, 3- do 10-očlani karbociklil, karbociklilalkil, 6- do 10-očlani aril, arilalkil, 3- do 14-očlani heterociklil, heterociklilalkil, 5- do 14-očlani heteroaril, heteroarilalkil, pri čemu je svaki alkil, karbociklil, heterociklil, aril, i heteroaril, sam ili kao dio druge grupe, nezavisno supstituiran sa 0, 1, 2, ili 3 R8;
R3a je vodik; ili alternativno, R3a i R3, zajedno sa atomom ili atomima za koji su vezani, formiraju 3- do 6-očlani karbociklični ili heterociklični prsten koji je opcionalno supstituiran sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, okso, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid;
R4 je vodik, C1-10 alkil, 3- do 10-očlani karbociklil, karbociklilalkil, 3- do 10-očlani heterociklil, heterociklilalkil, 6- do 10-očlani aril, arilalkil, 5- do 14-očlani heteroaril, heteroarilalkil, NRaRb, ORa, S(O)nR10, C(O)NRaRb, NHC(O)ORa, NHC(O)NRaRb, NHC(O)R10, OC(O)NRaRb, OC(O)R10, NHS(O)nNRaRb, ili NHS(O)nR10; pri čemu je svaki alkil, karbociklil, heterociklil, aril, i heteroaril, sam ili kao dio druge grupe, nezavisno supstituiran sa 0, 1, 2, ili 3 R9;
R5je vodik, R5a, ili strukturni segment odabran od
[image]
R5a i R5b su svaki nezavisno C1-6 alkil, fenil, benzil, ili 5- do 7-očlani heterociklil; pri čemu je alkil, fenil, i heterociklil svaki nezavisno supstituiran sa 0 do 3 R5d;
R5c je C1-6 alkil ili 5- do 7-očlani karbociklil; pri čemu je alkil, fenil, i heterociklil svaki nezavisno supstituiran sa 0 do 3 R5d;
R5d, u svakom slučaju, je nezavisno halo, OH, alkoksi, okso, ili alkil; ili alternativno, dva susjedna R5d, zajedno sa atomima za koji su vezani, formiraju karbociklil segment;
R6a i R6b su svaki nezavisno vodik ili C1-6 alkil;
R7a i R7b su svaki nezavisno halo, cijano, hidroksil, amino, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, ili sulfonamid;
R8 je svako nezavisno halo, cijano, OH, NRaRb, C1-6 alkil, alkoksi, alkilamino, haloalkil, haloalkoksi, haloaminoalkil, hidroksialkil, aminoalkil, alkilsulfonil, sulfonamid, 3 do 6-očlani karbociklil, 3 do 6-očlani heterociklil, 6- do 10-očlani aril, ili 5- do 10-očlani heteroaril; ili alternativno, dva R8 na susjednim pozicijama, zajedno sa atomima za koji su vezani, formiraju karbociklil ili heterociklil; pri čemu aril i heteroaril su svaki nezavisno supstituirani sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid; i karbociklil i heterociklil su svaki nezavisno supstituirani sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, okso, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid;
R9 u svakom slučaju je nezavisno halo, cijano, OH, NRaRb, C1-6 alkil, alkoksi, alkilamino, haloalkil, haloalkoksi, haloaminoalkil, hidroksialkil, aminoalkil, alkilsulfonil, sulfonamid, 3 do 6-očlani karbociklil, 3 do 6-očlani heterociklil, 6- do 10-očlani aril, ili 5- do 10-očlani heteroaril; ili alternativno, dva R9 na susjednim pozicijama, zajedno sa atomima za koji su vezani, formiraju karbociklil ili heterociklil; pri čemu su aril i heteroaril svaki nezavisno supstituirani sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid; i karbociklil i heterociklil su svaki nezavisno supstituirani sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, okso, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid;
R10 je C1-6 alkil, 3- do 10-očlani karbociklil, 3- do 10-očlani heterociklil, 6- do 10-očlani aril, ili 5- do 10-očlani heteroaril; pri čemu su alkil, karbociklil, heterociklil svaki nezavisno supstituiran sa 0, 1, 2, ili 3 R11;
R11 je halo, cijano, hidroksil, amino, amino, amido, karbamat, sulfonamid, C1-6 alkil, alkoksi, 3- do 10-očlani karbociklil, 3- to 10-očlani heterociklil, 6- do 10-očlani aril, ili 5- do 10-očlani heteroaril; pri čemu aril, alkil, cikloalkil, heteroaril, i cikloheteroalkil su svaki nezavisno supstituiran sa 0, 1, 2, ili 3 R12;
R12 i R13, u svakom slučaju, su nezavisno halo, cijano, OH, amino, C1-6 alkil, alkoksi, alkilamino, haloalkil, haloalkoksi, haloaminoalkil, 3 do 6-očlani karbociklil, ili 3 do 6-očlani heterociklil, 6- do 10-očlani aril, ili 5- do 10-očlani heteroaril; pri čemu pri čemu aril i heteroaril su svaki nezavisno supstituiran sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid; i karbociklil i heterociklil su svaki nezavisno supstituiran sa jednom ili više grupa nezavisno odabranih od halo, cijano, hidroksil, amino, okso, C1-6 alkil, haloalkil, hidroksialkil, aminoalkil, alkoksi, haloalkoksi, amido, karbamat, i sulfonamid;
Ra, Rb, i Rc, u svakom slučaju, su nezavisno vodik, C1-10 alkil, 3- do 10-očlani karbociklil, ili 3- do 10-očlani heterociklil; pri čemu alkil, karbociklil, heterociklil su svaki nezavisno supstituiran sa 0, 1, 2, ili 3 R13;
Re je OH, amino, amido, karbamat, sulfonamid, C1-4 alkil, halo, C1-4 haloalkil, ili C3-6 cikloalkil;
Rf je H, CH3, CH2CH3, C(O)OCH2CH3; i
Rg je CH3, CH2CH3, CH2CCl3, fenil, 4-fluorofenil, 4-metoksifenil, benzil,
[image]
ili farmaceutski prihvatljiva sol istog,.
2. Spoj iz patentnog zahtjeva 1 gdje Y je C(O).
3. Spoj iz patentnog zahtjeva 1 gdje X je C2-4 linearni alkilen.
4. Spoj iz patentnog zahtjeva 1 gdje je R1 odabran od strukturne formule odabrane iz grupe koja se sastoji od
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[image]
[image]
5. Spoj iz patentnog zahtjeva 1 gdje R4 je vodik i R3 je 3- do 10-očlani karbociklil, 6- do 10-očlani aril, 3- do 14-očlani heterociklil, 5- do 14-očlani heteroaril, pri čemu karbociklil, heterociklil, aril, i heteroaril su svaki nezavisno supstituiran sa 0, 1, 2, ili 3 R8.
6. Spoj iz patentnog zahtjeva 5 gdje R3 je odabran iz grupe koja se sastoji od vodika,
[image]
[image]
7. Spoj iz patentnog zahtjeva 1 gdje je R3 vodik i R4 je NRaRb, ORa, S(O)nR10, C(O)NRaRb, NHC(O)ORa, NHC(O)NRaRb, NHC(O)R10, OC(O)NRaRb, OC(O)R10, NHS(O)nNRaRb, ili NHS(O)nR10.
8. Spoj iz patentnog zahtjeva 7 gdje je R4 odabran od vodika i sljedećih strukturnih segmenata:
[image]
9. Spoj iz patentnog zahtjeva 1 gdje R5 je H ili R5a; i R5a je metil, etil, izopropil, n-butil, izopentil, ili strukturni segment odabran od
[image]
[image]
[image]
10. Spoj iz patentnog zahtjeva 1 gdje R2 je H; i R5 je H.
11. Farmaceutska kompoziciju koja sadrži spoj iz patentnog zahtjeva 1, ili njegovu farmaceutski prihvatljivu sol, i farmaceutski prihvatljiv nosač.
12. Spoj u skladu sa bilo kojim patentnim zahtjevom 1 do 10 za primjenu u terapiji.
13. Spoj iz patentnog zahtjeva 1, ili njegova farmaceutski prihvatljiva sol za primjenu u liječenju patološke fibroze, odbacivanja transplantata, raka, osteoporoze, ili inflamatornih poremećaja.
14. Spoj ili njegova farmaceutski prihvatljiva sol za primjenu u skladu sa patentnim zahtjevom 13 pri čemu je patološka fibroza plućna, jetre, renalna, srčana, kožna, okularna, ili fibroza pankreasa.
15. Spoj ili njegova farmaceutski prihvatljiva sol za primjenu u skladu sa patentnim zahtjevom 13 pri čemu je patološka fibroza idiopatska plućna fibroza (IPF), bezalkoholni steatohepatitis (NASH), kronična bolest bubrega, dijabetesna bolest bubrega, ili sustavna skleroza.
16. Spoj ili njegova farmaceutski prihvatljiva sol za primjenu u skladu sa patentnim zahtjevom 13 pri čemu je rak mjehura, krvi, kosti, mozga, grudi, centralnog nervnog sistema, grlića materice, debelog crijeva, endometrija, jednjaka, žučne vreće, genitalija, genitourinarnog trakta, glave, bubrega, larinksa, jetre, pluća, mišićnog tkiva, vrata, oralne ili nazalne sluznice, jajnika, gušterače, prostate, kože, slezene, tankog crijeva, debelog crijeva, želuca, testisa, ili tiroidne žljezde.
Applications Claiming Priority (3)
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| US201662418833P | 2016-11-08 | 2016-11-08 | |
| EP17801236.5A EP3538528B1 (en) | 2016-11-08 | 2017-11-07 | Pyrrole amides as alpha v integrin inhibitors |
| PCT/US2017/060392 WO2018089360A1 (en) | 2016-11-08 | 2017-11-07 | Pyrrole amides as alpha v integrin inhibitors |
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| HRP20210228T1 true HRP20210228T1 (hr) | 2021-03-19 |
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| HRP20210228TT HRP20210228T1 (hr) | 2016-11-08 | 2021-02-09 | Amidi pirola kao inhibitori alfa v integrina |
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| US (1) | US10717736B2 (hr) |
| EP (1) | EP3538528B1 (hr) |
| JP (1) | JP7220653B2 (hr) |
| KR (1) | KR102515507B1 (hr) |
| CN (1) | CN110139864B (hr) |
| AU (1) | AU2017359030A1 (hr) |
| BR (1) | BR112019009293A2 (hr) |
| CA (1) | CA3042693A1 (hr) |
| CY (1) | CY1123893T1 (hr) |
| DK (1) | DK3538528T3 (hr) |
| EA (1) | EA201991124A1 (hr) |
| ES (1) | ES2852351T3 (hr) |
| HR (1) | HRP20210228T1 (hr) |
| HU (1) | HUE053620T2 (hr) |
| IL (1) | IL266469A (hr) |
| LT (1) | LT3538528T (hr) |
| MX (1) | MX2019005233A (hr) |
| PL (1) | PL3538528T3 (hr) |
| PT (1) | PT3538528T (hr) |
| RS (1) | RS61453B1 (hr) |
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| WO (1) | WO2018089360A1 (hr) |
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| WO2018049068A1 (en) | 2016-09-07 | 2018-03-15 | Pliant Therapeutics, Inc. | N-acyl amino acid compounds and methods of use |
| MA46744A (fr) * | 2016-11-08 | 2019-09-18 | Bristol Myers Squibb Co | Composés mono et spirocycliques contenant du cyclobutane et de l'azétidine en tant qu'inhibiteurs de l'intégrine alpha v |
| KR20190100232A (ko) | 2016-12-29 | 2019-08-28 | 세인트 루이스 유니버시티 | 인테그린 길항제 |
| MA47692A (fr) | 2017-02-28 | 2020-01-08 | Morphic Therapeutic Inc | Inhibiteurs de l'intégrine (alpha-v) (bêta-6) |
| KR102605460B1 (ko) | 2017-02-28 | 2023-11-22 | 모픽 테라퓨틱, 인코포레이티드 | αvβ6 인테그린 억제제 |
| WO2020047239A1 (en) | 2018-08-29 | 2020-03-05 | Morphic Therapeutic, Inc. | INHIBITING αV β6 INTEGRIN |
| EP3843727A4 (en) * | 2018-08-29 | 2022-08-17 | Morphic Therapeutic, Inc. | INTEGRIN (ALPHA-V)(BETA-6) INHIBITORS |
| KR102652797B1 (ko) | 2018-10-30 | 2024-04-02 | 길리애드 사이언시즈, 인코포레이티드 | 알파4베타7 인테그린의 억제를 위한 화합물 |
| AU2019373245C1 (en) | 2018-10-30 | 2022-10-27 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4β7 integrin |
| WO2020092394A1 (en) | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Imidazopyridine derivatives as alpha4beta7 integrin inhibitors |
| KR102630416B1 (ko) | 2018-10-30 | 2024-02-01 | 길리애드 사이언시즈, 인코포레이티드 | 알파4베타7 인테그린 억제제로서의 퀴놀린 유도체 |
| JP7491996B2 (ja) | 2019-08-14 | 2024-05-28 | ギリアード サイエンシーズ， インコーポレイテッド | α４β７インテグリンの阻害のための化合物 |
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| US5849736A (en) | 1993-11-24 | 1998-12-15 | The Dupont Merck Pharmaceutical Company | Isoxazoline and isoxazole fibrinogen receptor antagonists |
| IL118325A0 (en) * | 1995-05-25 | 1996-10-31 | Pont Merck And Pharmaceutical | Integrin receptor antagonists and pharmaceutical compositions containing them |
| ZA972195B (en) | 1996-03-15 | 1998-09-14 | Du Pont Merck Pharma | Spirocycle integrin inhibitors |
| WO1999026945A1 (en) | 1997-11-26 | 1999-06-03 | Du Pont Pharmaceuticals Company | 1,3,4-THIADIAZOLES AND 1,3,4-OXADIAZOLES AS αvβ3 ANTAGONISTS |
| AU736026B2 (en) | 1997-12-17 | 2001-07-26 | Merck & Co., Inc. | Integrin receptor antagonists |
| EP1070060A1 (en) | 1998-04-10 | 2001-01-24 | G.D. Searle & Co. | Heterocyclic glycyl beta-alanine derivatives as vitronectin antagonists |
| AU748621B2 (en) | 1998-08-13 | 2002-06-06 | Merck & Co., Inc. | Integrin receptor antagonists |
| AUPP646598A0 (en) | 1998-10-12 | 1998-11-05 | Fujisawa Pharmaceutical Co., Ltd. | New processes for producing alpha-alanine derivative |
| DE19939981A1 (de) | 1999-08-24 | 2001-03-01 | Merck Patent Gmbh | Neue Inhibitoren des Integrins alphavß3 |
| EP1230240B1 (en) * | 1999-11-08 | 2003-07-23 | Merck & Co., Inc. | Process and intermediates for the preparation of imidazolidinone alpha v integrin antagonists |
| GB0001447D0 (en) * | 2000-01-21 | 2000-03-08 | Novartis Ag | Organic compounds |
| NZ539682A (en) | 2001-01-29 | 2006-03-31 | Dimensional Pharm Inc | Substituted indoles and their use as integrin antagonists |
| AU2003259891A1 (en) | 2002-08-16 | 2004-03-19 | Janssen Pharmaceutica N.V. | Piperidinyl compounds that selectively bind integrins |
| TW200526626A (en) | 2003-09-13 | 2005-08-16 | Astrazeneca Ab | Chemical compounds |
| CA2540730C (en) | 2003-10-01 | 2012-08-21 | Merck Patent Gmbh | Alfavbeta3 and alfavbeta6 integrin antagonists as antifibrotic agents |
| WO2006108040A1 (en) | 2005-04-05 | 2006-10-12 | Janssen Pharmaceutica, N.V. | Substituted indoles and their use as integrin antagonists |
| EP2049490A1 (en) | 2006-06-09 | 2009-04-22 | Astra Zeneca AB | N-(benzoyl)-o- [2- (pyridin- 2 -ylamino) ethyl]-l-tyrosine derivatives and related compounds as a5b1 antagonists for the treatment of solid tumors |
| WO2008125811A1 (en) | 2007-04-11 | 2008-10-23 | Astrazeneca Ab | N-[HETEROARYLCARBONYL]-S-THIENYL-L-ALANINE DERIVATIVES AS α5β1 ANTAGONISTS |
| EP2526095A1 (en) * | 2010-01-19 | 2012-11-28 | Theravance, Inc. | Dual-acting thiophene, pyrrole, thiazole and furan antihypertensive agents |
| ITFI20100019A1 (it) | 2010-02-12 | 2011-08-13 | Univ Firenze | Inibitori peptidomimetici di integrine basati sull'1,2,3-triazolo per la diagnosi e terapia dei tumori. |
| EP2576540B1 (en) | 2010-05-26 | 2019-09-04 | Sunovion Pharmaceuticals Inc. | Heteroaryl compounds and methods of use thereof |
| ES2763556T3 (es) * | 2013-02-07 | 2020-05-29 | Scifluor Life Sciences Inc | Antagonistas fluorados de integrina |
| GB201305668D0 (en) * | 2013-03-28 | 2013-05-15 | Glaxosmithkline Ip Dev Ltd | Avs6 Integrin Antagonists |
| TWI667233B (zh) | 2013-12-19 | 2019-08-01 | 德商拜耳製藥公司 | 新穎吲唑羧醯胺，其製備方法、含彼等之醫藥製劑及其製造醫藥之用途 |
| GB201417094D0 (en) * | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| GB201417018D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| GB201417002D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compound |
| GB201417011D0 (en) * | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
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| JP2018515424A (ja) | 2015-03-10 | 2018-06-14 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 抗アルファｖベータ１インテグリン阻害剤及び使用方法 |
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- 2017-11-07 DK DK17801236.5T patent/DK3538528T3/da active
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Also Published As
| Publication number | Publication date |
|---|---|
| IL266469A (en) | 2019-07-31 |
| RS61453B1 (sr) | 2021-03-31 |
| JP7220653B2 (ja) | 2023-02-10 |
| US10717736B2 (en) | 2020-07-21 |
| AU2017359030A1 (en) | 2019-06-20 |
| EP3538528A1 (en) | 2019-09-18 |
| ES2852351T3 (es) | 2021-09-13 |
| CA3042693A1 (en) | 2018-05-17 |
| PL3538528T3 (pl) | 2021-05-31 |
| EP3538528B1 (en) | 2020-12-23 |
| EA201991124A1 (ru) | 2019-10-31 |
| SI3538528T1 (sl) | 2021-03-31 |
| DK3538528T3 (da) | 2021-02-15 |
| PT3538528T (pt) | 2021-02-16 |
| WO2018089360A1 (en) | 2018-05-17 |
| KR102515507B1 (ko) | 2023-03-28 |
| BR112019009293A2 (pt) | 2019-07-30 |
| LT3538528T (lt) | 2021-03-10 |
| MX2019005233A (es) | 2019-08-12 |
| JP2020500182A (ja) | 2020-01-09 |
| US20190256512A1 (en) | 2019-08-22 |
| CN110139864A (zh) | 2019-08-16 |
| KR20190076031A (ko) | 2019-07-01 |
| HUE053620T2 (hu) | 2021-07-28 |
| CN110139864B (zh) | 2022-08-23 |
| CY1123893T1 (el) | 2022-05-27 |
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