EA038164B1 - 3-замещенные пропановые кислоты в качестве ингибиторов интегрина v - Google Patents

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Publication number

EA038164B1

EA038164B1 EA201991122A EA201991122A EA038164B1 EA 038164 B1 EA038164 B1 EA 038164B1 EA 201991122 A EA201991122 A EA 201991122A EA 201991122 A EA201991122 A EA 201991122A EA 038164 B1 EA038164 B1 EA 038164B1

Authority

EA

Eurasian Patent Office

Prior art keywords

tetrahydro

propanoic acid

propyl

naphthyridin

mmol

Prior art date

2016-11-08

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• 102000006495 integrins Human genes 0.000 title claims abstract description 27
• 108010044426 integrins Proteins 0.000 title claims abstract description 27
• -1 3-substituted propionic acids Chemical class 0.000 title claims description 355
• 239000003112 inhibitor Substances 0.000 title description 15
• 150000001875 compounds Chemical class 0.000 claims abstract description 194
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 59
• 208000035475 disorder Diseases 0.000 claims abstract description 37
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
• 201000010099 disease Diseases 0.000 claims abstract description 21
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
• 206010016654 Fibrosis Diseases 0.000 claims abstract description 16
• 230000004761 fibrosis Effects 0.000 claims abstract description 16
• 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 6
• 230000008482 dysregulation Effects 0.000 claims abstract description 5
• 208000001132 Osteoporosis Diseases 0.000 claims abstract description 3
• 206010052779 Transplant rejections Diseases 0.000 claims abstract 2
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 151
• 235000019260 propionic acid Nutrition 0.000 claims description 132
• 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 claims description 118
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 85
• 229910052739 hydrogen Inorganic materials 0.000 claims description 49
• 150000003839 salts Chemical class 0.000 claims description 46
• 125000000217 alkyl group Chemical group 0.000 claims description 36
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
• 239000001257 hydrogen Substances 0.000 claims description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
• 125000004321 azepin-2-yl group Chemical group [H]N1C([H])=C([H])C([H])=C([H])C([H])=C1* 0.000 claims description 20
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 19
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 14
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 13
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 11
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
• 239000010802 sludge Substances 0.000 claims description 10
• 210000004185 liver Anatomy 0.000 claims description 9
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• 201000009594 Systemic Scleroderma Diseases 0.000 claims description 6
• 206010042953 Systemic sclerosis Diseases 0.000 claims description 6
• ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical class CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 5
• 210000004072 lung Anatomy 0.000 claims description 5
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 5
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
• 210000001072 colon Anatomy 0.000 claims description 4
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
• 210000003734 kidney Anatomy 0.000 claims description 4
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
• 210000000496 pancreas Anatomy 0.000 claims description 4
• 210000003491 skin Anatomy 0.000 claims description 4
• CGNMIYRIWLHATI-QHCPKHFHSA-N (3S)-3-[1-(cyclopropylmethyl)-6-oxopyridin-3-yl]-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound OC(=O)C[C@H](N1C=CC(CCCC2=CC=C3CCCNC3=N2)=N1)C1=CN(CC2CC2)C(=O)C=C1 CGNMIYRIWLHATI-QHCPKHFHSA-N 0.000 claims description 3
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
• WETNDFFONPZIGS-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[1-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-3-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)C(CC(O)=O)C1=NN(CCCC2=CC=C3CCCNC3=N2)C=C1 WETNDFFONPZIGS-UHFFFAOYSA-N 0.000 claims description 3
• VXWFWYADNINHES-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound C1CNC2=C(C=CC(=N2)CCCC2=NN(C=C2)C(CC(=O)O)C2=CC=C(OC)N=C2)C1 VXWFWYADNINHES-UHFFFAOYSA-N 0.000 claims description 3
• PDJKPMYZSAIHDN-UHFFFAOYSA-N CC(C(O)=O)C1=NC(CCCCC2=NC(NCCC3)=C3C=C2)=CS1 Chemical compound CC(C(O)=O)C1=NC(CCCCC2=NC(NCCC3)=C3C=C2)=CS1 PDJKPMYZSAIHDN-UHFFFAOYSA-N 0.000 claims description 3
• 210000004369 blood Anatomy 0.000 claims description 3
• 239000008280 blood Substances 0.000 claims description 3
• 210000002784 stomach Anatomy 0.000 claims description 3
• ZKJMYZGFBDUOAC-HXUWFJFHSA-N (3R)-3-(2-methylpyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound Cc1ncc(cn1)[C@@H](CC(O)=O)n1ccc(CCCc2ccc3CCCNc3n2)n1 ZKJMYZGFBDUOAC-HXUWFJFHSA-N 0.000 claims description 2
• IABHYNPYOQIKNL-HXUWFJFHSA-N (3R)-3-(6-methoxypyridin-3-yl)-3-[1-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-4-yl]propanoic acid Chemical compound COc1ccc(cn1)[C@@H](CC(O)=O)c1cnn(CCCc2ccc3CCCNc3n2)c1 IABHYNPYOQIKNL-HXUWFJFHSA-N 0.000 claims description 2
• VUCPJDQRPNKODR-IBGZPJMESA-N (3S)-3-(6-oxo-1H-pyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound OC(=O)C[C@@H](c1ccc(=O)[nH]c1)n1ccc(CCCc2ccc3CCCNc3n2)n1 VUCPJDQRPNKODR-IBGZPJMESA-N 0.000 claims description 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• UBYJRGAFVQXRIU-UHFFFAOYSA-N 3-(2-methoxypyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COc1ncc(cn1)C(CC(O)=O)n1ccc(CCCc2ccc3CCCNc3n2)n1 UBYJRGAFVQXRIU-UHFFFAOYSA-N 0.000 claims description 2
• JUEJISWKTFLIGZ-KKFHFHRHSA-N 3-(2-methoxypyrimidin-5-yl)-3-[5-[3-[(2S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl]propyl]pyrazol-1-yl]propanoic acid Chemical compound COc1ncc(cn1)C(CC(O)=O)n1nccc1CCC[C@H]1CCc2cccnc2N1 JUEJISWKTFLIGZ-KKFHFHRHSA-N 0.000 claims description 2
• ZKJMYZGFBDUOAC-UHFFFAOYSA-N 3-(2-methylpyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound Cc1ncc(cn1)C(CC(O)=O)n1ccc(CCCc2ccc3CCCNc3n2)n1 ZKJMYZGFBDUOAC-UHFFFAOYSA-N 0.000 claims description 2
• GTSPHCCFRVTHLR-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[1-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]pyrazol-4-yl]propanoic acid Chemical compound N1(C=C(C(C2=CN=C(OC)C=C2)CC(=O)O)C=N1)CCCCC1=CC=C2CCCNC2=N1 GTSPHCCFRVTHLR-UHFFFAOYSA-N 0.000 claims description 2
• RNBMPWCNANEMEQ-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)phenyl]pyrazol-1-yl]propanoic acid Chemical compound COc1ccc(cn1)C(CC(O)=O)n1ccc(n1)-c1cccc(c1)-c1ccc2CCCNc2n1 RNBMPWCNANEMEQ-UHFFFAOYSA-N 0.000 claims description 2
• SQWANXBQZBKBBP-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propoxy]pyrazol-1-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)C(CC(O)=O)N1C=CC(OCCCC2=CC=C3CCCNC3=N2)=N1 SQWANXBQZBKBBP-UHFFFAOYSA-N 0.000 claims description 2
• VZKVXHYXNXGQDU-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[3-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]pyrazol-1-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)C(CC(=O)O)N1N=C(C=C1)CCCCC1=NC=2NCCCC=2C=C1 VZKVXHYXNXGQDU-UHFFFAOYSA-N 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
• 210000003169 central nervous system Anatomy 0.000 claims description 2
• 210000003679 cervix uteri Anatomy 0.000 claims description 2
• 210000004696 endometrium Anatomy 0.000 claims description 2
• 210000003238 esophagus Anatomy 0.000 claims description 2
• 210000001508 eye 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
• 210000002216 heart Anatomy 0.000 claims description 2
• 210000000867 larynx 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
• 210000002307 prostate Anatomy 0.000 claims description 2
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
• 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 2
• 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 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
• 210000001635 urinary tract Anatomy 0.000 claims description 2
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims 3
• LUNGOZZVVOHVRP-PKOBYXMFSA-N COC1=CC=C(C=N1)[C@@H](CC(=O)O)C=1SC=C(N=1)CCC[C@@H]1NC2=NC=CC=C2CC1 Chemical compound COC1=CC=C(C=N1)[C@@H](CC(=O)O)C=1SC=C(N=1)CCC[C@@H]1NC2=NC=CC=C2CC1 LUNGOZZVVOHVRP-PKOBYXMFSA-N 0.000 claims 2
• LUNGOZZVVOHVRP-IEBWSBKVSA-N COC1=CC=C(C=N1)[C@@H](CC(=O)O)C=1SC=C(N=1)CCC[C@H]1NC2=NC=CC=C2CC1 Chemical compound COC1=CC=C(C=N1)[C@@H](CC(=O)O)C=1SC=C(N=1)CCC[C@H]1NC2=NC=CC=C2CC1 LUNGOZZVVOHVRP-IEBWSBKVSA-N 0.000 claims 2
• LUNGOZZVVOHVRP-HKUYNNGSSA-N COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCC[C@@H]1NC2=NC=CC=C2CC1 Chemical compound COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCC[C@@H]1NC2=NC=CC=C2CC1 LUNGOZZVVOHVRP-HKUYNNGSSA-N 0.000 claims 2
• LUNGOZZVVOHVRP-MJGOQNOKSA-N COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCC[C@H]1NC2=NC=CC=C2CC1 Chemical compound COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCC[C@H]1NC2=NC=CC=C2CC1 LUNGOZZVVOHVRP-MJGOQNOKSA-N 0.000 claims 2
• 125000001475 halogen functional group Chemical group 0.000 claims 2
• 150000002431 hydrogen Chemical class 0.000 claims 2
• JEWVDLUACRWTEW-HXUWFJFHSA-N (3R)-3-(2-ethoxypyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound CCOC1=NC=C(C=N1)[C@@H](CC(O)=O)N1C=CC(CCCC2=CC=C3CCCNC3=N2)=N1 JEWVDLUACRWTEW-HXUWFJFHSA-N 0.000 claims 1
• QMBVMQULMAFHDB-HXUWFJFHSA-N (3R)-3-(2-ethoxypyrimidin-5-yl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CCOC1=NC=C(C=N1)[C@@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 QMBVMQULMAFHDB-HXUWFJFHSA-N 0.000 claims 1
• UBYJRGAFVQXRIU-LJQANCHMSA-N (3R)-3-(2-methoxypyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COc1ncc(cn1)[C@@H](CC(O)=O)n1ccc(CCCc2ccc3CCCNc3n2)n1 UBYJRGAFVQXRIU-LJQANCHMSA-N 0.000 claims 1
• CBEDCDMHOQWJRM-HXUWFJFHSA-N (3R)-3-(2-methoxypyrimidin-5-yl)-3-[3-[3-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COC1=NC=C(C=N1)[C@@H](CC(=O)O)N1N=C(C=C1)CCCC=1C=CC2=C(NCCCC2)N=1 CBEDCDMHOQWJRM-HXUWFJFHSA-N 0.000 claims 1
• IFPMYGLSHXXRFZ-LJQANCHMSA-N (3R)-3-(2-methoxypyrimidin-5-yl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=NC=C(C=N1)[C@@H](CC(=O)O)C=1SC=C(N=1)CCCCC1=NC=2NCCCC=2C=C1 IFPMYGLSHXXRFZ-LJQANCHMSA-N 0.000 claims 1
• BCBRXDHPNAOLSW-LJQANCHMSA-N (3R)-3-(2-methylpyrimidin-5-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound Cc1ncc(cn1)[C@@H](CC(O)=O)c1nc(CCCc2ccc3CCCNc3n2)cs1 BCBRXDHPNAOLSW-LJQANCHMSA-N 0.000 claims 1
• HVDGUXVTAKZNCH-LJQANCHMSA-N (3R)-3-(3,5-dimethylpyrazol-1-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CC1=NN(C(=C1)C)[C@H](CC(=O)O)C=1SC=C(N=1)CCCC1=NC=2NCCCC=2C=C1 HVDGUXVTAKZNCH-LJQANCHMSA-N 0.000 claims 1
• IRRAOOUFBQNPFO-GOSISDBHSA-N (3R)-3-(3-fluoro-4-methoxyphenyl)-3-[2-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-4-yl]propanoic acid Chemical compound COC1=C(F)C=C(C=C1)[C@@H](CC(O)=O)C1=CSC(CCCC2=CC=C3CCCNC3=N2)=N1 IRRAOOUFBQNPFO-GOSISDBHSA-N 0.000 claims 1
• LVZQWYRNDVVBAH-RUZDIDTESA-N (3R)-3-(3-morpholin-4-ylphenyl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound OC(=O)C[C@@H](C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1)C1=CC(=CC=C1)N1CCOCC1 LVZQWYRNDVVBAH-RUZDIDTESA-N 0.000 claims 1
• REHWTMUCNPCVOK-HXUWFJFHSA-N (3R)-3-(5-methylpyridin-3-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CC1=CN=CC(=C1)[C@@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 REHWTMUCNPCVOK-HXUWFJFHSA-N 0.000 claims 1
• VXWFWYADNINHES-HXUWFJFHSA-N (3R)-3-(6-methoxypyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)[C@@H](CC(=O)O)N1N=C(C=C1)CCCC1=NC=2NCCCC=2C=C1 VXWFWYADNINHES-HXUWFJFHSA-N 0.000 claims 1
• WWVUBEGMDOTPPR-LJQANCHMSA-N (3R)-3-(6-methoxypyridin-3-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COc1ccc(cn1)[C@@H](CC(O)=O)c1nc(CCCc2ccc3CCCNc3n2)cs1 WWVUBEGMDOTPPR-LJQANCHMSA-N 0.000 claims 1
• CGAASNMVFHAXRP-HXUWFJFHSA-N (3R)-3-(6-methoxypyridin-3-yl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)[C@@H](CC(=O)O)C=1SC=C(N=1)CCCCC1=NC=2NCCCC=2C=C1 CGAASNMVFHAXRP-HXUWFJFHSA-N 0.000 claims 1
• SXFILBGBIGGRAC-LJQANCHMSA-N (3R)-3-(6-methoxypyridin-3-yl)-3-[5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COc1ccc(cn1)[C@@H](CC(O)=O)c1ncc(CCCc2ccc3CCCNc3n2)s1 SXFILBGBIGGRAC-LJQANCHMSA-N 0.000 claims 1
• GUDIIKKLVLPESU-HSZRJFAPSA-N (3R)-3-[3-(dimethylcarbamoyl)phenyl]-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=CC=CC(=C1)[C@@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 GUDIIKKLVLPESU-HSZRJFAPSA-N 0.000 claims 1
• AABSHUYBOADMEL-OAQYLSRUSA-N (3R)-3-[4-(dimethylcarbamoyl)-3-fluorophenyl]-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=C(F)C=C(C=C1)[C@@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 AABSHUYBOADMEL-OAQYLSRUSA-N 0.000 claims 1
• JKZIDGVTCMWTAT-JOCHJYFZSA-N (3R)-3-[4-(dimethylcarbamoyl)-3-fluorophenyl]-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=C(F)C=C(C=C1)[C@@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 JKZIDGVTCMWTAT-JOCHJYFZSA-N 0.000 claims 1
• VSDHMCYRFWUCLN-HSZRJFAPSA-N (3R)-3-[4-(dimethylcarbamoyl)phenyl]-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=CC=C(C=C1)[C@@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 VSDHMCYRFWUCLN-HSZRJFAPSA-N 0.000 claims 1
• PMFSDJYOISLEPP-HXUWFJFHSA-N (3R)-3-[6-(dimethylamino)pyridin-3-yl]-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C1=CC=C(C=N1)[C@@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 PMFSDJYOISLEPP-HXUWFJFHSA-N 0.000 claims 1
• CNBKWJCVGKLONT-FQEVSTJZSA-N (3S)-3-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound OC(=O)C[C@@H](c1cnc2OCCOc2c1)n1ccc(CCCc2ccc3CCCNc3n2)n1 CNBKWJCVGKLONT-FQEVSTJZSA-N 0.000 claims 1
• JEWVDLUACRWTEW-FQEVSTJZSA-N (3S)-3-(2-ethoxypyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound CCOc1ncc(cn1)[C@H](CC(O)=O)n1ccc(CCCc2ccc3CCCNc3n2)n1 JEWVDLUACRWTEW-FQEVSTJZSA-N 0.000 claims 1
• QMBVMQULMAFHDB-FQEVSTJZSA-N (3S)-3-(2-ethoxypyrimidin-5-yl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound C(C)OC1=NC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCCCC1=NC=2NCCCC=2C=C1 QMBVMQULMAFHDB-FQEVSTJZSA-N 0.000 claims 1
• YGUFEJBKMLSYAH-MJGOQNOKSA-N (3S)-3-(2-methoxypyrimidin-5-yl)-3-[3-[3-[(2R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl]propyl]pyrazol-1-yl]propanoic acid Chemical compound COC1=NC=C(C=N1)[C@H](CC(=O)O)N1N=C(C=C1)CCC[C@H]1NC2=NC=CC=C2CC1 YGUFEJBKMLSYAH-MJGOQNOKSA-N 0.000 claims 1
• DAJVJLDTALOMRU-SFHVURJKSA-N (3S)-3-(2-methoxypyrimidin-5-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COc1ncc(cn1)[C@H](CC(O)=O)c1nc(CCCc2ccc3CCCNc3n2)cs1 DAJVJLDTALOMRU-SFHVURJKSA-N 0.000 claims 1
• IFPMYGLSHXXRFZ-IBGZPJMESA-N (3S)-3-(2-methoxypyrimidin-5-yl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=NC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCCCC1=NC=2NCCCC=2C=C1 IFPMYGLSHXXRFZ-IBGZPJMESA-N 0.000 claims 1
• ZKJMYZGFBDUOAC-FQEVSTJZSA-N (3S)-3-(2-methylpyrimidin-5-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound CC1=NC=C(C=N1)[C@H](CC(=O)O)N1N=C(C=C1)CCCC1=NC=2NCCCC=2C=C1 ZKJMYZGFBDUOAC-FQEVSTJZSA-N 0.000 claims 1
• BCBRXDHPNAOLSW-IBGZPJMESA-N (3S)-3-(2-methylpyrimidin-5-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CC1=NC=C(C=N1)[C@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 BCBRXDHPNAOLSW-IBGZPJMESA-N 0.000 claims 1
• HVDGUXVTAKZNCH-IBGZPJMESA-N (3S)-3-(3,5-dimethylpyrazol-1-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CC1=NN([C@@H](CC(O)=O)C2=NC(CCCC3=CC=C4CCCNC4=N3)=CS2)C(C)=C1 HVDGUXVTAKZNCH-IBGZPJMESA-N 0.000 claims 1
• IRRAOOUFBQNPFO-SFHVURJKSA-N (3S)-3-(3-fluoro-4-methoxyphenyl)-3-[2-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-4-yl]propanoic acid Chemical compound COC1=C(F)C=C(C=C1)[C@H](CC(O)=O)C1=CSC(CCCC2=CC=C3CCCNC3=N2)=N1 IRRAOOUFBQNPFO-SFHVURJKSA-N 0.000 claims 1
• ZDRWXUHIAQJLBM-IBGZPJMESA-N (3S)-3-(3-fluoro-4-methoxyphenyl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=C(F)C=C(C=C1)[C@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 ZDRWXUHIAQJLBM-IBGZPJMESA-N 0.000 claims 1
• YXDUBNYLAAIZFB-FQEVSTJZSA-N (3S)-3-(3-fluoro-4-methoxyphenyl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=C(F)C=C(C=C1)[C@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 YXDUBNYLAAIZFB-FQEVSTJZSA-N 0.000 claims 1
• QMQQAYAICVRTEQ-IBGZPJMESA-N (3S)-3-(3-fluoro-4-methoxyphenyl)-3-[5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=C(F)C=C(C=C1)[C@H](CC(O)=O)C1=NC=C(CCCC2=CC=C3CCCNC3=N2)S1 QMQQAYAICVRTEQ-IBGZPJMESA-N 0.000 claims 1
• LVZQWYRNDVVBAH-VWLOTQADSA-N (3S)-3-(3-morpholin-4-ylphenyl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound OC(=O)C[C@H](c1nc(CCCCc2ccc3CCCNc3n2)cs1)c1cccc(c1)N1CCOCC1 LVZQWYRNDVVBAH-VWLOTQADSA-N 0.000 claims 1
• DDEPDVDAXZTTNI-NRFANRHFSA-N (3S)-3-(5-methylpyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound CC=1C=C(C=NC=1)[C@H](CC(=O)O)N1N=C(C=C1)CCCC1=NC=2NCCCC=2C=C1 DDEPDVDAXZTTNI-NRFANRHFSA-N 0.000 claims 1
• IABHYNPYOQIKNL-FQEVSTJZSA-N (3S)-3-(6-methoxypyridin-3-yl)-3-[1-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-4-yl]propanoic acid Chemical compound COc1ccc(cn1)[C@H](CC(O)=O)c1cnn(CCCc2ccc3CCCNc3n2)c1 IABHYNPYOQIKNL-FQEVSTJZSA-N 0.000 claims 1
• VXWFWYADNINHES-FQEVSTJZSA-N (3S)-3-(6-methoxypyridin-3-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COc1ccc(cn1)[C@H](CC(O)=O)n1ccc(CCCc2ccc3CCCNc3n2)n1 VXWFWYADNINHES-FQEVSTJZSA-N 0.000 claims 1
• WWVUBEGMDOTPPR-IBGZPJMESA-N (3S)-3-(6-methoxypyridin-3-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)[C@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 WWVUBEGMDOTPPR-IBGZPJMESA-N 0.000 claims 1
• CGAASNMVFHAXRP-FQEVSTJZSA-N (3S)-3-(6-methoxypyridin-3-yl)-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCCCC1=NC=2NCCCC=2C=C1 CGAASNMVFHAXRP-FQEVSTJZSA-N 0.000 claims 1
• SXFILBGBIGGRAC-IBGZPJMESA-N (3S)-3-(6-methoxypyridin-3-yl)-3-[5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC(=CN=1)CCCC1=NC=2NCCCC=2C=C1 SXFILBGBIGGRAC-IBGZPJMESA-N 0.000 claims 1
• KWQAOJZTPSJWFI-FQEVSTJZSA-N (3S)-3-(6-methoxypyridin-3-yl)-3-[5-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound COC1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC(=CN=1)CCCCC1=NC=2NCCCC=2C=C1 KWQAOJZTPSJWFI-FQEVSTJZSA-N 0.000 claims 1
• GUDIIKKLVLPESU-QHCPKHFHSA-N (3S)-3-[3-(dimethylcarbamoyl)phenyl]-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=CC=CC(=C1)[C@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 GUDIIKKLVLPESU-QHCPKHFHSA-N 0.000 claims 1
• AABSHUYBOADMEL-NRFANRHFSA-N (3S)-3-[4-(dimethylcarbamoyl)-3-fluorophenyl]-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=C(F)C=C(C=C1)[C@H](CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 AABSHUYBOADMEL-NRFANRHFSA-N 0.000 claims 1
• JKZIDGVTCMWTAT-QFIPXVFZSA-N (3S)-3-[4-(dimethylcarbamoyl)-3-fluorophenyl]-3-[4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C)C(=O)C1=C(F)C=C(C=C1)[C@H](CC(O)=O)C1=NC(CCCCC2=CC=C3CCCNC3=N2)=CS1 JKZIDGVTCMWTAT-QFIPXVFZSA-N 0.000 claims 1
• PMFSDJYOISLEPP-FQEVSTJZSA-N (3S)-3-[6-(dimethylamino)pyridin-3-yl]-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CN(C1=CC=C(C=N1)[C@H](CC(=O)O)C=1SC=C(N=1)CCCC1=NC=2NCCCC=2C=C1)C PMFSDJYOISLEPP-FQEVSTJZSA-N 0.000 claims 1
• CNBKWJCVGKLONT-UHFFFAOYSA-N 3-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound OC(=O)CC(c1cnc2OCCOc2c1)n1ccc(CCCc2ccc3CCCNc3n2)n1 CNBKWJCVGKLONT-UHFFFAOYSA-N 0.000 claims 1
• JUEJISWKTFLIGZ-DUSLRRAJSA-N 3-(2-methoxypyrimidin-5-yl)-3-[5-[3-[(2R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl]propyl]pyrazol-1-yl]propanoic acid Chemical compound COC1=NC=C(C=N1)C(CC(=O)O)N1N=CC=C1CCC[C@H]1NC2=NC=CC=C2CC1 JUEJISWKTFLIGZ-DUSLRRAJSA-N 0.000 claims 1
• BCBRXDHPNAOLSW-UHFFFAOYSA-N 3-(2-methylpyrimidin-5-yl)-3-[4-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,3-thiazol-2-yl]propanoic acid Chemical compound CC1=NC=C(C=N1)C(CC(O)=O)C1=NC(CCCC2=CC=C3CCCNC3=N2)=CS1 BCBRXDHPNAOLSW-UHFFFAOYSA-N 0.000 claims 1
• PBWFOTQLLPUBFH-QSVWIEALSA-N 3-(2-methylpyrimidin-5-yl)-3-[5-[3-[(2R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl]propyl]pyrazol-1-yl]propanoic acid Chemical compound Cc1ncc(cn1)C(CC(O)=O)n1nccc1CCC[C@@H]1CCc2cccnc2N1 PBWFOTQLLPUBFH-QSVWIEALSA-N 0.000 claims 1
• PBWFOTQLLPUBFH-LROBGIAVSA-N 3-(2-methylpyrimidin-5-yl)-3-[5-[3-[(2S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl]propyl]pyrazol-1-yl]propanoic acid Chemical compound CC1=NC=C(C=N1)C(CC(O)=O)N1N=CC=C1CCC[C@H]1CCC2=CC=CN=C2N1 PBWFOTQLLPUBFH-LROBGIAVSA-N 0.000 claims 1
• BKTHKHWQJWMNPX-UHFFFAOYSA-N 3-(3-morpholin-4-ylphenyl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound O1CCN(CC1)C=1C=C(C=CC=1)C(CC(=O)O)N1N=C(C=C1)CCCC1=NC=2NCCCC=2C=C1 BKTHKHWQJWMNPX-UHFFFAOYSA-N 0.000 claims 1
• SPDUOUZUENXLAW-UHFFFAOYSA-N 3-(5-methoxypyrazin-2-yl)-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound C1CNC2=C(C1)C=CC(=N2)CCCC1=NN(C=C1)C(CC(=O)O)C1=CN=C(OC)C=N1 SPDUOUZUENXLAW-UHFFFAOYSA-N 0.000 claims 1
• LZTDUTCUYWTIAU-UHFFFAOYSA-N 3-(6-methoxypyridazin-3-yl)-3-[5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COc1ccc(nn1)C(CC(O)=O)n1nccc1CCCc1ccc2CCCNc2n1 LZTDUTCUYWTIAU-UHFFFAOYSA-N 0.000 claims 1
• IABHYNPYOQIKNL-UHFFFAOYSA-N 3-(6-methoxypyridin-3-yl)-3-[1-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-4-yl]propanoic acid Chemical compound COc1ccc(cn1)C(CC(O)=O)c1cnn(CCCc2ccc3CCCNc3n2)c1 IABHYNPYOQIKNL-UHFFFAOYSA-N 0.000 claims 1
• AYPNJPWKECOGBM-UHFFFAOYSA-N 3-[3-(3,5-dimethylpyrazol-1-yl)phenyl]-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound CC1=NN(C(=C1)C)C=1C=C(C=CC=1)C(CC(=O)O)N1N=C(C=C1)CCCC1=NC=2NCCCC=2C=C1 AYPNJPWKECOGBM-UHFFFAOYSA-N 0.000 claims 1
• ZVUWHFQRZDKPAU-UHFFFAOYSA-N 3-[5-(2-methoxyethoxy)pyridin-3-yl]-3-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]propanoic acid Chemical compound COCCOC=1C=C(C=NC=1)C(CC(=O)O)N1N=C(C=C1)CCCC1=NC=2NCCCC=2C=C1 ZVUWHFQRZDKPAU-UHFFFAOYSA-N 0.000 claims 1
• HISGHTPIEZQYSO-UHFFFAOYSA-N 4-[[4-[2-carboxy-1-[3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]ethyl]pyridin-2-yl]amino]butanoic acid Chemical compound OC(=O)CCCNC1=NC=CC(=C1)C(CC(O)=O)N1C=CC(CCCC2=CC=C3CCCNC3=N2)=N1 HISGHTPIEZQYSO-UHFFFAOYSA-N 0.000 claims 1
• FBLYTHMNJSRVGI-UHFFFAOYSA-N 4-[[4-[2-carboxy-1-[5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrazol-1-yl]ethyl]pyridin-2-yl]amino]butanoic acid Chemical compound OC(=O)CCCNC1=NC=CC(=C1)C(CC(O)=O)N1N=CC=C1CCCC1=CC=C2CCCNC2=N1 FBLYTHMNJSRVGI-UHFFFAOYSA-N 0.000 claims 1
• WBZRMZBFNZCTNF-UHFFFAOYSA-N N1=C(C=CC=2CCCNC12)CCCC1=NN(C=C1)C(C(=O)O)C Chemical compound N1=C(C=CC=2CCCNC12)CCCC1=NN(C=C1)C(C(=O)O)C WBZRMZBFNZCTNF-UHFFFAOYSA-N 0.000 claims 1
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
• 208000020832 chronic kidney disease Diseases 0.000 claims 1
• 239000005557 antagonist Substances 0.000 abstract description 5
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 258
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• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 68
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• 239000012267 brine Substances 0.000 description 31
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
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• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
• 238000004587 chromatography analysis Methods 0.000 description 28
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