CA3042684A1 - Azole amides and amines as .alpha.v integrin inhibitors - Google Patents

Azole amides and amines as .alpha.v integrin inhibitors Download PDF

Info

Publication number: CA3042684A1
Authority: CA; Canada
Prior art keywords: alkyl; aryl; heteroaryl; alkoxy; halo
Prior art date: 2016-11-08
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.): Abandoned

Application number

CA3042684A

Other languages

English (en)

French (fr)

Inventor

Pratik Devasthale

Wei Wang

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Bristol Myers Squibb Co

Original Assignee

Bristol Myers Squibb Co

Priority date (The priority date 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 date listed.)

2016-11-08

Filing date

2017-11-07

Publication date

2018-05-17

2017-11-07 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

2018-05-17 Publication of CA3042684A1 publication Critical patent/CA3042684A1/en

Status Abandoned legal-status Critical Current

Links

-1 Azole amides Chemical class 0.000 title claims description 241
102000006495 integrins Human genes 0.000 title abstract description 30
108010044426 integrins Proteins 0.000 title abstract description 30
239000003112 inhibitor Substances 0.000 title abstract description 21
150000001412 amines Chemical class 0.000 title description 8
KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title description 7
238000000034 method Methods 0.000 claims abstract description 327
150000001875 compounds Chemical class 0.000 claims abstract description 144
150000003839 salts Chemical class 0.000 claims abstract description 47
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
206010028980 Neoplasm Diseases 0.000 claims abstract description 19
206010016654 Fibrosis Diseases 0.000 claims abstract description 17
230000004761 fibrosis Effects 0.000 claims abstract description 17
201000011510 cancer Diseases 0.000 claims abstract description 13
208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
230000001575 pathological effect Effects 0.000 claims abstract description 7
208000001132 Osteoporosis Diseases 0.000 claims abstract description 3
206010052779 Transplant rejections Diseases 0.000 claims abstract 2
125000000217 alkyl group Chemical group 0.000 claims description 131
125000000623 heterocyclic group Chemical group 0.000 claims description 89
125000003118 aryl group Chemical group 0.000 claims description 86
125000003545 alkoxy group Chemical group 0.000 claims description 75
125000004452 carbocyclyl group Chemical group 0.000 claims description 73
125000005843 halogen group Chemical group 0.000 claims description 64
125000001072 heteroaryl group Chemical group 0.000 claims description 63
229910052739 hydrogen Inorganic materials 0.000 claims description 62
125000000753 cycloalkyl group Chemical group 0.000 claims description 57
239000001257 hydrogen Substances 0.000 claims description 54
125000001188 haloalkyl group Chemical group 0.000 claims description 49
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
229910052757 nitrogen Inorganic materials 0.000 claims description 43
229910003827 NRaRb Inorganic materials 0.000 claims description 42
125000004103 aminoalkyl group Chemical group 0.000 claims description 42
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
125000004438 haloalkoxy group Chemical group 0.000 claims description 38
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 38
125000004429 atom Chemical group 0.000 claims description 36
229940124530 sulfonamide Drugs 0.000 claims description 34
150000003456 sulfonamides Chemical group 0.000 claims description 34
125000004432 carbon atom Chemical group C* 0.000 claims description 31
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
125000004404 heteroalkyl group Chemical group 0.000 claims description 29
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 28
125000004093 cyano group Chemical group *C#N 0.000 claims description 28
125000003368 amide group Chemical group 0.000 claims description 27
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
239000004475 Arginine Substances 0.000 claims description 24
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 24
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 20
125000004043 oxo group Chemical group O=* 0.000 claims description 19
201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 15
208000036971 interstitial lung disease 2 Diseases 0.000 claims description 15
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
125000003710 aryl alkyl group Chemical group 0.000 claims description 13
239000003937 drug carrier Substances 0.000 claims description 13
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 12
125000002947 alkylene group Chemical group 0.000 claims description 10
125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 9
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
210000004185 liver Anatomy 0.000 claims description 8
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 7
201000009594 Systemic Scleroderma Diseases 0.000 claims description 6
206010042953 Systemic sclerosis Diseases 0.000 claims description 6
125000003282 alkyl amino group Chemical group 0.000 claims description 6
125000004104 aryloxy group Chemical group 0.000 claims description 6
125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 6
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 6
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
229910052705 radium Inorganic materials 0.000 claims description 5
229910052701 rubidium Inorganic materials 0.000 claims description 5
208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
208000033679 diabetic kidney disease Diseases 0.000 claims description 4
125000004992 haloalkylamino group Chemical group 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 3
210000004369 blood Anatomy 0.000 claims description 3
239000008280 blood Substances 0.000 claims description 3
208000020832 chronic kidney disease Diseases 0.000 claims description 3
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
210000002784 stomach Anatomy 0.000 claims description 3
229910052717 sulfur Inorganic materials 0.000 claims description 3
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
210000000988 bone and bone Anatomy 0.000 claims description 2
210000004556 brain Anatomy 0.000 claims description 2
210000000481 breast Anatomy 0.000 claims description 2
230000000747 cardiac effect Effects 0.000 claims description 2
210000003169 central nervous system Anatomy 0.000 claims description 2
210000003679 cervix uteri Anatomy 0.000 claims description 2
210000001072 colon Anatomy 0.000 claims description 2
230000002500 effect on skin Effects 0.000 claims description 2
210000004696 endometrium Anatomy 0.000 claims description 2
210000003238 esophagus Anatomy 0.000 claims description 2
210000000232 gallbladder Anatomy 0.000 claims description 2
210000004392 genitalia Anatomy 0.000 claims description 2
210000003128 head Anatomy 0.000 claims description 2
210000003734 kidney Anatomy 0.000 claims description 2
210000002429 large intestine Anatomy 0.000 claims description 2
210000000867 larynx Anatomy 0.000 claims description 2
210000004072 lung Anatomy 0.000 claims description 2
210000002200 mouth mucosa Anatomy 0.000 claims description 2
210000003205 muscle Anatomy 0.000 claims description 2
210000002850 nasal mucosa Anatomy 0.000 claims description 2
210000003739 neck Anatomy 0.000 claims description 2
210000001672 ovary Anatomy 0.000 claims description 2
210000000496 pancreas Anatomy 0.000 claims description 2
210000002307 prostate Anatomy 0.000 claims description 2
230000002685 pulmonary effect Effects 0.000 claims description 2
210000003491 skin Anatomy 0.000 claims description 2
210000000813 small intestine Anatomy 0.000 claims description 2
210000000952 spleen Anatomy 0.000 claims description 2
210000001550 testis Anatomy 0.000 claims description 2
210000001685 thyroid gland Anatomy 0.000 claims description 2
210000003932 urinary bladder Anatomy 0.000 claims description 2
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 53
208000035475 disorder Diseases 0.000 abstract description 34
239000012453 solvate Substances 0.000 abstract description 23
201000010099 disease Diseases 0.000 abstract description 18
230000008482 dysregulation Effects 0.000 abstract description 4
239000000543 intermediate Substances 0.000 description 311
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 279
241000282414 Homo sapiens Species 0.000 description 228
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 226
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 166
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 126
238000000547 structure data Methods 0.000 description 123
239000000203 mixture Substances 0.000 description 122
DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 116
235000019260 propionic acid Nutrition 0.000 description 116
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 105
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 105
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 87
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 73
238000005481 NMR spectroscopy Methods 0.000 description 73
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 59
239000007787 solid Substances 0.000 description 58
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 56
239000002253 acid Substances 0.000 description 54
239000003039 volatile agent Substances 0.000 description 53
239000005695 Ammonium acetate Substances 0.000 description 51
229940043376 ammonium acetate Drugs 0.000 description 51
239000011541 reaction mixture Substances 0.000 description 51
238000005160 1H NMR spectroscopy Methods 0.000 description 50
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 49
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 49
235000019257 ammonium acetate Nutrition 0.000 description 49
238000002953 preparative HPLC Methods 0.000 description 49
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
239000012043 crude product Substances 0.000 description 47
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 44
239000003814 drug Substances 0.000 description 39
239000002245 particle Substances 0.000 description 39
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 36
239000000460 chlorine Substances 0.000 description 36
239000002904 solvent Substances 0.000 description 35
239000012044 organic layer Substances 0.000 description 30
239000003921 oil Substances 0.000 description 29
235000019198 oils Nutrition 0.000 description 29
239000000243 solution Substances 0.000 description 29
229910052943 magnesium sulfate Inorganic materials 0.000 description 28
235000019341 magnesium sulphate Nutrition 0.000 description 28
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
230000001629 suppression Effects 0.000 description 27
150000002148 esters Chemical class 0.000 description 26
238000001914 filtration Methods 0.000 description 26
238000011282 treatment Methods 0.000 description 26
239000000706 filtrate Substances 0.000 description 24
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
239000000651 prodrug Substances 0.000 description 22
229940002612 prodrug Drugs 0.000 description 22
229940124597 therapeutic agent Drugs 0.000 description 21
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 20
229910000024 caesium carbonate Inorganic materials 0.000 description 18
229910052799 carbon Inorganic materials 0.000 description 18
125000001424 substituent group Chemical group 0.000 description 18
150000001204 N-oxides Chemical class 0.000 description 16
238000006243 chemical reaction Methods 0.000 description 16
239000000047 product Substances 0.000 description 16
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
125000005518 carboxamido group Chemical group 0.000 description 15
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 15
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 15
238000010898 silica gel chromatography Methods 0.000 description 15
238000010511 deprotection reaction Methods 0.000 description 14
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 13
238000002360 preparation method Methods 0.000 description 13
238000000746 purification Methods 0.000 description 13
230000002829 reductive effect Effects 0.000 description 13
238000003786 synthesis reaction Methods 0.000 description 13
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 13
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
239000004480 active ingredient Substances 0.000 description 12
239000012267 brine Substances 0.000 description 12
125000005842 heteroatom Chemical group 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
239000000725 suspension Substances 0.000 description 12
238000005406 washing Methods 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
229930182821 L-proline Natural products 0.000 description 11
150000001721 carbon Chemical group 0.000 description 11
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
125000004433 nitrogen atom Chemical group N* 0.000 description 11
229960002429 proline Drugs 0.000 description 11
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 11
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 10
238000003556 assay Methods 0.000 description 10
230000015572 biosynthetic process Effects 0.000 description 10
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
229940079593 drug Drugs 0.000 description 10
230000003176 fibrotic effect Effects 0.000 description 10
239000006260 foam Substances 0.000 description 10
229920006395 saturated elastomer Polymers 0.000 description 10
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 9
238000004519 manufacturing process Methods 0.000 description 9
125000002950 monocyclic group Chemical group 0.000 description 9
NXMFJCRMSDRXLD-UHFFFAOYSA-N 2-aminopyridine-3-carbaldehyde Chemical compound NC1=NC=CC=C1C=O NXMFJCRMSDRXLD-UHFFFAOYSA-N 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
239000003795 chemical substances by application Substances 0.000 description 8
238000001816 cooling Methods 0.000 description 8
238000003818 flash chromatography Methods 0.000 description 8
230000007062 hydrolysis Effects 0.000 description 8
238000006460 hydrolysis reaction Methods 0.000 description 8
239000000741 silica gel Substances 0.000 description 8
229910002027 silica gel Inorganic materials 0.000 description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
SZLPRRVCSGZARF-UHFFFAOYSA-N 2-(2-bromoethyl)-2-methyl-1,3-dioxolane Chemical compound BrCCC1(C)OCCO1 SZLPRRVCSGZARF-UHFFFAOYSA-N 0.000 description 7
101150041968 CDC13 gene Proteins 0.000 description 7
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
230000029936 alkylation Effects 0.000 description 7
238000005804 alkylation reaction Methods 0.000 description 7
239000003153 chemical reaction reagent Substances 0.000 description 7
229910052801 chlorine Inorganic materials 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
239000000463 material Substances 0.000 description 7
125000003367 polycyclic group Polymers 0.000 description 7
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
239000000556 agonist Substances 0.000 description 6
125000004448 alkyl carbonyl group Chemical group 0.000 description 6
125000004414 alkyl thio group Chemical group 0.000 description 6
239000002585 base Substances 0.000 description 6
125000002837 carbocyclic group Chemical group 0.000 description 6
208000019425 cirrhosis of liver Diseases 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
230000000694 effects Effects 0.000 description 6
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
ONGSQPYHCQJKPP-JTQLQIEISA-N ethyl (3s)-3-amino-3-(3-fluoro-4-methoxyphenyl)propanoate Chemical compound CCOC(=O)C[C@H](N)C1=CC=C(OC)C(F)=C1 ONGSQPYHCQJKPP-JTQLQIEISA-N 0.000 description 6
KACZQOKEFKFNDB-UHFFFAOYSA-N ethyl 1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1 KACZQOKEFKFNDB-UHFFFAOYSA-N 0.000 description 6
229910052731 fluorine Inorganic materials 0.000 description 6
238000004128 high performance liquid chromatography Methods 0.000 description 6
238000002868 homogeneous time resolved fluorescence Methods 0.000 description 6
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235000017557 sodium bicarbonate Nutrition 0.000 description 6
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230000009466 transformation Effects 0.000 description 6
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125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 5
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OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
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206010023421 Kidney fibrosis Diseases 0.000 description 5
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125000003342 alkenyl group Chemical group 0.000 description 5
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125000002619 bicyclic group Chemical group 0.000 description 5
125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
150000001732 carboxylic acid derivatives Chemical group 0.000 description 5
229910052736 halogen Inorganic materials 0.000 description 5
150000002367 halogens Chemical class 0.000 description 5
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238000004949 mass spectrometry Methods 0.000 description 5
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239000011734 sodium Substances 0.000 description 5
239000000126 substance Substances 0.000 description 5
238000002560 therapeutic procedure Methods 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- 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
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Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Medicinal Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Immunology (AREA)
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Cardiology (AREA)
Endocrinology (AREA)
Dermatology (AREA)
Urology & Nephrology (AREA)
Heart & Thoracic Surgery (AREA)
Gastroenterology & Hepatology (AREA)
Obesity (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Plural Heterocyclic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Pyridine Compounds (AREA)

CA3042684A 2016-11-08 2017-11-07 Azole amides and amines as .alpha.v integrin inhibitors Abandoned CA3042684A1 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US201662418838P	2016-11-08	2016-11-08
US62/418,838		2016-11-08
PCT/US2017/060390 WO2018089358A1 (en)	2016-11-08	2017-11-07	Azole amides and amines as alpha v integrin inhibitors

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CA3042684A Abandoned CA3042684A1 (en)	2016-11-08	2017-11-07	Azole amides and amines as .alpha.v integrin inhibitors

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US (1)	US10851098B2 (2)
EP (1)	EP3538527B1 (2)
JP (1)	JP7128811B2 (2)
KR (1)	KR102510858B1 (2)
CN (1)	CN110167933B (2)
AU (1)	AU2017359028A1 (2)
BR (1)	BR112019009245A2 (2)
CA (1)	CA3042684A1 (2)
EA (1)	EA201991121A1 (2)
ES (1)	ES2898835T3 (2)
IL (1)	IL266465A (2)
MA (1)	MA46746A (2)
MX (1)	MX2019005234A (2)
WO (1)	WO2018089358A1 (2)

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US11306084B2 (en)	2016-12-29	2022-04-19	Saint Louis University	Integrin antagonists
MA52117A (fr)	2017-02-28	2022-04-06	Morphic Therapeutic Inc	Inhibiteurs de l'intégrine (alpha-v) (bêta-6)
MX394210B (es)	2017-02-28	2025-03-04	Morphic Therapeutic Inc	INHIBIDORES DE INTEGRINA AVß6.
SI3844162T1 (sl)	2018-08-29	2025-06-30	Morphic Therapeutic, Inc.	Zaviralci integrina alfa v beta6
WO2020047239A1 (en)	2018-08-29	2020-03-05	Morphic Therapeutic, Inc.	INHIBITING αV β6 INTEGRIN
WO2020047208A1 (en)	2018-08-29	2020-03-05	Morphic Therapeutic, Inc.	Inhibitors of (alpha-v)(beta-6) integrin
JP7189368B2 (ja)	2018-10-30	2022-12-13	ギリアードサイエンシーズ，インコーポレイテッド	アルファ４ベータ７インテグリンの阻害のための化合物
ES3013256T3 (en)	2018-10-30	2025-04-11	Gilead Sciences Inc	Imidazo[1,2-a]pyridine derivatives as alpha4beta7 integrin inhibitors for the treatment of inflammatory diseases
EP3873605B1 (en)	2018-10-30	2024-10-23	Gilead Sciences, Inc.	Compounds for inhibition of alpha4beta7 integrin
FI3873884T3 (fi)	2018-10-30	2025-02-24	Gilead Sciences Inc	3-(kinolin-8-yyli)-1,4-dihydropyrido[3,4-d]pyrimidiini-2,4-dionijohdannaisia alfa-4-beta-7-integriinin estäjinä tulehdussairauksien hoidossa
WO2021030438A1 (en)	2019-08-14	2021-02-18	Gilead Sciences, Inc.	Compounds for inhibition of alpha 4 beta 7 integrin
GB202010626D0 (en) *	2020-07-10	2020-08-26	Univ Nottingham	Compound
WO2022167866A1 (en) *	2021-02-08	2022-08-11	Rappta Therapeutics Oy	Modulators of protein phosphatase 2a (pp2a) and methods using same
KR20230169979A (ko) *	2021-03-10	2023-12-18	다이스 몰레큘스 에스브이, 인크.	알파 v 베타 6 및 알파 v 베타 1 인테그린 억제제 및 그의 용도

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2017
- 2017-11-07 BR BR112019009245A patent/BR112019009245A2/pt not_active Application Discontinuation
- 2017-11-07 EA EA201991121A patent/EA201991121A1/ru unknown
- 2017-11-07 EP EP17801235.7A patent/EP3538527B1/en active Active
- 2017-11-07 US US16/347,829 patent/US10851098B2/en active Active
- 2017-11-07 WO PCT/US2017/060390 patent/WO2018089358A1/en not_active Ceased
- 2017-11-07 MX MX2019005234A patent/MX2019005234A/es unknown
- 2017-11-07 MA MA046746A patent/MA46746A/fr unknown
- 2017-11-07 ES ES17801235T patent/ES2898835T3/es active Active
- 2017-11-07 JP JP2019523847A patent/JP7128811B2/ja active Active
- 2017-11-07 AU AU2017359028A patent/AU2017359028A1/en not_active Abandoned
- 2017-11-07 CA CA3042684A patent/CA3042684A1/en not_active Abandoned
- 2017-11-07 CN CN201780082144.8A patent/CN110167933B/zh active Active
- 2017-11-07 KR KR1020197016076A patent/KR102510858B1/ko active Active
2019
- 2019-05-06 IL IL266465A patent/IL266465A/en unknown

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Publication number	Publication date
KR102510858B1 (ko)	2023-03-15
MX2019005234A (es)	2019-08-12
ES2898835T3 (es)	2022-03-09
US10851098B2 (en)	2020-12-01
JP7128811B2 (ja)	2022-08-31
KR20190076030A (ko)	2019-07-01
US20190256513A1 (en)	2019-08-22
IL266465A (en)	2019-07-31
EA201991121A1 (ru)	2019-11-29
CN110167933A (zh)	2019-08-23
MA46746A (fr)	2019-09-18
JP2019537603A (ja)	2019-12-26
CN110167933B (zh)	2022-06-21
AU2017359028A1 (en)	2019-06-20
EP3538527B1 (en)	2021-10-13
EP3538527A1 (en)	2019-09-18
BR112019009245A2 (pt)	2019-07-16
WO2018089358A1 (en)	2018-05-17

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2023-07-05	FZDE	Discontinued	Effective date: 20230509

Publication	Publication Date	Title
US11639353B2 (en)	2023-05-02	Cyclobutanes- and azetidine-containing mono and spirocyclic compounds as αV integrin inhibitors
CA3042684A1 (en)	2018-05-17	Azole amides and amines as .alpha.v integrin inhibitors
US11028071B2 (en)	2021-06-08	Indazole derivatives as alpha v integrin antagonists
US11884661B2 (en)	2024-01-30	3-substituted propionic acids as αV integrin inhibitors
EP3538528B1 (en)	2020-12-23	Pyrrole amides as alpha v integrin inhibitors
HK40009959A (en)	2020-07-03	3-substituted propionic acids as alpha v integrin inhibitors
HK40009959B (en)	2023-03-10	3-substituted propionic acids as alpha v integrin inhibitors
BR112019009199B1 (pt)	2025-04-15	Compostos de ácidos propiônicos 3-substituídos, composição farmacêutica e seus usos como inibidores de alfa v integrina