CHOU CHIENHUNG (US)
COTTELL JEROMY J (US)
HUNG CHAO-I (US)
MITCHELL MICHAEL L (US)
SCHROEDER SCOTT D (US)
SHAPIRO NATHAN D (US)
SZEWCZYK SUZANNE M (US)
TAYLOR JAMES G (US)
WRIGHT NATHAN E (US)
ZIPFEL SHEILA M (US)
WO2021018023A1 | 2021-02-04 | |||
WO2020103815A1 | 2020-05-28 | |||
WO2022068772A1 | 2022-04-07 | |||
WO2022078152A1 | 2022-04-21 | |||
WO2022040600A1 | 2022-02-24 |
US20180170908A1 | 2018-06-21 | |||
CN113480534A | 2021-10-08 |
FOSTER: "Deuterium Isotope Effects in Studies of Drug Metabolism", TRENDS PHARMACOL. SCI., vol. 5, no. 12, 1984, pages 524 - 527, XP025943358, DOI: 10.1016/0165-6147(84)90534-0
ROWE ET AL.: "Handbook of Pharmaceutical Excipients", 2009, AMERICAN PHARMACISTS ASSOCIATION
SMITH: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2013, WILEY-INTERSCIENCE
"Introduction to Modern Liquid Chromatography", 1979, JOHN WILEY AND SONS
"Thin Layer Chromatography", 1969, SPRINGER-VERLAG
WHAT IS CLAIMED IS: 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein each R1 is (a) a phenyl substituted with one to three R4, and optionally substituted with one to four R5; or (b) a phenyl, wherein the phenyl is fused to a 5- or 6-membered ring having zero to four heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally substituted with one to five R5; ring A is , or optionally substituted with one to three RA groups, each RA is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, -OH, - CN, or N(R10a)(R10b); ring B is each of which is optionally substituted with one to three RB groups, each independently C1-6 alkyl or halogen; V is -C(R7a)(R7b)-; R2 is H, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C1-6 alkyl-C3-10 cycloalkyl, C1-6 alkyl-heterocyclyl, or C1-6 alkyl-heteroaryl, wherein the alkyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is each optionally substituted with one to four Z1, wherein each Z1 is independently C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -OH, -CN, C1-6 alkyl-CN, -O-C3-6 cycloalkyl or heteroaryl optionally substituted with 1 to 4 groups each independently C1-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy; R3 is -C(O)OR3a; R3a is H, C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-N(R9a)C(O)-O-C1-4 alkyl-OP(O)(OR9c)2, C1-4 alkyl- C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-C1-4 alkyl, -C1-4 alkyl-O-C(O)-O-C1-4alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-O-C(O)-C1-4 alkyl-OP(O)(OR9c)2, - CH2CH(N(R9a)2)C(O)OR9b, -P(O)(OR9c)2, -OP(O)(OR9c)2, -CH2P(O)(OR9c)2, - CH2OP(O)(OR9c)2, -OCH2P(O)(OR9c)2, C(O)OCH2P(O)(OR9c)2, -P(O)(R9c)(OR9d), - OP(O)(R9c)(OR9d), -CH2P(O)(R9c)(OR9d), -OCH2P(O)(R9c)(OR9d), - C(O)OCH2P(O)(R9c)(OR9d), -P(O)(N(R9c)2)2, -OP(O)(N(R9c)2)2, -CH2P(O)(N(R9c)2)2, - OCH2P(O)(N(R9c)2)2, -C(O)OCH2P(O)(N(R9c)2)2, -P(O)(N(R9c)2)(OR9d), - OP(O)(N(R9c)2)(OR9d), -CH2P(O)(N(R9c)2)(OR9d), -OCH2P(O)(N(R9c)2)(OR9d), -C(O)OCH2P(O)(N(R9c)2)(OR9d), -P(O)(R9c)(N(R9d)2), -OP(O)(R9c)(N(R9d)2), -CH2P(O)(R9c)(N(R9d)2), -OCH2P(O)(R9c)(N(R9d)2), -C(O)OCH2P(O)(R9c)(N(R9d)2), or C1-6 alkyl-heterocyclyl, wherein the alkyl or heterocyclyl is each optionally substituted with one to four halogens; each R4 is C4-9 alkyl, C1-3 hydroxyalkyl, C1-3 cyanoalkyl, C4-8 haloalkyl, C4-6 alkoxy, C4-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -O(C1-3 hydroxyalkyl), -O(C1-3 cyanoalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), - O(heteroaryl), -C(O)-R10a, -C(O)O-R10a, -C(O)-N(R10a)(R10b), -N(R10a)(R10b), - N(R10a)2(R10b)+, -N(R10a)C(O)-R10b, -N(R10a)C(O)O-R10b, -N(R10a)C(O)N(R10b)(R10c), - N(R10a)S(O)2(R10b),-NR10aS(O)2N(R102b)(R10c), -N R10aS(O)2O(R10b), -OC(O) R10a, - OC(O)O R10a, -OC(O)-N(R10a)(R10b), -S- R10a, -S(O) R10a, -S(O)(NH) R10a, -S(O)2 R10a, -S(O)2N(R10a)(R10b), -S(O)(N R10a) R10b, or -Si(R10a)3, wherein each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to four R6a; each R5 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b),-N(R12a)(R12b), -N(R12a)2(R12b)+, -N(R12a)C(O)- R12b, -N(R12a)C(O)O-R12b, -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), - NR12aS(O)2N(R12b)(R12c), -NR12aS(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)- N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), - S(O)(NR12a)R12b, or -Si(R12a)3, wherein each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to four R6a; each R6a is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O- R10a, -C(O)- R10a, -C(O)O- R10a, -C(O)-N(R10a)(R R10b),-N(R10a)(R10b), -N(R10a)2(R10b)+, -N(R10a)C(O)- R10b, -N(R10a)C(O)O- R10b, -N(R10a)C(O)N(R10b)(R10c), -N(R10a)S(O)2(R10b), -N R10aS(O)2N(R10b)(R10c), -N R10aS(O)2O(R10b), -OC(O) R10a, -OC(O)O R10a, -OC(O)- N(R10a)(R10b), -S-R10a, -S(O) R10a, -S(O)(NH) R10a, -S(O)2 R10a, -S(O)2N(R10a)(R10b), - S(O)(N R10a) R10b, or -Si(R10a)3, wherein each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R6b; each R6b is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl)2, -N(heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10 aryl), -C(O)(heteroaryl), -C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), - C(O)O(heterocyclyl), -C(O)O(C6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(heterocyclyl), -S(C6-10 aryl), -S(heteroaryl), -S(O)N(C1-9 alkyl)2, - S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10 aryl), -S(O)(heteroaryl), -S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2- 6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H,-O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), - O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), - NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), - S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2, wherein the alkyl or heterocyclyl is each optionally substituted with one to four halogens; each R7a and R7b is independently -H, C1-6 alkyl, or halogen; each R9a and R9b is independently H, C1-6 alkyl, or C1-6 haloalkyl, or R9a and R9b together form a 6-membered heterocyclyl; each R9c, R9d, R10a, R10b, and R10c is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four R6b; wherein each heterocyclyl has three to twelve ring members and has one to four heteroatoms, each independently N, O, or S; and wherein each heteroaryl has five to twelve ring members and one to four heteroatoms, each independently N, O, or S. 2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is a phenyl substituted with one to three R4 and optionally substituted with one to four R5. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl, wherein the phenyl is fused to a 5- or 6-membered ring having zero to four heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally substituted with one to five R5. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl fused to a 5-membered ring having one to four heteroatoms, each independently N, O, or S, to form the fused ring system, wherein the fused ring system is optionally substituted with one to five R5. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted with one to five R5. 6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl fused to a 6-membered ring having one to four heteroatoms, each independently N, O, or S, to form the fused ring system, wherein the fused ring system is optionally substituted with one to five R5. 7. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is , which is optionally subisuted with one to three RA. 8. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is . 9. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein V is -CH2-. 10. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is , which is optionally substituted with one to three groups, each independently C1-6 alkyl or halogen. 11. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkyl, C1-6 alkyl-C3-10 cycloalkyl, heterocyclyl, or C1-6 alkyl-heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with one to three Z1, each independently C1-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl-heteroaryl. 12. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is 13. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is . 14. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is -C(O)OH. 15. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R4 is C1-3 hydroxyalkyl, C4-8 haloalkyl, C2-6 alkoxyalkyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, heteroaryl, -C(O)N(R10a)(R10b), or -S(O)2R10a. 16. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently C1-9 alkyl, C1-3 hydroxyalkyl, C1-3 cyanoalkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, oxo, -NO2, -N3, -CN, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, -C(O)-R10a, -C(O)O-R10a,- C(O)-N(R10a)(R10b), N(R10a)(R10b), -N(R10a)2(R10b)+, OC(O)R10a, -OC(O)OR10a, OC(O)- N(R10a)(R10b), -S-R10a, S(O)R10a, -S(O)(NH)R10a,or -S(O)2R10a. 17. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently C1-9 alkyl, C1-3 hydroxyalkyl, C1-8 haloalkyl, C1-6 alkoxy, C3-15 cycloalkyl, C6-10 aryl, heteroaryl, halogen, -CN, -C(O)-N(R10a)(R10b), or -S(O)2R10a. 18. The compound or any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, halogen, or -CN. 19. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently a H, C1-9 alkyl, halogen, haloalkyl, oxo, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl. 20. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R6a is independently C1-9 alkyl, halogen, oxo, haloalkyl, C3-15 cycloalkyl, or heteroaryl. 21. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, having the structure of a compound in Table 2. 22. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 23. The pharmaceutical composition of claim 22 further comprising one or more additional therapeutic agents. 24. The pharmaceutical composition of claim 22 for use in treating a glucagon-like peptide 1 receptor (GLP-1R) mediated disease or condition. 25. A method of treating GLP-1R mediated disease or condition comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof. 26. The method of claim 25, wherein the disease or condition comprises a liver disease. 27. The method of claim 26, wherein the disease or condition comprises liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, Primary Biliary Cirrhosis (PBC), or Primary Sclerosing Choleangitis (PSC). 28. The method of claim 27, wherein the disease or condition comprises non- alcoholic fatty liver disease (NAFLD). 29. The method of claim 27, wherein the disease or condition comprises non- alcoholic steatohepatitis (NASH). 30. The method of claim 25, wherein the disease or condition comprises a metabolic disease. 31. The method of claim 30, wherein the disease or condition comprises type 1 diabetes, type 2 diabetes, pre-diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, maturity onset diabetes of the young, early onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson’s Disease, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, vascular restenosis, dementia, or Alzheimer’s disease. 32. The method of any one of claims 25-31, wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent. 33. The pharmaceutical composition of claim 23 or the method of claim 32, wherein the additional therapeutic agent comprises an anti-obesity agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 agonist, an NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (MC4R) (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), apoptotic signal-regulating kinase (ASK-1) inhibitor, zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine/dopamine reuptake inhibitor (e.g., buproprion), an opioid receptor antagonist (e.g., naltrexone), a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and analogues thereof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin), a serotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or in combination with another GLP-1 R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a TGFβ antagonist, GFRAL agonist, and/or a pharmaceutically acceptable salt thereof. 34. A method for manufacturing a medicament for treating a GLP-1R mediated disease or condition in a human in need thereof, characterized in that a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, is used. 35. Use of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a GLP-1R mediated disease or condition. 36. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, for use in treating a GLP-1R mediated disease or condition in a human in need thereof. |
Scheme 2 Intermediate 2.1 may be assembled by reacting an intermediate of the type 1.3 with 2-chloro-1,1,1-trimethoxyethane in the presence of a suitable acid (e.g., pTSA, HCl, AcOH, etc.). Scheme 3 Intermediate 3.7 may be assembled by first reacting an intermediate of the type 3.1 where Z is –CH=, -CX=, or -N=, X 1 is a halogen or suitable leaving group (e.g., -SO 2 Me), and X 2 is a halogen with a suitable alcohol of the type 3.2 in the presence of a suitable base (e.g., DIPEA, KOtBu, NaH, Cs2CO3 etc.) or transition metal catalyst (e.g., RockPhos Pd G3, JohnPhos and Pd(OAc) 2 , etc.) with a base (e.g., Cs 2 CO 3 , K 2 CO 3 , etc.) to give intermediate 3.3. 3.3 can then be converted to 3.5 via coupling with an intermediate of the type 3.4 where M is a suitable metal species (e.g., -B(OH)2, -B-pinacol, -SnBu3, etc.) and Pg is a suitable amine protecting group (e.g., Boc) using a transition metal catalyst (e.g., Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , etc.) and a suitable base (e.g., Cs 2 CO 3 , K 2 CO 3 , etc.). 3.5 can then be converted to 3.6 via H 2 atmosphere and a suitable reduction catalyst (e.g., Pd/C, Pd(OH)2, PtO2, etc.) which can then be deprotected to intermediate 3.7 via acid treatment (e.g., TFA, HCl, etc.). Scheme 4 Alternately, intermediate 3.7 may be as,sembled by first converting 4.1 and 3.4 to intermediate 4.2 using a transition metal catalyst (e.g., Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , etc.) and a suitable base (e.g., Cs 2 CO 3 , K 2 CO 3 , etc.). 4.2 can be converted to 4.3 via H 2 atmosphere and a suitable reduction catalyst (e.g., Pd/C, Pd(OH)2, PtO2, etc.) after which intermediate 3.6 can be obtained through the reaction of 4.3 with intermediate 4.4 in the presence of a suitable base (e.g., Cs 2 CO 3 , Ag 2 CO 3 , etc.). 3.7 can be obtained from 3.6 as previously described. Intermediate 5.3 may first be assembled by reacting an intermediate of the type 3.3 where X 2 is a halogen with a suitably protected (e.g., Boc) piperazine of the type 5.1 in the presence of a suitable base (e.g., Cs 2 CO 3 ), transition metal catalyst (e.g., Pd 2 (dba) 3 )) and a ligand (e.g., BINAP) to give intermediate 5.2. 5.2 can then be deprotected to intermediate 5.3 via acid treatment (e.g., TFA, HCl, etc.). Scheme 6 Intermediate 6.4 may be assembled by reacting an amine with Intermediate 6.1, wherein X is a halide R is an alkyl, alkylaryl, or aryl, in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to give Intermediate 6.2. Intermediate 6.2 can be converted to Intermediate 6.3 using suitable reducing conditions (e.g., H 2 and Pd/C, Fe and HCl, etc.). Intermediate 6.4 can then be obtained through the reaction of 6.3 with 2-chloro-1,1,1-trimethoxyethane in the presence of a suitable acid (e.g., pTSA, HCl, AcOH, etc.). Scheme 7 Intermediate 7.4 may be assembled by reacting an amine with Intermediate 7.1, wherein X is a halide R is an alkyl, alkylaryl, or aryl, in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to give Intermediate 7.2. Intermediate 7.2 can be converted to Intermediate 7.3 using suitable reducing conditions (e.g., H 2 and Pd/C, Fe and HCl, etc.). Intermediate 7.4 can then be obtained through the reaction of 7.3 with 2-chloro-1,1,1-trimethoxyethane in the presence of a suitable acid (e.g., pTSA, HCl, AcOH, etc.). Scheme 8 Compounds of the 8.3 may be assembled by first reacting intermediates of the type 3.7 and 6.4 the the presence of a suitable base (e.g., Cs 2 CO 3 , K 2 CO 3 , etc.) to give intermediate 8.1. 8.1 can then be coupled with a metallated species of the type R11-M wherein M represents a suitable metal (e.g., -B(OH) 2 , -B-pinacol, -SnBu 3 , etc.) in the presence of a suitable transition metal catalyst (e.g., Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , etc.) and a suitable base (e.g., Cs2CO3, K2CO3, etc.) to give intermediate 8.2. Filly treatment of 8.2 with a suitable source of - OH (e.g., KOH, LiOH, etc.) when R is -Me or -Et or with a suitable acid (e.g., HCl, TFA, etc.) when R is -tBu will yield compound 8.3. IV. PHARMACEUTICAL FORMULATIONS In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments of the disclosure, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, as more fully set forth below. Pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice. Tablets may contain excipients including glidants, fillers, binders and the like. Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. In some embodiments, compositions may contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. In some embodiments, the composition is provided as a solid dosage form, including a solid oral dosage form. The compositions include those suitable for various administration routes, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if desired, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006. Compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, sachets or tablets each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition of the disclosure is a tablet. Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. The amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient varies from about 5 to about 95% of the total compositions (weight:weight). In some embodiments, a composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that compositions comprising a compound of the present disclosure in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure. It is also understood that any of the methods, kits, articles of manufacture and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure. In some embodiments, the pharmaceutical compositions described above are for use in a human or an animal. The disclosure further includes a compound of the present disclosure for administration as a single active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and/or inorganic carrier or excipient, or by mixing therewith. In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in known drugs, or administration of the compound of the present disclosure together with such drugs. The compound of the present disclosure may also be used in the form of a prodrug or other suitably modified form which releases the active ingredient in vivo. V. ROUTES OF ADMINISTRATION The compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally. A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life. The dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician. The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily. The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day. A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In some embodiments, a single dose can be administered once every week. A single dose can also be administered once every month. Kits that comprise a compound of the present disclosure, or an enantiomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above, are also included in the present disclosure. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, such as the diseases or conditions, described herein. In one embodiment, kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided. Provided herein are also articles of manufacture that include a compound of the present disclosure or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag. VI. COMBINATION THERAPY In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In some embodiments, the additional therapeutic agent comprises an apoptotic signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a TGFβ antagonist, a LPAR antagonist, a SGLT2 inhibitor, a Tpl2 inhibitor, or a GLP-1 agonist combination thereof. The benefit of combination may be increased efficacy and/or reduced side effects for a component as the dose of that component may be adjusted down to reduce its side effects while benefiting from its efficacy augmented by the efficacy of the compound of the present disclosure. In some embodiments, the therapeutic agent, or combination of therapeutic agents, are a(n) ACE inhibitor, 2-Acylglycerol O-acyltransferase 2 (DGAT2) inhibitor, Acetaldehyde dehydrogenase inhibitor, Acetyl CoA carboxylase inhibitor, Adrenergic receptor agonist, Alstrom syndrome protein 1(ALMS1)/PKC alpha protein interaction inhibitor, Apelin receptor agonist, Diacylglycerol O acyltransferase 2 inhibitor, Adenosine A3 receptor agonist, Adenosine A3 receptor antagonist, Adiponectin receptor agonist, Aldehyde dehydrogenase 2 stimulator, AKT protein kinase inhibitor, AMP-activated protein kinases (AMPK), AMP kinase activator, ATP citrate lyase inhibitor, AMP activated protein kinase stimulator, Endothelial nitric oxide synthase stimulator, NAD-dependent deacetylase sirtuin-1 stimulator, Adrenergic receptor antagonist, Androgen receptor agonist, Amylin receptor agonist, Angiotensin II AT-1 receptor antagonist, Apical sodium-dependent bile acid transport inhibitor, Autophagy protein modulator, Autotaxin inhibitors, Axl tyrosine kinase receptor inhibitor, Bax protein stimulator, Beta-catenin inhibitor, Bioactive lipid, Calcitonin agonist, Cannabinoid receptor modulator, Caspase inhibitor, Caspase-3 stimulator, Cathepsin inhibitor, Caveolin 1 inhibitor, CCK receptor antagonist, CCL26 gene inhibitor, CCR2 chemokine antagonist, CCR2 chemokine antagonist, Angiotensin II AT-1 receptor antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, CD3 antagonist, CDGSH iron sulfur domain protein modulator, chitinase inhibitor, Chloride channel stimulator, Chitotriosidase 1 inhibitor, CNR1 inhibitor, Connective tissue growth factor ligand inhibitor, COT protein kinase inhibitor, Cyclin D1 inhibitor, Cytochrome P4507A1 inhibitor, Cytochrome P450 reductase inhibitors, DGAT1/2 inhibitor, Diacylglycerol O acyltransferase 1 inhibitor (DGAT1), Cytochrome P4502E1 inhibitor (CYP2E1), CXCR3 chemokine antagonist, CXCR4 chemokine antagonist, Dihydroceramide delta 4 desaturase inhibitor, Dihydroorotate dehydrogenase inhibitor, Dipeptidyl peptidase IV inhibitor, Endosialin modulator, Eotaxin ligand inhibitor, Extracellular matrix protein modulator, Farnesoid X receptor agonist, Fatty acid synthase inhibitors, FGF1 receptor agonist, Fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, fibroblast activation protein inhibitor, Free fatty acid receptor 1 agonist, Galectin-3 inhibitor, GDNF family receptor alpha like agonist, Glucagon receptor agonist, Glucagon-like peptide 1 agonist, Glucocorticoid receptor antagonist, Glucose 6-phosphate 1-dehydrogenase inhibitor, G-protein coupled bile acid receptor 1 agonist, G- protein coupled receptor-119 agonist, G-protein coupled receptor 84 antagonist, Hedgehog (Hh) modulator, Hepatitis C virus NS3 protease inhibitor, Hepatocyte nuclear factor 4 alpha modulator (HNF4A), Hepatocyte growth factor modulator, Histone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, HSD17B13 gene inhibitor, 5-HT 2a receptor antagonist, Hydrolase inhibitor, Hypoxia inducible factor-2 alpha inhibitor, IL-10 agonist, IL-17 antagonist, IL-22 agonist, Ileal sodium bile acid cotransporter inhibitor, Insulin sensitizer, Insulin ligand agonist, Insulin receptor agonist, integrin modulator, Integrin Antagonist, Integrin alpha-V/beta-1 antagonist, Integrin alpha-V/beta-6 antagonist, intereukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, IL-6 receptor agonist, interleukin 17 ligand inhibitor, Jak2 tyrosine kinase inhibitor, Jun N terminal kinase-1 inhibitor, Kelch like ECH associated protein 1 modulator, Ketohexokinase (KHK) inhibitor, Klotho beta stimulator, Leukotriene A4 hydrolase inhibitor, 5-Lipoxygenase inhibitor, Lipoprotein lipase inhibitor, Liver X receptor, LPL gene stimulator, Lysophosphatidate-1 receptor antagonist, Lysyl oxidase homolog 2 inhibitor, LXR inverse agonists, Macrophage mannose receptor 1 modulator, Matrix metalloproteinases (MMPs) inhibitor, MEKK-5 protein kinase inhibitor, MCH receptor-1 antagonist, Membrane copper amine oxidase (VAP-1) inhibitor, Methionine aminopeptidase-2 inhibitor, Methyl CpG binding protein 2 modulator, MicroRNA-132 (miR-132) antagonist, MicroRNA-21(miR-21) inhibitor, Mitochondrial uncoupler, Mixed lineage kinase-3 inhibitor, Motile sperm domain protein 2 inhibitor, Myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), NFE2L2 gene inhibitor, Nicotinic acid receptor 1 agonist, Opioid receptor mu antagonist, P2Y13 purinoceptor stimulator, Nuclear erythroid 2-related factor 2 stimulator, Nuclear receptor modulators, Nuclear transport of transcription factor modulator, P2X7 purinoceptor modulator, PACAP type I receptor agonist, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, Phenylalanine hydroxylase stimulator, Phospholipase C inhibitor, Phosphoric diester hydrolase inhibitor, PPAR alpha agonist, PPAR delta agonist, PPAR gamma agonist, Peptidyl-prolyl cis-trans isomerase A inhibitor, PNPLA3 gene inhibitor, PPAR gamma modulator, Protease-activated receptor-2 antagonist, Protein kinase modulator, Protein NOV homolog modulator, PTGS2 gene inhibitor, renin inhibitor, Resistin/CAP1 (adenylyl cyclase associated protein 1) interaction inhibitor, Rho associated protein kinase inhibitor, RNA polymerase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitor, Sodium glucose transporter-2 inhibitor, Sphingolipid delta 4 desaturase DES1 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, Stearoyl CoA desaturase-1 inhibitor, STK25 inhibitor, Suppressor of cytokine signalling-1 stimulator, Suppressor of cytokine signalling-3 stimulator, Taste receptor type 2 agonist, Telomerase stimulator, TERT gene modulator, TGF beta (TGFB1) ligand inhibitor, TNF antagonist, Transforming growth factor β (TGF-β), Transforming growth factor β activated Kinase 1 (TAK1), Thyroid hormone receptor beta agonist, TLR-4 antagonist, Transglutaminase inhibitor, Tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, TLR-9 antagonist, VDR agonist, Vitamin D3 receptor modulators, WNT modulators, YAP/TAZ modulator or a Zonulin inhibitor, and combinations thereof. Non-limiting examples of the one or more additional therapeutic agents include: - ACE inhibitors, such as enalapril; - Acetaldehyde dehydrogenase inhibitors, such as ADX-629; - Acetyl CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, PF-05221304; - Acetyl CoA carboxylase/Diacylglycerol O acyltransferase 2 inhibitors, such as PF- 07055341; - Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101 (piclidenoson), CF-502, CGS21680; - Adenosine A3 receptor antagonist, such as FM-101; - Adiponectin receptor agonists, such as ADP-355, ADP-399, ALY668-SR; - Adrenergic receptor antagonist, such as bromocriptine, phentermine, VI-0521; - Aldehyde dehydrogenase 2 stimulators, such as FP-045; - Amylin/calcitonin receptor agonists, such as KBP-042, KBP-089; - AMP activated protein kinase stimulators, such as C-455, PXL-770, O-304; - AMP kinase activators/ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016); - AMP activated protein kinase/Endothelial nitric oxide synthase/NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil); - Androgen receptor agonists, such as LPCN-1144, LPCN-1148, testosterone prodrug; - Angiotensin II AT-1 receptor antagonists, such as irbesartan; - Angiopoietin-related protein-3 inhibitors, such as vupanorsen (IONIS-ANGPTL3-LRx); - Apelin receptor agonist, such as CB-5064, MBT-2; - Apical sodium-dependent bile acid transport inhibitors, such as A-3907; - Autophagy protein modulators, such as A-2906, GM-90194; - Autotaxin (ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors, such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC- 0265, TJC-0316, AM-063, BBT-877; - Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428); - Bax protein stimulators, such as CBL-514; - Bioactive lipids, such as DS-102; - Cannabinoid receptor modulators, such as namacizumab (nimacimab), GWP-42004, REV-200, CRB-4001, INV-101, SCN-002; - Caspase inhibitors, such as emricasan; - Pan cathepsin B inhibitors, such as VBY-376; - Pan cathepsin inhibitors, such as VBY-825; - CCK receptor antagonist, such as proglumide; - CCL26 gene inhibitor, such as mosedipimod, KDDF-201410-10; - CCR2/CCR5 chemokine antagonists, such as BMS-687681, cenicriviroc, maraviroc, CCX-872, leronlimab, WXSH-0213; - CCR2/CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc); - CCR2 chemokine antagonists, such as propagermanium; - CCR2 chemokine/Angiotensin II AT-1 receptor antagonists, such as DMX-200, DMX- 250; - CCR3 chemokine antagonists, such as bertilimumab; - CD3 antagonists, such as NI-0401 (foralumab); - CDGSH iron sulfur domain protein modulators, such as EYP-002; - Chitinase inhibitor, such as OATD-01; - Chitotriosidase 1 inhibitors, such as OAT-2068; - Chloride channel stimulators, such as cobiprostone, and lubiprostone; - Casein kinase-1 (CK1) delta/epsilon inhibitors, such as PF-05006739; - Connective tissue growth factor ligand inhibitor, such as PBI-4050; - COT protein kinase inhibitors, such as GS-4875, GS-5290; - CXCR4 chemokine antagonists, such as AD-214; - Cytochrome P450 reductase inhibitors, such as SNP-630; - Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx, PF- 06865571; - Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; - Diacylglycerol O acyltransferase 1 (DGAT1)/Cytochrome P4502E1 inhibitors (CYP2E1), such as SNP-610; - Dihydroorotate dehydrogenase inhibitor, such as vidofludimus; - Dipeptidyl peptidase IV inhibitors, such as linagliptin, evogliptin; - Eotaxin ligand inhibitors, such as bertilimumab, CM-101; - Extracellular matrix protein modulators, such as CNX-024; - Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, obeticholic acid, Px-102, Px- 103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, vonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, HPD-001, alendronate; - Farnesoid X receptor (FXR)/G-protein coupled bile acid receptor 1(TGR5) agonists, such as INT-767; - Fatty acid synthase inhibitors, such as TVB-2640, FT-8225; - Fibroblast growth factor 19 (rhFGF19)/cytochrome P450 (CYP) 7A1 inhibitors, such as aldafermin (NGM-282); - Fibroblast growth factor 21(FGF-21) ligand modulators, such as AP-025, BMS-986171, B-1654, BIO89-100, BOS-580, Pegbelfermin (BMS-986036), B-1344, NN-9499; - Fibroblast growth factor 21 (FGF-21)/glucagon like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241), efruxifermin (AKR-001); - FGF receptor agonists/Klotho beta stimulators, such as BFKB-8488A (RG-7992); - Free fatty acid receptor 1 agonist, such as SCO-267; - Galectin-3 inhibitors, such as belapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400), IMT-001; - GDNF family receptor alpha like agonist, such as NGM-395; - Glucagon-like peptide 1 (GLP1R) agonists, such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH- GLP1, RPC-8844, PB-718, PF-06882961, semaglutide; - Glucagon-like peptide 1 receptor agonist; Oxyntomodulin ligand; Glucagon receptor agonist, such as efinopegdutide; - Gastric inhibitory polypeptide/Glucagon-like peptide-1 (GIP/GLP-1) receptor co-agonist, such as tirzepatide (LY-3298176); - PEGylated long-acting glucagon-like peptide-1/glucagon (GLP-1R/GCGR) receptor dual agonist, such as DD-01; - Glucagon/GLP1-receptor agonist, such as BI-456906, NN-6177; - Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant); - Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001; - Glucokinase stimulator, such as dorzagliatin, sinogliatin (RO-5305552); - G-protein coupled bile acid receptor 1(TGR5) agonists, such as RDX-009, INT-777, HY-209; - G-protein coupled receptor 84 antagonist, such as PBI-4547; - G-protein coupled receptor-119 agonist, such as DA-1241; - Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201; - Hedgehog protein TGF beta ligand inhibitors, such as Oxy-210; - Histone deacetylase^inhibitors/STAT-3 modulators, such as SFX-01; - HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; - HSD17B13 gene inhibitor, such as ALN-HSD, ARO-HSD; - Hydrolase inhibitor, such as ABD-X; - Hypoxia inducible factor-2 alpha inhibitors, such as PT-2567; - IL-10 agonists, such as peg-ilodecakin; - Ileal sodium bile acid cotransporter inhibitors, such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, elobixibat (A-3309); - Insulin sensitizers, such as, KBP-042, azemiglitazone potassium (MSDC-0602K), ION- 224, MSDC-5514, Px-102, RG-125 (AZD4076), Tolimidone, VVP-100X, CB-4211, ETI-101; - Insulin ligand/dsInsulin receptor agonists, such as ORMD-0801; - Integrin antagonists, such as IDL-2965; - IL-6 receptor agonists, such as KM-2702; - Integrin alpha-V/beta-6 and alpha-V/beta-1 dual inhibitor; such as PLN-74809; - Interleukin 17 ligand inhibitor, such as netakimab; - Jak1/2 tyrosine kinase inhibitor, such as baricitinib; - Jun N terminal kinase-1 inhibitor, such as CC-90001; - Kelch like ECH associated protein 1 modulator, such as alpha-cyclodextrin-stabilized sulforaphane; - Ketohexokinase (KHK) inhibitors, such as PF-06835919, LY-3478045, LY-3522348; - beta Klotho (KLB)- FGF1c agonists, such as MK-3655 (NGM-313); - Leukotriene A4 hydrolase inhibitor, such as LYS-006; - 5-Lipoxygenase inhibitors, such as tipelukast (MN-001), epeleuton (DS-102, (AF-102); - Lipoprotein lipase inhibitors, such as CAT-2003; - LPL gene stimulators, such as alipogene tiparvovec; - Liver X receptor (LXR) inhibitors, such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238; - Lysophosphatidate-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198; - Lysyl oxidase homolog 2 inhibitors, such as simtuzumab, PXS-5382A (PXS-5338); - Macrophage mannose receptor 1 modulators, such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); - Matrix metalloprotease inhibitors, such as ALS-L1023; - Membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201, TT-01025; - MEKK-5 protein kinase (ASK-1) inhibitors, such as CJ-16871, CS-17919, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301; - MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158); - Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1 (SSAO/VAP-1) Inhibitors, such as PXS-4728A (BI-1467335); - Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, ZN-1345; - Methyl CpG binding protein 2 modulators, such as mercaptamine; - Mineralocorticoid receptor antagonists (MCRA), such as MT-3995 (apararenone); - Mitochondrial uncouplers, such as 2,4-dinitrophenol, HU6, Mito-99-0053; - Mixed lineage kinase-3 inhibitors, such as URMC-099-C; - Motile sperm domain protein 2 inhibitors, such as VB-601; - Myelin basic protein stimulators, such as olesoxime; - Myeloperoxidase inhibitors, such as PF-06667272, AZM-198; - NADPH oxidase inhibitors, such as GKT-831, GenKyoTex, APX-311, setanaxib; - Nicotinic acid receptor 1 agonists, such as ARI-3037MO; - NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349); - NFE2L2 gene inhibitor, such as GeRP-amiR-144; - Nuclear transport of transcription factor modulators, such as AMTX-100; - Nuclear receptor modulators, such as DUR-928 (DV-928); - Opioid receptor mu antagonists, such as methylnaltrexone; - P2X7 purinoceptor modulators, such as SGM-1019; - P2Y13 purinoceptor stimulators, such as CER-209; - PDE 3/4 inhibitors, such as tipelukast (MN-001); - PDE 5 inhibitors, such as sildenafil, MSTM-102; - PDGF receptor beta modulators, such as BOT-191, BOT-509; - Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, NV-556 (NVP-025); - Phenylalanine hydroxylase stimulators, such as HepaStem; - Phosphoric diester hydrolase inhibitor, such as ZSP-1601; - PNPLA3 gene inhibitor, such as AZD-2693; - PPAR agonists, such as Chiglitazar, elafibranor (GFT-505), seladelpar lysine (MBX- 8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), saroglitazar, lanifibranor (IVA-337), CHS-131, pemafibrate (K-877), ZG-0588, ZSP- 0678; ZSYM-008; - Protease-activated receptor-2 antagonists, such as PZ-235; - Protein kinase modulators, such as CNX-014; - Protein NOV homolog modulators, such as BLR-200; - PTGS2 gene inhibitors, such as STP-705, STP-707; - Renin inhibitors, such as PRO-20; - Resistin/CAP1 (adenylyl cyclase associated protein 1) interaction inhibitors, such as DWJ-211; - Rev protein modulator, such as ABX-464; - Rho associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325), KD-025, RXC-007, TDI-01; - RNA polymerase inhibitors, such as rifaximin; - Snitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; - Sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, sotagliflozin; - Sodium glucose transporter-1/2 (SGLT 1/2) inhibitors, such as licogliflozin bis(prolinate) (LIK-066); - SREBP transcription factor inhibitors, such as CAT-2003, HPN-01, MDV-4463; - Stearoyl CoA desaturase-1 inhibitors, such as aramchol; - Taste receptor type 2 agonists, such as ARD-101; - Thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101; CNPT-101207, CS-27186, KY-41111, resmetirom (MGL-3196), MGL-3745, TERN- 501, VK-2809, HP-515; - TLR-2/TLR-4 antagonists, such as VB-201 (CI-201); - TLR-4 antagonists, such as JKB-121, JKB-122, naltrexone; - Tyrosine kinase receptor modulators, such as CNX-025, GFE-2137 (repurposed nitazoxanide); - TLR-9 antagonist, such as GNKS-356, AVO-101; - TNF antagonist, such as ALF-421; - GPCR modulators, such as CNX-023; - Nuclear hormone receptor modulators, such as Px-102; - VDR agonist, such as CK-15; - Xanthine oxidase inhibitors, such as ACQT-1127; - Xanthine oxidase/Urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; or - Zonulin Inhibitors, such as larazotide acetate (INN-202). In certain specific embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, anti-CXCR3 antibodies, anti-TAGE antibody, aramchol, ARI-3037MO, ASP-8232, AXA-1125, bertilimumab, Betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT- 053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER- 209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran etexilate mesylate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, edaravone (TTYP-01), EDP- 305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS- 300, GS-4997, GS-9674, GS-4875, GS-5290, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide, icosabutate (PRC-4016), icosapent ethyl ester, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2Rx, ipragliflozin, Irbesarta, propagermanium, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP- 042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) tropifexor, LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB- N-008, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC- 0602K, namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, norursodeoxycholic acid, NV-422, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505, PAT-048, peg- ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS- 4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RP-005, RPI-500, S-723595, saroglitazar, SBP-301, semaglutide, SH-2442, SHC- 028, SHC-023, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, TQA-3526, TQA- 3563, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-611, TXR-612, TS-20004, UD-009, UN-03, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, volixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, XZP-5610, ZGN-839, ZG- 5216, ZSYM-008, or ZYSM-007. In some embodiments, the compound of the present disclosure is combined with one or more thereapeutic agents selected from an anti-obesity agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 agonist, an NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a famesoid X receptor (FXR) agonist (e.g., obeticholic acid), apoptotic signal-regulating kinase (ASK-1) inhibitor, zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine/dopamine reuptake inhibitor (e.g., buproprion), an opioid receptor antagonist (e.g., naltrexone), a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and analogues thereof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin), a serotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or in combination with another GLP-1 R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), an insulin sensitizer such as thiazolidinediones (TZDs), a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a transforming growth factor beta (TGFβ) antagonist, a GDNF family receptor alpha like (GFRAL) agonist, a melanocortin-4 receptor (MC4R) agonist, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts. VII. METHODS OF TREATMENT In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salt thereof, are useful in a method of treating and/or preventing a GLP-1R mediated disease or condition. In some embodiments, a method for treating and/or preventing a GLP-1R mediated disease or condition includes administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition comprises a liver disease or related diseases or conditions, e.g., liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, Primary Biliary Cirrhosis (PBC), or Primary Sclerosing Cholangitis (PSC). In some embodiments, the disease or condition comprises a metabolic disease or related diseases or conditions, such as diabetes mellitus, obesity, or cardiometabolic diseases. GLP-1R agonists are currently being investigated in connection with certain disorders and conditions, including for example diabetes. GLP-1 analogs that are DPP4 resistant and have longer half-lives than endogenous GLP-1 have been reported to be associated with weight loss and improved insulin action. Liraglutide, a peptide GLP-1R agonist approved in connection with treatment of diabetes, has been reported to show favorable improvements in outcomes in NASH subjects. In some embodiments, the present disclosure relates to the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of a disease or condition mediated by GLP-1R, such as a liver disease or metabolic disease. In some embodiments, the present disclosure relates to the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of a disease or condition mediated by GLP-1R, such as a liver disease or metabolic disease. For example, some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a use thereof, for treatment and/or prevention of chronic intrahepatic or some forms of extrahepatic cholestatic conditions, of liver fibrosis, of acute intraheptic cholestatic conditions, of obstructive or chronic inflammatory disorders that arise out of improper bile composition, of gastrointestinal conditions with a reduced uptake of dietary fat and fat-soluble dietary vitamins, of inflammatory bowel diseases, of lipid and lipoprotein disorders, of type II diabetes and clinical complications of type I and type II diabetes, of conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to enforced lipid and specifically triglyceride accumulation and subsequent activation of profibrotic pathways, of obesity and metabolic syndrome (combined conditions of dyslipidemia, diabetes and abnormally high body-mass index), of acute myocardial infarction, of acute stroke, of thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis, of persistent infections by intracellular bacteria or parasitic protozoae, of non-malignant hyperproliferative disorders, of malignant hyperproliferative disorders, of colon adenocarcinoma and hepatocellular carcinoma for instance, of liver steatosis and associated syndromes, of liver failure or liver malfunction as an outcome of chronic liver diseases or of surgical liver resection, of Hepatitis B infection, of Hepatitis C infection and/or of cholestatic and fibrotic effects that are associated with alcohol-induced cirrhosis or with viral- borne forms of hepatitis, of type I diabetes, pre-diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, maturity onset diabetes of the young, early onset diabetes, malnutrition- related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post- prandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson’s Disease, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, or vascular restenosis. In some embodiments, a method of treating and/or preventing a non-alcoholic fatty liver disease (NAFLD), comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The disclosure also relates to a compound according to Formula (I) or a pharmaceutical composition comprising said compound for preventive and posttraumatic treatment of a cardiovascular disorder, such as acute myocardial infarction, acute stroke, or thrombosis which occur as an endpoint of chronic obstructive atherosclerosis. In some embodiments, a method for treating and/or preventing cardiovascular disorder comprises administering a compounds of Formula (I) to a subject in need thereof. The disclosure further relates to a compound or pharmaceutical composition for the treatment and/or prevention of obesity and associated disorders such as metabolic syndrome (combined conditions of dyslipidemias, diabetes and abnormally high body-mass index) which can be overcome by GLP1R-mediated lowering of serum triglycerides, blood glucose and increased insulin sensitivity and GLP1R-mediated weight loss. In some embodiments, a method for treating and/or preventing a metabolic disease comprises administering a compounds of Formula (I) to a subject in need thereof. In some embodiments, a method for treating and/or preventing a metabolic disease comprises administering a compounds of Formula (I), to a subject in need thereof. In a further embodiment, the compounds or pharmaceutical composition of the present disclosure are useful in preventing and/or treating clinical complications of Type I and Type II Diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathies, or Peripheral Arterial Occlusive Disease (PAOD). Other clinical complications of diabetes are also encompassed by the present disclosure. In some embodiments, a method for treating and/or preventing complications of Type I and Type II Diabetes comprises administering a compounds of Formula (I) to a subject in need thereof. In some embodiments, a method for treating and/or preventing complications of Type I and Type II Diabetes comprises administering a compounds of Formula (I) to a subject in need thereof. Furthermore, conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to enforced lipid and/or triglyceride accumulation and subsequent activation of profibrotic pathways may also be prevented and/or treated by administering the compounds or pharmaceutical composition of the present disclosure. Such conditions and diseases can include NASH and chronic cholestatic conditions in the liver, Glomerulosclerosis and Diabetic Nephropathy in the kidney, Macular Degeneration and Diabetic Retinopathy in the eye and neurodegenerative diseases, such as Alzheimer´s Disease in the brain, or Diabetic Neuropathies in the peripheral nervous system. In some embodiments, a method for treating and/or preventing conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to enforced lipid and/or triglyceride accumulation and subsequent activation of profibrotic pathways comprises administering a compounds of Formula (I) to a subject in need thereof. In some embodiments, a method for treating and/or preventing conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to enforced lipid and/or triglyceride accumulation and subsequent activation of profibrotic pathways comprises administering a compounds of Formula (I) to a subject in need thereof. In some embodiments, a method for treating and/or preventing NASH comprises administering a compounds of Formula (I) to a subject in need thereof. In some embodiments, a method for treating and/or preventing NASH comprises administering a compounds of Formula (I) to a subject in need thereof. Further provided herein is a pharmaceutical composition for use in treating a GLP-1R mediated disease or condition described herein, comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure also describes a use for the manufacture of a medicament in treating a GLP-1R mediated disease or condition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Medicaments as referred to herein may be prepared by conventional processes, including the combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier. Also disclosed is a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the treatment of a GLP-1R mediated disease or condition. Also disclosed is a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the prevention of a GLP-1R mediated disease or condition. VIII. EXAMPLES Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013.). Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high-performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. For example, the disclosed compounds can be purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969. During any of the processes for preparation of the subject compounds, it may be desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the pendant groups. Each of the reactions depicted in the general schemes can be run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step. In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The embodiments are also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof. The following description is, therefore, not intended to limit the scope of the present disclosure. In some embodiments, the present disclosure generally provides a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure. Representative syntheses of compounds of the present disclosure are described in schemes below, and the examples that follow. The compounds detailed in the Examples were synthesized according to the general synthetic methods described below. Compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.) unless otherwise indicated. Abbreviations Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms. Table 1. List of Abbreviations and Acronyms A. SYNTHESIS OF INTERMEDIATES Intermediate I-1 Methyl 2-[[4-(6-hydroxy-2-pyridyl)-1-piperidyl]methyl]-3-[[(2S)-oxe tan-2- yl]methyl]benzimidazole-5-carboxylate (I-1): A flask of methyl 2-[[4-[6-[(4-cyano-2-fluoro- phenyl)methoxy]-2-pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxet an-2-yl]methyl]benzimidazole-5- carboxylate (1.6 g, 2.81 mmol) in 10 mL of EtOH and 10 mL of EtOAc was evacuated and backfilled with nitrogen gas.300 mg of 10% Palladium on carbon was added to the reaction. A balloon of hydrogen was attached to the flask with an adapter. The flask was evacuated until the solvent began to bubble, and then the flask was opened the balloon and stirred overnight. Nitrogen was bubbled through the mixture for 10 minutes and the reaction was filtered. The filtrate was concentrated and purified by silica gel chromatography (eluent: DCM/MeOH) to give desired product. ES/MS: 437.2 (M+H + ). Intermediate I-2 Methyl 2-[[4-[6-[(4-bromo-2-fluoro-phenyl)methoxy]-2-pyridyl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate: Potassium carbonate (190 mg, 1.37 mmol) was added to a solution of methyl 2-[[4-(6-hydroxy-2-pyridyl)- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol e-5-carboxylate (300 mg, 0.69 mmol) and 4-bromo-1-(bromomethyl)-2-fluoro-benzene (193 mg, 0.72 mmol) in 5 mL of acetonitrile. The mixture was stirred at r.t. for 2 hours. Filtered and the filtrated was concentrated. Purified by silica gel chromatography (eluent: DCM/MeOH) to give desired product. ES/MS: 623.5 (M+H + ). Intermediate I-3 [2-fluoro-4-(triazol-1-yl)phenyl]methanol: (4-azido-2-fluoro-phenyl)methanol (300 mg, 1.79 mmol), ethynyl(trimethyl)silane (0.37 mL, 2.69 mmol), sodium ascorbate (126 mg, 0.72 mmol), copper sulfate monohydrate (64 mg, 0.36 mmol) and potassium carbonate (298 mg, 2.15 mmol) were combined in THF (5 mL) and stirred at room temperature for 15 hours. Upon completion the reaction contents were poured into water (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by flash chromatography (Eluent: EtOAc/hexane/MeOH) to give the desired product. ES/MS: 194.1 (M+H + ). 1-[4-(bromomethyl)-3-fluoro-phenyl]triazole (I-3): PBr 3 (0.15 mL, 1.59 mmol) was added dropwise to a solution of [2-fluoro-4-(triazol-1-yl)phenyl]methanol (245 mg, 1.27 mmol) in DCM (2 mL). The resulting mixture was stirred for 3 hours at room temperature. Upon completion the reaction contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO4, filtered, concentrated, and used without further purification. ES/MS: 256.1 (M+H + ). Intermediate I-4 [4-(4-cyclopropyltriazol-1-yl)-2-fluoro-phenyl]methanol: (4-azido-2-fluoro- phenyl)methanol (200 mg, 1.20 mmol), ethynylcyclopropane (0.15 mL, 1.79 mmol) and copper(I) thiophene-2-carboxylate (23 mg, 0.12 mmol) were combined in THF (2 mL). The mixture was stirred at room temperature for 1.5 hours. Upon completion the reaction contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO4, filtered, concentrated, and carried forward without further purification ES/MS: 234.2 (M+H + ). 1-[4-(bromomethyl)-3-fluoro-phenyl]-4-cyclopropyl-triazole (I-4): PBr 3 (0.14 mL, 1.50 mmol) was added dropwise to a solution of [4-(4-cyclopropyltriazol-1-yl)-2-fluoro- phenyl]methanol (279 mg, 1.20 mmol) in DCM (2 mL). The resulting mixture was stirred for 3 hours at room temperature. Upon completion the reaction contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO 4 , filtered, concentrated, and used without further purification. ES/MS: 298.2 (M+H + ).
Methyl 2-[[4-[6-[(2,2-difluoro-1,3-benzodioxol-4-yl)methoxy]-2-pyri dyl]-1- piperidyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxyl ate: Methyl 2-[[4-(6- hydroxy-2-pyridyl)-1-piperidyl]methyl]-3-(2-methoxyethyl)ben zimidazole-5-carboxylate (50 mg, 0.12 mmol), 4-(bromomethyl)-2,2-difluoro-1,3-benzodioxole (53 mg, 0.21 mmol), and silver carbonate (97 mg, 0.35 mmol) were taken up in toluene (2.5 mL). The mixture was stirred at 90 °C for 2 h. Following this time, the mixture was filtered through a plug of Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: EtOAc/hexanes). ES/MS: 595.4 (M+H + ). 2-((4-(6-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyri din-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid (Example 1): Methyl 2-[[4-[6-[(2,2-difluoro-1,3-benzodioxol-4-yl)methoxy]-2-pyri dyl]-1- piperidyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxyl ate (20 mg, 0.037 mmol) was taken up in acetonitrile (0.4 mL) and aqueous lithium hydroxide (0.3 M, 0.4 mL, 0.12 mmol) was added. The mixture was heated to 50 °C for two hours. Following this time, the mixture was diluted with water (5 mL), the pH adjusted to ~5 with 5% aqueous citric acid solution and the mixture extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 SO 4 , concentrated in vacuo, and purified by RP-HPLC (eluent: MeCN/water with 0.1% TFA) to yield Example 1 as bis-trifluoroacetate salt. ES/MS: 581.2 (M+H+); 1 H NMR (400 MHz, Methanol- d4) δ 8.33 (d, J = 1.6 Hz, 1H), 8.03 (dd, J = 8.5, 1.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.3, 7.3 Hz, 1H), 7.26 (dt, J = 7.0, 4.0 Hz, 1H), 7.21 – 7.11 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 5.49 (s, 2H), 4.82 (s, 2H), 4.62 (t, J = 4.8 Hz, 2H), 3.91 (d, J = 12.2 Hz, 2H), 3.78 – 3.71 (m, 2H), 3.46 – 3.35 (m, 2H), 3.31 (s, 3H), 3.06 (dt, J = 10.1, 5.2 Hz, 1H), 2.33 – 2.16 (m, 4H). Example 2.2-((4-(6-((4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) benzyl)oxy)pyridin- 2-yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]im idazole-6-carboxylic acid. 2-((4-(6-((4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)be nzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.66 (dd, J = 8.3, 7.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.47 (s, 2H), 4.81 (s, 2H), 4.62 (t, J = 4.8 Hz, 2H), 3.90 (d, J = 12.2 Hz, 2H), 3.75 (dd, J = 5.3, 4.2 Hz, 2H), 3.46 – 3.36 (m, 2H), 3.31 (s, 3H), 3.09 – 3.00 (m, 1H), 2.32 – 2.13 (m, 4H). Example 3.1-(2-methoxyethyl)-2-((4-(6-(quinolin-6-ylmethoxy)pyridin- 2-yl)piperidin-1- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-(quinolin-6-ylmethoxy)pyridin-2- yl)piperidin-1- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 9.12 (d, J = 5.1 Hz, 1H), 9.03 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 4.4 Hz, 2H), 8.28 – 8.13 (m, 2H), 8.03 (dd, J = 8.6, 1.5 Hz, 1H), 7.97 (dd, J = 8.3, 5.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.71 (s, 2H), 4.82 (s, 2H), 4.62 (t, J = 4.9 Hz, 2H), 3.91 (d, J = 12.1 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.41 (td, J = 12.3, 3.6 Hz, 2H), 3.30 (s, 3H), 3.16 – 3.01 (m, 1H), 2.23 (qd, J = 14.8, 13.2, 3.8 Hz, 4H). Example 4.2-((4-(6-((4-chloronaphthalen-1-yl)methoxy)pyridin-2-yl)pi peridin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((4-chloronaphthalen-1-yl)methoxy)pyridin-2-yl)pipe ridin-1-yl)methyl)- 1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.37 – 8.27 (m, 2H), 8.22 – 8.12 (m, 1H), 8.03 (dd, J = 8.6, 1.5 Hz, 1H), 7.71 – 7.64 (m, 3H), 7.63 – 7.56 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 6.75 (dd, J = 8.3, 0.7 Hz, 1H), 5.87 (s, 2H), 4.79 (s, 2H), 4.60 (t, J = 4.8 Hz, 2H), 3.89 (d, J = 12.2 Hz, 2H), 3.77 – 3.69 (m, 2H), 3.41 (td, J = 12.3, 3.7 Hz, 2H), 3.28 (s, 3H), 3.17 – 3.01 (m, 1H), 2.37 – 2.17 (m, 4H). Example 5.1-(2-methoxyethyl)-2-((4-(6-(naphthalen-1-ylmethoxy)pyridi n-2-yl)piperidin-1- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-(naphthalen-1-ylmethoxy)pyridin- 2-yl)piperidin-1- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.32 (dd, J = 1.6, 0.7 Hz, 1H), 8.14 – 8.07 (m, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.90 (dd, J = 7.5, 1.9 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.79 (dd, J = 8.5, 0.6 Hz, 1H), 7.67 (dd, J = 8.3, 7.3 Hz, 1H), 7.62 (dd, J = 7.0, 1.1 Hz, 1H), 7.58 – 7.42 (m, 3H), 6.94 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.87 (s, 2H), 4.78 (s, 2H), 4.60 (t, J = 4.8 Hz, 2H), 3.88 (s, 2H), 3.76 – 3.67 (m, 2H), 3.40 (td, J = 12.2, 3.5 Hz, 2H), 3.28 (s, 3H), 3.18 – 3.01 (m, 1H), 2.40 – 2.13 (m, 4H). Example 6.2-((4-(6-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methoxy)py ridin-2-yl)piperidin- 1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carbo xylic acid. 2-((4-(6-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methoxy)pyri din-2-yl)piperidin- 1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carbo xylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 1.6, 0.7 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (dd, J = 8.6, 0.7 Hz, 1H), 7.66 (dd, J = 8.3, 7.3 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 8.2, 1.6 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.74 (dd, J = 8.3, 0.7 Hz, 1H), 5.42 (s, 2H), 4.83 (s, 2H), 4.62 (t, J = 4.8 Hz, 2H), 3.93 (d, J = 12.2 Hz, 2H), 3.76 (dd, J = 5.3, 4.2 Hz, 2H), 3.42 (t, J = 11.9 Hz, 2H), 3.31 (s, 3H), 3.14 – 2.97 (m, 1H), 2.34 – 2.18 (m, 4H). Example 7.2-((4-(6-(benzo[d][1,3]dioxol-5-ylmethoxy)pyridin-2-yl)pip eridin-1-yl)methyl)- 1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-(benzo[d][1,3]dioxol-5-ylmethoxy)pyridin-2-yl)piper idin-1-yl)methyl)- 1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 1.5 Hz, 1H), 7.91 (dd, J = 8.5, 1.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 9.1, 6.9 Hz, 1H), 6.89 – 6.76 (m, 2H), 6.23 (d, J = 9.1 Hz, 1H), 6.05 (s, 1H), 5.98 (s, 1H), 4.81 (s, 2H), 4.62 (t, J = 5.0 Hz, 2H), 4.39 (s, 2H), 3.65 (s, 5H), 3.27 (d, J = 16.0 Hz, 2H), 3.22 (s, 3H), 2.82 – 2.66 (m, 1H), 2.11 (d, J = 13.6 Hz, 2H), 1.94 (s, 2H). Example 8.1-(2-methoxyethyl)-2- 1-methyl-1H-indazol-4-yl)methoxy)pyridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-((1-methyl-1H-indazol-4-yl)metho xy)pyridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1, 1H NMR (400 MHz, Acetonitrile-d3) δ 8.33 (dd, J = 1.6, 0.7 Hz, 1H), 8.02 (dd, J = 8.5, 1.6 Hz, 1H), 7.95 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 (dq, J = 1.6, 0.9 Hz, 1H), 7.60 (dd, J = 9.1, 7.1 Hz, 1H), 7.55 – 7.47 (m, 1H), 7.42 (dd, J = 8.7, 1.5 Hz, 1H), 6.52 (d, J = 9.0 Hz, 1H), 6.36 (d, J = 7.1 Hz, 1H), 4.68 (s, 1H), 4.65 (s, 2H), 4.56 (t, J = 4.9 Hz, 2H), 4.05 (s, 3H), 3.84 (d, J = 12.4 Hz, 2H), 3.77 – 3.67 (m, 2H), 3.36 – 3.21 (m, 4H), 3.00 – 2.86 (m, 0H), 2.26 – 2.13 (m, 4H). Example 9.1-(2-methoxyethyl)-2-((4-(6-((4-(methylsulfonyl)benzyl)oxy )pyridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-((4-(methylsulfonyl)benzyl)oxy)p yridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1, 1H NMR (400 MHz, Acetonitrile-d3) δ 8.49 – 8.21 (m, 1H), 8.01 (dd, J = 8.5, 1.5 Hz, 1H), 7.98 – 7.89 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.76 – 7.64 (m, 3H), 6.91 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 5.52 (s, 2H), 4.63 (s, 2H), 4.56 (t, J = 4.8 Hz, 2H), 3.81 (d, J = 12.6 Hz, 3H), 3.78 – 3.73 (m, 2H), 3.45 – 3.31 (m, 2H), 3.31 (s, 3H), 3.07 (s, 3H), 3.05 – 2.98 (m, 1H), 2.16 – 2.08 (m, 4H). Example 10.1-(2-methoxyethyl)-2- 5-methyl-1,2,4-oxadiazol-3- yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d ]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-((3-(5-methyl-1,2,4-oxadiazol-3- yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d ]imidazole-6-carboxylic acid was made according to Porcedure 1.1H NMR (400 MHz, Acetonitrile-d3) δ 8.32 (dd, J = 1.6, 0.6 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.00 (td, J = 8.2, 1.6 Hz, 2H), 7.90 – 7.75 (m, 1H), 7.75 – 7.61 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H), 6.81 – 6.59 (m, 1H), 5.50 (s, 2H), 4.64 (s, 2H), 4.56 (t, J = 4.8 Hz, 2H), 3.83 (s, 1H), 3.79 – 3.69 (m, 2H), 3.37 (dd, J = 15.5, 12.4 Hz, 2H), 3.31 (s, 3H), 3.10 – 2.95 (m, 1H), 2.58 (s, 3H), 2.29 – 2.13 (m, 4H). Example 11.2-((4-(6-((4-(dimethylcarbamoyl)-2-fluorobenzyl)oxy)pyrid in-2-yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((4-(dimethylcarbamoyl)-2-fluorobenzyl)oxy)pyridin- 2-yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acidwas made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.74 – 7.64 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.30 – 7.20 (m, 2H), 6.95 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.54 (s, 2H), 4.82 (s, 2H), 4.63 (s, 3H), 3.90 (s, 1H), 3.77 (t, J = 4.8 Hz, 2H), 3.10 (s, 3H), 3.01 (s, 3H), 2.23 (s, 5H). Example 12.2-((4-(6-([1,1'-biphenyl]-4-ylmethoxy)pyridin-2-yl)piperi din-1-yl)methyl)-1- (2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-([1,1'-biphenyl]-4-ylmethoxy)pyridin-2-yl)piperidin -1-yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1, 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.05 (dd, J = 8.5, 1.6 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.74 – 7.57 (m, 5H), 7.53 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.38 – 7.30 (m, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.49 (s, 2H), 4.80 (s, 3H), 4.61 (s, 2H), 3.90 (s, 2H), 3.76 (s, 2H), 3.44 (s, 1H), 2.27 (q, J = 15.5, 13.8 Hz, 4H). Example 13.2-((4-(6-((4-ethynylbenzyl)oxy)pyridin-2-yl)piperidin-1-y l)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-((4-ethynylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)m ethyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 1.3 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.52 – 7.40 (m, 4H), 6.93 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.45 (s, 2H), 4.81 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.90 (s, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.50 (s, 1H), 3.42 (s, 2H), 3.07 (s, 1H), 2.25 (d, J = 19.5 Hz, 4H). Example 14.1-(2-methoxyethyl)-2-((4-(6-((perfluorophenyl)methoxy)pyr idin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-((perfluorophenyl)methoxy)pyridi n-2-yl)piperidin- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 1.1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 – 7.61 (m, 1H), 7.04 – 6.92 (m, 1H), 6.70 (dd, J = 8.3, 3.4 Hz, 1H), 5.52 (d, J = 16.9 Hz, 2H), 4.85 (s, 2H), 4.64 (t, J = 4.9 Hz, 2H), 4.11 (s, 1H), 3.96 (d, J = 12.0 Hz, 2H), 3.78 (t, J = 4.7 Hz, 2H), 3.59 – 3.38 (m, 2H), 3.22 – 2.90 (m, 2H), 2.30 (s, 4H).
Methyl 2-[[4-[6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methoxy]- 2- pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]ben zimidazole-5-carboxylate: Methyl 2-[[4-[6-[(4-bromo-2-fluoro-phenyl)methoxy]-2-pyridyl]-1-pip eridyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-2, 50 mg, 0.08 mmol), (1-methylpyrazol-4- yl)boronic acid (20.2 mg, 0.16 mmol), 2 N aqueous sodium carbonate (0.08 mL, 0.16 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (5.7 mg, 0.008 mmol) was suspended in dioxane (0.5 mL). The reaction mixture was degassed by nitrogen. Next, the mixture was heated to 120 °C in a microwave reactor for 30 minutes. The solvent was then removed, and the residue dissolved in 1 mL of DMF. The mixture was filtered and purified by RP-HPLC (eluent: water / MeCN 0.1% TFA) to give the desired product. ES/MS: 625.1 (M+H + ). 2-[[4-[6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methoxy]- 2-pyridyl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylic acid (Example 15): Methyl 2-[[4-[6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methoxy]- 2-pyridyl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (24.5 mg, 0.041 mmol) was taken up in 1 mL of ACN and 0.3 mL of 1 N lithium hydroxide. The mixture was heated to 80 °C for 30 minutes. The filtrate was purified by RP-HPLC (eluent: water / MeCN *0.1% TFA) to give the desired product. ES/MS: 611.2 (M+H+); 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 1.4 Hz, 1H), 8.07 (dd, J = 8.6, 1.5 Hz, 1H), 8.00 (s, 1H), 7.91 – 7.74 (m, 2H), 7.68 (dd, J = 8.3, 7.3 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.44 – 7.26 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 5.47 (s, 2H), 5.25 (d, J = 7.3 Hz, 1H), 4.79 (dd, J = 15.9, 6.7 Hz, 1H), 4.75 – 4.57 (m, 2H), 4.46 (dt, J = 11.5, 5.9 Hz, 1H), 3.94-3.71 (m, 5H), 3.44 (s, 2H), 3.09 (s, 1H), 2.83 (dt, J = 16.7, 7.9 Hz, 1H), 2.53 (q, J = 9.9, 9.0 Hz, 1H), 2.24 (s, 6H). Example 16.2- 1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)oxy)pyrid in- 2-yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]im idazole-6-carboxylic acid. 2-((4-(6-((4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobe nzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid was made according to Procedure 2.1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.39 – 8.28 (m, 1H), 8.12 (s, 1H), 8.09 – 7.97 (m, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.68 (q, J = 6.9, 6.1 Hz, 1H), 7.60 – 7.31 (m, 4H), 6.95 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.50 (s, 2H), 4.83 (s, 2H), 4.63 (t, J = 4.9 Hz, 2H), 3.93 (d, J = 12.2 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.44 (t, J = 12.1 Hz, 2H), 3.11 (td, J = 12.4, 10.7, 7.4 Hz, 1H), 2.47 – 2.16 (m, 4H). Example 17.2-((4-(6-((2-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)ben zyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid. 2-((4-(6-((2-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl )oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid was made according to Procedure 2.1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 1.4 Hz, 1H), 8.05 (dd, J = 8.6, 1.5 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.77 – 7.65 (m, 2H), 7.47 – 7.35 (m, 2H), 6.97 (d, J = 7.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.57 (s, 2H), 4.84 (s, 2H), 4.64 (t, J = 4.8 Hz, 2H), 4.15 (s, 3H), 4.05 – 3.86 (m, 2H), 3.83 – 3.71 (m, 2H), 3.55 – 3.39 (m, 2H), 3.13 (ddd, J = 16.1, 7.1, 3.9 Hz, 1H), 2.46 – 2.19 (m, 4H). Example 18. (S)-2-((4-(6-((2-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)be nzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid. (S)-2-((4-(6-((2-fluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)be nzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid was made according to Procedure 2.1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 1.5 Hz, 1H), 8.10 – 8.03 (m, 1H), 7.90 – 7.78 (m, 2H), 7.76 – 7.64 (m, 2H), 7.50 – 7.37 (m, 2H), 6.96 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.57 (s, 2H), 5.25 (d, J = 7.1 Hz, 1H), 4.82 – 4.63 (m, 3H), 4.46 (dt, J = 9.1, 5.8 Hz, 1H), 4.14 (s, 3H), 3.92 (s, 2H), 3.44 (s, 3H), 3.09 (t, J = 7.8 Hz, 1H), 2.93 – 2.74 (m, 1H), 2.52 (dt, J = 18.4, 8.1 Hz, 1H), 2.24 (s, 5H). Example 19. (S)-2-((4-(6-((4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2- fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxet an-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid. (S)-2-((4-(6-((4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2- fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxet an-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid was made according to Procedure 2.1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.12 (s, 1H), 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.74 – 7.64 (m, 1H), 7.60 – 7.32 (m, 4H), 6.94 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 5.49 (s, 2H), 5.25 (q, J = 6.7 Hz, 1H), 4.85 – 4.61 (m, 3H), 4.45 (dt, J = 9.2, 5.9 Hz, 1H), 3.91 (s, 2H), 3.54 – 3.38 (m, 3H), 3.14 – 3.02 (m, 1H), 2.94 – 2.71 (m, 1H), 2.64 – 2.41 (m, 1H), 2.23 (s, 5H). Example 20. (S)-2-((4-(6-((4-(2-cyclopropyloxazol-5-yl)-2-fluorobenzyl)o xy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid. (S)-2-((4-(6-((4-(2-cyclopropyloxazol-5-yl)-2-fluorobenzyl)o xy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acidwas made according to Procedure 2. 1H NMR (400 MHz, Methanol-d4) δ 8.36 (t, J = 1.0 Hz, 1H), 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 8.3, 7.3 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.52 – 7.36 (m, 3H), 6.94 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.50 (s, 2H), 5.31 – 5.18 (m, 1H), 4.79 (dd, J = 15.9, 6.8 Hz, 1H), 4.74 – 4.60 (m, 2H), 4.46 (dt, J = 9.3, 5.9 Hz, 1H), 3.91 (s, 2H), 3.54 – 3.37 (m, 3H), 3.18 – 2.98 (m, 1H), 2.91 – 2.73 (m, 1H), 2.59 – 2.43 (m, 1H), 2.33 – 2.10 (m, 5H), 1.21 – 1.05 (m, 4H). Example 21.2-((4-(6-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)ox y)pyridin-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid. 2-((4-(6-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)oxy)p yridin-2- yl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imid azole-6-carboxylic acid was made according to Procedure 2.1H NMR (400 MHz, Methanol-d4) δ 8.43 – 8.29 (m, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 8.00 (s, 1H), 7.84 (d, J = 0.9 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 8.3, 7.3 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.44 – 7.26 (m, 2H), 6.95 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 5.47 (s, 2H), 4.82 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.93 (s, 5H), 3.77 (t, J = 4.8 Hz, 2H), 3.54 – 3.39 (m, 2H), 3.20 – 3.03 (m, 1H), 2.28 (q, J = 13.9, 12.9 Hz, 4H).
Methyl 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-6- azaspiro[2.5]octan-1-yl)-1-(2-methoxyethyl)-1H-benzo[d]imida zole-6-carboxylate: Methyl 2-[[4-[6-[(4-bromo-2-fluoro-phenyl)methoxy]-2-pyridyl]-1-pip eridyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (50 mg, 0.08 mmol), 4-ethynyl-1-methyl-pyrazole (85 mg, 0.8 mmol), copper iodide (3 mg, 0.16 mmol), bis(triphenylphosphine)palladium chloride (11.3 mg, 0.016 mmol) and diisopropylamine (0.11 mL, 0.8 mmol) were suspended in THF (0.5 mL). The reaction mixture was degassed by nitrogen. Next, the mixture was heated to 80 °C for 1 hour. The solvent was removed, and the residue dissolved in 1 mL of DMF. The mixture was filtered and purified by RP-HPLC (eluent: water / MeCN 0.1% TFA) to give the desired product. ES/MS: 649.3 (M+H + ). 2-[[4-[6-[[2-fluoro-4-[2-(1-methylpyrazol-4-yl)ethynyl]pheny l]methoxy]-2- pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]ben zimidazole-5-carboxylic acid (Example 22): Methyl 2-[[4-[6-[[2-fluoro-4-[2-(1-methylpyrazol-4- yl)ethynyl]phenyl]methoxy]-2-pyridyl]-1-piperidyl]methyl]-3- [[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (30 mg, 0.046 mmol) was taken up in 1 mL of ACN and 0.3 mL of 1 N lithium hydroxide. The mixture was heated to 80 °C for 30 minutes. The filtrate was purified by RP-HPLC (eluent: water / MeCN *0.1% TFA) to give the desired product. ES/MS: 635.6 (M+H+); 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 1.4 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.92 – 7.79 (m, 2H), 7.68 (dd, J = 8.3, 7.3 Hz, 1H), 7.63 (s, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.32 – 7.19 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.49 (s, 2H), 5.24 (dd, J = 7.3, 5.1 Hz, 1H), 4.84 – 4.65 (m, 3H), 4.45 (dt, J = 9.3, 5.9 Hz, 1H), 3.92 (s, 4H), 3.43 (s, 3H), 3.36 (s, 1H), 3.19 – 3.01 (m, 1H), 2.94 – 2.77 (m, 1H), 2.70 – 2.45 (m, 1H), 2.21 (s, 5H).
Methyl 2-[[4-[6-[[2-fluoro-4-(2-trimethylsilylethynyl)phenyl]methox y]-2- pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]ben zimidazole-5-carboxylate: N- ethyldiisopropylamine (2.76 mL, 15.8 mmol) was added to a mixture of [2-fluoro-4-(2- trimethylsilylethynyl)phenyl]methanol (1.76 g, 7.92 mmol) and p-tolylsulfonyl 4- methylbenzenesulfonate (2.58 g, 7.92 mmol) in 10 mL of DCM,. The reaction was stirred overnight at room temperature. The organic layer was washed with 20 mL of NaHCO 3(aq) and 20 mL of brine. The organic layer was dried and concentrated. Potassium carbonate (317 mg, 2.29 mmol) was added to a suspension of the the crude product, [2-fluoro-4-(2- trimethylsilylethynyl)phenyl]methyl 4-methylbenzenesulfonate (181 mg, 0.48 mmol) and methyl 2-[[4-(6-hydroxy-2-pyridyl)-1-piperidyl]methyl]-3-[[(2S)-oxe tan-2- yl]methyl]benzimidazole-5-carboxylate (200 mg, 0.46 mmol) in 5 mL of acetonitrile.The mixture was stirred at r.t. for 2 hours. Filtered and the filtrated was concentrated. Purified by silica gel chromatography (eluent: DCM/MeOH) to give desired product. ES/MS: 641.5 (M+H+). Methyl 2-[[4-[6-[(4-ethynyl-2-fluoro-phenyl)methoxy]-2-pyridyl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate: Potassium carbonate (27 mg, 0.2 mmol) was added to a solution methyl 2-[[4-[6-[(4-ethynyl-2-fluoro- phenyl)methoxy]-2-pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxet an-2-yl]methyl]benzimidazole-5- carboxylate (250 mg, 0.39 mmol) in 10 mL of MeOH. The mixture was stirred at r.t. for 2 hours. The solvent was removed. The residue was dissolved in 50 mL of EtOAc and washed with 20 mL of brine twice. The organic layer was dried and concentrated and used without further purification. ES/MS: 569.3 (M+H + ). Methyl 2-[[4-[6-[[4-(1-cyclopropyltriazol-4-yl)-2-fluoro-phenyl]met hoxy]-2- pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]ben zimidazole-5-carboxylate: Methyl 2-[[4-[6-[(4-ethynyl-2-fluoro-phenyl)methoxy]-2-pyridyl]-1-p iperidyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate (28.5 mg, 0.05 mmol), azidocyclopropane (8.34 mg, 0.1 mmol) were dissolved in 1 mL of tert-butanol to form a solution. To the solution was added 1 mL of CAN, then sodium ascorbate (2 mg, 0.01 mmol) and copper(II) sulfate pentahydrate (2.5 mg, 0.01 mmol) in 0.5 mL of water. The reaction was stirred at room temperature overnight. The mixture was diluted with 5 mL of EtOAc and washed with 3 mL of brine. The organic layer was dried and concentrated and used without further purification. ES/MS: 652.7 (M+H+). 2-[[4-[6-[[4-(1-Cyclopropyltriazol-4-yl)-2-fluoro-phenyl]met hoxy]-2-pyridyl]- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol e-5-carboxylic acid (Example 23): 1 mL of ACN and 0.3 mL of 1 N lithium hydroxide was added to methyl 2-[[4-[6-[[4-(1- cyclopropyltriazol-4-yl)-2-fluoro-phenyl]methoxy]-2-pyridyl] -1-piperidyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate (15 mg, 0.023 mmol). The mixture was heated to 80 °C for 30 minutes. The filtrate was purified by RP-HPLC (eluent: water / MeCN *0.1% TFA) to give the desired product. ES/MS: 638.3 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.39 (d, J = 1.4 Hz, 1H), 7.91 (dd, J = 8.4, 1.6 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.76 – 7.57 (m, 4H), 6.95 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.45 (s, 2H), 5.05 (d, J = 7.6 Hz, 1H), 4.96 – 4.75 (m, 3H), 4.68 (d, J = 15.3 Hz, 1H), 4.50 (d, J = 7.2 Hz, 1H), 4.35 (q, J = 7.5, 6.9 Hz, 1H), 4.03 (tt, J = 7.3, 4.0 Hz, 1H), 3.80 (s, 2H), 2.97 (s, 1H), 2.85 – 2.60 (m, 2H), 2.33 (q, J = 1.8 Hz, 1H), 2.13 (s, 5H), 1.18 (ddt, J = 12.6, 5.0, 2.4 Hz, 4H). Example 24. (S)-2- 2-fluoro-4-(1-(oxetan-3-yl)-1H-1,2,3-triazol-4- yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid. (S)-2-((4-(6-((2-fluoro-4-(1-(oxetan-3-yl)-1H-1,2,3-triazol- 4- yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid was made according to Procedure 4. 1H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.36 (d, J = 1.3 Hz, 1H), 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 – 7.65 (m, 3H), 7.60 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 5.97 – 5.80 (m, 1H), 5.52 (s, 2H), 5.25 (d, J = 7.1 Hz, 1H), 5.18 (t, J = 7.4 Hz, 2H), 5.13 – 5.03 (m, 2H), 4.94 (d, J = 20.5 Hz, 1H), 4.83 – 4.74 (m, 1H), 4.74 – 4.64 (m, 2H), 4.46 (dd, J = 9.7, 5.6 Hz, 1H), 3.91 (s, 2H), 3.43 (s, 2H), 3.08 (s, 1H), 2.91 – 2.75 (m, 1H), 2.52 (dt, J = 18.2, 8.1 Hz, 1H), 2.23 (s, 5H).
Tert-butyl 4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piperidin e-1- carboxylate: 4-(hydroxymethyl)naphthalene-1-carbonitrile (100 mg, 0.55 mmol), cesium carbonate (356 mg, 1.09 mmol), 2-(di-t-butylphosphino)biphenyl (33 mg, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.055 mmol) was added to a solution of tert- butyl 4-(6-chloro-2-pyridyl)piperidine-1-carboxylate (194 mg, 0.66 mmol) in 1,4-dioxane (2 mL). The resulting solution was degassed by bubbling argon for 1 minute, sealed and heated to 90 °C for 2 hours. Upon completion of the reaction, the contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (Eluent: EtOAc/hexane/MeOH) to give the desired product. Methyl 2-((4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piper idin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy late: Para-toluenesulfonic acid, monohydrate (163 mg, 0.86 mmol) was added to a solution of tert-butyl 4-(6-((4- cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piperidine-1-carbo xylate (127 mg, 0.29 mmol) in EtOAc (3 mL). The resulting mixture was heated to 60 °C for 2.5 hours. Upon completion, the reaction mixture was filtered, the solid was rinsed with EtOAc (1 x 10 mL) and dried. The dried solid was carried forward without purification. The crude tert-butyl 4-[6-[(4-cyano-1- naphthyl)methoxy]-2-pyridyl]piperidine-1-carboxylate, 4-methylbenzenesulfonic acid salt (176 mg, 0.29 mmol) was combined with methyl 2-(chloromethyl)-3-(2- methoxyethyl)benzimidazole-5-carboxylate (89 mg, 0.31 mmol), and potassium carbonate (198 mg, 1.43 mmol) in acetonitrile (3 mL). The resulting mixture was heated to 60 °C for 16 hours after which the reaction contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (Eluent: EtOAc/hexane/MeOH) to give the desired product. 2-((4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piper idin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid (Example 25): Methyl 2-((4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piper idin-1-yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.085 mmol) was taken up in acetonitrile (2 mL). Next, aqueous lithium hydroxide (0.84 M, 0.20 mL, 0.17 mmol) was added. The reaction was heated to 100 °C for 7 minutes then cooled to r.t. and diluted with 5% aqueous citric acid to a pH of ~5. The mixture was extracted with EtOAc (2 x 15 mL) and the combined organic extracts dried over MgSO 4 and concentrated in vacuo. The material was purified by RP- HPLC (eluent: MeCN/water gradient with 0.1% TFA) to yield Example 25 as the trifluoroacetate salt. ES/MS: 576.6 (M+H + ); 1H NMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.27 – 8.21 (m, 1H), 8.08 – 7.96 (m, 2H), 7.86 – 7.62 (m, 5H), 6.95 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 5.98 (s, 2H), 4.76 (s, 2H), 4.59 (t, J = 4.9 Hz, 2H), 3.95 – 3.78 (m, 2H), 3.73 (t, J = 4.8 Hz, 2H), 3.42 – 3.33 (m, 2H), 3.27 (s, 3H), 3.10 – 2.96 (m, 1H), 2.25 – 2.11 (m, 4H).
d i c a c i l yxo b r a c - 5 - e l o z a d i m i z n e b ) l y h t eyxoh t e m -2 ( - 3 - ] l yh t e 17m ] l y d i r e p i p - 1 - ] l yd i r y p -2- ) yxoh t e m l y l o n i uq o s i -6 ( -6 [ - 4 [ [ -2 . 6 2 6 e l e r p ud ma e c x o E r P Methyl 2-[[4-[6-[(5-cyano-3-fluoro-2-thienyl)methoxy]-2-pyridyl]-1- piperidyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxyl ate.6-isoquinolylmethanol (43 mg, 0.27 mmol), cesium carbonate (253 mg, 0.78 mmol), 2-(di-t-butylphosphino)biphenyl (23 mg, 0.078 mmol), and tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.039 mmol) was added to a solution of methyl 2-[[4-(6-chloro-2-pyridyl)-1-piperidyl]methyl]-3-(2- methoxyethyl)benzimidazole-5-carboxylate (100 mg, 0.23 mmol) in 1,4-dioxane (2 mL). The resulting solution was degassed by bubbling argon for 1 minute, sealed and heated to 90 °C for 2 hours. Upon completion the reaction contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (Eluent: EtOAc/hexane/MeOH) to give the desired product. 2-[[4-[6-(6-isoquinolylmethoxy)-2-pyridyl]-1-piperidyl]methy l]-3-(2- methoxyethyl)benzimidazole-5-carboxylic acid (Example 26): Methyl 2-[[4-[6-[(5-cyano-3- fluoro-2-thienyl)methoxy]-2-pyridyl]-1-piperidyl]methyl]-3-( 2-methoxyethyl)benzimidazole-5- carboxylate (84 mg, 0.15 mmol) was taken up in acetonitrile (2 mL). Next, aqueous lithium hydroxide (0.84 M, 0.24 mL, 0.18 mmol) was added. The reaction was heated to 100 °C for 7 minutes then cooled to r.t. and diluted with 5% aqueous citric acid to a pH of ~5. The mixture was extracted with EtOAc (2 x 15 mL) and the combined organic extracts dried over MgSO4 and concentrated in vacuo. The material was purified by RP-HPLC (eluent: MeCN/water gradient with 0.1% TFA) to yield Example 26 as the trifluoroacetate salt. ES/MS: 552.6 (M+H + ); 1H NMR (400 MHz, Methanol-d4) δ 9.65 (s, 1H), 8.55 (d, J = 6.4 Hz, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.39 – 8.27 (m, 3H), 8.16 – 8.00 (m, 2H), 7.81 (d, J = 8.6 Hz, 1H), 7.74 (dd, J = 8.3, 7.3 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.78 (s, 2H), 4.82 (s, 2H), 4.63 (t, J = 4.9 Hz, 2H), 3.90 (d, J = 12.2 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.39 (d, J = 15.3 Hz, 2H), 3.32 (s, 3H), 3.12 – 3.01 (m, 1H), 2.22 (d, J = 6.7 Hz, 4H). Example 27.2-((4-(6-(benzo[c][1,2,5]oxadiazol-5-ylmethoxy)pyridin-2- yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-(benzo[c][1,2,5]oxadiazol-5-ylmethoxy)pyridin-2-yl) piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid was made according to Procedure 6, 1H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J = 1.5 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.94 – 7.88 (m, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.70 (dd, J = 8.3, 7.3 Hz, 1H), 7.59 (dd, J = 9.5, 1.2 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.55 (d, J = 1.2 Hz, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.89 (d, J = 12.3 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.40 (td, J = 11.9, 4.8 Hz, 2H), 3.15 – 3.01 (m, 1H), 2.34 – 2.10 (m, 4H). Additional peak obscured by solvent. Example 28.2- 6-(benzo[d]thiazol-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)m ethyl)-1- (2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-(benzo[d]thiazol-6-ylmethoxy)pyridin-2-yl)piperidin -1-yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 9.23 (s, 1H), 8.37 – 8.27 (m, 1H), 8.20 – 8.14 (m, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 – 7.59 (m, 2H), 6.93 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 5.59 (s, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.98 – 3.82 (m, 2H), 3.75 (t, J = 4.7 Hz, 2H), 3.46 – 3.36 (m, 2H), 3.13 – 3.01 (m, 1H), 2.41 – 2.13 (m, 4H). Additional peak (s, 3H) obscured by solvent. Example 29.2-((4-(6-((4-(2-hydroxypropan-2-yl)benzyl)oxy)pyridin-2-y l)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((4-(2-hydroxypropan-2-yl)benzyl)oxy)pyridin-2-yl)p iperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid was made according to Procedure 6, 1H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 1.5, 0.7 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (dd, J = 8.5, 0.6 Hz, 1H), 7.64 (dd, J = 8.3, 7.3 Hz, 1H), 7.53 – 7.47 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 7.2 Hz, 1H), 6.72 (dd, J = 8.3, 0.7 Hz, 1H), 5.39 (s, 2H), 4.81 (s, 3H), 4.62 (t, J = 4.8 Hz, 2H), 3.91 (d, J = 12.2 Hz, 2H), 3.75 (dd, J = 5.3, 4.2 Hz, 2H), 3.46 – 3.36 (m, 2H), 3.12 – 3.01 (m, 1H), 2.38 – 2.14 (m, 4H), 1.52 (s, 6H). Additional peak (s, 3H) obscured by solvent. Example 30.1-(2-methoxyethyl)-2-((4-(6-((4-(methoxymethyl)benzyl)oxy )pyridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-((4-(methoxymethyl)benzyl)oxy)py ridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 1.6, 0.7 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (dd, J = 8.5, 0.6 Hz, 1H), 7.65 (dd, J = 8.3, 7.3 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.73 (dd, J = 8.3, 0.7 Hz, 1H), 5.41 (s, 2H), 4.80 (s, 2H), 4.62 (t, J = 4.8 Hz, 2H), 4.44 (s, 2H), 3.89 (d, J = 12.1 Hz, 2H), 3.75 (dd, J = 5.3, 4.2 Hz, 2H), 3.45 – 3.37 (m, 2H), 3.36 (s, 3H), 3.13 – 3.00 (m, 1H), 2.34 – 2.14 (m, 4H). Additional peak (s, 3H) obscured by solvent. Example 31.2- 7-chlorobenzofuran-4-yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((7-chlorobenzofuran-4-yl)methoxy)pyridin-2-yl)pipe ridin-1-yl)methyl)- 1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 8.37 – 8.27 (m, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.3, 7.3 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.07 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.65 (s, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.88 (d, J = 12.2 Hz, 2H), 3.79 – 3.71 (m, 2H), 3.40 (td, J = 12.0, 4.7 Hz, 2H), 3.30 (s, 3H), 3.06 (tt, J = 10.2, 4.9 Hz, 1H), 2.36 – 2.13 (m, 4H).;1H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 1.6, 0.7 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.66 (dd, J = 8.3, 7.3 Hz, 1H), 7.48 – 7.42 (m, 1H), 7.34 – 7.25 (m, 2H), 6.98 (dd, J = 2.2, 1.0 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.66 (s, 2H), 4.79 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.95 – 3.82 (m, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.46 – 3.34 (m, 2H), 3.10 – 3.02 (m, 1H), 2.36 – 2.11 (m, 4H). Example 32.2- 6-(benzofuran-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-(benzofuran-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 8.37 – 8.27 (m, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.3, 7.3 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.07 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.65 (s, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.88 (d, J = 12.2 Hz, 2H), 3.79 – 3.71 (m, 2H), 3.40 (td, J = 12.0, 4.7 Hz, 2H), 3.30 (s, 3H), 3.06 (tt, J = 10.2, 4.9 Hz, 1H), 2.36 – 2.13 (m, 4H).;1H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 1.6, 0.7 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.66 (dd, J = 8.3, 7.3 Hz, 1H), 7.48 – 7.42 (m, 1H), 7.34 – 7.25 (m, 2H), 6.98 (dd, J = 2.2, 1.0 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.66 (s, 2H), 4.79 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.95 – 3.82 (m, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.46 – 3.34 (m, 2H), 3.10 – 3.02 (m, 1H), 2.36 – 2.11 (m, 4H). Example 33.2- 1H-benzo[d]imidazol-4-yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((1H-benzo[d]imidazol-4-yl)methoxy)pyridin-2-yl)pip eridin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid was made according to Procedure 6. 1H NMR (400 MHz, Methanol-d4) δ 9.08 (s, 1H), 8.34 (d, J = 1.5 Hz, 1H), 8.20 (dd, J = 7.0, 2.4 Hz, 1H), 8.12 – 7.97 (m, 2H), 7.80 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 4.7 Hz, 1H), 7.56 – 7.43 (m, 3H), 5.11 (s, 2H), 4.63 (t, J = 4.8 Hz, 2H), 3.98 (d, J = 12.3 Hz, 2H), 3.76 (t, J = 4.8 Hz, 2H), 3.55 – 3.41 (m, 2H), 2.60 – 2.22 (m, 4H). Additional peak (s, 2H), (s, 3H), (m, 1H) osbcured by solvent. Example 34.2- 6-(benzo[d]thiazol-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)m ethyl)-1- (2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-(benzo[d]thiazol-4-ylmethoxy)pyridin-2-yl)piperidin -1-yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 9.29 (s, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.74 – 7.60 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 5.97 (s, 2H), 4.79 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 4.02 – 3.81 (m, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.39 (t, J = 12.2 Hz, 2H), 3.11 – 3.01 (m, 1H), 2.35 – 2.12 (m, 4H). Additional peak (s, 3H) obscured by solvent. Example 35.2- 6-(isoquinolin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methy l)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-(isoquinolin-7-ylmethoxy)pyridin-2-yl)piperidin-1-y l)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acidwas made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 9.71 (s, 1H), 8.56 (d, J = 6.4 Hz, 1H), 8.52 (s, 1H), 8.41 (d, J = 6.5 Hz, 1H), 8.36 – 8.21 (m, 3H), 8.02 (dd, J = 8.6, 1.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.73 (s, 2H), 4.81 (s, 2H), 4.62 (t, J = 4.9 Hz, 2H), 3.91 (d, J = 12.2 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.42 (dt, J = 13.6, 6.9 Hz, 2H), 3.30 (s, 3H), 3.19 – 2.99 (m, 1H), 2.34 – 2.13 (m, 4H). Example 36.1-(2-methoxyethyl)-2- 6-(quinolin-7-ylmethoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2- yl)piperidin-1- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 9.08 (dd, J = 5.2, 1.5 Hz, 1H), 8.95 (d, J = 8.3 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.29 – 8.22 (m, 2H), 8.03 (dd, J = 8.5, 1.4 Hz, 1H), 7.96 (dd, J = 8.5, 1.4 Hz, 1H), 7.92 (dd, J = 8.4, 5.1 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.75 (s, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.9 Hz, 2H), 3.89 (d, J = 12.2 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.47 – 3.35 (m, 2H), 3.30 (s, 3H), 3.06 (p, J = 5.4 Hz, 1H), 2.32 – 2.13 (m, 4H). Example 37. 2- carbamoyl-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((4-carbamoyl-2,6-difluorobenzyl)oxy)pyridin-2-yl)p iperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.75 – 7.62 (m, 1H), 7.56 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 5.52 (s, 2H), 4.89 (s, 4H), 4.64 (t, J = 4.9 Hz, 2H), 3.96 (d, J = 12.1 Hz, 2H), 3.78 (t, J = 4.8 Hz, 2H), 3.45 (s, 4H), 2.29 (s, 4H). Example 38.2-((4-(6-((4-cyclopropylbenzyl)oxy)pyridin-2-yl)piperidin -1-yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-((4-cyclopropylbenzyl)oxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 7.3 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.35 (s, 2H), 4.81 (s, 2H), 4.62 (s, 0H), 3.90 (s, 2H), 3.77 (d, J = 4.8 Hz, 2H), 3.08 (s, 2H), 2.23 (s, 4H), 1.90 (s, 2H), 1.10 (d, J = 15.7 Hz, 1H), 0.95 (dd, J = 8.3, 2.2 Hz, 1H), 0.70 – 0.60 (m, 2H). Example 39. 2- fluoro-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid. 2-((4-(6-((6-fluoro-1H-indazol-5-yl)methoxy)pyridin-2-yl)pip eridin-1- yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxy lic acid was made according to Procedure 6.1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 11.3 Hz, 1H), 8.33 (d, J = 22.3 Hz, 2H), 8.06 (d, J = 10.0 Hz, 1H), 8.01 – 7.89 (m, 3H), 7.82 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 6.8 Hz, 1H), 4.81 (s, 4H), 4.66 (t, J = 4.8 Hz, 2H), 4.02 (d, J = 13.3 Hz, 2H), 3.78 (t, J = 4.8 Hz, 2H), 3.56 – 3.42 (m, 1H), 2.42 (s, 4H).
- 2 -na t e xo- ) S2 ( [ [ - 3 - ] l yh t e m ] l y d i r e p i p - 1 - ] l yd i r y p -2- ] yxoh t e 77m ] l y n e h p - o r o u l f - 2 - ) l y -1- l o z a i r d t l i c y a p c o r i l y p x o l o c b y r c - a 4 c - ( - 5 - 4 [ e l [ - o z 6 [ a - d 4 i [ [ - m 2 i z . 0 n e 4 b ] e l 7 l y e r p h u t e d ma e m c x o E ] l y r P Methyl 2-[[4-[6-[[4-(4-cyclopropyltriazol-1-yl)-2-fluoro-phenyl]met hoxy]-2- pyridyl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]ben zimidazole-5-carboxylate: 1- [4-(bromomethyl)-3-fluoro-phenyl]-4-cyclopropyl-triazole (49 mg, 0.16 mmol) followed by cesium carbonate (64 mg, 0.20 mmol) was added to a solution of methyl 2-[[4-(6-hydroxy-2- pyridyl)-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]ben zimidazole-5-carboxylate (60 mg, 0.14 mmol) in acetonitrile (1.5 mL). The resulting solution was stirred and heated to 60 °C for 16 hours after which the reaction contents were poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (Eluent: EtOAc/hexane/MeOH) to give the desired product. 2-[[4-[6-[[4-(4-cyclopropyltriazol-1-yl)-2-fluoro-phenyl]met hoxy]-2-pyridyl]- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol e-5-carboxylic acid (Example 40): Methyl 2-[[4-[6-[[4-(4-cyclopropyltriazol-1-yl)-2-fluoro-phenyl]met hoxy]-2-pyridyl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (63 mg, 0.097 mmol) was taken up in acetonitrile (2 mL). Next, aqueous lithium hydroxide (0.84 M, 0.35 mL, 0.29 mmol) was added. The solution was heated to 100 °C for 7 minutes then cooled to r.t. and diluted with 5% aqueous citric acid to a pH of ~5. The mixture was extracted with EtOAc (2 x 15 mL) and the combined organic extracts dried over MgSO4 and concentrated in vacuo. The material was purified by RP-HPLC (eluent: MeCN/water gradient with 0.1% TFA) to yield Example 40 as the trifluoroacetate salt. ES/MS: 638.6 (M+H + ); 1H NMR (400 MHz, Methanol- d4) δ 8.36 (d, J = 1.5 Hz, 1H), 8.29 (s, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.76 – 7.62 (m, 4H), 6.92 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 5.54 (s, 2H), 5.26 (qd, J = 7.1, 2.4 Hz, 1H), 4.86 – 4.80 (m, 1H), 4.70 (ddd, J = 13.5, 7.2, 4.2 Hz, 2H), 4.62 (s, 2H), 4.47 (dt, J = 9.2, 5.9 Hz, 1H), 3.66 (t, J = 14.2 Hz, 2H), 3.20 – 3.07 (m, 2H), 2.97 (p, J = 7.9 Hz, 1H), 2.89 – 2.76 (m, 1H), 2.53 (ddt, J = 11.5, 9.1, 7.3 Hz, 1H), 2.20 – 2.07 (m, 4H), 2.08 – 2.00 (m, 1H), 1.10 – 0.99 (m, 2H), 0.92 – 0.80 (m, 2H). Example 41. (S)-2- 2-fluoro-4-(1H-1,2,3-triazol-1-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid. (S)-2-((4-(6-((2-fluoro-4-(1H-1,2,3-triazol-1-yl)benzyl)oxy) pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid was made according to Procedure 7.1H NMR (400 MHz, Methanol-d4) δ 8.60 (d, J = 1.2 Hz, 1H), 8.45 – 8.23 (m, 1H), 8.07 (dd, J = 8.6, 1.5 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.92 – 7.74 (m, 4H), 7.70 (dd, J = 8.3, 7.3 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.57 (d, J = 1.1 Hz, 2H), 5.25 (qd, J = 7.1, 2.4 Hz, 1H), 4.86 – 4.63 (m, 5H), 4.46 (dt, J = 9.3, 5.8 Hz, 1H), 3.92 (s, 2H), 3.44 (s, 2H), 3.14 – 3.02 (m, 1H), 2.93 – 2.73 (m, 1H), 2.63 – 2.43 (m, 1H), 2.23 (s, 4H). Example 42.2-((4-(6-((5-cyanoquinolin-8-yl)methoxy)pyridin-2-yl)pipe ridin-1-yl)methyl)- 1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid. 2-((4-(6-((5-cyanoquinolin-8-yl)methoxy)pyridin-2-yl)piperid in-1-yl)methyl)-1- (2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid was made according to Procedure 7. 1H NMR (400 MHz, Chloroform-d) δ 9.08 (d, 1H), 8.58 (dd, 1H), 8.00 (s, 2H), 7.92 (s, 1H), 7.75 – 7.61 (m, 3H), 7.59 – 7.49 (m, 1H), 6.83 (dd, 2H), 6.17 (s, 2H), 4.97 (s, 2H), 4.76 (s, 2H), 4.03 (s, 7H), 3.64 (t, 2H), 3.43 (s, 2H), 3.24 (s, 3H), 3.03 (s, 1H), 2.29 (d, 4H)
-H 1 - ) l yh t e m ) l y - 1 - n i d i r e p i p ) l y - 2 - n i d i ry p ) yxoh t e m ) l y - 5 -n a r u f 08 o z n e bo s i o r dy h i d - 3 , 1 -ox o - 1 ( ( -6 ( - 4 ( ( . - d 2 - i c ) l a y c h i l t e yx y o xo b r h t a e c - M - 6 -2 e l ( - o z 1 . a : 3 d i 4 m 8 e l i ] e r p d [ u a o d m z e n c x o E e b r P Methyl 1-(2-methoxyethyl)-2-((4-(6-((1-oxo-1,3-dihydroisobenzofuran -5- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]im idazole-6-carboxylate: Methyl 1-(2-methoxyethyl)-2-((4-(6-((1-oxo-1,3-dihydroisobenzofuran -5-yl)methoxy)pyridin-2- yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate was synthesized as described in Procedure 7, step 1, using methyl 2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(2- methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate and 5-(hydroxymethyl)isobenzofuran- 1(3H)-one. ES/MS: 571.3 (M+H + ). 1-(2-methoxyethyl)-2-((4-(6-((1-oxo-1,3-dihydroisobenzofuran -5- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]im idazole-6-carboxylic acid (Example 43): To a seal tube containing a solution of methyl 1-(2-methoxyethyl)-2-((4-(6-((1- oxo-1,3-dihydroisobenzofuran-5-yl)methoxy)pyridin-2-yl)piper idin-1-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate (12.5 mg, 0.022 mmol) in pyridine (0.5 mL), lithium iodide (29.3 mg) was added.The reaction vessel was sealed and heated at 150 °C for 4 hours. The reaction mixture was cooled, concentrated in vacuo, and purified RP-HPLC (eluent: water / MeCN 0.1% TFA) to provide Example 43. ES/MS: 557.2 (M+H + ); 1H NMR (400 MHz, Methanol-d4) δ 8.33 (t, J = 0.9 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.72 – 7.59 (m, 3H), 6.93 (d, J = 7.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 5.58 (s, 2H), 5.40 (s, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.89 (d, J = 12.2 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.45 – 3.33 (m, 2H), 3.11 – 2.99 (m, 1H), 2.19 (s, 4H). Example 44.1-(2-methoxyethyl)-2- 3-oxo-1,3-dihydroisobenzofuran-5- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]im idazole-6-carboxylic acid. 1-(2-methoxyethyl)-2-((4-(6-((3-oxo-1,3-dihydroisobenzofuran -5- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]im idazole-6-carboxylic acid was made according to Procedure 8.1H NMR (400 MHz, Methanol-d4) δ 8.45 – 8.30 (m, 1H), 8.04 (dd, J = 8.6, 1.5 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75 – 7.59 (m, 3H), 6.93 (d, J = 7.3 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.58 (s, 2H), 5.40 (s, 2H), 4.80 (s, 2H), 4.61 (t, J = 4.9 Hz, 2H), 3.95 – 3.83 (m, 2H), 3.80 – 3.69 (m, 2H), 3.45 – 3.34 (m, 2H), 3.09 – 3.00 (m, 1H), 2.31 – 2.10 (m, 4H). Additional peak (s, 3H) obscured by solvent.
28 s dnuop mo C . 2 e l ba T 38
48 58 68 78 88 98 09 19 29 39 49 59 69 79 89 C. BIOLOGICAL DATA GLP-1R ACTIVATION – cAMP Assay 1 GLP-1R activation by a compound of the present disclosure was quantified by measuring cAMP increase in CHO cells stably expressing GLP-1R (MultiSpan product # C1267-1a). The cells were harvested and plated in growth medium (DMEM/F-12 (Corning product # 10-090-CV) supplemented with 10% FBS (HyClone product # SH30071-03), penicillin/streptomycin (Corning product # 30-002CI) and 10μg/ml puromycin (Gibco product # A11138-03)) at 1,000 cells/well in a 384-well plate (Greiner product # 781080). The cells were then incubated overnight at 37 °C, 5% CO 2 . The next day, the medium was removed and the cells were washed with DPBS (Corning product # 21-031-CM) before adding the assay medium (HBSS, Corning product # 21-023-CV) with 20mM Hepes (Gibco product # 15630-080) and 0.1% BSA (Rockland Immunochemicals product # BSA-1000)). Following the medium change, the cells were incubated for 1 hour at 37 °C, 5% CO 2 . The tested GLP-1 compound was added to the cells in a 10 point dose response followed by a 30 minutes incubation at 37 °C, 5% CO2. cAMP concentration increase was then detected using Cisbio’s cAMP Gs Dynamic Kit (product # 62AM4PEC) according to the manufacturer’s protocol. The response was plotted against the log of the agonist concentration and fitted to a sigmoidal equation to determine the EC50. GLP-1R ACTIVATION – cAMP Assay 2 GLP-1R activation by small molecule agonists is quantified by measuring cAMP increase in CHO cells stably expressing GLP-1R (MultiSpan product # C1267-1a). 50nL of agonists are pre-spotted in a 10 point dose response onto 384-well plate (Corning product # CL3826) using the Labcyte Echo System. The cells are harvested and plated in assay buffer (HBSS (Corning product # 21-023-CV) with 20mM Hepes (Gibco product # 15630-080) and 0.1% BSA (Rockland Immunochemicals product # BSA-1000)) or 100% Human Plasma (Innovative Research product #50-643-396) at 1,000 cells/well, 10μL/well, onto the pre-spotted plates. The cells are then incubated for 30 minutes at 37 °C, 5% CO 2 . cAMP concentration increase is then detected using Cisbio’s cAMP Gs Dynamic Kit (product # 62AM4PEC) according to the manufacturer’s protocol. The response is plotted against the log of the agonist concentration and fitted to a sigmoidal equation to determine the EC 50 . Table 3. Activity Although the foregoing has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.
Next Patent: EGFR INHIBITORS