Tetrahydro-benzo [ D ] azepin slow derivatives as GPR120 modulators
阅读说明：本技术 四氢-苯并[d]氮杂环庚熳衍生物作为gpr120调节剂 (Tetrahydro-benzo [ D ] azepin slow derivatives as GPR120 modulators ) 是由 简·布朗 斯蒂芬·康诺利 斯特芬·V·F·汉森 加文·米尔恩 巴拉特·史姆普卡德 唐·史密 于 2018-03-26 设计创作，主要内容包括：能够调节G蛋白偶联受体GPR120的式(I)的新型四氢异喹啉和四氢苯并氮杂环庚熳化合物,包括该化合物的组合物,以及使用它们来控制体内胰岛素水平和治疗诸如糖尿病、炎症、肥胖和代谢性疾病的病症的方法。<Image he="382" wi="700" file="DDA0002282729150000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Novel tetrahydroisoquinoline and tetrahydrobenzazepin slow-release compounds of formula (I) that modulate the G-protein coupled receptor GPR120, compositions comprising the compounds, and methods of using the same to control insulin levels in vivo and to treat disordersSuch as diabetes, inflammation, obesity, and metabolic disorders.)
1. A compound of formula (I):
wherein Ar is 6-membered aryl, 5-or 6-membered heteroaryl or 5-or 6-membered cycloalkyl;
m1is 1 and m2Is 2, or m1Is 2 and m2Is 1;
j is-C (R)21R22)-、-O-、-N(R21) -or-S-, with the proviso that when J is-O-, -N (R)21) or-S-, m1Is 2;
x is-O-, -S-or-C (R)31R32) -, Y is-O-or-C (R)41R42) -, Z is-C (R)51R52) -, and n1、n2And n3Independently selected from 0 or 1, provided that n1、n2And n3Must be 1, and at least one of X, Y or Z must be-C (R), respectively31R32)-、-C(R41R42) -or-C (R)51R52)-；
When X and Y are each-C (R)31R32) -and-C (R)41R42) When is, R31And R41Can be combined with X and Y to form (C)3-C5) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
when Y and Z are each-C (R)41R42) -and-C (R)51R52) When is, R41And R51Can be combined with Y and Z to form (C)3-C5) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
when X, Y and Z are each independently-C(R31R32)-、-C(R41R42) -and-C (R)51R52) When is, R31And R51May be formed with X, Y and Z (C)4-C7) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
R1、R2、R11、R12、R21、R22、R31、R32、R41、R42、R51and R52Independently selected from hydrogen, deuterium, halogen or (C) optionally substituted by halogen1-C3) An alkyl group;
a is-CO2H、-CO2R3、-CH2OH, tetrazolyl, 3-hydroxyisoxazol-5-yl or acid bioisosteres;
R3is (C)1-C6) Alkyl or (C)1-C6) A cycloalkyl group;
ar is optionally substituted 1,2 or 3 times by W, wherein W is (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, (C)1-C10) Alkoxy group, (C)2-C10) Dialkylamino group, (C)1-C10) Alkylthio group, (C)2-C10) Heteroalkyl group, (C)3-C10) Cycloalkyl group, (C)3-C10) Heterocycloalkyl, halogen, (C)1-C10) Haloalkyl, (C)1-C10) Perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted arylalkyl, and when Ar is substituted with multiple substituents, each substituent is independently selected;
g is an optionally substituted 6-to 10-membered aryl, 5-to 10-membered heteroaryl or fused aryl or heteroaryl ring system;
g is optionally substituted one or more times by B, wherein B is (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, (C)1-C10) Alkoxy group, (C)2-C10) Dialkyl radicalAmino group, (C)1-C10) Alkylthio group, (C)2-C10) Heteroalkyl group, (C)3-C10) Cycloalkyl group, (C)3-C10) Heterocycloalkyl, halogen, (C)1-C10) Haloalkyl, (C)1-C10) Perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, cyano or E-M, wherein E is-O-, -S-or-N (R)4) -, and M is optionally substituted (C)1-C7) Alkyl, (C)3-C7) Cycloalkyl, fluoro (C)1-C3) An alkyl group, a 5-to 10-membered heterocyclic group, or an optionally substituted 6-to 10-membered aryl group, and when G is substituted with a plurality of substituents, each substituent is independently selected;
R4is hydrogen, deuterium or (C) optionally substituted by halogen1-C3) An alkyl group;
or a pharmaceutically acceptable salt or solvate (e.g. hydrate) thereof, or a corresponding N-oxide or prodrug (e.g. ester prodrug).
2. The compound of claim 1, wherein J is-C (R)21R22)-。
3. A compound according to any one of the preceding claims, wherein R1、R2、R11、R12、R21And R22Is hydrogen.
4. A compound according to any one of the preceding claims, wherein Ar is 6-membered aryl.
5. The compound of any one of the preceding claims, which is a compound of formula (Id):
R1、R2、R11、R12、R21and R22Independently selected from hydrogen and (C)1-C3) An alkyl group;
x is-O-, -S-or-C (R)31R32) -, Y is-O-or-C (R)41R42) -, Z is-C (R)51R52) -, and n1、n2And n3Independently selected from 0 or 1, provided that n1、n2And n3Must be 1, and at least one of X, Y or Z must be-C (R), respectively31R32)-、-C(R41R42) -or-C (R)51R52)-；
When X and Y are each-C (R)31R32) -and-C (R)41R42) When is, R31And R41Can be combined with X and Y to form (C)3-C6) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
when Y and Z are each-C (R)41R42) -and-C (R)51R52) When is, R41And R51Can be combined with Y and Z to form (C)3-C6) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
when X, Y and Z are each-C (R)31R32)-、-C(R41R42) -and-C (R)51R52) When is, R31And R51May be formed with X, Y and Z (C)4-C7) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
R31、R32、R41、R42、R51and R52Independently selected from hydrogen, deuterium, halogen or (C) optionally substituted by halogen1-C3) An alkyl group;
a is-CO2H、-CO2R3、-CH2OH, tetrazolyl, 3-hydroxyisoxazol-5-yl or acid bioisosteres;
R3is (C)1-C6) Alkyl or (C)3-C6) A cycloalkyl group;
the phenyl ring being optionally substituted 1,2 or 3 times by W, wherein W is (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, (C)1-C10) Alkoxy group, (C)2-C10) Dialkylamino group, (C)1-C10) Alkylthio group, (C)2-C10) Heteroalkyl group, (C)3-C10) Cycloalkyl group, (C)3-C10) Heterocycloalkyl, halogen, (C)1-C10) Haloalkyl, (C)1-C10) Perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted arylalkyl, and wherein when the phenyl ring is substituted with multiple substituents, each substituent is independently selected;
g is an optionally substituted 6-to 10-membered aryl, 5-to 10-membered heteroaryl or fused aryl or heteroaryl ring system;
g is optionally substituted one or more times by B, wherein B is (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, (C)1-C10) Alkoxy group, (C)2-C10) Dialkylamino group, (C)1-C10) Alkylthio group, (C)2-C10) Heteroalkyl group, (C)3-C10) Cycloalkyl group, (C)3-C10) Heterocycloalkyl, halogen, (C)1-C10) Haloalkyl, (C)1-C10) Perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, cyano or E-M, wherein E is-O-, -S-or-N (R)4) -, and M is optionally substituted (C)1-C7) Alkyl, (C)3-C7) Cycloalkyl, fluoro (C)1-C3) An alkyl group, a 5-to 10-membered heterocyclic group, or an optionally substituted 6-to 10-membered aryl group, and wherein when G is substituted with a plurality of substituents, each substituent is independently selected;
R4is hydrogen, deuterium or (C) optionally substituted by halogen1-C3) An alkyl group;
or a pharmaceutically acceptable salt or solvate (e.g. hydrate) thereof, or a corresponding N-oxide or prodrug (e.g. ester prodrug).
6. The compound of claim 5, wherein R1、R2、R11、R12、R21And R22Is hydrogen.
7. A compound according to claim 5 or claim 6, wherein n is1Is 0, Y is-C (R)41R42) -and Z is-C (R)51R52)-。
8. The compound of claim 5 or 6, wherein X and Y are each-C (R)31R32) -and-C (R)41R42) -, and R31And R41Taken together with X and Y to form a cyclopropyl ring, e.g.
9. The compound of claim 5 or 6, wherein X, Y and Z are each-C (R)31R32)-、-C(R41R42) -and-C (R)51R52) -, and R31And R51Form a cyclobutyl ring together with X, Y and Z, e.g.
10. The compound of any one of claims 5 to 9, wherein a is-CO2H。
11.A compound according to any one of claims 5 to 10, wherein X-Y-Z-A is attached to the 2-or 3-position of the phenyl ring.
12. According to any of claims 5-8 or 10-11The compound of (1), wherein X-Y-Z-A is-CH2-CH2-COOH、-CH2CH(CH3) COOH or
13. The compound of any one of claims 5 to 12, wherein W is optionally substituted (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halogen or optionally substituted (C)1-C6) An alkoxy group.
14. A compound according to any one of claims 5 to 12, wherein the phenyl ring is unsubstituted by W.
15. The compound of any one of claims 5 to 14, wherein G is optionally substituted 6-membered aryl or 6-membered heteroaryl.
16. The compound of claim 15, wherein G is optionally substituted phenyl.
17. A compound according to any one of claims 5 to 16, wherein G is substituted 1,2 or 3 times with B.
18. The compound of claim 17, wherein B is selected from halogen and E-M, wherein E is-O-and M is optionally substituted (C)1-C7) Alkyl, (C)3-C7) Cycloalkyl, fluoro (C)1-C3) An alkyl group or an optionally substituted 6-to 10-membered aryl group.
19. The compound of claim 18, wherein B is selected from fluoro, phenoxy, -OCF3、-O-CH(CH3)2、
20. A compound according to any one of claims 5 to 19, wherein G is phenyl substituted with fluorine in the 2-or 3-position.
21. A compound according to any one of claims 5 to 19, wherein G is phenyl substituted at the 5-position by B, wherein B is selected from the group consisting of phenoxy, -OCF3、-O-CH(CH3)2、
22. The compound of claim 21, wherein B is phenoxy.
23. The compound according to any one of claims 1 to 4, which is a compound of formula (Ie):
R1、R2、R11、R12、R21and R22Independently selected from hydrogen and (C)1-C3) An alkyl group;
x is-O-, -S-or-C (R)31R32) -, Y is-O-or-C (R)41R42) -, Z is-C (R)51R52) -, and n1、n2And n3Independently selected from 0 or 1, provided that n1、n2And n3Must be 1, and at least one of X, Y or Z must be-C (R), respectively31R32)-、-C(R41R42) -or-C (R)51R52)-；
When X and Y are each-C (R)31R32) -and-C (R)41R42) When is, R31And R41Can be combined with X and Y to form (C)3-C6) A cycloalkyl ring, which canTo be optionally (C)1-C3) Alkyl or halogen substitution;
when Y and Z are each-C (R)41R42) -and-C (R)51R52) When is, R41And R51Can be combined with Y and Z to form (C)3-C6) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
when X, Y and Z are each-C (R)31R32)-、-C(R41R42) -and-C (R)51R52) When is, R31And R51May be formed with X, Y and Z (C)4-C7) A cycloalkyl ring, which may optionally be substituted by (C)1-C3) Alkyl or halogen substitution;
R31、R32、R41、R42、R51and R52Independently selected from hydrogen, deuterium, halogen or (C) optionally substituted by halogen1-C3) An alkyl group;
a is-CO2H、-CO2R3、-CH2OH, tetrazolyl, 3-hydroxyisoxazol-5-yl or acid bioisosteres;
R3is (C)1-C6) Alkyl or (C)3-C6) A cycloalkyl group;
the phenyl ring being optionally substituted 1,2 or 3 times by W, wherein W is (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, (C)1-C10) Alkoxy group, (C)2-C10) Dialkylamino group, (C)1-C10) Alkylthio group, (C)2-C10) Heteroalkyl group, (C)3-C10) Cycloalkyl group, (C)3-C10) Heterocycloalkyl, halogen, (C)1-C10) Haloalkyl, (C)1-C10) Perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted arylalkyl, and wherein when the phenyl ring is substituted with multiple substituents, each substituent is independently selected;
g is an optionally substituted 6-to 10-membered aryl, 5-to 10-membered heteroaryl or fused aryl or heteroaryl ring system;
g is optionally substituted one or more times by B, wherein B is (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, (C)1-C10) Alkoxy group, (C)2-C10) Dialkylamino group, (C)1-C10) Alkylthio group, (C)2-C10) Heteroalkyl group, (C)3-C10) Cycloalkyl group, (C)3-C10) Heterocycloalkyl, halogen, (C)1-C10) Haloalkyl, (C)1-C10) Perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, cyano or E-M, wherein E is-O-, -S-or-N (R)4) -, and M is optionally substituted (C)1-C7) Alkyl, (C)3-C7) Cycloalkyl, fluoro (C)1-C3) An alkyl group, a 5-to 10-membered heterocyclic group, or an optionally substituted 6-to 10-membered aryl group, and wherein when G is substituted with a plurality of substituents, each substituent is independently selected;
R4is hydrogen, deuterium or (C) optionally substituted by halogen1-C3) An alkyl group;
or a pharmaceutically acceptable salt or solvate (e.g. hydrate) thereof, or a corresponding N-oxide or prodrug (e.g. ester prodrug).
24. The compound of claim 23, wherein R1、R2、R11、R12、R21And R22Is hydrogen.
25. A compound according to claim 23 or claim 24, wherein n is1Is 0, Y is-C (R)41R42) -and Z is-C (R)51R52)-。
26. The compound of claim 23 or 24, wherein X and Y are each-C (R)31R32) -and-C (R)41R42) -, and R31And R41Taken together with X and Y to form a cyclopropyl ring, e.g.
27. The compound of claim 23 or 24, wherein X, Y and Z are each-C (R)31R32)-、-C(R41R42) -and-C (R)51R52) -, and R31And R51Form a cyclobutyl ring together with X, Y and Z, e.g.
28. The compound of any one of claims 23 to 27, wherein a is-CO2H。
29.A compound according to any one of claims 23 to 28, wherein X-Y-Z-A is attached to the 2-or 3-position of the phenyl ring.
30. The compound of any one of claims 23-26 or 28-29, wherein X-Y-Z-A is-CH2-CH2-COOH、-CH2CH(CH3) COOH or
31. The compound of any one of claims 23 to 30, wherein W is optionally substituted (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halogen or optionally substituted (C)1-C6) An alkoxy group.
32. A compound according to any one of claims 23 to 30, wherein the phenyl ring is unsubstituted by W.
33. The compound of any one of claims 23 to 32, wherein G is optionally substituted 6-membered aryl or 6-membered heteroaryl.
34. The compound of claim 33, wherein G is optionally substituted phenyl.
35. A compound according to any one of claims 23 to 34, wherein G is substituted 1,2 or 3 times with B.
36. The compound of claim 35, wherein B is selected from halogen and E-M, wherein E is-O-and M is optionally substituted (C)1-C7) Alkyl, (C)3-C7) Cycloalkyl, fluoro (C)1-C3) An alkyl group or an optionally substituted 6-to 10-membered aryl group.
37. The compound of claim 36, wherein B is selected from fluoro, phenoxy, -OCF3、-O-CH(CH3)2、
38. A compound according to any one of claims 23 to 37, wherein G is phenyl substituted with fluorine in the 2-or 3-position.
39. The compound of any one of claims 23 to 37, wherein G is phenyl substituted at the 5-position with B, wherein B is selected from the group consisting of phenoxy, -OCF3、-O-CH(CH3)2、Group (d) of (a).
40. The compound of claim 39, wherein B is-OCF3。
41. The compound of claim 1, wherein the compound is selected from the group consisting of:
3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid,
3- (3- (5-cyclobutoxy-2-fluorophenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid,
3- (3- (5-Cyclopropoxy-2-fluorophenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid,
3- (3- (3-fluoro-5-isopropoxyphenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid,
3- (3- (2-fluoro-5-isopropoxyphenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid,
3- (3- (2-fluoro-5-phenoxyphenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid
(R) -3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) -2-methylpropionic acid,
2- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) cyclopropanecarboxylic acid,
3- (3- (5-cyclobutoxy-2-fluorophenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid, and
3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-7-yl) propionic acid;
or a pharmaceutically acceptable salt thereof.
42. A compound according to any one of the preceding claims for use as a medicament.
43. A compound according to any one of claims 1 to 41 for use in the treatment of a disease or disorder associated with GPR120 activity.
44. The compound for use according to claim 43, wherein said disease or condition associated with GPR120 activity is selected from the group consisting of: type 1 or type 2 diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, lipid metabolism disorders, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, ketoacidosis, thrombotic disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, edema.
45. A method of treating a subject suffering from or susceptible to a disease or disorder associated with GPR120 activity, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of any one of claims 1 to 41.
46. The method of claim 45, wherein the disease or condition associated with GPR120 activity is selected from the group consisting of: type 1 or type 2 diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, lipid metabolism disorders, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, ketoacidosis, thrombotic disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, hypertension, cancer, NASH and edema.
47. A method for modulating circulating insulin concentration in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 41.
48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 and one or more pharmaceutically acceptable excipients.
49. The pharmaceutical composition of claim 48, wherein said composition further comprises one or more other therapeutically active compounds for the treatment of type 2 diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, lipid metabolism disorders, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, ketoacidosis, thrombotic disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer, NASH, and edema.
50. A process for preparing a compound according to any one of claims 1 to 41, comprising:
reacting a compound of formula (II)
With compounds of the formula (III)
Examples
General experimental conditions
All starting materials and solvents were obtained from commercial sources or prepared according to literature methods.
Silica gel chromatography is performed on automated flash chromatography systems, such as the CombiFlash company, CombiFlash Rf system, or reveliers X2 flash system, using
Analytical LCMS experiments were performed to determine retention times and associated mass ions using the following methods:
a Waters Acquity H-grade UPLC system with QDa mass detector;
an Agilent 1200 series HPLC system coupled to an Agilent 6110 or 6120 series single quadrupole mass spectrometer; or
A Dionex Ultimate 3000 series HPLC system coupled to CMS expressed by Advion was ionized using APCI.
Preparative HPLC purification was performed using Waters X-Select CSH C18, 5 μm, 9X50 mm column, using 0.1% formic acid and 0.1% aqueous formic acid in gradient MeCN. Fractions were collected after UV detection at a single wavelength measured by a variable wavelength detector on Gilson 215 or varianpstar preparative HPLC, or after mass ion and UV detection by electrospray with positive and negative ions and dual wavelength detection on Waters fraction lynx LCMS at a single wavelength measured by a ZQ single quadrupole mass spectrometer.
NMR spectra were recorded using either a Bruker Avance III 400MHz instrument or a Bruker Avance III HD 500MHz instrument, using residual non-deuterated solvents or tetramethylsilane as reference.
High Resolution Mass Spectra (HRMS) were obtained on a Bruker microOTOF-Q II (ESI).
pEC50 data were obtained by the following procedure:
human GPR120- β arrestin 2 Bioluminescence Resonance Energy Transfer (BRET) agonist assay procedure
At 37 deg.C, 5% CO2Next, the mixture was purified by a method comprising adding 10% (v: v) Fetal Bovine Serum (FBS) and 1% (v: v)10,000 units of penicillin/10 mgml-1HEK293T cells were cultured in growth medium consisting of DMEM L-glutamine medium of streptomycin HEK293T cells transiently co-expressing human GPR120(FFA1) and β -arrestin 2 were generated by transfecting a plasmid encoding the hGPR120(FFA1) construct fused at its C-terminus to enhanced yellow fluorescent protein (eYFP) and another plasmid encoding β -arrestin 2 fused to Renilla luciferase (RLuc) using Polyethyleneimine (PEI) as a transfection reagent.
Transfected cells were cryopreserved in batches to ensure consistency between replicates. Twenty-four hours after transfection, cells were harvested with non-enzymatic cell dissociation buffer and resuspended in DMEM medium supplemented with 10% DMSO and 10% FBS, then first transferred to-80 ℃ overnight and then transferred to liquid nitrogen for long-term storage. The day before the experiment, cells were thawed at 37 ℃ and resuspended in growth medium. Then, 96-well white opaque bottom microtiter plates were seeded with 40,000 cells in a volume of 100. mu.l per well of growth medium, and the seeded plates were then plated at 37 ℃ with 5% CO2Incubate overnight. On the day of the BRET assay, cells were washed twice with BRET assay buffer (hanks Balanced salt solution (HBSS) (pH 7.4) supplemented with 10mM HEPES), then 80. mu.l of BRET assay buffer was added to each well, after which the plates were placed on a flat plate37℃、5％CO2Incubate for 30 minutes. Then, the Renilla luciferase substrate coelenterazine h (5 μ M) was added to the cells and incubated at 37 ℃ for 10 minutes, followed by addition of GPR120 agonist (TUG-891) or test compound and incubation at 37 ℃ for an additional 5 minutes.
The bioluminescence at λ 535nm and λ 475nm was then measured with a Pherastar FsX instrument and BRET values were then calculated using the λ 535/λ 475 ratio of bioluminescence. Calculation of the gpr120 agonist potency value (pEC) by normalizing BRET values to DMSO vehicle (0% control) and TUG-891 (100% control) and then fitting the normalized data to a 3-parameter concentration-response curve50)。
Experimental protocol 1
The compound 13- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a) Preparation procedure of 1b
A mixture of 6-bromoisoquinoline 1a (5.0g, 24mmol), tetrabutylammonium chloride hydrate (0.71g, 2.4mmol), Pd-162(0.48g, 1.2mmol), tert-butyl acrylate (3.9mL, 26mmol) and N-cyclohexyl-N-methylcyclohexylamine (7.7mL, 36mmol) in 1, 4-dioxane (100mL) was stirred at 80 ℃ for 20 h. The mixture was cooled to RT and then concentrated in vacuo. The residue was partitioned between water (100mL) and DCM (100mL) and the resulting white precipitate was collected by filtration. The solid was dissolved in a mixture of methanolic ammonia (1M, 100mL) and DCM (100mL) and the solution was washed with water (100 mL). The residual product was extracted from the aqueous solution using DCM (300mL) and the combined organic phases were passed through a hydrophobic membrane and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to give (E) -tert-butyl 3- (isoquinolin-6-yl) acrylate 1b as a light brown solid: m/z 256[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ9.24(s,J＝1.0Hz,1H),8.56(d,J＝5.7Hz,1H),7.97(dd,J＝8.6,0.8Hz,1H),7.90–7.87(m,1H),7.77(dd,J＝8.6,1.7Hz,1H),7.73(d,J＝16.1Hz,1H),7.66(dd,J＝5.8,1.0Hz,1H),6.55(d,J＝16.0Hz,1H),1.56(s,9H)。
b) Preparation procedure of 1c
A mixture of (E) -tert-butyl 3- (isoquinolin-6-yl) acrylate 1b (1.1g, 4.2mmol) and carbon-supported platinum (0.82g, 0.21mmol) in AcOH (50mL) was heated at 50 ℃ in hydrogen (5Bar) for 2 h. The mixture was cooled to RT, filtered and the solvent was concentrated in vacuo. NaOH solution (2M) was added until pH > 10, and the product was then extracted with EtOAc (600 mL). Dissolving the organic solution in Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% (0.7M ammonia/MeOH) in DCM) to give tert-butyl 3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 1c as a colorless solid: m/z 262[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ6.98–6.86(m,3H),3.83(s,2H),2.96(t,J＝5.9Hz,2H),2.73(t,J＝7.5Hz,2H),2.66(t,J＝6.0Hz,2H),2.46(t,J＝7.5Hz,2H),1.37(s,9H)。
c) Preparation procedure of 1d
Tert-butyl 3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 1c (3.0g, 11mmol), Cs2CO3(6.0g, 18mmol), Pd-176(1.7g, 2.2mmol) and BINAP (1.5g, 2.4mmol) were placed in a sealed vial, which was then evacuated and backfilled with nitrogen three times. A solution of 2-bromo-1-fluoro-4- (trifluoromethoxy) benzene (2ml, 12mmol) in 1, 4-dioxane (50ml) was added and the mixture was stirred under nitrogen at 105 ℃. After 16h, Cs was added2CO3(6.0g, 18mmol) and DMF (6mL) and the mixture was stirred at 115 ℃ for 3h and then cooled to RT and filtered. The filtrate was diluted with EtOAc (200mL) and then with 20% NaCl solution (200mL)) And (6) washing. The organic solution was washed with MgSO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-20% EtOAc in isohexane) to afford tert-butyl 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 1d: M/z 440[ M + H ] 440]+(ES+)。1H NMR(400MHz,CDCl3)δ7.08-6.97(m,4H),6.84(dd,J＝7.2,2.7Hz,1H),6.80-6.72(m,1H),4.28(s,2H),3.46(t,J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H),2.88(t,J＝7.8Hz,2H),2.53(t,J＝7.8Hz,2H),1.43(s,9H)。
d) Preparation of compound 13- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
A solution of tert-butyl 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 1d (3.0g, 6.8mmol) in DCM (10mL) was treated with TFA (6.0mL, 78mmol), and the mixture was stirred at RT for 2h and then concentrated in vacuo. Residual solvent was removed by co-evaporation with toluene (10mL), and the product was then purified by reverse phase flash chromatography (15-75% MeCN in water, 0.1% formic acid, C18) to give 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 1 as a milk solid: m/z 384[ M + H ]]+(ES+),382[M-H]-(ES-)。1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),7.29(dd,J＝12.5,8.8Hz,1H),7.13-7.00(m,4H),6.98-6.89(m,1H),4.25(s,2H),3.41(t,J＝5.8Hz,2H),2.89(t,J＝5.8Hz,2H),2.78(t,J＝7.6Hz,2H),2.56-2.51(m,2H)。
Human GPR120 pEC50:7.4
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 1. When the starting material is not described in the literature, its synthesis is as follows.
Intermediate 1(I-1)
Step 1: sodium tetrahydroborate (0.6g, 16mmol) was added proportionally to a solution of 3- (benzyloxy) cyclobutanone I-1a (2.8g, 16mmol) in MeOH (50mL) at 0 deg.C and the mixture was stirred at 0 deg.C for 3 h. Adding saturated NaHCO3The solution (70mL) was extracted with EtOAc (300 mL). The organic solution was washed with MgSO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to give (1s,3s) -3- (benzyloxy) cyclobutanol I-1b as a colorless oil:1H NMR(400MHz,CDCl3)δ7.32–7.16(m,5H),4.34(s,2H),3.84(dtd,J＝7.9,7.2,6.5Hz,1H),3.56(tt,J＝7.0,6.2Hz,1H),2.65(dtd,J＝9.4,6.6,3.0Hz,2H),1.86(dtd,J＝9.4,7.6,2.9Hz,2H)。
step 2: NaH (60% w/w in oil, 0.6g, 14mmol) was added to a solution of (1s,3s) -3- (benzyloxy) cyclobutanol I-1b (1.7g, 9.4mmol) in THF (30mL) at 0 deg.C. The mixture was stirred for 15min, then MeI (0.7mL, 11mmol) was added. The mixture was stirred at 0 ℃ for a further 15min, then warmed to RT and stirred for 16 h. Adding saturated NaHCO3The solution (100mL) was extracted with DCM (300 mL). The combined organic phases were washed with Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to give (((1s,3s) -3-methoxycyclobutoxy) methyl) benzene I-1c as a colorless oil: M/z193[ M + H ] 193]+(ES+)。1H NMR(400MHz,CDCl3)δ7.31–7.16(m,5H),4.35(s,2H),3.66–3.56(m,1H),3.48–3.39(m,1H),3.16(s,3H),2.61–2.51(m,2H),1.92–1.81(m,2H)。
And step 3: a mixture of (((1s,3s) -3-methoxycyclobutoxy) methyl) benzene I-1C (1.4g, 7.3mmol) and Pd/C (JMType 39, 10%, 50% w/w) (0.155g, 0.073mmol) in EtOH (50mL) was stirred at RT under a hydrogen atmosphere (5Bar) for 16 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0-60% EtOAc in isohexane) to give (1s,3s) -3-methoxycyclobutanol I-1d as a yellow oil:1HNMR(400MHz,CDCl3)δ3.92(quint,J＝7.2Hz,1H),3.46(quint,J＝6.8Hz,1H),3.23(s,3H),2.79–2.64(m,2H),2.01(s,1H),1.91–1.79(m,2H)。
and 4, step 4: mixing (1s,3s) -3-methoxycyclobutanol I-1d (0.15g, 1.5mmol), 3-bromo-4-fluorophenol I-1e (0.28g, 1.5mmol), and Ph3A mixture of P (0.39g, 1.5mmol) and DIAD (0.286mL, 1.469mmol) in THF (20mL) was heated at 80 deg.C for 2 days. The reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by silica gel chromatography (0-20% EtOAc in isohexane) to give 2-bromo-1-fluoro-4- ((1r,3r) -3-methoxycyclobutoxy) benzene I-1 as a colorless oil:1H NMR(400MHz,CDCl3)δ6.95(dd,J＝9.0,8.1Hz,1H),6.88(dd,J＝5.6,3.0Hz,1H),6.62(ddd,J＝9.0,3.8,3.0Hz,1H),4.69(tt,J＝6.7,4.5Hz,1H),4.05(tt,J＝6.8,4.5Hz,1H),3.20(s,3H),2.45-2.25(m,4H)。
intermediate 2(I-2)
Step 1: 4, 5-difluoro-2-nitrophenol I-2a (2.2g, 13mmol), bromocyclobutane (2.4mL, 25mmol), TBAI (4.7g, 13mmol) and Cs2CO3A mixture of (4.1g, 13mmol) in DMF (10mL) was stirred at 90 ℃ for 16 h. The mixture was cooled to RT, diluted with water (100mL) and the product extracted with TBME (300 mL). The organic solution was washed with brine (50mL) and washed with Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to give 1-cyclobutoxy-4, 5-difluoro-2-nitrobenzene I-2b as a light yellow solid:1H NMR(400MHz,CDCl3)δ7.83(dd,J＝9.6,8.1Hz,1H),6.74(dd,J＝11.5,6.5Hz,1H),4.69(quint,J＝7.5Hz,1H),2.56–2.42(m,2H),2.36–2.21(m,2H),2.01–1.86(m,1H),1.81–1.66(m,1H)。
step 2: 1-Cyclobutoxy-4, 5-difluoro-2-nitrobenzene I-2b (1.3g, 5.6mmol), NH4A mixture of Cl (3.0g, 56mmol) and iron (1.6g, 28mmol) in MeOH (30mL) was stirred at 90 deg.C for 1h, then cooled to RT and filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc (50mL) and water (50 mL). The residual product was extracted from the aqueous solution with EtOAc (100 mL). The combined organic phases were washed with Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-100% EtOAc in isohexane) to give 2-cyclobutoxy-4, 5-difluoroaniline I-2c as a red oil: m/z 200[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ6.53–6.42(m,2H),4.61–4.49(m,1H),3.74–3.63(m,2H),2.50–2.37(m,2H),2.24–2.10(m,2H),1.92–1.80(m,1H),1.76–1.61(m,1H)。
And step 3: adding Br2(0.3mL, 6mmol) was added dropwise to a solution of 2-cyclobutoxy-4, 5-difluoroaniline I-2c (1.0g, 5mmol) in AcOH (35 mL). The reaction was stirred at RT for 16h and then saturated Na was added2S2O3Solution (50 mL). The product was extracted with EtOAc (125mL) and the organic solution was taken over Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to give 2-bromo-6-cyclobutoxy-3, 4-difluoroaniline I-2d as a yellow solid: m/z 278[ M + H]+(ES+)。1H NMR(400MHz,CDCl3)δ6.49(dd,J＝11.4,7.1Hz,1H),4.57(quint,J＝7.1Hz,1H),4.11(s,2H),2.52–2.39(m,2H),2.25–2.11(m,2H),1.95–1.83(m,1H),1.78–1.61(m,1H)。
And 4, step 4: isoamyl nitrite (0.73mL, 5.4mmol) was added to a solution of 2-bromo-6-cyclobutoxy-3, 4-difluoroaniline I-2d (0.75g, 2.7mmol) in THF (10mL) and the mixture was stirred at 70 ℃ for 16h and then cooled to RT. Water (50mL) was added and the product was extracted with DCM (150 mL). The organic solution is passed through a hydrophobic membrane and then under vacuumAnd (5) concentrating. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to give 1-bromo-5-cyclobutoxy-2, 3-difluorobenzene I-2 as a colorless oil:1H NMR(400MHz,CDCl3)δ6.74(ddd,J＝4.9,3.0,2.2Hz,1H),6.59(ddd,J＝11.5,6.1,3.0Hz,1H),4.60–4.49(m,1H),2.50–2.37(m,2H),2.21–2.07(m,2H),1.94–1.81(m,1H),1.76–1.61(m,1H)。
intermediate 3(I-3)
A solution of cyclobutanol (125. mu.L, 1.60mmol) in dry THF (1mL) was added dropwise under nitrogen to a suspension of NaH (60% w/w in oil, 65mg, 1.6mmol) in dry THF (5 mL). The mixture was stirred at RT for 10min, then a solution of 2, 4-dichloro-5-fluoropyrimidine I-3a (250mg, 1.5mmol) in THF (1mL) was added dropwise. The reaction mixture was stirred at RT for 16h, then saturated NH4Partition between aqueous Cl (50mL) and EtOAc (100 mL). The organic solution was washed with MgSO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in isohexane) to give 2-chloro-4-cyclobutoxy-5-fluoropyrimidine I-3 as a colorless oil:1H NMR(400MHz,CDCl3)δ8.19(d,J＝2.3Hz,1H),5.41–5.28(m,1H),2.60-2.44(m,2H),2.35-2.16(m,2H),1.99-1.85(m,1H),1.82-1.65(m,1H)。
intermediate 4(I-4)
The vial was charged with 3-bromo-4-fluorophenol I-1e (300mg, 1.57mmol), copper (I) iodide (30mg, 0.157mmol), 2-pyridinecarboxylic acid (39mg, 0.314mmol), anhydrous tripotassium phosphate (0.67g, 3.14mmol), and anhydrous DMSO (3.1 mL). The vial was evacuated and back filled with argon (4 ×). Iodobenzene (641mg, 3.14mmol) was added and the mixture was heated at 90 ℃ for 36 h. The reaction mixture was cooled to RT, diluted with 2mL of water and the product was extracted with EtOAc (4 ×). The combined organic phases were washed with brine and Na2SO4Dried, filtered and concentrated under vacuumAnd (4) shrinking. The residue was purified by chromatography on silica gel (petroleum ether) to give 2-bromo-1-fluoro-4-phenoxybenzene as a colorless oil:1H NMR(400MHz,CDCl3)δ7.39–7.33(m,2H),7.19(dd,J＝5.7,2.9Hz,1H),7.16–7.11(m,1H),7.11–7.06(m,1H),7.01–6.97(m,2H),6.96–6.90(m,1H)。
experimental scheme 2
The compound 103- (2- (3- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a) Preparation procedure of 10a
Tert-butyl 3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 1c (100mg, 0.4mmol), and NaOtBu (60mg, 0.62mmol), 1-bromo-3- (trifluoromethoxy) benzene (100mg, 0.4mmol) and RuPhos precatalyst G3(10mg, 12. mu. mol) were placed in a sealed vial, which was then evacuated and backfilled with nitrogen three times. 1, 4-dioxane (2mL) was added and the vial was again evacuated and backfilled with nitrogen three times. The mixture was stirred at 85 ℃ under nitrogen for 30min and then cooled to RT and AcOH (50. mu.L, 0.9mmol) was added. With saturated NH4The mixture was diluted with aqueous Cl (5mL) and the product was extracted with EtOAc (5 mL). The organic solution was washed with MgSO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to give tert-butyl 3- (2- (3- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 10 a: m/z 422[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ7.26(d,J＝16.5Hz,1H),7.12-6.99(m,3H),6.87(d,J＝8.5Hz,1H),6.76(s,1H),6.67(d,J＝8.0Hz,1H),4.39(s,2H),3.56(t,J＝5.9Hz,2H),2.96(t,J＝5.9Hz,2H),2.88(t,J＝7.8Hz,2H),2.53(t,J＝7.8Hz,2H),1.42(s,9H)。
b) Preparation procedure for compound 103- (2- (3- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
A solution of tert-butyl 3- (2- (3- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 10a (60mg, 0.14mmol) in DCM (200. mu.L) was treated with TFA (100. mu.L, 0.14mmol) and the mixture was stirred at RT for 2h and then concentrated in vacuo. By reaction with 10% (7N NH)3In MeOH) in DCM to remove residual solvent, and then purify the product by silica gel chromatography (0-50% EtOAc in isohexane) to give 3- (2- (3- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 10 as a white solid: m/z 366[ M + H]+(ES+)。1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.31(t,J＝8.3Hz,1H),7.15(d,J＝7.9Hz,1H),7.09-7.02(m,2H),6.98(dd,J＝8.5,2.5Hz,1H),6.87(s,1H),6.65(d,J＝7.8Hz,1H),4.39(s,2H),3.55(t,J＝5.9Hz,2H),2.87(t,J＝5.9Hz,2H),2.78(t,J＝7.6Hz,2H),2.56-2.51(m,2H)。
Human GPR120 pEC50：6.8
The following compounds were prepared using the appropriate starting materials in a similar procedure as described in experimental scheme 2. When the starting material is not described in the literature, its synthesis is as follows.
Intermediate 5(I-5)
3-bromo-4-methylphenol I-5a (250mg, 1.3mmol), K2CO3A mixture of (380mg, 2.8mmol), KI (10mg, 60. mu. mol) and a solution of bromocyclobutane (0.2mL, 2mmol) in DMF (3mL) was stirred at 95 ℃ for 16h, then cooled to RT and 20% w/w NaCl solution (50mL) was added. The product was extracted with EtOAc (20mL) and the organic solution was over MgSO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to give 2-bromo-4-cyclobutoxy-1-methylbenzene I-5 as a colorless oil:1H NMR(400MHz,CDCl3)δ7.12(dd,J＝8.4,0.8Hz,1H),7.02(d,J＝2.6Hz,1H),6.70(dd,J＝8.4,2.6Hz,1H),4.66-4.54(m,1H),2.52-2.39(m,2H),2.33(d,J＝0.6Hz,3H),2.24-2.08(m,2H),1.94-1.80(m,1H),1.78-1.61(m,1H)。
intermediate 6(I-6)
3-bromo-4-chlorophenol I-4a (0.3g, 1.446mmol), K2CO3A mixture of (0.50g, 3.6mmol) and a solution of bromocyclobutane (0.16mL, 1.7mmol) in DMF (5mL) was stirred at 100 deg.C for 16h, then cooled to RT and saturated NaHCO was added3Solution (15 mL). The product was extracted with MTBE (90mL) and the organic solution was taken up in Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to give 2-bromo-1-chloro-4-cyclobutoxybenzene I-4 as a colorless oil:1H NMR(400MHz,CDCl3)δ7.31–7.21(m,1H),7.03(d,J＝2.8Hz,1H),6.68(dd,J＝8.9,2.9Hz,1H),4.61–4.50(m,1H),2.47–2.35(m,2H),2.19–2.05(m,2H),1.90–1.78(m,1H),1.74–1.59(m,1H)。
experimental protocol 3
Compound 263- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -2-methylpropionic acid
a)26a preparation procedure
The flask was charged with 6-bromoisoquinoline 1a (500mg, 2.4mmol), Pd (OAc)2(22mg, 0.10mmol), tri (o-tolyl) phosphine (52mg, 0.17mmol), DIPEA (0.84mL, 4.8mmol), and DMF (4.8 mL). The flask was evacuated and backfilled with argon three times, then methyl methacrylate (0.5mL, 0.2mmol) was added. The mixture was stirred at 80 ℃ for 2.5h and then cooled to RT, diluted with EtOAc and filtered. The filtrate was diluted with water and extracted with EtOAc (× 3). The combined organic phases were washed with brine and washed with Na2SO4Dried over celite, filtered over celite and concentrated in vacuo. Purification by silica gel chromatography (25-50% EtOAc in petroleum ether) afforded a mixture of 3- (isoquinolin-6-yl) -2-methyl methacrylate 26a (contaminated with a small amount of the isomer methyl 2- (isoquinolin-6-ylmethyl) acrylate) as a yellow oil, which was used in the next step without further purification:1HNMR(400MHz,CDCl3) δ 9.25(s,1H),8.55(d, J ═ 5.8Hz,1H),7.96(d, J ═ 8.5Hz,1H),7.80(d, J ═ 12.1Hz,2H), 7.67-7.56 (m,2H),3.86(s,3H),2.18(d, J ═ 1.5Hz, 3H); calculation of C by ESI-HRMS14H14NO2(M+H+)228.1019, to give 228.1024.
b)26b preparation procedure
A mixture of methyl 3- (isoquinolin-6-yl) -2-methacrylate and methyl 2- (isoquinolin-6-ylmethyl) acrylate 26a (278mg, 1.22mmol) and 5% Pt/C (239.2mg, 61. mu. mol Pt) in AcOH (12mL) was stirred at 50 ℃ in H2Of (2) atmosphereAnd (4) heating. After 22h, the mixture was cooled to RT and filtered through a plug of celite, washing with EtOAc. The filtrate was concentrated in vacuo and the oil was taken up in EtOAc and saturated Na2CO3(30 mL). Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo to give methyl 2-methyl-3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 26b as a yellow oil, which was used without further purification:1HNMR(400MHz,CDCl3) δ 6.93-6.91 (m,2H),6.88(s,1H),3.98(s,2H),3.65(s,3H),3.12(t, J ═ 6.0Hz,2H), 3.01-2.93 (m,1H),2.76(t, J ═ 5.8Hz,2H), 2.75-2.66 (m,1H),2.59(dd, J ═ 13.3,7.8Hz,1H),1.14(d, J ═ 6.9Hz, 3H); calculation of C by ESI-HRMS14H20NO2(M+H+)234.1489, to give 234.1494.
c)26c preparation procedure
Mixing methyl 2-methyl-3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 26b (110mg, 0.48mmol) with Cs2CO3(310mg，0.96mmol)、Pd2(dba)3(45mg, 49. mu. mol), BINAP (60.9mg, 98. mu. mol), 2-bromo-1-fluoro-4- (trifluoromethoxy) benzene (140mg, 0.54mmol) and DMF (3.7mL) were placed in a sealed vial, which was then evacuated and backfilled with nitrogen three times. The mixture was heated at 90 ℃ for 24h, and then cooled to room temperature and filtered through a plug of silica gel (EtOAc as eluent). The filtrate was diluted with water and the product was extracted with EtOAc. Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (1-5% EtOAc in petroleum ether) to give methyl 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -2-methylpropionate 26c as a colorless oil:1HNMR(400MHz,CDCl3)δ7.06–6.94(m,4H),6.85–6.80(m,1H),6.79–6.73(m,1H),4.27(s,2H),3.65(s,3H),3.45(t,J＝5.9Hz,2H),3.04–2.94(m,3H),2.78–2.68(m,1H),2.66–2.59(m,1H),1.16(d, J ═ 6.9Hz, 3H); calculation of C by ESI-HRMS21H22F4NO3(M+H+)412.1530, to give 412.1519.
d) Preparation procedure of compound 263- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -2-methylpropanoic acid
3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -2-methylpropanoic acid methyl ester 26c (81mg, 0.20mmol) and LiOH2A mixture of O (35mg, 0.84mmol) in THF (1.5mL) and water (1.5mL) was stirred at 45 ℃ for 5 h. The reaction mixture was cooled to RT and acidified (pH 1) by addition of 1M HCl (aq). The product was extracted with EtOAc and the organic solution was washed with brine, over Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (38% EtOAc with 0.01% AcOH in petroleum ether) to afford 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -2-methylpropanoic acid 26 as a white solid:1H NMR(400MHz,CDCl3) δ 7.06-6.97 (m,4H),6.83(dd, J ═ 7.2,2.7Hz,1H), 6.79-6.74(m,1H), 4.27(s,2H),3.45(t, J ═ 5.8Hz,2H), 3.09-3.01 (m,1H),2.98(t, J ═ 5.8Hz,2H), 2.81-2.72 (m,1H), 2.68-2.60 (m,1H),1.19(d, J ═ 6.9Hz, 3H); calculation of C by ESI-HRMS20H20F4NO3(M+H+)398.1374, to give 398.1383.
Human GPR120 pEC50：7.1
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 3.
Experimental protocol 4
The compound 283- (2- (3-isopropoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a)28a preparation procedure
The flask was charged with 6-bromoisoquinoline 1a (5.1g, 24mmol), Pd (OAc)2(58mg, 0.26mmol), tri (o-tolyl) phosphine (156mg, 0.513mmol), DMF (33mL) and DIPEA (8.4mL, 48 mmol). The flask was evacuated and backfilled with argon three times, then ethyl acrylate (3.9mL, 37mmol) was added and heated at 90 ℃ for 18 h. The reaction was cooled to RT, diluted with EtOAc and filtered through a short plug of silica gel. The filtrate was diluted with water and the product was extracted with EtOAc. Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by recrystallization from EtOAc to give ethyl (E) -3- (isoquinolin-6-yl) acrylate 28a as light yellow crystals:1H NMR(400MHz,CDCl3) δ 9.25(s,1H),8.57(d, J ═ 5.7Hz,1H),7.97(d, J ═ 8.5Hz,1H),7.90(s,1H),7.83(d, J ═ 16.1Hz,1H),7.78(dd, J ═ 8.6,1.6Hz,1H),7.66(d, J ═ 5.8Hz,1H),6.61(d, J ═ 16.0Hz,1H),4.31(q, J ═ 7.1Hz,2H),1.37(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS14H14NO2(M+H+)228.1019, to give 228.1024.
b)28b preparation procedure
Ethyl (E) -3- (isoquinolin-6-yl) acrylate 28a (3.1g, 14mmol) was dissolved in glacial AcOH (130mL) and 5% Pt/C (2.3g, 0.58mmol) was added under an argon blanket. The flask was evacuated and charged with H2Backfilling three times and reacting at 50 deg.C in H2The mixture was stirred under an atmosphere. After 18h, the mixture was cooled to RT, filtered through a plug of celite, and washed with EtOAc. The filtrate was concentrated in vacuo, then the residue was dissolved in DCM and concentrated in vacuo. Cooling the resulting oil to 0 deg.C and adding two4M HCl in dioxane (12 mL). The mixture was stirred for 5min, after which a white precipitate formed. The solid was resuspended in DCM and concentrated in vacuo to afford ethyl 3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride 28b as a white solid:1H NMR(400MHz,CDCl3) δ 8.68(br s,2H), 7.13-6.96 (m,3H),4.27(br s,2H),4.13(q, J ═ 7.1Hz,2H),3.39(br s,2H),3.09(br s,2H),2.90(t, J ═ 7.7Hz,2H),2.59(t, J ═ 7.7Hz,2H),1.24(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS14H20NO2(M+H+)234.1489, to give 234.1493.
c)28c preparation procedure
Adding ethyl 3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride 28b (136.2mg, 0.50mmol), and Cs2CO3(586mg, 1.8mmol), XPhos Pd G4 precatalyst (12.4mg, 14.5 μmol), 1-bromo-3-isopropoxybenzene (119.5mg, 0.55mmol) and dioxane (2mL) were placed in a sealed vial, which was then evacuated and backfilled with argon three times. The mixture was stirred at 90 ℃ for 18h and then cooled to RT. The mixture was filtered through a plug of silica gel, washed with EtOAc and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0-8% EtOAc in petroleum ether) to afford ethyl 3- (2- (3-isopropoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 28c as a colorless oil:1H NMR(400MHz,CDCl3) δ 7.16(t, J ═ 8.2Hz,1H), 7.09-6.97 (m,3H),6.55(dd, J ═ 8.2,2.0Hz,1H),6.49(t, J ═ 2.1Hz,1H),6.37(dd, J ═ 8.1,1.9Hz,1H), 4.61-4.50 (m,1H),4.36(s,2H),4.13(q, J ═ 7.1Hz,2H),3.52(t, J ═ 5.8Hz,2H), 2.97-2.87 (m,4H),2.60(t, J ═ 7.8Hz,2H),1.34(d, J ═ 6.1Hz,6H),1.24(t, J ═ 7.1, 3H); calculation of C by ESI-HRMS23H30NO3(M+H+)368.2220, to give 368.2233.
d) Preparation procedure for compound 283- (2- (3-isopropoxybenzene) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
Ethyl 3- (2- (3-isopropoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 28c (120mg, 0.32mmol) and LiOH2A mixture of O (54mg, 1.3mmol) in THF (5mL) and water (5mL) was stirred at RT for 18 h. The mixture was acidified (pH 4) by addition of 1M HCl (aq) and the product was extracted with EtOAc. Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-22% (0.01% AcOH in EtOAc) in petroleum ether) to afford 3- (2- (3-isopropoxybenzene) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 28 as a white solid:1H NMR(400MHz,CDCl3) δ 7.16(t, J ═ 8.2Hz,1H), 7.10-6.99 (m,3H),6.56(dd, J ═ 8.1,2.1Hz,1H),6.50(t, J ═ 2.3Hz,1H),6.37(dd, J ═ 8.0,2.2Hz,1H), 4.61-4.50 (m,1H),4.36(s,2H),3.53(t, J ═ 5.9Hz,2H),2.93(dd, J ═ 11.9,6.7Hz,4H),2.68(t, J ═ 7.8Hz,2H),1.34(d, J ═ 6.1Hz, 6H); calculation of C by ESI-HRMS21H26NO3(M+H+)340.1907, to give 340.1917.
Human GPR120 pEC50：6.3
The following compounds were prepared using the appropriate starting materials in a similar procedure as described in experimental scheme 4.
Experimental protocol 5
The compound 303- (2- (3, 5-dimethylphenyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) propionic acid
a) Preparation procedure of 24b
From 7-bromoisoquinoline using essentially the same procedure as for Compound 1a(5g, 24mmol)30a preparation of tert-butyl (E) -3- (isoquinolin-7-yl) acrylate 30 b: m/z 256[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.58(d,J＝5.7Hz,1H),8.07(s,1H),7.91(dd,J＝8.6,1.7Hz,1H),7.86(d,J＝8.6Hz,1H),7.78(d,J＝16.0Hz,1H),7.69(dt,J＝5.8,1.0Hz,1H),6.55(d,J＝16.0Hz,1H),1.58(s,9H)。
b)30c preparation procedure
Preparation of tert-butyl 3- (1,2,3, 4-tetrahydroisoquinolin-7-yl) propionate 30c from tert-butyl (E) -3- (isoquinolin-7-yl) acrylate 30b using essentially the same procedure as for compound 1 c: m/z 262[ M + H ]]+(ES+)；1H NMR(400MHz,CDCl3)δ6.97-6.86(m,2H),6.81-6.75(m,1H),3.91(d,J＝1.0Hz,2H),3.05(t,J＝6.0Hz,2H),2.77(t,J＝7.9Hz,2H),2.69(t,J＝6.0Hz,2H),2.48-2.39(m,2H),1.36(s,9H)。
c) Process for the preparation of the compound 303- (2- (3, 5-dimethylphenyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) propionic acid
RuPhos G3 precatalyst (10mg, 12. mu. mol) and NaOtBu (75mg, 0.78mmol) was placed in a sealed vial, and the vial was then evacuated and backfilled with nitrogen three times. A solution of tert-butyl 3- (1,2,3, 4-tetrahydroisoquinolin-7-yl) propionate 30c (100mg, 0.4mmol) and 1-bromo-3, 5-dimethylbenzene (55 μ L, 0.41mmol) in 1, 4-dioxane (2mL) was added under nitrogen at 90 deg.C and the mixture was stirred. The mixture was cooled to RT and AcOH (55. mu.L, 0.96mmol) was added. The mixture was dissolved in EtOAc (5mL) and saturated NH4The Cl solution (5mL) was partitioned and the organic solution was MgSO4Dried, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-20% EtOAc in isohexane) to give a mixture of the title compound and its tert-butyl ester. The mixture was dissolved in DCM (2mL) and washed with TFA (1)mL, 13mmol) for 16h and then concentrated in vacuo. Partial oxidation of the heterocycle was observed and the residue was dissolved in DCM (5mL), sodium triacetoxyborohydride (50mg, 0.24mmol) was added and the mixture was stirred at RT for 10min and then concentrated in vacuo. The product was purified by reverse phase flash chromatography (15-75% MeCN in water with 0.1% formic acid) to afford 3- (2- (3, 5-dimethylphenyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) propionic acid 30 as a yellow gum: m/z 310[ M + H ]]+(ES+)；1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),7.09-6.97(m,3H),6.60(d,J＝1.4Hz,2H),6.39(s,1H),4.29(s,2H),3.46(t,J＝5.9Hz,2H),2.84(t,J＝5.8Hz,2H),2.78(t,J＝7.6Hz,2H),2.57-2.51(m,2H),2.21(s,6H)。
Human GPR120 pEC50：5.8
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 5.
Experimental scheme 6
Compound 342- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropane-1-carboxylic acid
a)34a preparation procedure
A solution of trimethylsulfoxonium iodide (13g, 59mmol) in DMSO (75mL) was added dropwise to a suspension of NaH (60% w/w in oil, 2.1g, 53mmol) in DMSO (40mL) under nitrogen. The mixture was stirred at RT for 1h, then 3- (isoquinolin-6-yl) propan was added dropwiseA solution of (E) -tert-butyl enoate 1b (10g, 36mmol) in DMSO (50 mL). The mixture was stirred at RT for 16h and then partitioned between 20% w/w NaCl solution (1L) and TBME (1L). The organic solution was washed with 20% w/w NaCl solution (1L) and over MgSO4Dried, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (10-30% EtOAc in isohexane) to give tert-butyl 2- (isoquinolin-6-yl) cyclopropanecarboxylate 34a as a colorless solid: m/z 270[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.49(d,J＝5.9Hz,1H),7.92(d,J＝8.5Hz,1H),7.62(d,J＝5.8Hz,1H),7.56(s,1H),7.34(dd,J＝8.5,1.7Hz,1H),2.68-2.59(m,1H),2.05-1.95(m,1H),1.72-1.63(m,1H),1.51-1.46(m,9H),1.43-1.31(m,1H)。
b)34b preparation procedure
2- (isoquinolin-6-yl) cyclopropanecarboxylic acid tert-butyl ester 34a (2g, 7.4mmol) and Pt-C5% (50% w/w with water J)&Form M117) (500mg, 0.06mmol) in AcOH (20mL) was stirred under an atmosphere of hydrogen (5Bar) at RT for 18h and then filtered. The filtrate was concentrated in vacuo, and the residue was partitioned between 1N NaOH (50mL) and EtOAc (100 mL). The organic solution was washed with MgSO4Dried, filtered and concentrated in vacuo to afford tert-butyl 2- (1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 34b as a colorless oil that crystallized upon standing: m/z 274[ M + H]+(ES+)。1H NMR(400MHz,CDCl3) δ 6.92(d, J ═ 7.9Hz,1H), 6.91-6.80 (m,2H),3.97(s,2H),3.12(t, J ═ 6.0Hz,2H),2.76(t, J ═ 6.0Hz,2H), 2.43-2.33 (m,1H), 1.84-1.74 (m,1H), 1.54-1.46 (m,1H),1.46(s,9H), 1.23-1.14 (m,1H), -NH is not observed.
c)34c preparation procedure
Will contain Cs2CO3(3.7g，11mmol)、BINAP(0.2g，0.4mmol) and Pd-176[ BINAP Pd (allyl)]A flask of Cl 0.5C7H8(0.2g, 0.3mmol) was evacuated and backfilled with nitrogen (3 times). A solution of tert-butyl 2- (1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 34b (2.1g, 7.5mmol) and 2-bromo-4-cyclobutoxy-1-fluorobenzene (2.0g, 8.3mmol) in 1, 4-dioxane (25mL) was added, and the flask was again evacuated and backfilled with nitrogen (4 times). The resulting mixture was heated at 95 deg.C (internal temperature) for 16h, then cooled to RT and partitioned between 20% w/w NaCl solution (100mL) and EtOAc (200 mL). The organic solution was washed with 20% w/w NaCl solution (10mL) over MgSO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in isohexane) to give tert-butyl 2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 34c as a thick colorless oil: m/z 438[ M + H]+(ES+)。1H NMR(400MHz,CDCl3)δ6.93(d,J＝7.8Hz,1H),6.90–6.78(m,3H),6.49(s,1H),6.25(d,J＝8.7Hz,1H),4.47(quint,J＝7.2Hz,1H),4.19(s,2H),3.36(t,J＝5.8Hz,2H),2.88(s,2H),2.39–2.26(m,3H),2.13–1.98(m,2H),1.83–1.68(m,2H),1.67–1.50(m,1H),1.48–1.38(m,1H),1.39(s,9H),1.16–1.09(m,1H)。
c) Preparation procedure of 342- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid
To a solution of tert-butyl 2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 34c (2.5g, 5.8mmol) in DCM (20mL) was added TFA (5mL, 65mmol) and sodium triacetoxyborohydride (0.25g, 1.2 mmol). The resulting mixture was stirred at RT for 3h and then partitioned between DCM (25mL) and water (50 mL). The residual product was further extracted from the aqueous phase with DCM (150 mL). The combined organics were washed with brine (50mL), passed through a hydrophobic frit and then concentrated in vacuo. The residue was purified by silica gel chromatography (30-100% (1:1DCM/EtOAc) in isohexane) to give 2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,23, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid 34c is a racemic mixture of an off-white solid and the trans enantiomer: m/z 382[ M + H ]]+(ES+)。1H NMR(400MHz,DMSO-d6) δ 7.08(d, J ═ 7.9Hz,1H),7.02(dd, J ═ 12.6,8.8Hz,1H), 6.99-6.92 (m,2H),6.47(dd, J ═ 7.5,3.0Hz,1H),6.36(dt, J ═ 8.8,3.1Hz,1H),4.61 (quant, J ═ 7.1Hz,1H),4.18(s,2H),3.34(t, J ═ 5.8Hz,2H),2.83(t, J ═ 5.8Hz,2H), 2.43-2.27 (m,3H), 2.06-1.92 (m,2H), 1.81-1.69 (m,2H), 1.69-1.49 (m,1H), 1.46-1.46 (m,1H), 1H, 26-1H), and-26 (COOH), all of which were not observed.
Human GPR120 pEC50：6.8
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 6.
Experimental scheme 7
Compound 382- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropane-1-carboxylic acid
a)38a preparation procedure
Will contain Cs2CO3Vials of (0.21G, 0.64mmol), tert-butyl 2- (1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 34b (0.12G, 0.42mmol) and RuPhos Pd G3(11mg, 0.013mmol) were evacuated under vacuum and backfilled with nitrogen 3 times. A solution of 1-bromo-3-phenoxybenzene (0.12g, 0.47mmol) in 1, 4-dioxane (2mL) was added and the vial was again evacuated under vacuum and backfilled 3 times with nitrogen. Mixing the obtained mixtureHeated at 90 ℃ for 16h, then cooled to RT and water (5mL) was added. The product was extracted with DCM (15mL) and the organic solution was passed through a hydrophobic membrane and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in isohexane) to give tert-butyl 2- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 38a as a thick colorless oil: m/z 422[ M + H ]]+(ES+)。1H NMR(400MHz,CDCl3)δ7.38–7.29(m,2H),7.22(t,J＝8.2Hz,1H),7.12–7.00(m,4H),6.91(d,J＝8.6Hz,2H),6.72(d,J＝7.1Hz,1H),6.65(s,1H),6.44(d,J＝7.5Hz,1H),4.37(s,2H),3.53(t,J＝5.8Hz,2H),2.93(t,J＝5.5Hz,2H),2.45–2.36(m,1H),1.86–1.73(m,1H),1.52(dt,J＝9.5,4.8Hz,1H),1.47(s,9H),1.26–1.18(m,1H)。
b) Preparation procedure of compound 382- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid
A solution of tert-butyl 2- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylate 38a (125mg, 0.28mmol) in DCM (2mL) was treated with sodium triacetoxyborohydride (60mg, 0.28mmol) and TFA (1mL, 13mmol) and the mixture was stirred at RT for 1 h. Water (2mL) was added and the product was extracted with DCM (15 mL). The organic solution was passed through a hydrophobic membrane and then concentrated in vacuo. The product was purified by reverse phase flash chromatography (25-100% MeCN in water with 0.1% formic acid) to afford 2- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid 38 as a colorless solid: m/z 386[ M + H ]]+(ES+)。1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),7.41–7.32(m,2H),7.20(t,J＝8.2Hz,1H),7.15–7.07(m,2H),7.01–6.94(m,4H),6.77(dd,J＝8.3,2.4Hz,1H),6.65(t,J＝2.3Hz,1H),6.29(dd,J＝7.9,2.2Hz,1H),4.34(s,2H),3.50(t,J＝5.9Hz,2H),2.84(t,J＝5.8Hz,2H),2.37–2.29(m,1H),1.80–1.72(m,1H),1.39(dt,J＝9.2,4.6Hz,1H),1.35–1.26(m,1H)。
Human GPR120 pEC50：7.2
Experimental scheme 8
Compound 34-isomer 1 and 34-isomer 22- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropane-1-carboxylic acid
a)34d preparation procedure
Oxalyl chloride (0.5mL, 6mmol) and DMF (1 drop) were added sequentially to a solution of 2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid 34(1.9g, 4.7mmol) in DCM (20mL) at 0 ℃. The mixture was stirred at 0 ℃ for 15min, then warmed to RT and stirred for a further 2 h. The mixture was concentrated in vacuo to afford 2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarbonyl chloride 34d as a yellow foam, which was used directly in the next step without purification or analysis.
b)34 e: procedure for the preparation of isomer 1 and isomer 2
A solution of (S) -4-isopropyloxazolidin-2-one (1.3g, 9.9mmol) in THF (20mL) was cooled to-78 deg.C and n-butyllithium (2.5M in hexane, 3.8mL, 9.5mmol) was added dropwise, keeping the internal temperature below-40 deg.C. The mixture was stirred at-78 ℃ for 30min, warmed to 0 ℃ and then cooled again to-78 ℃. A solution of 2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarbonyl chloride 34d (1.9g, 4.7mmol) in THF (20mL) was added dropwise while maintaining the internal temperature below-55 ℃. The resulting mixture was stirred at-78 deg.C for 30min, then at-40 deg.C for 60 min. By adding saturated NH4The reaction was quenched with Cl (25mL) and the product was extracted with EtOAc (100 mL). The organic solution was washed with brine (25mL) over MgSO4Drying, filteringAnd concentrated in vacuo. The residue was purified by silica gel chromatography (0-35% EtOAc in isohexane) to give (S) -3- (2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarbonyl) -4-isopropyloxazolidin-2-one 34e, isomer 1 and isomer 2 as a concentrated colorless oil: isomer 1:1H NMR(400MHz,CDCl3)δ7.05–6.87(m,4H),6.53(s,1H),6.36–6.27(m,1H),4.60–4.51(m,2H),4.50–4.41(m,1H),4.34–4.18(m,4H),3.60–3.51(m,1H),3.42(t,J＝5.8Hz,2H),2.95(t,J＝5.9Hz,2H),2.65–2.55(m,1H),2.46–2.32(m,2H),2.21–2.07(m,2H),1.91–1.77(m,1H),1.78–1.68(m,1H),1.73–1.58(m,1H),1.46–1.34(m,1H),0.92(t,J＝6.8Hz,6H)。
isomer 2: m/z 493[ M + H]+(ES+).1H NMR(400MHz,CDCl3) δ 1H NMR (400MHz, chloroform-d) δ 7.12-6.87 (m,4H),6.58(s,1H),6.33(d, J ═ 8.8Hz,1H),4.55(p, J ═ 7.2Hz,1H), 4.51-4.43 (m,1H), 4.33-4.18 (m,4H), 3.61-3.51 (m,1H),3.45(t, J ═ 5.9Hz,2H),2.97(s,2H), 2.69-2.59 (m,1H), 2.47-2.30 (m,2H), 2.22-2.07 (m,2H),1.84(q, J ═ 10.5Hz,1H), 1.75-1.60 (m,2H), 1.44-1.34 (m,1H), 1.91, 0.11, 7H), 7.9, 7H (ddh, 0H).
c) 34: procedure for the preparation of isomer 1 and isomer 2
Isomer 1: 27% (w/w) hydrogen peroxide (90. mu.l, 0.793mmol) was added dropwise to a solution of LiOH (14mg, 0.585mmol) in water (0.1ml) at room temperature. The resulting solution was stirred for 30min and then cooled to 0 ℃. This cooled solution was added dropwise to a cooled solution of (S) -3- (2- (2- (5-cyclobutoxy-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarbonyl) -4-isopropyloxazolidin-2-one 34e isomer 1(95mg, 0.193mmol) in THF (0.3 ml). The reaction mixture was stirred at 0 ℃ for 60 minutes and then at room temperature for another 60 minutes. Sodium sulfite (100mg, 0.793mmol) in water (0.3ml) was added and the reaction mixture was stirred for a further 10 min. The mixture was acidified to pH 5 with 1M HCl and the product was extracted with EtOAc (2X 5 ml). The combined organic phases were washed with brine (5ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in isohexane) to give 34 isomer 1 asColorless solid: m/z 382[ M + H ]]+(ES+)；1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),7.09(d,J＝7.9Hz,1H),7.03(dd,J＝12.6,8.8Hz,1H),6.99-6.93(m,2H),6.48(dd,J＝7.5,3.0Hz,1H),6.37(dt,J＝8.8,3.1Hz,1H),4.61(p,J＝7.1Hz,1H),4.18(s,2H),3.35(t,J＝5.9Hz,2H),2.84(t,J＝5.9Hz,2H),2.44-2.29(m,3H),2.08-1.92(m,2H),1.83-1.70(m,2H),1.74-1.53(m,1H),1.45-1.35(m,1H),1.37-1.25(m,1H
Human GPR120 pEC50：6.8
Isomer 2: 34 isomer 2 using essentially the same procedure as for 34 isomer 1, 34 isomer 2 was prepared from (S) -3- (2- (2- (5-cyclobutyl-2-fluorophenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarbonyl) -4-isopropyloxazolidin-2-one 34e isomer 2 to give 34 isomer 2 as a colorless solid: m/z 382[ M + H ]]+(ES+)；1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),7.09(d,J＝7.8Hz,1H),7.03(dd,J＝12.6,8.8Hz,1H),7.00-6.92(m,2H),6.48(dd,J＝7.5,2.9Hz,1H),6.37(dt,J＝8.8,3.2Hz,1H),4.61(p,J＝7.1Hz,1H),4.18(s,2H),3.35(t,J＝5.8Hz,2H),2.84(t,J＝5.9Hz,2H),2.44-2.29(m,3H),2.00(dtd,J＝12.6,10.0,7.9Hz,2H),1.83-1.69(m,2H),1.70-1.53(m,1H),1.45-1.36(m,1H),1.37-1.27(m,1H)。
Human GPR120 pEC50：7.1
The following compounds were prepared using the appropriate starting materials in a similar procedure as described in experimental scheme 8.
Experimental protocol 9
Compound 38-isomer 1 and 38-isomer 2
Purification of 2- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid 38(55mg, 0.14mmol) by preparative HPLC (ChiralPak IA column, 15mL/min, 10% EtOH in isohexane (0.2% TFA)) to give 2- (2- (3-phenoxyphenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) cyclopropanecarboxylic acid 38 isomer 1 and isomer 2 as tan solids: isomer 1: m/z 386[ M + H ]]+(ES+)；1H NMR (500MHz, DMSO) δ 7.40-7.33(m,2H),7.20(t, J ═ 8.2Hz,1H),7.14-7.08(m,2H),7.01-6.99(m,1H),6.99-6.95(m,3H),6.80-6.75(m,1H),6.65(t, J ═ 2.3Hz,1H),6.33-6.27(m,1H),4.34(s,2H),3.50(t, J ═ 5.9Hz,2H),2.85(t, J ═ 5.9Hz,2 ddh), 2.32(d, J ═ 4.1,6.4,9.1Hz,1H),1.77(d, J ═ 4.1,5.3,8.3, 1H, 1H),1.39(d, J ═ 4.1,6.4, 9.1H), 1H, 1H),1.77(d, J ═ 4.1,5.3,8.3, 8, 1H.
Human GPR120 pEC 50: 7.3
Isomer 2: m/z 386[ M + H ]]+(ES+)；1H NMR (500MHz, DMSO) δ 7.40-7.33(m,2H),7.20(t, J ═ 8.2Hz,1H),7.14-7.08(m,2H), 7.01-6.98 (m,1H), 6.98-6.95 (m,3H), 6.80-6.74 (m,1H),6.65(t, J ═ 2.3Hz,1H), 6.32-6.28 (m,1H),4.34(s,2H),3.50(t, J ═ 5.9Hz,2H),2.85(t, J ═ 5.9Hz,2 ddh), 2.33(d, J ═ 4.0,6.4,9.2Hz,1H),1.77(d, J ═ 4.1,5.2,8.3, 1H, 1, 1.39, 1H, 1,3, 8.3, 1H, 1, 3.7 (d ═ 4.1,5.2,8, 3,8, 1H),3, 1H, 3, 1H, 3 ddh, 1H, 3, 1H, and 1H.
Human GPR120 pEC 50: 7.4
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 9.
Experimental protocol 10
The compound 393- (2- (5-cyclobutoxy-2-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a)39b preparation procedure
A solution of 4-bromo-3-fluorobenzaldehyde 39a (5.0g, 25mmol), 2-dimethoxyethylamine (2.7mL, 25mmol) in dry toluene (60mL) was heated at 135 ℃ for two days using a Dean stark apparatus. The reaction mixture was cooled to RT, concentrated in vacuo, diluted with MeOH and cooled to 0 ℃ under argon. Sodium borohydride (2.8g, 74mmol) was added in proportion and the mixture was stirred at 0 ℃ for 30min, then warmed to RT and stirred overnight. The reaction mixture was concentrated in vacuo, diluted with water and the product extracted with EtOAc. Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo to afford N- (4-bromo-3-fluorobenzyl) -2, 2-dimethoxyethan-1-amine 39b as an orange oil, which was used in the next step without further purification.
b)39c preparation procedure
Triethylamine (6.7mL, 48mmol) and DMAP (150mg, 1.2mmol) were added to a solution of N- (4-bromo-3-fluorobenzyl) -2, 2-dimethoxyethan-1-amine 39b (7.0g, 24mmol) in dry DCM (70mL) under argon at 0 ℃. After 10min p-toluenesulfonyl chloride (4.8g, 25mmol) was added and the mixture was warmed to RT and stirred overnight. The mixture was diluted with DCM and washed with water and brine. Dissolving the organic solution in Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc in petroleum ether) to give N- (4-bromo-3-fluorobenzyl) -N- (2, 2-dimethoxyethyl) -4-methylbenzenesulfonamide 39c as a yellow oil:1H NMR(400MHz,CDCl3) δ 7.74-7.69 (m,2H),7.45(dd, J ═ 8.1,7.1Hz,1H),7.32(d, J ═ 7.9Hz,2H),6.98(dd, J ═ 9.4,2.0Hz,1H),6.91(dd, J ═ 8.2,1.5Hz,1H),4.41(s,2H),4.35(t, J ═ 5.3Hz,1H),3.25(s,6H),3.22(d, J ═ 5.3Hz,2H),2.45(s, 3H); calculation of C by ESI-HRMS18H21BrFNO4SNa(M+Na+)468.0251, to give 468.0268.
c)39d preparation procedure
A suspension of anhydrous aluminum chloride (10.4g, 78.0mmol) in anhydrous DCM (100mL) was cooled to-20 deg.C under argon, and then a solution of N- (4-bromo-3-fluorobenzyl) -N- (2, 2-dimethoxyethyl) -4-methylbenzenesulfonamide 39c (7.0g, 16mmol) in anhydrous dichloromethane (100mL) was added. The mixture was warmed to RT and stirred for 2 days, then concentrated in vacuo. The residue was cooled to 0 ℃ and water was added slowly, followed by 2M potassium hydroxide solution (pH > 10). The mixture was diluted with EtOAc and filtered through a pad of celite. The layers were separated and the residual product was extracted from the aqueous phase with EtOAc (3 ×). The combined organic phases were washed with brine and washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-35% EtOAc in petroleum ether) to give 6-bromo-7-fluoroisoquinoline 39d as a light brown solid:1H NMR(400MHz,CDCl3) δ 9.21(s,1H),8.55(d, J ═ 5.8Hz,1H),8.12(d, J ═ 6.5Hz,1H),7.66(d, J ═ 8.3Hz,1H),7.59(d, J ═ 5.8Hz, 1H); calculation of C by ESI-HRMS9H6BrFN(M+H+)225.9668, to give 225.9664.
d)39e preparation procedure
Vial contained 6-bromo-7-fluoroisoquinoline 39d (1.2g, 5.3mmol), Pd (OAc)2(30mg, 0.1mmol), tri (o-tolyl) phosphine (8mg, 0.3mmol), anhydrous DMF (6mL) and DIPEA (6 mL). The vial was evacuated and backfilled with nitrogen three times, then ethyl acrylate (0.69mL, 6.4mL) was added and the mixture was heated under argon at 100 ℃ overnight. The mixture was cooled to RT and water was added. The product was extracted with EtOAc and the combined organic solution was washed with brine, over Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to afford (E) -3Ethyl- (7-fluoroisoquinolin-6-yl) acrylate 39e is a yellow solid:1H NMR(400MHz,CDCl3) δ 9.21(s,1H),8.55(d, J ═ 5.7Hz,1H),8.02(d, J ═ 7.0Hz,1H),7.90(d, J ═ 16.2Hz,1H),7.64(t, J ═ 9.0Hz,2H),6.76(d, J ═ 16.2Hz,1H),4.31(q, J ═ 7.1Hz,2H),1.37(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS14H13FNO2(M+H+)246.0925, to give 246.0931.
e)39f preparation procedure
A mixture of ethyl (E) -3- (7-fluoroisoquinolin-6-yl) acrylate 39E (1.9g, 7.8mmol), acetic acid (38mL) and Pt-C (0.7g, 0.2mmol, 5% w/w) was heated at 70 ℃ under a hydrogen (balloon) atmosphere overnight. The mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was taken up in EtOAc and added saturated NaHCO3The solutions (100mL) were partitioned between. Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo. The residue was dissolved in DCM and treated with 4M HCl in dioxane solution (4.5mL) at 0 ℃ then concentrated in vacuo to afford ethyl 3- (7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride 39f as a white solid:1H NMR(400MHz,CDCl3)δ10.18(s,2H),7.03(d,J＝7.3Hz,1H),6.80(d,J＝9.9Hz,1H),4.30(s,2H),4.13(q,J＝7.1Hz,2H),3.42(s,2H),3.10(t,J＝5.8Hz,2H),2.93(t,J＝7.6Hz,2H),2.60(t,J＝7.6Hz,2H),1.24(t,J＝7.1Hz,3H),NH2 +not observed; calculation of C by ESI-HRMS14H19FNO2(M+H+)252.1394, to give 252.1400.
f) Preparation procedure of 39g
Under argon, a vial was charged with ethyl 3- (7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride 39f (100mg, 0.4mmol), Cs2CO3(450mg，1.4mmol)、Pd2(dba)3(16mg, 0.017mmol), SPhos (20mg, 0.05mmol), 2-bromo-4-cyclobutoxy-1-fluorobenzene (115mg, 0.470mmol), and anhydrous dioxane (1.4 mL). The vial was sealed, evacuated and backfilled with argon three times, then heated at 100 ℃ for 48 h. The mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5% EtOAc in petroleum ether) to yield ethyl 3- (2- (5-cyclobutoxy-2-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate 39g as a colorless oil:1HNMR(400MHz,CDCl3) δ 6.97(d, J ═ 7.6Hz,1H),6.91(dd, J ═ 12.2,8.8Hz,1H),6.76(d, J ═ 10.4Hz,1H),6.47(dd, J ═ 7.4,2.9Hz,1H),6.31(dt, J ═ 8.8,3.1Hz,1H),4.55(p, J ═ 6.8Hz,1H),4.21(s,2H),4.13(q, J ═ 7.1Hz,2H),3.40(t, J ═ 5.9Hz,2H),2.91(dt, J ═ 11.5,6.7Hz,4H), 2.63-2.56 (m,2H), 2.45-2.33 (m,2H), 2.19.19, 2.56(m, 1H), 1.3.1H, 1H), 1H (m,1H), 1H); calculation of C by ESI-HRMS24H27F2NO3Na(M+Na+)438.1851, to give 438.1854.
g) Preparation procedure for 393- (2- (5-cyclobutoxy-2-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
39g (36mg, 0.087mmol) of ethyl 3- (2- (5-cyclobutoxy-2-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate and LiOH2A mixture of O (11mg, 0.26mmol) in THF (0.6mL) and water (0.3mL) was stirred at RT overnight. The mixture was cooled to 0 ℃ and 1M HCl (aq) was added until the mixture was acidified to pH 1. The mixture was warmed to RT and the product was extracted with EtOAc. Washing the organic solution with brine in Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc (with 1% AcOH) in petroleum ether) to afford 3- (2- (5-cyclobutoxy-2-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 39 as a white solid:1H NMR(400MHz,CDCl3)δ6.97(d,J＝7.6Hz,1H),6.92(dd,J＝12.2,8.8Hz,1H),6.77(d, J ═ 10.4Hz,1H),6.47(dd, J ═ 7.3,2.9Hz,1H),6.31(dt, J ═ 8.8,3.1Hz,1H),4.55(p, J ═ 6.8Hz,1H),4.22(s,2H),3.40(t, J ═ 5.8Hz,2H),2.92(dt, J ═ 11.4,6.7Hz,4H),2.68(t, J ═ 7.7Hz,2H), 2.44-2.35 (m,2H), 2.19-2.07 (m,2H), 1.89-1.78 (m,1H), 1.74-1.59 (m,1H), -COOH; calculation of C by ESI-HRMS22H24F2NO3(M+H+)388.1719, to give 388.1715.
Human GPR120 pEC50：7.2
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 13. When the starting material is not described in the literature, its synthesis is as follows.
Intermediate 7(I-7)
Step 1: using essentially the same procedure as for 39c (scheme 10), N- (4-bromo-2-fluorobenzyl) -N- (2, 2-dimethoxyethyl) -4-methylbenzenesulfonamide I-7b was prepared from 4-bromo-2-fluorobenzaldehyde I-7 a:1H NMR(400MHz,CDCl3) δ 7.72-7.61 (m,2H), 7.35-7.23 (m,4H),7.16(d, J ═ 1.8Hz,1H),4.45(s,2H),4.38(t, J ═ 5.3Hz,1H),3.25(s,8H),2.43(s, 3H); calculation of C by ESI-HRMS18H21BrFNO4SNa(M+Na+)468.0251 gave 468.0262.
Step 2: using essentially the same procedure as for 39d (scheme 10), 6-bromo-8-fluoroisoquinoline I-7c was prepared from N- (4-bromo-2-fluorobenzyl) -N- (2, 2-dimethoxyethyl) -4-methylbenzenesulfonamide I-7 b:1H NMR(400MHz,CDCl3) δ 9.48(s,1H),8.62(d, J ═ 5.8Hz,1H),7.79(s,1H),7.57(dd, J ═ 5.8,1.3Hz,1H),7.38(dd, J ═ 9.5,1.6Hz, 1H); calculation of C by ESI-HRMS9H6BrFN(M+H+)225.9662 gave 225.9672.
And step 3: use substantially as for 39e (case 10)The same procedure was used to prepare ethyl (E) -3- (8-fluoroisoquinolin-6-yl) acrylate I-7d from 6-bromo-8-fluoroisoquinoline I-7 c:1H NMR(400MHz,CDCl3) δ 9.52(s,1H),8.65(d, J ═ 5.8Hz,1H),7.78(dd, J ═ 16.0,1.1Hz,1H),7.70(s,1H),7.68(dd, J ═ 5.8,1.3Hz,1H),7.42(dd, J ═ 11.1,1.3Hz,1H),6.56(d, J ═ 16.0Hz,1H),4.31(q, J ═ 7.1Hz,2H),1.37(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS14H13FNO2(M+H+)246.0925 gave 246.0919.
And 4, step 4: using essentially the same procedure as for 39f (scheme 10), ethyl 3- (8-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride I-7 was prepared from ethyl (E) -3- (8-fluoroisoquinolin-6-yl) acrylate I-7 d: m/z 252[ M + H ]]+(APCI+)；1H NMR(400MHz,CDCl3)δ10.27(br s,2H),6.85–6.79(m,2H),4.32(s,2H),4.13(q,J＝7.1Hz,2H),3.49–3.41(m,2H),3.17(t,J＝5.8Hz,2H),2.90(t,J＝7.6Hz,2H),2.59(t,J＝7.6Hz,2H),1.25(t,J＝7.1Hz,3H)。
Experimental protocol 11
The compound 423- (2- (3-cyclobutoxy-5-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a)42a preparation procedure
Under argon, a vial was charged with ethyl 3- (7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride 39f (125mg, 0.43mmol), Cs2CO3(425mg, 1.3mmol), Xphos Pd G4(10mg, 0.03mmol), 1-bromo-3-cyclobutoxy-5-fluorobenzene (120mg, 0.50mmol) and anhydrous dioxane (2.2 mL). The vial was sealed, evacuated and backfilled with argon three times, then heated at 100 ℃. After 22h the mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc (with 1% AcOH) in petroleum ether) to give 3- (2-, (2: (r))Ethyl 3-cyclobutoxy-5-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate 42a as an amorphous solid:1HNMR(400MHz,CDCl3) δ 6.97(dd, J ═ 12.4,5.8Hz,1H),6.80(d, J ═ 10.3Hz,1H),6.22(dt, J ═ 12.1,2.2Hz,1H),6.16(t, J ═ 1.8Hz,1H),5.98(dt, J ═ 10.5,2.1Hz,1H), 4.64-4.55 (m,1H),4.31(s,2H),4.13(q, J ═ 7.1Hz,2H),3.49(t, J ═ 5.9Hz,2H),2.90(dt, J ═ 11.5,6.7Hz,4H),2.61(t, J ═ 7.7Hz,2H), 2.47-2.38 (m,2H), 2.21-2.21, 10.5, 6.7Hz,4H), 1.63 (t, J ═ 7, 1H), 1H, 3.1H, 1H; calculation of C by ESI-HRMS24H28F2NO3(M+H+)416.2032 gave 416.2037.
b) Process for the preparation of 423- (2- (3-cyclobutoxy-5-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
Using substantially the same procedure as for compound 39, 3- (2- (3-cyclobutoxy-5-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 42a was prepared from ethyl 3- (2- (3-cyclobutoxy-5-fluorophenyl) -7-fluoro-1, 2,3, 4-tetrahydroisoquinolin-6-yl) propionate 42 a:1H NMR(400MHz,CDCl3) δ 6.99(d, J ═ 7.5Hz,1H),6.81(d, J ═ 10.2Hz,1H),6.22(d, J ═ 12.1Hz,1H),6.16(s,1H), 6.02-5.95 (m,1H),4.60(p, J ═ 7.2Hz,1H),4.31(s,2H),3.50(t, J ═ 5.8Hz,2H),2.95(t, J ═ 7.7Hz,2H),2.88(t, J ═ 5.7Hz,2H),2.68(t, J ═ 7.7Hz,2H), 2.48-2.38 (m,2H), 2.22-2.09 (m,2H), 1.91-1.80 (m,1H),1.75 (m,1H), -1H); ESI-HRMS calculation of C22H24F2NO3(M + H +)388.1719 gave 388.1715.
Human GPR120 pEC50：6.5
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 11. When the starting material is not described in the literature, its synthesis is as follows.
Intermediate 8(I-8)
The vial is filled with K2CO3(2.07g, 15mmol), DMF (5mL), 3-bromo-5-chlorophenol I-8a (1.57g, 7.5mmol) and KI (620mg, 3.75mmol) and the mixture was stirred at RT for 10 min. Bromocyclobutane (1.06ml, 11.3mmol) was added and the mixture was heated at 90 ℃ for 20 h. The reaction was cooled to RT, filtered through a plug of silica gel (EtOAc), diluted with water and the product extracted with EtOAc (× 3). The combined organic phases were washed with brine and Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether) to give 1-bromo-3-chloro-5-cyclobutoxybenzene I-8 as a colorless oil:1H NMR(400MHz,CDCl3)δ7.08–7.06(m,1H),6.86–6.84(m,1H),6.74–6.73(m,1H),4.63–4.54(m,1H),2.49–2.40(m,2H),2.20–2.08(m,2H),1.93–1.82(m,1H),1.75–1.62(m,1H)。
experimental protocol 12
The compound 443- (2- (6-cyclobutoxy-3, 5-difluoropyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a)44a preparation procedure
The vial was charged with ethyl 3- (1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate hydrochloride 28c (103mg, 0.38mmol), Cs2CO3(259mg, 0.79mmol), 2-cyclobutoxy-3, 5, 6-trifluoropyridine I-9(116mg, 0.57mmol), and DMF (1 mL). The mixture was heated at 100 ℃ for 20 h. The reaction was cooled to RT and filtered through a plug of silica gel (eluent EtOAc). The filtrate was diluted with water and the product was extracted with EtOAc (3 ×). The combined organic phases were washed with brine and washed with Na2SO4Dried, filtered and concentrated in vacuo. By silica gelThe residue was purified by chromatography on (0-5% EtOAc in petroleum ether) to give ethyl 3- (2- (6-cyclobutoxy-3, 5-difluoropyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 44a as a colorless oil:1HNMR(400MHz,CDCl3)δ7.12(dd,J＝11.0,8.9Hz,1H),7.08–6.96(m,3H),5.16–5.05(m,1H),4.55(s,2H),4.13(q,J＝7.1Hz,2H),3.69(t,J＝5.9Hz,2H),2.97–2.88(m,4H),2.63–2.58(m,2H),2.47–2.38(m,2H),2.25–2.13(m,2H),1.90–1.80(m,1H),1.75–1.63(m,1H),1.24(t,J＝7.1Hz,3H)；
b) process for preparing 443- (2- (6-cyclobutoxy-3, 5-difluoropyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
Using substantially the same procedure as for compound 29, 3- (2- (6-cyclobutoxy-3, 5-difluoropyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 44a was prepared from ethyl 3- (2- (6-cyclobutoxy-3, 5-difluoropyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionate 44 a. The product was purified by column chromatography (0-25% (0.01% AcOH in EtOAc) in petroleum ether) to afford 3- (2- (6-cyclobutoxy-3, 5-difluoropyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid 44 as a white solid:1H NMR(400MHz,CDCl3) δ 7.13(dd, J ═ 11.0,8.9Hz,1H), 7.09-6.97 (m,3H), 5.16-5.05 (m,1H),4.55(s,2H),3.70(t, J ═ 5.9Hz,2H), 2.95-2.89 (m,4H), 2.71-2.64 (m,2H), 2.46-2.37 (m,2H), 2.25-2.13 (m,2H), 1.90-1.80 (m,1H), 1.75-1.62 (m,1H) -COOH were not observed; calculation of C by ESI-HRMS21H23F2N2O3(M+H+)389.1671, to give 389.1671.
Human GPR120 pEC50：7.6
Intermediate 9(I-9)
The vial is filled with K2CO3(1.10g, 7.94mmol), MeCN (10mL), 2,3,5, 6-TetrafluorosilanePyridine I-9a (0.66mL, 6.6mmol), cyclobutanol (0.52mL, 6.6mmol), and the mixture was stirred at RT for 18 h. An additional portion of cyclobutanol (0.4mL, 5.1mmol) was added and the mixture was heated at 120 ℃ for 3 days. The reaction was cooled to RT, filtered through a plug of silica gel (eluent EtOAc) and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether) to give 2-cyclobutoxy-3, 5, 6-trifluoropyridine I-9 as a colorless oil:1H NMR(400MHz,CDCl3)δ7.36(td,J＝8.1,7.2Hz,1H),5.17–5.09(m,1H),2.53–2.43(m,2H),2.25–2.12(m,2H),1.92–1.81(m,1H),1.75–1.62(m,1H)。
experimental protocol 13
The compound 453- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) propionic acid
a)45b and 45c preparation procedure
Step 1 a: adding NaN at 0 deg.C3(0.36g, 5.6mmol) was carefully added to a solution of 6-bromo-3, 4-dihydronaphthalen-2 (1H) -one 45a (1.0g, 4.4mmol) in methanesulfonic acid (5 mL). The reaction mixture was warmed to RT overnight. The mixture was poured into a mixture of 1M KOH and ice and the product was extracted with EtOAc. Washing the organic solution with brine in Na2SO4Dried and filtered. The solution was concentrated in vacuo to afford 7-bromo-1, 3,4, 5-tetrahydro-2H-benzo [ d]Azepan-2-ones and 7-bromo-1, 2,4, 5-tetrahydro-3H-benzo [ c]A 1:1 mixture of azepin-3-ones, which is used without purification.
Step 1 b: borane dimethyl sulfide complex (1M, 8.9mL, 8.9mmol) was added dropwise to a solution of the mixture obtained in step 1a in DME (5mL) at 0 ℃. The mixture was heated under argon at reflux overnight and then cooled to 0 ℃. The reaction was quenched by addition of MeOH and the solution was concentrated in vacuo to give a mixture of 7-bromo-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin and 7-bromo-2, 3,4, 5-tetrahydro-1H-benzo [ c ] azepin, which was used in the next step without purification.
Step 1 c: the mixture from step 1b was dissolved in anhydrous DCM (10mL) and the solution was cooled to 0 deg.C and Et was added sequentially3N (1.2g, 12mmol), DMAP (57mg, 0.47mmol) and di-tert-butyl dicarbonate (1.3g, 6.1 mmol). The mixture was stirred at RT overnight and then the product was extracted with DCM. The organic solution was washed with 1M HCl and brine, washed over Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to yield 7-bromo-1, 2,4, 5-tetrahydro-3H-benzo [ d%]Azepane-3-carboxylic acid tert-butyl ester 45b and 7-bromo-1, 3,4, 5-tetrahydro-2H-benzo [ c ]]Azepin slow-2-carboxylic acid tert-butyl ester 45c as a clear oil: 45b:1H NMR(500MHz,CDCl3) δ 7.27-7.23(m,2H),6.98(d, J ═ 7.9Hz,1H),3.53(q, J ═ 5.4Hz,4H),2.88-2.79(m,4H),1.47(s, 9H); calculation of C by ESI-HRMS15H20BrNNaO2(M+Na+)348.0570 gave 348.0572.
45c:1H NMR(500MHz,CDCl3) δ 7.32(br s,1H),7.30-7.25(m,2H),4.35(br s,2H),3.70(br s,2H),2.96-2.89(m,2H),1.78(s,2H),1.41(s,9H), 3.73-3.61(m,2H),2.93-2.87(m,2H),1.81-1.70(m,2H),1.38(s, 9H); calculation of C by ESI-HRMS15H20BrNNaO2(M+Na+)348.0570, to give 348.0558.
d)45d preparation procedure
Reacting 7-bromo-1, 2,4, 5-tetrahydro-3H-benzo [ d]Tert-butyl azepin-3-carboxylate 45b (170mg, 0.52mmol), palladium (II) acetate (2.9mg, 2.5 mol%) and tri-o-tolylphosphine (7.9mg, 5.0 mol%) were placed in a sealed vial, which was then evacuated and backfilled with argon three times. A solution of ethyl acrylate (63mg, 0.63mmol) and DMF: DIPEA (1:1, 2ml) was added and the mixture was heated in a microwave reactor at 120 ℃ for 30 minutes. The reaction was cooled to RT andwater was added. The product was extracted with diethyl ether. The combined organic phases were washed with 1M HCl, brine, over Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give (E) -7- (3-ethoxy-3-oxoprop-1-en-1-yl) -1,2,4, 5-tetrahydro-3H-benzo [ d]Azepin slow-3-carboxylic acid tert-butyl ester 45d as clear oil:1H NMR(500MHz,CDCl3) δ 7.66(d, J ═ 16.0Hz,1H),7.34-7.29(m,2H),7.15(d, J ═ 7.7Hz,1H),6.42(d, J ═ 16.0Hz,1H),4.28(q, J ═ 7.1Hz,2H),3.58(d, J ═ 6.6Hz,4H),2.98-2.84(m,4H),1.47(d, J ═ 7.2Hz,9H),1.36(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS20H27NNaO4(M+Na+)368.1832, to give 368.1846.
e)45e preparation procedure
Pd/C (110mg, 10 mol%) was added to (E) -7- (3-ethoxy-3-oxoprop-1-en-1-yl) -1,3,4, 5-tetrahydro-3H-benzo [ d]A solution of tert-butyl azepin-3-carboxylate 45d (712mg, 2.06mmol) in MeOH (5 ml). The mixture was flushed with argon for 15 minutes and stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-20% EtOAc/petroleum ether) to give 7- (3-ethoxy-3-oxopropyl) -1,2,4, 5-tetrahydro-3H-benzo [ d]Azepin slow-3-carboxylic acid tert-butyl ester 45e as clear oil:1H NMR(400MHz,CDCl3) δ 7.04-6.99(m,1H),6.97-6.92(m,2H),4.12(q, J ═ 7.1Hz,2H),3.52(broad s,4H),2.91-2.80(m,6H),2.61-2.56(m,2H),1.47(s,9H),1.23(t, J ═ 7.2Hz, 3H); calculation of C by ESI-HRMS20H29NNaO4(M+Na+)370.1989, to give 370.1999.
e)45f preparation procedure
Step 1. add 7- (3-ethoxy-3-oxopropyl) -1,2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-carboxylic acid tert-butyl ester 45e (570mg, 1.6mmol) to a solution of HCl in 1, 4-dioxane (4M, 10 ml). The mixture was stirred at room temperature for 16H, and then concentrated in vacuo to give ethyl 3- (2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionate hydrochloride, which was used in the next step without purification.
Step 2. under argon, the vial was charged with 3- (2,3,4, 5-tetrahydro-1H-benzo [ d ] hydrochloride]Azepin-7-yl) propionic acid ethyl ester (30mg, 0.11mmol), 2-bromo-1-fluoro-4- (trifluoromethoxy) benzene (41mg, 0.16mmol), cesium carbonate (121mg, 0.37mmol), Pd-BINAP G4 precatalyst (5mg, 4 mol%) and anhydrous dioxane (2 ml). The vial was sealed, evacuated and backfilled with argon three times, then heated at 100 ℃ for 48 h. The reaction was cooled and water was added. The product was extracted with EtOAc (3 ×). The combined organic phases were washed with brine and washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc in petroleum ether) to give 3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d]Azepin slow-7-yl) propionic acid ethyl ester 45f as clear oil:1H NMR(400MHz,CDCl3) δ 7.08-7.02(m,1H),7.01-6.96(m,3H),6.79-6.74(m,1H),6.74-6.68(m,1H),4.14(q, J ═ 7.1Hz,2H),3.35-3.29(m,4H),3.06-3.00(m,4H),2.94-2.88(m,2H),2.64-2.58(m,2H),1.24(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS22H24F4NO3(M+H+)426.1687, to give 426.1678.
f) Preparation procedure for 453- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) propionic acid
Aqueous lithium hydroxide (0.6M, 0.5ml) was added to 3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ]]Azepin-7-yl) propionic acid ethyl ester 45f (8mg, 0.02mmol) in THF (1ml) and the mixture was stirred at RT for 16 h. 1M HCl was added until the mixture was acidified topH 3. The product was extracted with EtOAc (3X) and the combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated in vacuo to give 3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d]Azepin slow-7-yl) propionic acid as amorphous solid:1H NMR(400MHz,CDCl3) δ 7.07(d, J ═ 7.7Hz,1H),7.04-6.96(m,3H),6.79-6.74(m,1H),6-74-6.68(m,1H),3.36-3.29(m,4H),3.07-3.00(m,4H),2.93(t, J ═ 7.8Hz,2H),2.68(t, J ═ 7.8Hz,2H), COOH was not observed; calculation of C by ESI-HRMS20H20F4NO3(M+H+)398.1374, to give 398.1383.
Human GPR120 pEC50：7.6
The following compounds were prepared using suitable starting materials in a similar procedure as described in experimental scheme 13. When the starting material is not described in the literature, its synthesis is as follows.
Intermediate 10(I-10)
Bromocyclopropane (0.94g, 7.8mmol) was added to a solution of 3-bromo-4-fluorophenol I-1e (1g, 5.2mmol) and potassium carbonate (904mg, 6.54mmol) in anhydrous MeCN (5 ml). The resulting mixture was heated at reflux for 16 h. The mixture was concentrated in vacuo and water was added. The product was extracted with EtOAc (3 ×). The combined organic phases were washed with brine and washed with Na2SO4Dried, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give 2-bromo-4-cyclopropoxy-1-fluorobenzene I-10 as a clear oil: m/z 229.9[ M79Br]And 231.9[ M ]81Br](ES+)；1H NMR(400MHz,CDCl3)δ7.25-7.21(m,1H),7.05-6.98(m,1H),6.94-6.88(m,1H),3.71-3.65(m,1H),0.82-0.71(m,4H)；
Experimental protocol 14
The compound 51(R) -3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) -2-methylpropionic acid
a)51a preparation procedure
Adding 7-bromo-1, 2,4, 5-tetrahydro-3H-benzo [ d ] to a sealed vial]Azepane-3-carboxylic acid tert-butyl ester 45b (130mg, 0.4mmol), PdCl2(3.5mg, 0.020mmol), tri-o-tolylphosphine (12mg, 0.040mmol), and anhydrous THF (2.0 mL). The vial was evacuated and backfilled with argon 3 times. A solution of (S) - (3-methoxy-2-methyl-3-oxopropyl) zinc (II) bromide in THF (0.5M, 1.6mL, 0.8mmol) was added and the mixture was heated at reflux. After 3h, the reaction mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (1-15% EtOAc in petroleum ether) to give (R) -7- (3-methoxy-2-methyl-3-oxopropyl) -1,2,4, 5-tetrahydro-3H-benzo [ d [ -c]Tert-butyl azepin-3-carboxylate 51a is a light yellow oil.1H NMR(400MHz,CDCl3) δ 7.02(d, J ═ 7.5Hz,1H), 6.94-6.87 (m,2H),3.65(s,3H), 3.58-3.48 (m,4H),2.98(dd, J ═ 13.4,6.7Hz,1H), 2.90-2.80 (m,4H), 2.76-2.66 (m,1H),2.60(dd, J ═ 13.4,7.8Hz,1H),1.48(s,9H),1.15(d, J ═ 6.9Hz, 3H); calculation of C by ESI-HRMS20H29NO4Na(M+Na+)370.1994, to give 370.1991.
b)51b preparation procedure
HCl was added to dioxane (4M,0.51mL, 2.04mmol) was added (R) -7- (3-methoxy-2-methyl-3-oxopropyl) -1,2,4, 5-tetrahydro-3H-benzo [ d ]]A solution of tert-butyl azepin-3-carboxylate 51a (71mg, 0.20mmol) in anhydrous dioxane (0.5 mL). The reaction mixture was warmed to RT 16 h. The reaction mixture was concentrated in vacuo to give (R) -2-methyl-3- (2,3,4, 5-tetrahydro-1H-benzo [ d ] hydrochloride]Azepin slow-7-yl) propionic acid methyl ester 51b as a white solid:1H NMR(400MHz,CDCl3) δ 9.97(s,2H),7.06(d, J ═ 7.6Hz,1H), 7.01-6.97 (m,1H), 6.96-6.92 (m,1H),3.64(s,3H), 3.43-3.29 (m,4H), 3.28-3.14 (m,4H),2.98(dd, J ═ 13.3,6.9Hz,1H), 2.76-2.66 (m,1H),2.62(dd, J ═ 13.3,7.5Hz,1H),1.15(d, J ═ 6.9Hz, 3H); calculation of C by ESI-HRMS15H22NO2(M+H+)248.1645, to give 248.1656.
c) Preparation procedure of 51c
Under argon, the vial was charged with (R) -2-methyl-3- (2,3,4, 5-tetrahydro-1H-benzo [ d ] hydrochloride]Azepin-7-yl) propionic acid methyl ester 51b (53mg, 0.19mmol), 2-bromo-1-fluoro-4- (trifluoromethoxy) benzene (68mg, 0.26mmol), cesium carbonate (186mg, 0.57mmol), Pd-BINAP G4 precatalyst (7mg, 4 mol%) and anhydrous dioxane (2 ml). The vial was sealed, evacuated and backfilled with argon three times, then heated at 100 ℃ for 48 h. The reaction was cooled and water was added. The product was extracted with EtOAc (3 ×). The combined organic phases were washed with brine and washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to give (R) -3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d [ -d)]Azepin-7-yl) -2-methylpropanoic acid methyl ester 51c as colorless oil:1HNMR(400MHz,CDCl3) δ 7.05(d, J ═ 7.6Hz,1H),7.00(dd, J ═ 12.2,8.8Hz,1H), 6.96-6.92 (m,2H),6.76(dd, J ═ 7.3,2.6Hz,1H), 6.74-6.69 (m,1H),3.65(s,3H),3.32(dd, J ═ 5.2,2.8Hz,4H), 3.06-2.96 (m,5H), 2.78-2.68 (m,1H),2.61(dd, J ═ 13.4,7.8Hz,1H),1.16(d, J ═ 6.9Hz, 3H); calculation of C by ESI-HRMS22H23F4NO3Na(M+Na+)448.1506, to give 448.1510.
d) Preparation of 51(R) -3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) -2-methylpropionic acid
Using essentially the same procedure as for compound 45, starting from (R) -3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d]Preparation of methyl azepin-7-yl) -2-methylpropionate 51c (R) -3- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d)]Azepin-7-yl) -2-methylpropanoic acid 51:1H NMR(400MHz,CDCl3) δ 7.06(d, J ═ 7.4Hz,1H), 7.03-6.94 (m,3H),6.76(dd, J ═ 7.2,2.6Hz,1H), 6.74-6.68(m,1H), 3.36-3.27 (m,4H), 3.08-2.99 (m,5H), 2.81-2.71 (m,1H), 2.66-2.58 (m,1H),1.19(d, J ═ 6.9Hz,3H), COOH were not observed; calculation of C by ESI-HRMS21H22F4NO3(M+Na+)412.1530, to give 412.1535.
Human GPR120 pEC50：6.3
Experimental protocol 15
Compound 522- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) cyclopropanecarboxylic acid
a)52a preparation procedure
To a solution of trimethylsulfoxonium iodide (0.22g, 1.0mmol) in DMSO (5ml) was added sodium hydride (0.04g, 0.89mmol) in proportion. The reaction was stirred at RT for 1 h. (E) -7-bromo-1, 2,4, 5-tetrahydro-3H-benzo [ d ] is added dropwise]Tert-butyl azepin-3-carboxylate 45d (0.22g,0.64mmol) in DMSO (5ml) and the reaction stirred at RT for 20 h. To a solution of trimethylsulfoxonium iodide (0.31g, 1.4mmol) in DMSO (5ml) was added sodium hydride (0.05g, 1.3mmol) in a separate flask in proportion. The mixture was stirred for 1h and then added dropwise to the original reaction mixture. The resulting mixture was stirred at RT for 20 h. Brine (20% w/w, 100ml) was added and the product extracted with TBME (4X 50 ml). The combined organic phases were washed with brine (20% w/w, 70ml) over MgSO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/isohexane) to give 7- (2- (ethoxycarbonyl) cyclopropyl) -4, 5-dihydro-1H-benzo [ d []Azepin-3 (2H) -carboxylic acid tert-butyl ester 52a as a colorless oil: m/z 260[ M-CO2 tBu](ES+)；1H NMR(500MHz,CDCl3)δ7.04(d,J＝7.6Hz,1H),6.92-6.85(m,2H),4.18(q,J＝7.2Hz,2H),3.55(s,4H),2.87(s,4H),2.49(ddd,J＝9.2,6.5,4.1Hz,1H),1.96-1.85(m,1H),1.62-1.56(m,1H),1.50(s,9H),1.31-1.28(m,4H)。
b)52b preparation procedure
To 7- (2- (ethoxycarbonyl) cyclopropyl) -4, 5-dihydro-1H-benzo [ d]To a solution of azepin-3 (2H) -carboxylic acid tert-butyl ester 52a (0.124g, 0.345mmol) in DCM (5ml) was added TFA (0.266ml, 3.45 mmol). The resulting mixture was stirred at RT for 1 h. The reaction mixture was diluted with MeOH (20ml) and MP-carbonate resin (4.1g, 2.98mmol/g) was added and the mixture was stirred for 15 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield 2- (2,3,4, 5-tetrahydro-1H-benzo [ d ]]Azepin-7-yl) cyclopropanecarboxylic acid ethyl ester 52b is a colorless oil: m/z 260[ M + H ]+](ES+)；1HNMR(500MHz,CDCl3)δ7.09–7.04(m,1H),6.93–6.88(m,2H),4.28(s,1H),4.19(q,J＝7.2Hz,2H),3.21–3.10(m,4H),3.10–3.03(m,4H),2.49(ddd,J＝9.1,6.5,4.1Hz,1H),1.90(ddd,J＝8.4,5.3,4.1Hz,1H),1.60(ddd,J＝9.2,5.3,4.6Hz,1H),1.34–1.26(m,4H)。
c)52c preparation procedure
The vial was charged with cesium carbonate (85mg, 0.26mmol), BINAP (3mg, 5. mu. mol) and Pd-176(4.35mg, 5.21. mu. mol). The vial was sealed, evacuated and backfilled with nitrogen three times. Adding 2- (2,3,4, 5-tetrahydro-1H-benzo [ d ]]A solution of azepin-7-yl) cyclopropanecarboxylic acid ethyl ester 52b (0.045g, 0.174mmol) and 2-bromo-1-fluoro-4- (trifluoromethoxy) benzene (49.4mg, 0.191mmol) in dioxane (2ml) and the vial was evacuated and backfilled with nitrogen three times. The reaction was heated at 90 ℃ for 16 h. An additional portion of Pd-176(4mg, 5. mu. mol) and cesium carbonate (85mg, 0.26mmol) was added and the mixture was heated at 100 ℃ for 20 h. The reaction was cooled and water (2ml) was added. The product was extracted with DCM (3 × 5 ml). The combined organic phases were passed through a hydrophobic membrane and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-10% EtOAc/isohexane) to give 2- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d]Azepin-7-yl) cyclopropanecarboxylic acid ethyl ester 52c is a colorless oil: m/z 438[ M + H]+(ES+)；1H NMR(500MHz,CDCl3)δ7.11-7.06(m,1H),7.03(dd,J＝12.1,8.8Hz,1H),6.93-6.89(m,2H),6.80-6.77(m,1H),6.76-6.71(m,1H),4.20(q,J＝7.1Hz,2H),3.39-3.29(m,4H),3.09-3.00(m,4H),2.51(ddd,J＝9.2,6.5,4.2Hz,1H),1.91(ddd,J＝8.4,5.3,4.2Hz,1H),1.61(ddd,J＝9.2,5.3,4.5Hz,1H),1.34-1.31(m,1H),1.31(t,J＝7.1Hz,3H)。
d) Preparation procedure for 522- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) cyclopropanecarboxylic acid
To 2- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d)]To a solution of azepin-7-yl) cyclopropanecarboxylic acid ethyl ester 52c (0.03g, 0.069mmol) in THF (2ml) and MeOH (1ml) was added a solution of lithium hydroxide (4.93mg, 0.206mmol) in water (1 ml). Mixing the obtained mixture at 40 deg.CThe mixture was stirred for 2 h. The reaction was cooled and concentrated in vacuo. Water (5ml) was added and the pH adjusted to 1 with 1M HCl (0.5 ml). The crude material was extracted with DCM (2 × 5 ml). The combined organic phases were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (C18, 15-75% MeCN in water, 0.1% formic acid) to give 2- (3- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d [ -C]Azepin-7-yl) cyclopropanecarboxylic acid 52 was a colorless solid: m/z 410.3[ M + H ]]+(ES+)；1H NMR(500MHz,DMSO-d6)δ12.28(s,1H),7.24(dd,J＝8.8,12.7Hz,1H),7.07(d,J＝7.7Hz,1H),6.99-6.93(m,2H),6.92(dd,J＝2.0,7.7Hz,1H),6.89-6.83(m,1H),3.31-3.25(m,4H),2.99-2.94(m,4H),2.33(ddd,J＝4.0,6.5,9.2Hz,1H),1.77(ddd,J＝4.0,5.3,8.3Hz,1H),1.39(ddd,J＝4.2,5.3,9.2Hz,1H),1.31(ddd,J＝4.2,6.5,8.3Hz,1H)；
Human GPR120 pEC50：6.9
The following compounds were prepared using suitable starting materials in a similar procedure to that described in experimental scheme 15.
Experimental protocol 16
The compound 543- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-7-yl) propionic acid
a)54a preparation procedure
Using essentially the same procedure as for compound 45d, starting from 7-bromo-1, 3,4, 5-tetrahydro-2H-benzo [ c]Aza derivativesPreparation of (E) -7- (3-ethoxy-3-oxoprop-1-en-1-yl) -1,3,4, 5-tetrahydro-2H-benzo [ c ] core-2-carboxylic acid tert-butyl ester 45c]Azepin slow-2-carboxylic acid tert-butyl ester 54 a:1H NMR(400MHz,CDCl3) δ 7.67-7.61(m,1H),7.34-7.29(m,2H),7.21-7.17(m,1H),6.45-6.38(m,1H),4.42(s,1H),4.37(s,1H),4.26(q, J ═ 7.1Hz,2H),3.75-3.64(m,2H),2.98-2.92(m,2H),1.82-1.73(m,2H),1.39(s,9H),1.33(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS20H27NNaO4(M+Na+)368.1832, to give 368.1846.
b)54b preparation procedure
Pd/C (14.6mg, 10 mol%) was added to (E) -7- (3-ethoxy-3-oxoprop-1-en-1-yl) -1,3,4, 5-tetrahydro-2H-benzo [ C ]]Tert-butyl azepin-2-carboxylate 54a (112mg, 0.32mmol) in EtOAc (5 ml). The mixture was flushed with argon for 15 minutes and stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-20% EtOAc in petroleum ether) to give 7- (3-ethoxy-3-oxopropyl) -1,2,4, 5-tetrahydro-3H-benzo [ d]Azepin slow-3-carboxylic acid tert-butyl ester 54b as colorless oil:1H NMR(400MHz,CDCl3) δ 7.04-6.99(m,1H),6.97-6.92(m,2H),4.12(q, J ═ 7.2Hz,2H),3.52(s,4H),2.91-2.80(m,6H),2.61-2.56(m,2H),1.47(s,9H),1.23(t, J ═ 7.2Hz, 3H); calculation of C by ESI-HRMS20H29NNaO4(M+Na+)370.1989 gave 370.1999.
c)54c preparation procedure
Step 1. tert-butyl 7- (3-ethoxy-3-oxopropyl) -1,3,4, 5-tetrahydro-2H-benzo [ c ] azepin-2-carboxylate 54b (60mg, 0.17mmol) was added to a solution of HCl in dioxane (4M, 2 ml). The mixture was stirred at RT for 16H and then concentrated in vacuo to give ethyl 3- (2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-7-yl) propionate hydrochloride, which was used in the next step without purification.
Step 2. under argon, the vial was charged with 3- (2,3,4, 5-tetrahydro-1H-benzo [ c ] hydrochloride]Azepin-7-yl) propionic acid ethyl ester (20mg, 0.07mmol), 2-bromo-1-fluoro-4- (trifluoromethoxy) benzene (27mg, 0.11mmol), cesium carbonate (68mg, 0.21mmol), Pd-BINAP G4 precatalyst (3mg, 4 mol%) and anhydrous dioxane (2 ml). The vial was sealed, evacuated and backfilled with argon three times, then heated at 100 ℃ for 48 h. The reaction was cooled and water was added. The product was extracted with EtOAc (3 ×). The combined organic phases were washed with brine and washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to give 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ c ]]Azepin slow-7-yl) propionic acid ethyl ester 54c as colorless oil:1H NMR(400MHz,CDCl3) δ 7.15-7.11(m,1H),7.00-6.89(m,3H),6.72-6.67(m,1H),6-57-6.52(m,1H),4.47(s,2H),4.14-4.07(m,2H),3.69-3.63(m,2H),3.01-2.95(m,2H),2.91-2.85(m,2H),2.61-2.55(m,2H),1.97-1.89(m,2H),1.20(t, J ═ 7.1Hz, 3H); calculation of C by ESI-HRMS22H24F4NO3(M+H+)426.1687, to give 426.1676.
d) Preparation of 543- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-7-yl) propionic acid
Using essentially the same procedure as for compound 45, starting from 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ c)]Preparation of ethyl azepin-7-yl) propionate 54c 3- (2- (2-fluoro-5- (trifluoromethoxy) phenyl) -2,3,4, 5-tetrahydro-1H-benzo [ c]Azepin slow-7-yl) propionic acid 54:1H NMR(400MHz,CDCl3)δ7.14(d,J＝7.1Hz,1H),7.00-6.89(m,3H),6.73-6.68(m,1H),6.58-6.53(m,1H),4.47(s,2H),3.69-3.63(m,2H),3.01-2.96(m,2H),2.89(t,J＝7.8Hz,2H),2.96-2.61(m,2H),1.98-1.90(m, 2H); calculation of C by ESI-HRMS20H20F4NO3(M+H+)398.1374 to give 398.1391
Human GPR120 pEC50：6.7。
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