CN113563260A - Benzamide compound, preparation method and application - Google Patents
Benzamide compound, preparation method and application Download PDFInfo
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Abstract
The invention discloses a benzamide compound with a structure shown in a formula I, a preparation method and application thereof, wherein the compound is used as a PD-L1 inhibitor, has an obvious effect of blocking a PD-1/PD-L1 signal path, and can effectively relieve and treat related diseases such as cancer.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a benzamide compound serving as a PD-L1 inhibitor, a preparation method and application thereof.
Background
Malignant tumors are a serious health and life threatening disease. At present, the tumor treatment modes include surgery, radiotherapy, chemotherapy, targeted therapy and the like. The tumor immunotherapy refers to a therapeutic method for enhancing the anti-tumor immune effect by stimulating the immune system of the body, thereby inhibiting and killing tumor cells. The research of immunotherapy has been in the history of nearly one hundred years, and along with comprehensive development and cross infiltration of oncology, immunology and molecular biology, immunotherapy achieves multiple achievements and brings new hopes for tumor therapy.
Programmed Cell Death-1 (PD-1) and its ligand PD-L1 (B7. H1) belong to the CD28/B7 superfamily. PD-1 is mainly expressed on the membrane surface of T Cells, B Cells and natural Killer Cells (NK Cells), and PD-L1 is mainly expressed on the membrane surface of mature CD4T Cells, CD8T Cells, B Cells, monocytes, Dendritic Cells (DCs), macrophages and other hematopoietic Cells and some non-hematopoietic Cells, such as endothelial Cells, islet Cells, mast Cells and the like. Wherein PD-L1 is highly expressed in various tumors, such as lung cancer, gastric cancer, multiple myeloma, melanoma, breast cancer and the like. The expression of PD-L1 on the surface of the tumor cell interacts with the ligand on the surface of the T cell, can induce the apoptosis of the T cell or reduce the reactivity of the T cell, thereby inhibiting the tumor immune response and leading the tumor cell to escape from immune attack. Therefore, the antagonist for blocking a PD1/PD-L1 signal channel can promote the activation of T cells, reverse a tumor immune microenvironment and enhance an endogenous anti-tumor immune effect. The targeted PD-1/PD-L1 inhibitor has wide application prospect in the field of tumor immunotherapy. Currently, anti-PD-1/PD-L1 antibody therapy has been shown to have a superior effect clinically, however, biological macromolecules also have some disadvantages, such as immunogenicity and limitations on the route of administration. Therefore, there is still a need to develop targeted PD-1/PD-L1 inhibitors with better efficacy. The inventor of the invention finds that a small molecule drug can specifically regulate and/or modulate the transduction of PD-L1 and related protein kinase, thereby being used for treating diseases related to PD-1/PD-L1.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide benzamide compounds.
The invention also aims to provide a preparation method of the benzamide compound.
The invention also aims to provide application of the benzamide compound.
The technical scheme is as follows: the invention provides a benzamide compound with a structure shown as a formula I:
wherein ring a and ring B are independently an aromatic ring or an aromatic heterocycle;
l is a bond, -CH2O-、-OCH2-、-CH2CH2-、-NH(C=O)-、-(C=O)NH-、-(S=O)2NH-、-NH(S=O)2-, -O (C ═ O) -, - (C ═ O) O-, or two adjacent R —4And the two atoms of the phenyl ring to which they are attached together form a 5-7 membered substituted or unsubstituted carbocyclic oxy group, substituted or unsubstituted carbocyclic oxy group;
R1independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R2independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R3independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl;
R4independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl;
m is 1 or 2;
n is 1 or 2;
d is 1, 2 or 3.
Further, R1When said substituted alkyl or said substituted alkoxy is present, the substituent is one or more of the following substituents: halogen, C1-C4 alkyl, hydroxy,Benzyl, benzyl with cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; the substituents in said substituted hydroxy or said substituted amino are one or more of the following substituents: C1-C4 alkyl, benzyl, cyano-substituted benzyl, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; when the number of the substituents is plural, the substituents may be the same or different;
R2when said substituted alkyl or said substituted alkoxy is present, the substituent is one or more of the following substituents: halogen, C1-C4 alkyl, hydroxy,Benzyl, benzyl with cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; the substituents in said substituted hydroxy or said substituted amino are one or more of the following substituents: C1-C4 alkyl, benzyl, cyano-substituted benzyl, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; when the number of the substituents is plural, the substituents may be the same or different;
in, R5And R6Independently hydrogen, substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl or aminoalkyl groups; or R5、R6Together with the nitrogen atom to which they are attached form a 5-7 membered substituted or unsubstituted carbon heterocyclic ring; in the carbon heterocycle, the heteroatom is nitrogen or nitrogen and oxygen, and the number of the heteroatoms is 1-4;
R5or R6Wherein the substituents in said substituted alkyl are one or more of the following groups: halogen, C1-C4 alkyl, hydroxy,C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; r5、R6And the nitrogen atom to which they are attached, form a 5-to 7-membered substituted carbon heterocyclic ring. The substituents in the substituted carbon heterocycle are one or more of the following groups: halogen, C1-C4 alkyl, hydroxy,C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; when the number of the substituents is plural, the substituents may be the same or different;in, R7And R8Independently hydrogen or C1-C4 alkyl.
Further, the aromatic ring is preferably a C6-C14 aromatic ring. The C6-C14 aromatic ring is preferably a C6-C10 aromatic ring, and is more preferably a benzene ring; the heteroaromatic ring is preferably a C2-C10 heteroaromatic ring with 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. The C2-C10 heteroaromatic ring is preferably C2-C6 heteroaromatic ring with the heteroatom of nitrogen or oxygen being 1-3, and the C2-C6 heteroaromatic ring is preferably a pyridine ring.
Further, the air conditioner is provided with a fan,
Further, the benzamide compound with the structure shown in the formula I is any one of the following compounds:
further, the compound also comprises pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof.
A pharmaceutical composition comprises one or more benzamide compounds with a structure shown in formula I in a therapeutically effective amount, and a pharmaceutically acceptable carrier or auxiliary material.
The preparation method of the benzamide compound with the structure shown in the formula I comprises the following steps:
(1) carrying out condensation reaction on the compound of the formula II and the compound of the formula III to obtain a compound of a formula IV;
(2) carrying out Suzuki reaction on the compound of the formula IV and the compound of the formula V to obtain a compound of a formula VI;
(3) deprotection of the compound of formula VI via tetrabutylammonium fluoride-OPg1Is converted into-OH;
(4) carrying out hydroxyl selective oxidation reaction on the compound of the formula VII to obtain a compound of a formula VIII;
(5) carrying out reductive amination reaction on the compound shown in the formula VIII to obtain a compound shown in the formula IX;
(6) carrying out Suzuki reaction on the compound of the formula X and the compound of the formula XI to obtain a compound of a formula XII;
(7) carrying out reductive amination reaction on the compound shown in the formula XII to obtain a compound shown in the formula XIII;
(8) the compound of formula XIV and the compound of formula XV undergo a reductive amination reaction to give the compound of formula XVI.
The benzamide compound with the structure shown in the formula I is used for preparing immune checkpoint inhibitors, inhibitors with the inhibitory activity of a PD-L/PD-L1 signal channel, antitumor drugs and anti-infective drugs.
The pharmaceutical composition is used for preparing an immune checkpoint inhibitor, an inhibitor with the inhibitory activity of a PD-L/PD-L1 signal channel, an anti-tumor medicament and an anti-infection medicament.
Has the advantages that: the benzamide compound has an obvious effect on blocking a PD1/PD-L1 signal path, and can effectively relieve and treat related diseases such as cancer and the like.
Detailed Description
Example 1: synthesis of Compound JL-1: (R) -4- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The method comprises the following steps: synthesis of Compound 3
Raw material 2(2.34g, 10mmol) was weighed out and dissolved in anhydrous DMF, HATU (4.18g, 11mmol) was added at 0 ℃ and DIPEA (8.71mL 50mmol) was added and reacted at room temperature for 10 min. Another 1(4.77mL, 20mmol) of starting material was added at room temperature, and the reaction was allowed to warm to 60 ℃ for 12 h. When the reaction was completed, EA was added and extracted (50mL × 3), washed once with water (30mL), washed once with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give a yellow oil, which was granulated and purified by column chromatography (PE: EA 50: 1) to give colorless oil 3(3.92g, 86%).1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.13(d,J=1.5Hz,1H),7.86(dd,J=7.5,1.7Hz,1H),7.77(dd,J=7.6,1.6Hz,1H),7.66-7.53(m,2H),7.37(t,J=7.5Hz,1H),4.89(s,2H),0.88(s,9H),0.09(s,6H).MS(ESI,m/z):455.1[M+1]+.
Step two: synthesis of Compound 5
Weighing Compound 3(4.56g, 10mmol), phenylboronic acid (1.34g, 11mmol), Pd (dppf) Cl2(0.73g,1.0mmol),K2CO3(2.76g, 20mmol) was dissolved in dioxane (60mL) and water (6mL) under argon and refluxed at 85 ℃ for 6 h. After the reaction is completed, the reaction solution is dried by spinning, EA is added for dissolution, and filtration is carried out,the filtrate was concentrated to give a sand, which was purified by column chromatography (PE: EA: 80: 1) to give compound 5(4.21g, 93%).1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.14(d,J=1.5Hz,1H),7.87(dd,J=6.7,2.2Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.58(d,J=7.6Hz,1H),7.54-7.41(m,6H),7.39-7.30(m,1H),4.90(s,2H),0.89(s,9H),0.10(s,6H).MS(ESI,m/z):453.2[M+1]+.
Step three: synthesis of Compound 6
Compound 5(4.53g, 10mmol) was dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (3.92g, 15mmol) was added and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (DCM: MeOH ═ 60: 1) to obtain compound 6(3.35g, 99%).1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.18(d,J=1.6Hz,1H),7.96(dd,J=7.5,1.7Hz,1H),7.76(dd,J=7.5,1.7Hz,1H),7.61(d,J=7.5Hz,1H),7.53(dd,J=7.6,1.6Hz,1H),7.50-7.41(m,5H),7.36(ddt,J=6.6,5.6,2.9Hz,1H),5.25-4.38(m,3H).MS(ESI,m/z):339.1[M+1]+.
Step four: synthesis of Compound 7
Weighing the compound 6(3.39g, 10mmol) and dissolving in dichloromethane, adding active manganese dioxide (8.69g, 100mmol), under the protection of argon, heating to 50 ℃, and reacting for 15 h. After completion of the reaction, the reaction mixture was filtered by suction, the filtrate was concentrated, and then, sand was prepared and purified by column chromatography (DCM: MeOH: 100: 1) to obtain compound 7(3.00g, 89%).1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.06(s,1H),9.12(d,J=1.4Hz,1H),8.29(dd,J=7.7,1.6Hz,1H),7.96(dd,J=7.5,1.7Hz,1H),7.65(d,J=7.4Hz,1H),7.53(dd,J=7.6,1.6Hz,1H),7.50-7.41(m,5H),7.41-7.31(m,1H).MS(ESI,m/z):337.1[M+1]+.
Step five: synthesis of Compound JL-1
Compound 7(337mg, 1.0mmol), (R) - (+) -4-amino-3-hydroxybutyric acid (420mg, 5.0 mm) was weighed outol) is dissolved in DMF, and a 1N aqueous solution of sodium hydroxide (2mL, 2mmol) is added and reacted under protection of argon at room temperature. After 3h, add NaBH (OAc)3(1.06g, 5.0mmol) and reacted at room temperature for 1 h. After the reaction was completed, excess trifluoroacetic acid was added to quench the reaction, the reaction solution was filtered with suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (DCM: MeOH ═ 10: 1) to obtain compound JL-1(286mg, 65%).1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.14(s,1H),8.21(tt,J=9.2,7.9Hz,1H),8.16(d,J=1.5Hz,1H),7.86(dd,J=6.8,2.1Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.53-7.41(m,6H),7.39-7.32(m,1H),4.75(d,J=7.5Hz,1H),4.51-3.77(m,3H),3.31-2.78(m,2H),2.57-2.16(m,2H).MS(ESI,m/z):440.1[M+1]+.
Example 2: synthesis of Compound JL-38: 2-chloro-N- (5- (4, 5-dihydro-1H-imidazol-2-yl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The method comprises the following steps: synthesis of Compound JL-38
Compound 7(3.39g, 10mmol) was weighed out and dissolved in dichloromethane, ethylenediamine (3.34mL, 50mmol) was added, under argon, and NBS (4.24mL, 50mmol) was added slowly. After the reaction was completed, dichloromethane was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA 100: 1) to obtain compound JL-38(3.39g, 90%).1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.66(d,J=1.5Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),7.93(dd,J=7.1,2.1Hz,1H),7.60(d,J=7.5Hz,1H),7.54-7.42(m,6H),7.37(ddd,J=8.9,4.8,3.9Hz,1H),5.81-5.33(m,1H),3.52(td,J=7.1,4.9Hz,2H),3.32(t,J=7.1Hz,2H).MS(ESI,m/z):377.1[M+1]+.
Example 3: synthesis of Compound JL-56: (S) -4- (((6- (2-chloro-3-cyclohexylbenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The method comprises the following steps: synthesis of Compound 10
Weighing Compound 3(4.56g, 10mmol), cyclohexen-1-ylboronic acid 9(1.39g, 11mmol), Pd (dppf) Cl2(0.73g,1.0mmol),K2CO3(2.76g, 20mmol) was dissolved in dioxane (60mL) and water (6mL) under argon and refluxed at 85 ℃ for 6 h. After the reaction was completed, the reaction solution was spin-dried, EA was added to dissolve, suction filtration was performed, the filtrate was concentrated to prepare sand, and column chromatography purification (PE: EA 90: 1) was performed to obtain compound 10(3.89g, 85%).1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.14(d,J=1.5Hz,1H),7.76(ddd,J=13.9,7.5,1.5Hz,2H),7.58(d,J=7.6Hz,1H),7.54(dd,J=7.5,1.4Hz,1H),7.34(t,J=7.5Hz,1H),6.09(tt,J=6.2,1.0Hz,1H),4.90(s,2H),2.80(ddt,J=8.0,7.1,1.0Hz,2H),2.16-1.94(m,2H),1.71(pd,J=6.7,1.3Hz,2H),1.67-1.57(m,2H),0.89(s,9H),0.10(s,6H).MS(ESI,m/z):457.2[M+1]+.
Step two: synthesis of Compound 11
Weighing compound 10(4.57g, 10mmol) and dissolving in methanol, adding 10% Pd-C (500mg), introducing hydrogen, heating to 65 deg.C, reacting for 8 h. After the reaction was completed, the reaction solution was filtered by suction, the filtrate was concentrated, made into sand, and purified by column chromatography (PE: EA 100: 1) to obtain compound 11(3.90g, 85%).1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.14(d,J=1.5Hz,1H),7.78(dd,J=7.5,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.58(d,J=7.5Hz,1H),7.51(t,J=7.5Hz,1H),7.35(dd,J=7.6,1.9Hz,1H),4.90(s,2H),3.18(pd,J=7.0,0.6Hz,1H),2.06-1.84(m,2H),1.69-1.48(m,6H),1.46-1.35(m,2H),0.89(s,9H),0.10(s,6H).MS(ESI,m/z):459.2[M+1]+.
Step three: synthesis of Compound 12
Compound 11(4.59g, 10mmol) was dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (3.92g, 15mmol) was added and reacted at room temperature for 2 h. After the reaction was completed, the reaction mixture was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (DCM: MeOH ═ 100: 1) to obtain compound 12(3.41g, 99%).1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.18(d,J=1.6Hz,1H),7.87(dd,J=7.4,1.6Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.61(d,J=7.5Hz,1H),7.48(t,J=7.5Hz,1H),7.35(ddd,J=7.5,1.6,0.6Hz,1H),5.01-4.69(m,3H),3.18(pd,J=7.0,0.6Hz,1H),2.14-1.75(m,4H),1.70-1.50(m,4H),1.49-1.37(m,2H).MS(ESI,m/z):345.1[M+1]+.
Step four: synthesis of Compound 13
Weighing compound 12(3.45g, 10mmol) and dissolving in dichloromethane, adding active manganese dioxide (8.69g, 100mmol), under argon protection, heating to 50 ℃, and reacting for 15 h. After completion of the reaction, the reaction mixture was filtered by suction, the filtrate was concentrated, and then, sand was prepared and purified by column chromatography (DCM: MeOH: 120: 1) to obtain compound 13(3.05g, 89%).1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),10.06(s,1H),9.12(d,J=1.6Hz,1H),8.44-8.20(m,1H),7.87(dd,J=7.4,1.6Hz,1H),7.65(d,J=7.5Hz,1H),7.48(t,J=7.4Hz,1H),7.36(ddd,J=7.5,1.5,0.6Hz,1H),3.18(pd,J=7.0,0.6Hz,1H),2.16-1.74(m,4H),1.70-1.50(m,4H),1.50-1.36(m,2H).MS(ESI,m/z):343.1[M+1]+.
Step five: synthesis of Compound JL-56
Compound 13(343mg, 1.0mmol), (S) - (+) -4-amino-3-hydroxybutyric acid (420mg, 5.0mmol) was weighed out and dissolved in DMF, and a 1N aqueous solution of sodium hydroxide (2mL, 2mmol) was added and reacted under argon atmosphere at room temperature. After 3h, add NaBH (OAc)3(1.06g, 5.0mmol) and reacted at room temperature for 1 h. Adding excessive trifluoroacetic acid to quench reaction after the reaction is completed, filtering the reaction solution, concentrating the filtrate, preparing sand, and purifying by column chromatography (DCM: MeOH is 10: 1)) Compound JL-62(290mg, 65%) was obtained.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.39(s,1H),8.32-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.79(dd,J=7.5,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.50(t,J=7.5Hz,1H),7.34(ddd,J=7.5,1.5,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.38-3.92(m,3H),3.41-3.11(m,1H),3.11-2.88(m,2H),2.55-2.24(m,2H),2.19-1.82(m,2H),1.72-1.50(m,6H),1.48-1.31(m,2H).MS(ESI,m/z):446.2[M+1]+.
Example 4: synthesis of Compound JL-73: (R) -4- (((6- (3- ((S) -1- ((5- ((((R) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The method comprises the following steps: synthesis of Compound 15
Compound 3(4.56g, 10mmol) was dissolved in tetrahydrofuran, tetrabutylammonium fluoride (3.92g, 15mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction mixture was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (DCM: MeOH ═ 50: 1) to obtain compound 15(3.38g, 99%).1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.18(d,J=1.6Hz,1H),7.77(td,J=7.3,1.5Hz,2H),7.66-7.59(m,1H),7.59-7.50(m,1H),7.41(t,J=7.5Hz,1H),4.91(dd,J=8.4,6.3Hz,1H),4.82(dd,J=7.3,1.0Hz,2H).MS(ESI,m/z):341.0[M+1]+.
Step two: synthesis of Compound 16
Compound 15(3.42 g) was weighed10mmol) was dissolved in dichloromethane, activated manganese dioxide (8.69g, 100mmol) was added, under argon, and the temperature was raised to 50 ℃ for 15 h. After completion of the reaction, the reaction mixture was filtered by suction, the filtrate was concentrated, and then, sand was prepared and purified by column chromatography (DCM: MeOH: 100: 1) to obtain compound 16(3.06g, 90%).1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.07(d,J=1.0Hz,1H),9.12(d,J=1.4Hz,1H),8.48-8.11(m,1H),7.76(dd,J=7.5,1.5Hz,1H),7.65(d,J=7.5Hz,1H),7.59(dd,J=7.6,1.5Hz,1H),7.41(t,J=7.5Hz,1H).MS(ESI,m/z):339.0[M+1]+.
Step three: synthesis of Compound 19
Compound 17(2.64g, 10mmol) and compound 18(4.29g, 25mmol) were weighed out and dissolved in dry toluene, Pd (dppf) Cl was added2(731mg, 1.0mmol), cesium carbonate (8.15g, 25mmol), under argon, and warm to 40 ℃ for 15 h. After completion of the reaction, the reaction solution was filtered by suction, the filtrate was concentrated, and then, sand was prepared and purified by column chromatography (PE: EA 150: 1) to obtain compound 26(3.24g, 81%).1H NMR(400MHz,DMSO-d6)δ9.90(d,J=0.5Hz,1H),7.90(dd,J=7.5,0.3Hz,1H),7.15(t,J=7.5Hz,1H),7.06(ddd,J=7.6,1.6,0.6Hz,1H),6.68(dd,J=7.4,1.6Hz,1H),6.61(d,J=7.5Hz,1H),5.17(td,J=7.0,0.7Hz,1H),4.00(s,3H),3.49-2.83(m,2H),2.51(q,J=7.1Hz,2H),1.01(s,9H),0.20(s,6H).MS(ESI,m/z):400.2[M+1]+.
Step four: synthesis of Compound 20
Compound 19(4.00g, 10mmol) was dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (3.92g, 15mmol) was added and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (DCM: MeOH ═ 100: 1) to obtain compound 20(2.82g, 99%).1H NMR(400MHz,DMSO-d6)δ9.93(d,J=0.5Hz,1H),8.95(s,1H),7.94(dd,J=7.5,0.5Hz,1H),7.44-6.92(m,2H),6.80-6.32(m,2H),5.17(td,J=7.0,0.5Hz,1H),3.96(s,3H),3.10-2.95(m,1H),2.89(dt,J=12.4,7.1Hz,1H),2.62-2.25(m,2H).MS(ESI,m/z):283.1[M+1]+.
Step five: synthesis of Compound 21
Weighing compound 20(2.85g, 10mmol), dissolving in dichloromethane, adding pyridine (2.01mL, 25mmol), triethylamine (2.78mL, 20mmol), DMAP (122mg, 1.0mmol), and under the protection of argon, slowly adding trifluoromethanesulfonic anhydride (2.02mL, 12mmol) at-20 deg.C, and reacting for 30 min. The temperature is increased to room temperature, and the reaction is carried out for 6 h. Dichloromethane (100mL) was added to dissolve, water washed, brine washed, dried over anhydrous sodium sulfate, filtered, the solvent evaporated to dryness, and the residue was washed with sand and purified by column chromatography (PE: EA 60: 1) to obtain compound 21(3.76g, 90%).1H NMR(400MHz,DMSO-d6)δ9.90(d,J=0.5Hz,1H),7.90(dd,J=7.5,0.4Hz,1H),7.23(t,J=7.4Hz,1H),7.15(ddd,J=7.5,1.7,0.6Hz,1H),7.01(dd,J=7.3,1.7Hz,1H),6.61(d,J=7.5Hz,1H),5.11(td,J=7.0,0.7Hz,1H),4.00(s,3H),3.43-2.75(m,2H),2.73-2.27(m,2H).MS(ESI,m/z):418.0[M+1]+.
Step six: synthesis of Compound 22
Compound 21(4.17g, 10mmol) was weighed out and dissolved in dioxane, pinacol diborate (3.05g, 12mmol), potassium acetate (2.94g, 30mmol), Pd (dppf) Cl and added2(731mg, 1.0mmol), under the protection of argon, and reacting at 85 ℃ for 16 h. The reaction mixture was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 50: 1) to give compound 22(3.36g, 85%).1H NMR(400MHz,DMSO-d6)δ9.90(d,J=0.5Hz,1H),7.89(dd,J=7.5,0.4Hz,1H),7.44-7.19(m,2H),7.13(t,J=7.4Hz,1H),6.62(d,J=7.5Hz,1H),5.08(td,J=7.0,0.7Hz,1H),4.00(s,3H),3.59-2.85(m,2H),2.49(q,J=7.0Hz,2H),1.27(s,6H),1.22(s,6H).MS(ESI,m/z):396.2[M+1]+.
Step seven: synthesis of Compound 23
Weighing Compound 22(3.95g, 10mmol) dissolved in DMF (15mL) and DCM (15mL) was added Palou' Chlor 2-chloro-1, 3-bis (methoxycarbonyl) guanidine (2.52g, 12mmol), trifluoroacetic acid (74uL, 1.0mmol), and reacted at room temperature for 12h under argon protection. Adding Na2CO3Saturated solution (20mL) Na252O3The saturated solution (10mL) was extracted with DCM (100mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 50: 1) to give compound 23(3.48g, 81%).1H NMR(400MHz,DMSO-d6)δ9.93(d,J=0.5Hz,1H),7.95(d,J=0.3Hz,1H),7.27(d,J=0.9Hz,1H),7.25(s,1H),7.15(s,1H),5.11(t,J=7.0Hz,1H),4.01(s,3H),3.35-2.83(m,2H),2.48(qd,J=7.0,1.5Hz,2H),1.27(s,6H),1.22(s,6H).MS(ESI,m/z):430.2[M+1]+.
Step eight: synthesis of Compound 24
Compound 23(4.30g, 10mmol) and compound 16(3.40g, 10mmol) were weighed out and dissolved in a mixed solution of dioxane (60mL) and water (10mL), and Pd (dppf) Cl was added2(731mg, 1.0mmol), potassium carbonate (6.52g, 20mmol), under argon, and warmed to 85 ℃ for 15 h. After the reaction was completed, the reaction mixture was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 5: 1) to obtain compound 24(4.84g, 86%).1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.07(d,J=0.9Hz,1H),9.93(d,J=0.5Hz,1H),9.09(d,J=1.5Hz,1H),8.35-8.21(m,1H),8.08(d,J=0.5Hz,1H),7.85(dd,J=6.1,2.9Hz,1H),7.66(d,J=7.5Hz,1H),7.54-7.44(m,2H),7.43-7.32(m,2H),7.26(ddd,J=5.7,3.3,0.7Hz,1H),5.15(td,J=7.0,0.6Hz,1H),3.96(s,3H),3.02(dt,J=12.3,7.1Hz,1H),2.77(ddd,J=12.3,7.3,6.7Hz,1H),2.66-2.17(m,2H).MS(ESI,m/z):562.1[M+1]+.
Step nine: synthesis of Compound JL-73
Compound 24(562mg, 1.0mmol), (R) - (+) -4-amino-3-hydroxybutyric acid (840mg, 10mmol) was weighed out and dissolvedA1N aqueous solution of sodium hydroxide (4mL, 4mmol) was added to DMF and reacted under argon at room temperature. After 3h, add NaBH (OAc)3(2.12g, 10mmol), and reacted at room temperature for 1 h. When the reaction was completed, the reaction was quenched by addition of excess trifluoroacetic acid, filtered, the filtrate was concentrated, made into sand, and purified by column chromatography (DCM: MeOH ═ 8: 1) to give compound JL-73(546mg, 71%).1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.02-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.79-7.72(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.28-4.00(m,6H),3.92(s,3H),3.13-2.88(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.32(m,6H).MS(ESI,m/z):768.2[M+1]+.
Example 5: synthesis of Compound JL-170: (R) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The method comprises the following steps: synthesis of Compound 25
Compound 16(340mg, 1.0mmol), (S) - (+) -4-amino-3-hydroxybutyric acid (420mg, 5.0mmol) was weighed out and dissolved in DMF, and 1N aqueous sodium hydroxide solution (2mL, 2mmol) was added and reacted under argon atmosphere at room temperature. After 3h, add NaBH (OAc)3(1.06g, 5.0mmol) and reacted at room temperature for 1 h. After the reaction was completed, excess trifluoroacetic acid was added to quench the reaction, the reaction solution was filtered with suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (DCM: MeOH 15: 1) to obtain compound 25(288mg, 65%).1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.48(s,1H),8.16(d,J=1.6Hz,1H),7.92-7.74(m,2H),7.70(dd,J=7.5,1.4Hz,1H),7.64-7.60(m,1H),7.60-7.53(m,1H),7.37(t,J=7.5Hz,1H),4.75(d,J=7.6Hz,1H),4.33-3.95(m,3H),3.20-2.80(m,2H),2.56-2.16(m,2H).MS(ESI,m/z):442.0[M+1]+.
Step two: synthesis of Compound 26
Compound 23(430mg, 1.0mmol), (R) - (+) -4-amino-3-hydroxybutyric acid (420mg, 5.0mmol) was weighed out and dissolved in DMF, and 1N aqueous sodium hydroxide solution (2mL, 2mmol) was added and reacted under argon atmosphere at room temperature. After 3h, add NaBH (OAc)3(1.06g, 5.0mmol) and reacted at room temperature for 1 h. After the reaction was completed, excess trifluoroacetic acid was added to quench the reaction, the reaction solution was filtered with suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (DCM: MeOH 15: 1) to obtain compound 26(368mg, 69%).1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),7.98-7.80(m,1H),7.78(s,1H),7.34-7.22(m,2H),7.18-7.06(m,1H),5.13(td,J=7.0,0.7Hz,1H),4.76(d,J=7.6Hz,1H),4.21-4.00(m,3H),3.92(s,3H),3.55-2.37(m,4H),2.75-1.98(m,4H),1.27(s,6H),1.22(s,6H).MS(ESI,m/z):533.2[M+1]+.
Step three: synthesis of Compound JL-170
Compound 25(441mg, 1.0mmol) and compound 26(533mg, 1.0mmol) were weighed out and dissolved in a mixed solution of dioxane (10mL) and water (1mL), and Pd (dppf) Cl was added2(731mg, 1.0mmol), potassium carbonate (6.52g, 20mmol), under argon, and warmed to 85 ℃ for 15 h. After the reaction was completed, the reaction solution was dried by spinning, MeOH (50mL) was added and dissolved, the reaction solution was filtered by suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (DCM: MeOH 15: 1) to obtain compound JL-170(546mg, 71%).1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.03-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.62(d,J=2.8Hz,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.40-3.97(m,6H),3.92(s,3H),3.20-2.84(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.24(m,6H).MS(ESI,m/z):768.2[M+1]+.
Example 6: synthesis of Compound JL-207: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- (4, 5-dihydro-1H-imidazol-2-yl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The method comprises the following steps: synthesis of Compound 27
Compound 16(3.38g, 10mmol) was weighed out and dissolved in dichloromethane, ethylenediamine (3.34mL, 50mmol) was added, under argon, and NBS (4.24mL, 50mmol) was added slowly. After completion of the reaction, dichloromethane was extracted, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, and subjected to sand making and column chromatography purification (PE: EA 100: 1) to obtain compound 27(3.40g, 90%).1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.65(d,J=1.4Hz,1H),8.07(dd,J=7.5,1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.63(d,J=7.6Hz,1H),7.58(dd,J=7.5,1.5Hz,1H),7.38(t,J=7.5Hz,1H),5.87(t,J=5.0Hz,1H),3.52(tdd,J=7.1,5.0,0.9Hz,2H),3.33(td,J=7.0,0.9Hz,2H).MS(ESI,m/z):379.0[M+1]+.
Step two: synthesis of Compound JL-207
Compound 27(378mg, 1.0mmol) and compound 26(533mg, 1.0mmol) were weighed out and dissolved in a mixed solution of dioxane (10mL) and water (1mL), and Pd (dppf) Cl was added2(731mg, 1.0mmol), potassium carbonate (6.52g, 20mmol), under argon, and warmed to 85 ℃ for 15 h. After the reaction was completed, the reaction solution was dried by spinning, MeOH (50mL) was added and dissolved, the reaction solution was filtered by suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (DCM: MeOH 15: 1) to obtain compound JL-207(501mg, 71%).1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.66(s,1H),8.69(d,J=1.6Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),7.96-7.78(m,2H),7.77(s,1H),7.66-7.53(m,2H),7.47(t,J=7.4Hz,1H),7.42-7.33(m,2H),7.32-7.17(m,1H),5.60(t,J=5.0Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.76(d,J=7.6Hz,1H),4.30-3.99(m,3H),3.92(s,3H),3.59-3.44(m,2H),3.41-3.29(m,2H),3.17-2.94(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.28(m,4H).MS(ESI,m/z):705.2[M+1]+.
Example 7: synthesis of Compound JL-276: (S) -4- (((6- (3- ((S) -1- ((3-bromo-5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
Step seven: synthesis of Compound 28
Compound 22(3.95g, 10mmol) was weighed out and dissolved in a mixture of DMF (15mL) and DCM (15mL), and NBS (2.14g, 12mmol) was added under argon protection and reacted at room temperature for 12 h. Adding Na2CO3Saturated solution (20mL) Na2S2O3The saturated solution (10mL) was extracted with DCM (100mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 50: 1) to give compound 28(3.83g, 81%).1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.14(s,1H),7.36-7.21(m,2H),7.13(t,J=7.5Hz,1H),5.30-4.95(m,1H),4.00(s,3H),3.39-2.85(m,2H),2.46(qd,J=7.0,2.0Hz,2H),1.24(d,J=20.1Hz,12H).MS(ESI,m/z):474.1[M+1]+.
Step eight: synthesis of Compound 29
Compound 28(4.74g, 10mmol) and compound 16(3.40g, 10mmol) were weighed out and dissolved in a mixed solution of dioxane (60mL) and water (10mL), Pd (dppf) Cl was added2(731mg, 1.0mmol), potassium carbonate (6.52g, 20mmol), under argon, and heated to 85 ℃ for 15 h. After the reaction was completed, the reaction mixture was spin-dried, EA (150mL) was added and dissolved, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, made into sand, and purified by column chromatography (PE: EA ═ 5: 1) to obtain compound 29(5.20g, 86%).1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.07(d,J=0.9Hz,1H),9.93(s,1H),9.09(d,J=1.5Hz,1H),8.26(dd,J=7.4,1.8Hz,1H),8.21(s,1H),7.83(dd,J=7.2,1.8Hz,1H),7.66(d,J=7.5Hz,1H),7.57-7.45(m,2H),7.42-7.34(m,2H),7.31-7.22(m,1H),5.26-4.97(m,1H),3.96(s,3H),3.01(dt,J=12.5,7.2Hz,1H),2.77(dt,J=12.2,7.1Hz,1H),2.49(q,J=7.0Hz,2H).MS(ESI,m/z):606.0[M+1]+.
Step nine: synthesis of Compound JL-276
Compound 29(606mg, 1.0mmol), (S) - (+) -4-amino-3-hydroxybutyric acid (840mg, 10mmol) was weighed out and dissolved in DMF, and 1N aqueous sodium hydroxide (4mL, 4mmol) was added and reacted under argon atmosphere at room temperature. After 3h, add NaBH (OAc)3(2.12g, 10mmol), and reacted at room temperature for 1 h. After the reaction was completed, excess trifluoroacetic acid was added to quench the reaction, the reaction solution was filtered with suction, the filtrate was concentrated, and sand was prepared and purified by column chromatography (DCM: MeOH ═ 8: 1) to obtain compound JL-276(576mg, 71%).1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,7.9Hz,1H),7.82(d,J=7.3Hz,2H),7.75(dd,J=7.5,1.5Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.29(dd,J=7.2,2.2Hz,1H),5.51-4.95(m,1H),4.75(d,J=7.5Hz,2H),4.21-3.98(m,6H),3.91(s,3H),3.21-2.89(m,5H),2.78(dt,J=12.5,7.1Hz,1H),2.55-2.31(m,6H).MS(ESI,m/z):812.2[M+1]+.
Example 8: synthesis of Compound JL-2: (S) -4- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.14(s,1H),8.29-8.18(m,1H),8.16(d,J=1.6Hz,1H),7.86(dd,J=6.6,2.3Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.54-7.40(m,6H),7.40-7.31(m,1H),4.75(d,J=7.6Hz,1H),4.34-3.89(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.55-2.25(m,2H).MS(ESI,m/z):440.1[M+1]+.
Example 9: synthesis of Compound JL-3: (S) -2- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropionic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.14(s,1H),8.19(d,J=1.5Hz,1H),7.86(dd,J=6.6,2.3Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.6Hz,1H),7.54-7.40(m,6H),7.40-7.30(m,1H),6.03(t,J=9.7Hz,1H),4.76(t,J=7.0Hz,1H),4.31-3.97(m,2H),3.97-3.51(m,2H),1.51(s,3H).MS(ESI,m/z):440.1[M+1]+.
Example 10: synthesis of Compound JL-4: (R) -2- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropionic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.14(s,1H),8.19(d,J=1.5Hz,1H),7.86(dd,J=6.6,2.3Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.6Hz,1H),7.53-7.40(m,6H),7.40-7.31(m,1H),6.03(t,J=9.7Hz,1H),4.76(t,J=7.0Hz,1H),4.42-3.97(m,2H),3.97-3.68(m,2H),1.51(s,3H).MS(ESI,m/z):440.1[M+1]+.
Example 11: synthesis of Compound JL-5: 2- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -2-methylpropanoic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.14(s,1H),8.19(d,J=1.5Hz,1H),7.88(dd,J=6.9,2.1Hz,1H),7.69(dd,J=7.5,1.5Hz,1H),7.58(d,J=7.4Hz,1H),7.54-7.40(m,6H),7.41-7.32(m,1H),5.33(t,J=10.1Hz,1H),4.25(d,J=10.1Hz,2H),1.50(s,6H).MS(ESI,m/z):424.1[M+1]+.
Example 12: synthesis of Compound JL-6: ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamide) pyridin-3-yl) methyl)
Glycine
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),10.72(s,1H),8.19(d,J=1.5Hz,1H),7.91(dd,J=6.5,2.5Hz,1H),7.65(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.54-7.42(m,6H),7.42-7.32(m,1H),4.90-4.09(m,2H),3.90-3.28(m,3H).MS(ESI,m/z):396.1[M+1]+.
Example 13: synthesis of Compound JL-7: ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamide) pyridin-3-yl) methyl)
Glycine
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.14(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=5.7,3.2Hz,1H),7.68(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.53-7.40(m,6H),7.39-7.27(m,1H),5.02-4.23(m,1H),4.17(dd,J=9.6,0.5Hz,2H),2.53(s,2H),1.40(s,6H).MS(ESI,m/z):438.1[M+1]+.
Example 14: synthesis of Compound JL-8: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.14(s,1H),8.23(d,J=1.4Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.67(dd,J=7.5,1.4Hz,1H),7.60(d,J=7.4Hz,1H),7.55-7.40(m,6H),7.40-7.29(m,1H),4.01(td,J=7.0,0.9Hz,1H),3.85(d,J=1.6Hz,2H),3.35-2.85(m,2H),2.12(q,J=7.0Hz,2H).MS(ESI,m/z):422.1[M+1]+.
Example 15: synthesis of Compound JL-9: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.14(s,1H),8.23(d,J=1.4Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.67(dd,J=7.5,1.4Hz,1H),7.60(d,J=7.4Hz,1H),7.56-7.40(m,6H),7.40-7.30(m,1H),4.01(td,J=7.0,1.0Hz,1H),3.85(d,J=1.6Hz,2H),3.35-2.82(m,2H),2.37-1.91(m,2H).MS(ESI,m/z):422.1[M+1]+.
Example 16: synthesis of Compound JL-10: 1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamide) pyridin-3-yl) methyl) azetidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.14(s,1H),8.18(d,J=1.6Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.40-7.30(m,1H),3.85(s,2H),3.58-3.17(m,4H),3.07-2.82(m,1H).MS(ESI,m/z):422.1[M+1]+.
Example 17: synthesis of Compound JL-11: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.08(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.55-7.40(m,6H),7.40-7.32(m,1H),3.78(s,2H),3.20-3.04(m,1H),3.03-2.86(m,3H),2.75(p,J=7.0Hz,1H),2.17-1.55(m,2H).MS(ESI,m/z):436.1[M+1]+.
Example 18: synthesis of Compound JL-12: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.08(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.56-7.40(m,6H),7.40-7.30(m,1H),3.78(s,2H),3.08-2.83(m,4H),2.75(p,J=7.0Hz,1H),2.23-1.45(m,2H).MS(ESI,m/z):436.1[M+1]+.
Example 19: synthesis of Compound JL-13: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.40-7.31(m,1H),3.79(s,2H),3.27-2.90(m,2H),2.88-2.67(m,1H),2.57-2.36(m,1H),2.14-1.88(m,2H),1.28(s,3H).MS(ESI,m/z):450.2[M+1]+.
Example 20: synthesis of Compound JL-14: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.57-7.40(m,6H),7.39-7.30(m,1H),3.79(s,2H),3.13(dd,J=12.4,0.8Hz,1H),3.05-2.92(m,1H),2.76(ddd,J=12.2,7.4,6.7Hz,1H),2.51(dt,J=12.3,7.0Hz,1H),2.15-1.79(m,2H),1.28(s,3H).MS(ESI,m/z):450.2[M+1]+.
Example 21: synthesis of Compound JL-15: (2S, 4S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -4-hydroxypyrrolidine-2-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),10.28(s,1H),8.18(d,J=1.4Hz,1H),7.89(dd,J=7.0,2.0Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.58(d,J=7.4Hz,1H),7.55-7.40(m,6H),7.40-7.31(m,1H),4.38-4.14(m,2H),4.04-3.74(m,2H),3.69(td,J=7.0,0.6Hz,1H),3.40-3.08(m,1H),3.07-2.84(m,1H),2.54-2.24(m,1H),2.18-1.95(m,1H).MS(ESI,m/z):452.1[M+1]+.
Example 22: synthesis of Compound JL-16: (3R, 4R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -4-isopropylpyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.40(s,1H),8.17(d,J=1.4Hz,1H),7.91-7.79(m,1H),7.72(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.4Hz,1H),7.55-7.47(m,2H),7.47-7.40(m,4H),7.40-7.29(m,1H),3.95-3.62(m,2H),3.52-3.09(m,1H),3.05-2.85(m,1H),2.82-2.39(m,3H),2.01(dddd,J=8.5,5.4,3.0,1.5Hz,1H),1.81(dpd,J=13.7,6.8,0.8Hz,1H),0.95(ddd,J=15.0,6.8,1.5Hz,6H).MS(ESI,m/z):478.2[M+1]+.
Example 23: synthesis of Compound JL-17: (3R, 4R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.41(m,6H),7.40-7.30(m,1H),3.89-3.62(m,2H),3.30-3.08(m,1H),3.02-2.84(m,1H),2.74-2.42(m,3H),2.24(p,J=6.9Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):450.2[M+1]+.
Example 24: synthesis of Compound JL-18: (3S, 4S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.39-7.31(m,1H),3.99-3.50(m,2H),3.20-2.95(m,1H),2.95-2.78(m,1H),2.70-2.46(m,3H),2.24(p,J=6.8Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):450.2[M+1]+.
Example 25: synthesis of Compound JL-19: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.28(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.67(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.40-7.31(m,1H),3.84(s,2H),3.12(t,J=6.9Hz,1H),2.99-2.71(m,2H),1.98-1.23(m,6H).MS(ESI,m/z):450.2[M+1]+.
Example 26: synthesis of Compound JL-20: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.28(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.67(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.57-7.41(m,6H),7.40-7.32(m,1H),3.84(s,2H),3.12(t,J=6.9Hz,1H),2.94-2.72(m,2H),2.05-1.44(m,6H).MS(ESI,m/z):450.2[M+1]+.
Example 27: synthesis of Compound JL-21: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.56-7.41(m,6H),7.40-7.31(m,1H),3.79(d,J=1.5Hz,2H),3.14-2.27(m,5H),2.18-1.38(m,4H).MS(ESI,m/z):450.2[M+1]+.
Example 28: synthesis of Compound JL-22: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.56-7.41(m,6H),7.40-7.31(m,1H),3.79(d,J=1.5Hz,2H),3.18-2.82(m,2H),2.80-2.66(m,2H),2.61-2.44(m,1H),1.96-1.48(m,4H).MS(ESI,m/z):450.2[M+1]+.
Example 29: synthesis of Compound JL-23: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.42(m,6H),7.41-7.29(m,1H),3.77(s,2H),3.25-2.83(m,2H),2.80-2.56(m,2H),1.95-1.68(m,4H),1.16(s,3H).MS(ESI,m/z):464.2[M+1]+.
Example 30: synthesis of Compound JL-24: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.40(m,6H),7.41-7.30(m,1H),3.77(s,2H),3.14-2.82(m,2H),2.83-2.52(m,2H),1.93-1.60(m,4H),1.16(s,3H).MS(ESI,m/z):464.2[M+1]+.
Example 31: synthesis of Compound JL-25: (R) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.41-7.30(m,1H),5.06(s,1H),3.81(s,2H),3.11(d,J=2.2Hz,2H),2.86-2.64(m,2H),2.15-1.63(m,4H).MS(ESI,m/z):466.2[M+1]+.
Example 32: synthesis of Compound JL-26: (S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.41-7.30(m,1H),5.06(s,1H),3.81(s,2H),3.11(s,2H),2.95-2.46(m,2H),2.23-1.57(m,4H).MS(ESI,m/z):466.2[M+1]+.
Example 33: synthesis of Compound JL-27: (2S, 3S) -1- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -2-methylpiperidine-3-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.42(m,6H),7.41-7.31(m,1H),4.01-3.42(m,2H),3.07-2.64(m,3H),2.52(q,J=6.9Hz,1H),2.17-1.49(m,4H),1.17(d,J=6.8Hz,3H).MS(ESI,m/z):464.2[M+1]+.
Example 34: synthesis of Compound JL-28: 2- ((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) -2-azabicyclo [2.2.2] octane-4-carboxylic acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),10.43(s,1H),8.17(d,J=1.5Hz,1H),7.93-7.78(m,1H),7.72(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.54-7.40(m,6H),7.40-7.28(m,1H),3.79(s,2H),3.36(d,J=12.4Hz,1H),3.17(d,J=12.3Hz,1H),3.04-2.73(m,1H),2.15-1.70(m,8H).MS(ESI,m/z):476.2[M+1]+.
Example 35: synthesis of Compound JL-29: 2-chloro-N- (5- ((dimethylamino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.18(d,J=1.6Hz,1H),7.94(dd,J=6.5,2.4Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.4Hz,1H),7.56-7.42(m,6H),7.42-7.32(m,1H),3.76(s,2H),2.29(s,6H).MS(ESI,m/z):366.1[M+1]+.
Example 36: synthesis of Compound JL-30: 2-chloro-N- (5- (((2-hydroxyethyl) amino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.16(d,J=1.5Hz,1H),7.90(dd,J=6.6,2.4Hz,1H),7.81(tt,J=9.1,7.1Hz,1H),7.68(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.5Hz,1H),7.54-7.42(m,6H),7.38(tq,J=5.0,3.5Hz,1H),4.56(t,J=6.4Hz,1H),4.21(d,J=9.0Hz,2H),3.66(td,J=7.1,6.3Hz,2H),2.87(q,J=7.0Hz,2H).MS(ESI,m/z):382.1[M+1]+.
Example 37: synthesis of Compound JL-31: 2-chloro-N- (5- ((3-methylazetidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=6.7,2.3Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.42(m,6H),7.42-7.34(m,1H),3.83(s,2H),3.00(d,J=7.0Hz,4H),2.35-1.73(m,J=6.9Hz,1H),1.00(d,J=6.8Hz,3H).MS(ESI,m/z):392.2[M+1]+.
Example 38: synthesis of Compound JL-32: 2-chloro-N- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.18(d,J=1.4Hz,1H),7.91(dd,J=6.5,2.5Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.43(m,6H),7.42-7.34(m,1H),4.09-3.91(m,2H),3.83(s,2H),3.29-2.99(m,4H).MS(ESI,m/z):394.1[M+1]+.
Example 39: synthesis of Compound JL-33: 2-chloro-N- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.4Hz,1H),7.56-7.41(m,6H),7.40-7.33(m,1H),4.65(s,1H),3.86(s,2H),3.52-2.90(m,4H),1.32(s,3H).MS(ESI,m/z):408.1[M+1]+.
Example 40: synthesis of Compound JL-34: 2-chloro-N- (5- ((3-methoxyazetidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.40(m,6H),7.40-7.32(m,1H),3.96(pq,J=7.0,1.4Hz,1H),3.80(s,2H),3.26-3.13(m,5H),3.07(dd,J=12.4,7.0Hz,2H).MS(ESI,m/z):408.1[M+1]+.
Example 41: synthesis of Compound JL-35: 2-chloro-N- (5- ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
Synthetic methods as examples1。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.6Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.39-7.29(m,1H),4.32(t,J=6.4Hz,1H),3.83(s,2H),3.49(d,J=6.4Hz,2H),3.27-2.83(m,4H),1.07(s,3H).MS(ESI,m/z):422.2[M+1]+.
Example 42: synthesis of Compound JL-36: 2-chloro-N- (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.61(d,J=7.6Hz,1H),7.55-7.41(m,6H),7.40-7.32(m,1H),3.82(s,2H),3.54(dd,J=7.0,6.0Hz,2H),3.17(t,J=6.1Hz,1H),3.07(d,J=7.0Hz,4H),2.18(p,J=7.0Hz,1H).MS(ESI,m/z):408.1[M+1]+.
Example 43: synthesis of Compound JL-37: 2-chloro-N- (5- ((((((1 r, 3r) -3-hydroxycyclobutyl) methyl) amino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.5Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.60(d,J=7.4Hz,1H),7.55-7.41(m,6H),7.41-7.31(m,1H),5.94(tt,J=9.4,7.1Hz,1H),4.30-4.02(m,3H),3.81(hd,J=7.0,2.4Hz,1H),2.70(t,J=7.0Hz,2H),2.20-2.02(m,1H),2.03-1.69(m,4H).MS(ESI,m/z):422.2[M+1]+.
Example 44: synthesis of Compound JL-39: 2-chloro-N- (5- (((5-oxopyrrolidin-3-yl) amino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.5Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.59(s,1H),7.54-7.42(m,6H),7.41-7.32(m,1H),7.31-7.24(m,1H),4.21-3.81(m,2H),3.61-3.21(m,3H),2.69-2.40(m,2H),2.25-2.02(m,1H).MS(ESI,m/z):421.1[M+1]+.
Example 45: synthesis of Compound JL-40: (R) -2-chloro-N- (5- ((3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.4Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.40-7.32(m,1H),4.19(h,J=7.0Hz,1H),3.97(d,J=7.1Hz,1H),3.77(s,2H),3.47-3.17(m,1H),2.98-2.53(m,3H),1.93-1.50(m,2H).MS(ESI,m/z):408.1[M+1]+.
Example 46: synthesis of Compound JL-41: 2-chloro-N- (5- ((((1R, 2S) -2-hydroxycyclopentyl) amino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.5Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.69(dd,J=7.5,1.5Hz,1H),7.58(d,J=7.4Hz,1H),7.54-7.41(m,6H),7.41-7.30(m,1H),4.50(d,J=5.7Hz,1H),4.08-3.92(m,2H),3.87(qd,J=7.0,5.8Hz,1H),3.12(dq,J=8.4,7.0Hz,1H),2.91(td,J=9.0,8.4Hz,1H),1.88-1.50(m,6H).MS(ESI,m/z):422.2[M+1]+.
Example 47: synthesis of Compound JL-42: (S) -2-chloro-N- (5- (((((5-oxapyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.76-7.65(m,2H),7.57(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.40-7.30(m,1H),6.79(tt,J=9.2,7.6Hz,1H),4.42-3.92(m,2H),3.72(dp,J=8.2,7.0Hz,1H),3.22-2.64(m,2H),2.48-2.15(m,2H),2.13-1.86(m,1H),1.74(dq,J=12.5,7.1Hz,1H).MS(ESI,m/z):435.2[M+1]+.
Example 48: synthesis of Compound JL-43: 2-chloro-N- (5- ((6-oxo-2, 5-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.17(d,J=1.5Hz,1H),7.85(dd,J=7.1,1.9Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64-7.57(m,2H),7.55-7.41(m,6H),7.39-7.29(m,1H),3.84(s,2H),3.36(d,J=3.3Hz,4H),2.37(t,J=7.1Hz,2H),2.09-1.73(m,2H).MS(ESI,m/z):447.2[M+1]+.
Example 49: synthesis of Compound JL-44: 2-chloro-N- (5- ((7-oxo-2, 6-diazaspiro [3.4] oct-2-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.17(d,J=1.5Hz,1H),7.85(dd,J=7.1,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.65-7.41(m,8H),7.39-7.30(m,1H),3.82(s,2H),3.46(dt,J=5.1,0.6Hz,2H),3.28-2.90(m,4H),2.40(d,J=0.7Hz,2H).MS(ESI,m/z):447.2[M+1]+.
Example 50: synthesis of Compound JL-45: 2-chloro-N- (5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=7.2,1.8Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.63-7.56(m,2H),7.56-7.42(m,6H),7.41-7.30(m,1H),3.75(d,J=2.4Hz,2H),3.50-3.22(m,2H),2.92-2.66(m,3H),2.66-2.33(m,3H),1.92-1.67(m,2H).MS(ESI,m/z):461.2[M+1]+.
Example 51: synthesis of Compound JL-46: (R) -N- (5- ((3- (1H-tetrazol-5-yl) pyrrolidin-1-yl) methyl) pyridin-2-yl) -2-chloro- [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),10.43(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=7.2,1.8Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.6Hz,1H),7.54(dd,J=7.5,1.8Hz,1H),7.51-7.42(m,5H),7.42-7.31(m,1H),4.05(p,J=7.0Hz,1H),3.77(s,2H),3.63-3.31(m,2H),3.01(ddd,J=12.3,7.4,6.7Hz,1H),2.61-2.37(m,1H),2.28-2.09(m,2H).MS(ESI,m/z):460.2[M+1]+.
Example 52: synthesis of Compound JL-47: 2-chloro-N- (5- ((1-oxo-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=7.2,1.8Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.6Hz,1H),7.56-7.41(m,7H),7.40-7.32(m,1H),3.77(s,2H),3.45(d,J=5.9Hz,2H),3.02-2.52(m,4H),1.96(td,J=7.1,4.3Hz,4H).MS(ESI,m/z):461.2[M+1]+.
Example 53: synthesis of Compound JL-48: 2-chloro-N- (5- ((3-oxo-2, 8-diazaspiro [4.5] decaalk-8-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.17(d,J=1.5Hz,1H),7.93-7.80(m,1H),7.76(dd,J=7.5,1.4Hz,1H),7.64-7.55(m,2H),7.54-7.48(m,2H),7.48-7.41(m,4H),7.39-7.29(m,1H),3.78(s,2H),3.52-3.21(m,2H),2.76(dt,J=12.4,7.1Hz,2H),2.63(dt,J=12.4,7.1Hz,2H),2.39(d,J=0.7Hz,2H),2.08-1.62(m,4H).MS(ESI,m/z):475.2[M+1]+.
Example 54: synthesis of Compound JL-49: 2-chloro-N- (5- ((1-oxo-2, 9-diazaspiro [5.5] undecan-9-yl) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.17(d,J=1.5Hz,1H),7.94-7.80(m,1H),7.76(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.6Hz,1H),7.56-7.47(m,3H),7.44(d,J=4.0Hz,4H),7.41-7.32(m,1H),3.78(s,2H),3.24(td,J=7.0,6.0Hz,2H),2.76(dt,J=12.4,7.1Hz,2H),2.64(dt,J=12.4,7.1Hz,2H),2.16(dt,J=12.4,7.1Hz,2H),1.96(dt,J=12.4,7.1Hz,2H),1.76(ddd,J=18.1,7.6,6.4Hz,2H),1.67-1.54(m,2H).MS(ESI,m/z):489.2[M+1]+.
Example 55: synthesis of Compound JL-50: (S) -4- (((6- (2-cyano- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.40(s,1H),8.32-8.12(m,2H),8.04-7.95(m,1H),7.87-7.79(m,2H),7.73-7.64(m,3H),7.62-7.48(m,3H),7.46-7.36(m,1H),4.75(d,J=7.6Hz,1H),4.31-3.93(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.55-2.26(m,2H).MS(ESI,m/z):431.2[M+1]+.
Example 56: synthesis of Compound JL-51: (S) -4- (((6- (2-methyl- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.40(s,1H),8.28-8.14(m,2H),7.80(dd,J=7.5,1.5Hz,1H),7.69(dd,J=7.5,1.4Hz,1H),7.60(d,J=1.7Hz,1H),7.58(d,J=1.7Hz,1H),7.54-7.47(m,2H),7.46-7.34(m,4H),4.75(d,J=7.6Hz,1H),4.35-3.96(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.53-2.31(m,5H).MS(ESI,m/z):420.2[M+1]+.
Example 57: synthesis of Compound JL-52: (S) -4- (((6- ([1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.38(s,1H),8.29-8.14(m,2H),8.11(t,J=1.4Hz,1H),7.97(ddd,J=6.6,2.4,1.5Hz,1H),7.69(dd,J=7.5,1.5Hz,1H),7.67-7.50(m,5H),7.49-7.39(m,2H),7.38-7.30(m,1H),4.75(d,J=7.6Hz,1H),4.30-3.97(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.57-2.31(m,2H).MS(ESI,m/z):406.2[M+1]+.
Example 58: synthesis of Compound JL-53: ((S) -4- (((6- (2-chloro-3- (2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-yl) benzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.43(s,1H),8.32-8.12(m,2H),7.79(dd,J=7.0,2.0Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.53-7.36(m,2H),7.32(dd,J=7.5,1.5Hz,1H),7.09(d,J=1.6Hz,1H),6.96(d,J=7.5Hz,1H),4.75(d,J=7.6Hz,1H),4.28(d,J=1.4Hz,4H),4.21-3.98(m,3H),3.33-2.83(m,2H),2.53-2.26(m,2H).MS(ESI,m/z):498.1[M+1]+.
Example 59: synthesis of Compound JL-54: (S) -4- (((6- (2-chloro-3- (2, 3-dihydrobenzofuran-6-yl) benzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.43(s,1H),8.31-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.77(dd,J=7.4,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.52-7.40(m,2H),7.37-7.27(m,2H),7.07(d,J=1.5Hz,1H),4.75(d,J=7.6Hz,1H),4.56(td,J=7.0,1.5Hz,2H),4.28-3.98(m,3H),3.23(td,J=7.1,1.0Hz,2H),3.13-2.88(m,2H),2.52-2.31(m,2H).MS(ESI,m/z):482.1[M+1]+.
Example 60: synthesis of Compound JL-55: (S) -4- ((((6- (2-chloro-2 ', 3 ', 4 ', 5 ' -tetrahydro- [1, 1 ' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.28(s,1H),8.31-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.80(dd,J=7.5,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.61-7.51(m,2H),7.34(t,J=7.5Hz,1H),6.09(tt,J=6.2,1.0Hz,1H),4.75(d,J=7.6Hz,1H),4.38-3.93(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.80(tq,J=7.0,1.0Hz,2H),2.53-2.29(m,2H),2.19-1.99(m,2H),1.87-1.51(m,4H).MS(ESI,m/z):444.2[M+1]+.
Example 61: synthesis of compound JL 57: (S) -4- (((6- (2-chloro-3 '-methoxy- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.28(s,1H),8.29-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.78(dd,J=7.5,1.5Hz,1H),7.70(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.50-7.34(m,3H),7.31(dd,J=7.5,1.5Hz,1H),7.17-7.07(m,1H),7.00-6.87(m,1H),4.75(d,J=7.6Hz,1H),4.37-4.00(m,3H),3.83(s,3H),3.38-2.87(m,2H),2.58-2.29(m,2H).MS(ESI,m/z):470.1[M+1]+.
Example 62: synthesis of Compound JL-58: (S) -4- (((6- (2-chloro-3 ' -fluoro-5 ' -methoxy- [1, 1 ' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),10.40(s,1H),8.29-8.18(m,1H),8.16(d,J=1.6Hz,1H),7.84(dd,J=7.5,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.43(t,J=7.5Hz,1H),7.30(dd,J=7.5,1.6Hz,1H),7.07(dt,J=8.0,1.5Hz,1H),6.98(t,J=1.5Hz,1H),6.79(dt,J=7.9,1.5Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.98(m,3H),3.81(s,3H),3.25-2.90(m,2H),2.57-2.29(m,2H).MS(ESI,m/z):488.1[M+1]+.
Example 63: synthesis of Compound JL-59: (S) -2-chloro-3- (2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-yl) -N- (5- (((((5-oxapyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.16(d,J=1.6Hz,1H),7.79(dd,J=6.3,2.7Hz,1H),7.75-7.72(m,1H),7.70(d,J=1.6Hz,1H),7.57(d,J=7.5Hz,1H),7.48-7.39(m,2H),7.32(dd,J=7.5,1.5Hz,1H),7.09(d,J=1.6Hz,1H),6.96(d,J=7.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),4.28(d,J=1.4Hz,4H),4.19-4.01(m,2H),3.75(dp,J=8.2,7.0Hz,1H),3.05-2.72(m,2H),2.42-2.22(m,2H),2.07-1.87(m,1H),1.74(dq,J=12.4,7.0Hz,1H).MS(ESI,m/z):493.2[M+1]+.
Example 64: synthesis of Compound JL-60: (S) -2-chloro-3- (1-methyl-1H-indazol-4-yl) -N- (5- ((((5-oxapyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.22-8.13(m,2H),7.87-7.66(m,5H),7.57(d,J=7.5Hz,1H),7.51(q,J=7.5Hz,2H),7.36(dd,J=7.5,1.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),4.31-3.98(m,2H),3.81(s,3H),3.73(dq,J=8.2,7.0Hz,1H),3.19-2.68(m,2H),2.43-2.22(m,2H),1.98(dq,J=13.0,7.1Hz,1H),1.74(dq,J=12.5,7.0Hz,1H).MS(ESI,m/z):489.2[M+1]+.
Example 65: synthesis of Compound JL-61: (S) -2-chloro-3- (2, 3-dihydrobenzofuran-6-yl) -N- (5- (((((5-oxapyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.16(d,J=1.6Hz,1H),7.77(dd,J=7.4,1.5Hz,1H),7.75-7.68(m,2H),7.57(d,J=7.5Hz,1H),7.51-7.40(m,2H),7.37-7.27(m,2H),7.07(d,J=1.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),4.56(td,J=7.0,1.5Hz,2H),4.31-3.99(m,2H),3.75(dp,J=8.2,7.0Hz,1H),3.23(td,J=7.1,1.0Hz,2H),3.05-2.68(m,2H),2.41-2.18(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.74(dq,J=12.4,7.1Hz,1H).MS(ESI,m/z):477.2[M+1]+.
Example 66: synthesis of Compound JL-62: (S) -2-chloro-3 '-methoxy-N- (5- ((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.16(d,J=1.6Hz,1H),7.77(dd,J=7.5,1.5Hz,1H),7.75-7.67(m,2H),7.57(d,J=7.5Hz,1H),7.49-7.36(m,3H),7.31(dd,J=7.5,1.5Hz,1H),7.20-7.07(m,1H),7.01-6.88(m,1H),6.79(tt,J=9.2,7.6Hz,1H),4.27-3.97(m,2H),3.87-3.63(m,4H),2.99-2.75(m,2H),2.46-2.19(m,2H),2.08-1.88(m,1H),1.74(dq,J=12.5,7.1Hz,1H).MS(ESI,m/z):465.2[M+1]+.
Example 67: synthesis of Compound JL-63: (S) -4- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) -2- ((5-cyanopyridin-3-yl) methoxy) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.74(s,1H),8.76(d,J=1.6Hz,1H),8.73-8.61(m,1H),8.14(t,J=1.5Hz,1H),7.94-7.74(m,2H),7.71(d,J=7.6Hz,1H),7.60-7.48(m,2H),7.48-7.42(m,2H),7.42-7.31(m,3H),7.25(d,J=7.5Hz,1H),5.38-5.08(m,2H),4.75(d,J=7.6Hz,1H),4.28-4.04(m,1H),3.99(dd,J=12.4,9.2Hz,1H),3.73(dd,J=12.4,9.1Hz,1H),3.04(qdd,J=12.4,8.0,7.0Hz,2H),2.58-2.28(m,2H).MS(ESI,m/z):572.2[M+1]+.
Example 68: synthesis of Compound JL-64: (S) -4- (((2- (benzyloxy) -6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.74(s,1H),7.91-7.75(m,2H),7.70(d,J=7.5Hz,1H),7.56(dd,J=7.5,1.6Hz,1H),7.51-7.46(m,1H),7.46-7.25(m,11H),5.23(qt,J=12.4,0.9Hz,2H),4.75(d,J=7.6Hz,1H),4.25-3.88(m,3H),3.04(qdd,J=12.4,8.0,7.0Hz,2H),2.60-2.27(m,2H).MS(ESI,m/z):546.2[M+1]+.
Example 69: synthesis of Compound JL-65: (S) -4- (((5- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyrazin-2-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),10.86(s,1H),8.34(s,1H),8.13-7.94(m,2H),7.86(dd,J=5.7,3.4Hz,1H),7.60-7.40(m,6H),7.40-7.30(m,1H),4.75(d,J=7.6Hz,1H),4.42-4.03(m,3H),3.08(qdd,J=12.4,9.0,7.0Hz,2H),2.54-2.29(m,2H).MS(ESI,m/z):441.1[M+1]+.
Example 70: synthesis of Compound JL-66: (S) -4- (((2- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyrimidin-5-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),11.21(s,1H),8.43(s,2H),8.18-7.84(m,2H),7.65-7.40(m,6H),7.40-7.26(m,1H),4.75(d,J=7.6Hz,1H),4.56-4.17(m,2H),4.16-4.03(m,1H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.58-2.30(m,2H).MS(ESI,m/z):441.1[M+1]+.
Example 71: synthesis of Compound JL-67: (S) -4- (((6- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) pyridazin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),10.82(s,1H),8.02(p,J=9.1Hz,1H),7.85(dd,J=5.7,3.4Hz,1H),7.73(d,J=7.5Hz,1H),7.66(d,J=7.4Hz,1H),7.56-7.40(m,6H),7.39-7.30(m,1H),4.75(d,J=7.6Hz,1H),4.39-3.99(m,3H),3.08(qdd,J=12.4,9.0,7.0Hz,2H),2.52-2.32(m,2H).MS(ESI,m/z):441.1[M+1]+.
Example 72: synthesis of Compound JL-68: (S) -4- ((4- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) benzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),9.25(s,1H),8.19(tt,J=8.6,7.9Hz,1H),7.88(dd,J=5.4,3.5Hz,1H),7.81-7.69(m,2H),7.54-7.40(m,7H),7.40-7.32(m,2H),4.75(d,J=7.6Hz,1H),4.21-4.00(m,1H),3.95-3.71(m,2H),3.17-2.90(m,2H),2.49-2.32(m,2H).MS(ESI,m/z):439.1[M+1]+.
Example 73: synthesis of Compound JL-69: (S) -4- ((4- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) -2-methylbenzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.33(s,1H),8.02-7.81(m,1H),7.67-7.52(m,1H),7.52-7.41(m,6H),7.40-7.30(m,3H),7.15(dt,J=7.5,1.0Hz,1H),4.75(d,J=7.6Hz,1H),4.26-4.03(m,1H),3.97-3.65(m,2H),3.04(qdd,J=12.3,7.9,7.0Hz,2H),2.58-2.27(m,2H),2.26-2.17(m,3H).MS(ESI,m/z):453.2[M+1]+.
Example 74: synthesis of Compound JL-70: (S) -4- ((4- (2-chloro- [1, 1' -biphenyl ] -3-carboxamido) -2-methoxybenzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.48(s,1H),7.83(dd,J=6.1,2.9Hz,1H),7.66-7.55(m,1H),7.54-7.41(m,6H),7.40-7.29(m,3H),7.22(t,J=0.8Hz,1H),4.75(d,J=7.6Hz,1H),4.09(dq,J=7.8,7.0Hz,1H),3.96-3.69(m,5H),3.03(qdd,J=12.4,8.0,7.0Hz,2H),2.52-2.21(m,2H).MS(ESI,m/z):469.1[M+1]+.
Example 75: synthesis of Compound JL-71: (S) -2-chloro-N- (4- (((((5-oxapyrrolidin-2-yl) methyl) amino) methyl) phenyl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.88(dd,J=5.4,3.5Hz,1H),7.76(d,J=1.3Hz,1H),7.75-7.67(m,2H),7.56-7.47(m,3H),7.47-7.31(m,6H),6.77(tt,J=8.4,7.6Hz,1H),4.00-3.82(m,2H),3.72(dp,J=8.2,7.0Hz,1H),3.05-2.73(m,2H),2.31(td,J=7.1,1.5Hz,2H),2.05-1.89(m,1H),1.82-1.66(m,1H).MS(ESI,m/z):434.2[M+1]+.
Example 76: synthesis of Compound JL-72: (S) -2-chloro-N- (3-methoxy-4- ((((5-oxapyrrolidin-2-yl) methyl) amino) methyl) phenyl) - [1, 1' -biphenyl ] -3-carboxamide
The synthesis was as in example 1.1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.88(dd,J=5.7,3.3Hz,1H),7.73(d,J=8.2Hz,1H),7.56-7.41(m,6H),7.42-7.30(m,3H),7.22(t,J=0.8Hz,1H),6.94(tt,J=8.3,7.7Hz,1H),3.91-3.78(m,5H),3.76-3.66(m,1H),3.10-2.76(m,2H),2.47-2.18(m,2H),2.08-1.89(m,1H),1.74(dq,J=12.5,7.1Hz,1H).MS(ESI,m/z):464.2[M+1]+.
Example 77: synthesis of Compound JL-74: (S) -4- (((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl)
-2-chlorobenzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthetic method is as followsExample 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.01-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.31-4.00(m,6H),3.92(s,3H),3.25-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.27(m,6H).MS(ESI,m/z):768.2[M+1]+.
Example 78: synthesis of Compound JL-75: (S) -2- (((6- (3- ((S) -1- ((5- (((S) -2-carboxy-1-hydroxypropan-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropanoic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),11.99(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.10-6.01(m,1H),6.00-5.91(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.90-4.77(m,1H),4.77-4.68(m,1H),4.26-3.99(m,4H),3.97-3.79(m,7H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.42(m,2H),1.51(d,J=5.0Hz,6H).MS(ESI,m/z):768.2[M+1]+.
Example 79: synthesis of Compound JL-76: (R) -2- (((6- (3- ((S) -1- ((5- ((((R) -2-carboxy-1-hydroxypropan-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropanoic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),11.99(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.12-6.01(m,1H),6.01-5.92(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.90-4.77(m,1H),4.77-4.70(m,1H),4.30-3.98(m,4H),3.98-3.71(m,7H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.62-2.43(m,2H),1.51(d,J=5.0Hz,6H).MS(ESI,m/z):768.2[M+1]+.
Example 80: synthesis of Compound JL-77: (S) -2- (((6- (3- (1- ((5- (((2-carboxypropan-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridinyl-3-yl) methyl) amino) -2-methylpropanoic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),11.86(s,1H),10.61(s,1H),8.17(d,J=1.5Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.75(dd,J=7.5,1.4Hz,1H),7.62(d,J=2.7Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.52(t,J=10.2Hz,1H),5.36(t,J=10.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.50-4.17(m,4H),3.92(s,3H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.51(d,J=7.2Hz,1H),2.46(d,J=7.4Hz,1H),1.54(d,J=1.5Hz,6H),1.49(d,J=1.5Hz,6H).MS(ESI,m/z):736.2[M+1]+.
Example 81: synthesis of Compound JL-78: (S) - ((6- (3- (1- ((5- (((carboxymethyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) glycine
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),12.22(s,1H),10.61(s,1H),8.18(d,J=1.6Hz,1H),7.87-7.75(m,2H),7.72(dd,J=7.5,1.5Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.27(ddd,J=6.1,2.8,0.6Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.49-4.15(m,4H),3.92(s,3H),3.60-3.40(m,4H),3.39-3.21(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.51(d,J=7.2Hz,1H),2.46(d,J=7.4Hz,1H).MS(ESI,m/z):680.2[M+1]+.
Example 82: synthesis of Compound JL-79: (S) -3- (((6- (3- (1- ((5- (((1-carboxy-2-methylpropan-2-yl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) amino) -3-methylbutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.85(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,1H),7.28(ddd,J=6.8,2.1,0.5Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.54(td,J=9.6,5.7Hz,2H),4.32-4.05(m,4H),3.92(s,3H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.66-2.40(m,6H),1.42(d,J=0.8Hz,6H),1.37(d,J=0.8Hz,6H).MS(ESI,m/z):764.2[M+1]+.
Example 83: synthesis of Compound JL-80: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -2-carboxyazetidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78-7.68(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.09-3.95(m,2H),3.94-3.76(m,7H),3.22-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.41(m,2H),2.13(qd,J=7.1,4.5Hz,4H).MS(ESI,m/z):732.2[M+1]+.
Example 84: synthesis of Compound JL-81: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -2-carboxyazetidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78-7.69(m,2H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.33(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.99(tdd,J=7.0,2.1,0.9Hz,2H),3.95-3.69(m,7H),3.22-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.38(m,2H),2.29-1.97(m,4H).MS(ESI,m/z):732.2[M+1]+.
Example 85: synthesis of Compound JL-82: (S) -1- ((6- (3- (1- ((5- ((3-carboxyazetidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamide)
Pyridin-3-yl) methyl) azetidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.33(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.01-3.86(m,5H),3.86(s,2H),3.46-3.25(m,8H),3.04(dt,J=12.4,7.1Hz,1H),2.93(p,J=7.0Hz,2H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.51(d,J=7.2Hz,1H),2.46(d,J=7.4Hz,1H).MS(ESI,m/z):732.2[M+1]+.
Example 86: synthesis of Compound JL-83: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -3-carboxypyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzol
Carboxamidopyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.69(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.58(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.02-3.67(m,7H),3.22-2.89(m,9H),2.85-2.71(m,3H),2.49(q,J=7.3Hz,2H),1.96-1.71(m,4H).MS(ESI,m/z):760.2[M+1]+.
Example 87: synthesis of Compound JL-84: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxypyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoic acid methyl ester
Amidopyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.69(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.55(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.81(m,2H),3.81-3.71(m,2H),3.10-2.93(m,7H),2.93-2.72(m,5H),2.49(q,J=7.3Hz,2H),2.05-1.70(m,4H).MS(ESI,m/z):760.2[M+1]+.
Example 88: synthesis of Compound JL-85: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -3-carboxy-3-methylpyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.79(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.99-3.84(m,5H),3.84-3.71(m,2H),3.20-2.93(m,5H),2.90-2.70(m,3H),2.57-2.40(m,4H),2.11-1.84(m,4H),1.28(d,J=0.8Hz,6H).MS(ESI,m/z):788.3[M+1]+.
Example 89: synthesis of Compound JL-86: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-3-methylpyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.79(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.00-3.82(m,5H),3.82-3.71(m,2H),3.22-3.09(m,2H),3.08-2.94(m,3H),2.87-2.69(m,3H),2.57-2.44(m,4H),2.10-1.89(m,4H),1.28(d,J=0.8Hz,6H)..MS(ESI,m/z):788.3[M+1]+.
Example 90: synthesis of Compound JL-87: (2S, 4S) -1- ((6- (3- ((S) -1- ((5- ((((2S, 4S) -2-carboxy-4-hydroxypyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) -4-hydroxypyrrolidine-2-carboxylic acid
Synthetic methods as examples4。1H NMR(400MHz,DMSO-d6)δ12.05(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77-7.72(m,2H),7.66-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.34-4.14(m,4H),3.96-3.87(m,5H),3.82(dd,J=12.4,2.5Hz,2H),3.62(tdd,J=7.0,1.7,0.6Hz,2H),3.33-3.16(m,2H),3.12-2.89(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.44(m,2H),2.41-2.28(m,1H),2.12-1.89(m,3H).MS(ESI,m/z):792.2[M+1]+.
Example 91: synthesis of Compound JL-88: (3R, 4R) -1- ((6- (3- ((S) -1- ((5- (((3R, 4R) -3-carboxy-4-isopropylpyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) -4-isopropylpyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.81(s,2H),10.61(s,1H),8.14(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.62(d,J=1.3Hz,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.37(m,1H),7.34(dd,J=7.5,1.9Hz,1H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.96-3.82(m,5H),3.81-3.71(m,2H),3.32-3.19(m,2H),3.09-2.89(m,3H),2.84-2.67(m,5H),2.66-2.56(m,2H),2.49(q,J=7.3Hz,2H),2.19-1.95(m,2H),1.74(dqdd,J=13.6,6.8,3.0,0.7Hz,2H),0.94(dd,J=6.8,1.5Hz,6H),0.89(dd,J=6.8,1.5Hz,6H).MS(ESI,m/z):844.3[M+1]+.
Example 92: synthesis of Compound JL-89: (3R, 4R) -1- ((6- (3- ((S) -1- ((5- (((3R, 4R) -3-carboxy-4-methylpyrrolidin-1-yl) methyl) -3) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.87(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.81-3.72(m,2H),3.30-3.15(m,2H),3.11-2.89(m,3H),2.78(ddd,J=12.4,7.4,6.7Hz,1H),2.70-2.40(m,8H),2.21(dt,J=13.7,6.9Hz,2H),0.99(d,J=1.7Hz,3H),0.97(d,J=1.6Hz,3H).MS(ESI,m/z):788.3[M+1]+.
Example 93: synthesis of Compound JL-90: (3S, 4S) -1- ((6- (3- ((S) -1- ((5- (((3S, 4S) -3-carboxy-4-methylpyrrolidin-1-yl) methyl) -3) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.87(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.81-3.73(m,2H),3.09-2.98(m,3H),2.97-2.85(m,2H),2.78(ddd,J=12.4,7.4,6.7Hz,1H),2.70-2.44(m,8H),2.21(dt,J=13.7,6.9Hz,2H),0.99(d,J=1.7Hz,3H),0.97(d,J=1.6Hz,3H).MS(ESI,m/z):788.3[M+1]+.
Example 94: synthesis of Compound JL-91: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -2-carboxypiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77-7.69(m,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.91(s,3H),3.90-3.79(m,4H),3.12(td,J=6.9,3.2Hz,2H),3.06-2.98(m,1H),2.97-2.71(m,5H),2.55-2.42(m,2H),1.92-1.43(m,12H).MS(ESI,m/z):788.3[M+1]+.
Example 95: synthesis of Compound JL-92: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -2-carboxypiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.4Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78-7.69(m,2H),7.65-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.91(s,3H),3.90-3.78(m,4H),3.12(td,J=6.9,3.2Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.93-2.69(m,5H),2.58-2.40(m,2H),1.88-1.48(m,12H).MS(ESI,m/z):788.3[M+1]+.
Example 96: synthesis of Compound JL-93: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -3-carboxypiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methylpiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),10.68(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.81-3.72(m,2H),3.14(dd,J=12.4,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.86(m,3H),2.84-2.62(m,5H),2.60-2.43(m,4H),1.85-1.53(m,8H).MS(ESI,m/z):788.3[M+1]+.
Example 97: synthesis of Compound JL-94: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxypiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methylpiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),10.68(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.80-3.72(m,2H),3.10-2.94(m,3H),2.88(ddd,J=12.4,6.9,3.7Hz,2H),2.83-2.66(m,5H),2.61-2.42(m,4H),1.85-1.55(m,8H).MS(ESI,m/z):788.3[M+1]+.
Example 98: synthesis of Compound JL-95: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-3-methylpiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.76(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.08-3.82(m,5H),3.82-3.72(m,2H),3.16-2.97(m,3H),2.93(dd,J=12.4,4.4Hz,2H),2.85-2.64(m,5H),2.54-2.43(m,2H),1.98-1.63(m,8H),1.16(s,6H).MS(ESI,m/z):816.3[M+1]+.
Example 99: synthesis of Compound JL-96: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -3-carboxy-3-methylpiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.76(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.66-7.60(m,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.00-3.82(m,5H),3.77(d,J=3.0Hz,2H),3.09-2.95(m,3H),2.87(dd,J=12.4,3.4Hz,2H),2.84-2.60(m,5H),2.54-2.44(m,2H),1.93-1.68(m,8H),1.16(s,6H).MS(ESI,m/z):816.3[M+1]+.
Example 100: synthesis of Compound JL-97: (R) -1- ((6- (3- ((S) -1- ((5- (((R) -3-carboxy-3-hydroxypiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.66(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.71(m,2H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.0,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.86(d,J=12.9Hz,2H),3.92(s,3H),3.89-3.75(m,4H),3.20-2.95(m,5H),2.87-2.69(m,5H),2.56-2.43(m,2H),2.07-1.76(m,8H).MS(ESI,m/z):820.2[M+1]+.
Example 101: synthesis of Compound JL-98: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-3-hydroxypiperidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.66(s,2H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.71(m,2H),7.66-7.60(m,1H),7.60-7.52(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.88(s,1H),4.84(s,1H),3.92(s,3H),3.89-3.74(m,4H),3.20-2.95(m,5H),2.90-2.65(m,5H),2.55-2.43(m,2H),2.03-1.70(m,8H).MS(ESI,m/z):820.2[M+1]+.
Example 102: synthesis of Compound JL-99: (2S, 3S) -1- ((6- (3- ((S) -1- ((5- ((((2S, 3S) -3-carboxy-2-methylpiperidin-1-yl) methyl) -3) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) -2-methylpiperidine-3-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.80(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.64-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.90-3.79(m,2H),3.79-3.65(m,2H),3.15-2.98(m,3H),2.83-2.68(m,5H),2.63-2.42(m,4H),1.99-1.58(m,8H),1.19(d,J=3.7Hz,3H),1.17(d,J=3.7Hz,3H).MS(ESI,m/z):816.3[M+1]+.
Example 103: synthesis of Compound JL-100: (S) -2- ((6- (3- (1- ((5- ((4-carboxy-2-azabicyclo [2.2.2]) octan-2-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) -2-azabicyclo [2.2.2] octane-4-carboxylic acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),11.85(s,1H),10.61(s,1H),8.14(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.47(t,J=7.4Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.94-3.82(m,5H),3.80(s,2H),3.34(dd,J=21.0,12.4Hz,2H),3.17(dd,J=12.4,5.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.88-2.70(m,3H),2.57-2.44(m,2H),2.09-1.72(m,16H).MS(ESI,m/z):840.3[M+1]+.
Example 104: synthesis of Compound JL-101: (S) -2-chloro-3- (1- (((3-chloro-5- ((dimethylamino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((dimethylamino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.80(dd,J=7.1,1.9Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.64-7.56(m,2H),7.56-7.49(m,1H),7.42-7.33(m,2H),7.31-7.22(m,1H),5.13(td,J=7.0,0.7Hz,1H),3.93(s,3H),3.91-3.63(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.49(q,J=7.1Hz,2H),2.37(s,6H),2.33(s,6H).MS(ESI,m/z):620.2[M+1]+.
Example 105: synthesis of Compound JL-102: (S) -2-chloro-3- (1- ((3-chloro-5- ((((2-hydroxyethyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((((2-hydroxyethyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.91(tt,J=9.1,7.1Hz,1H),8.15(d,J=1.6Hz,1H),7.87-7.76(m,3H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=2.6Hz,1H),7.58-7.53(m,1H),7.49(t,J=7.4Hz,1H),7.37(dd,J=4.6,0.6Hz,2H),7.31-7.23(m,1H),5.13(td,J=7.0,0.7Hz,1H),4.54(dt,J=8.5,6.3Hz,2H),4.38-4.09(m,4H),3.93(s,3H),3.80-3.57(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.94-2.71(m,5H),2.49(q,J=6.8Hz,2H).MS(ESI,m/z):652.2[M+1]+.
Example 106: synthesis of Compound JL-103: (S) -2-chloro-3- (1- (((3-chloro-6-methoxy-5- ((3-methylazetidin-1-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-methylazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.77(ddd,J=10.9,7.4,1.5Hz,2H),7.70(s,1H),7.60(d,J=4.3Hz,1H),7.58-7.54(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.27(ddd,J=6.1,2.8,0.6Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.08-3.77(m,7H),3.14-2.95(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.43(m,2H),2.06(dpd,J=13.8,6.9,4.8Hz,2H),1.01(d,J=1.7Hz,3H),0.99(d,J=1.8Hz,3H).MS(ESI,m/z):672.2[M+1]+.
Example 107: synthesis of Compound JL-104: (S) -2-chloro-3- (1- ((3-chloro-5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.79(dd,J=7.4,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.72(s,1H),7.64-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.27(ddd,J=6.1,2.8,0.6Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.09-3.76(m,11H),3.24-2.89(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.38(m,2H).MS(ESI,m/z):676.2[M+1]+.
Example 108: synthesis of Compound JL-105: (S) -2-chloro-3- (1- ((3-chloro-5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-hydroxy-3-methylazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.76-7.69(m,2H),7.61(d,J=4.0Hz,1H),7.60-7.55(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.32-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),4.65(s,1H),4.54(s,1H),3.92(d,J=6.0Hz,4H),3.89-3.81(m,3H),3.30(qd,J=12.4,8.3Hz,8H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.41(m,2H),1.35(s,3H),1.34(s,3H).MS(ESI,m/z):704.2[M+1]+.
Example 109: synthesis of Compound JL-106: (S) -2-chloro-3- (1- (((3-chloro-6-methoxy-5- ((3-methoxyazetidin-1-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-
Methoxyazetidin-1-yl) methyl) pyridin-2-yl) benzamides
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77-7.69(m,2H),7.66-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.34(m,2H),7.31-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),4.06-3.90(m,6H),3.89-3.75(m,3H),3.24-3.19(m,7H),3.19-3.12(m,3H),3.11-2.98(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.49(q,J=7.3Hz,2H).MS(ESI,m/z):704.2[M+1]+.
Example 110: synthesis of Compound JL-107: (S) -2-chloro-3- (1- ((3-chloro-5- ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.64-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.25(t,J=6.4Hz,2H),4.00-3.74(m,7H),3.52(s,2H),3.49(s,2H),3.24-2.95(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.38(m,2H),1.11(s,3H),1.07(s,3H).MS(ESI,m/z):732.3[M+1]+.
Example 111: synthesis of Compound JL-108: (S) -2-chloro-3- (1- ((3-chloro-5- ((3- (hydroxymethyl) azepine)
Cyclobutan-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.66-7.60(m,1H),7.60-7.55(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.34(m,2H),7.32-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),3.91(d,J=8.3Hz,5H),3.82(s,2H),3.54(ddd,J=6.9,6.0,0.8Hz,4H),3.23-2.91(m,11H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.41(m,2H),2.19(p,J=7.0Hz,2H).MS(ESI,m/z):704.2[M+1]+.
Example 112: synthesis of Compound JL-109: 2-chloro-3- ((S) -1- ((3-chloro-5- (((((((1R, 3S) -3-hydroxycyclobutyl) methyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N-
(5- (((((1R, 3R) -3-Hydroxycyclobutyl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.70(m,2H),7.62(d,J=3.4Hz,1H),7.59(d,J=1.7Hz,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.89(tt,J=9.4,7.1Hz,1H),6.50(tt,J=9.4,7.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.33-4.12(m,6H),3.92(s,3H),3.79(hd,J=7.0,2.7Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.87-2.58(m,5H),2.54-2.40(m,2H),2.28-1.69(m,10H).MS(ESI,m/z):732.3[M+1]+.
Example 113: synthesis of Compound JL-110: (S) -2-chloro-3- (1- ((3-chloro-5- (4, 5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (4, 5-dihydro-1H-imidazol-2-)
Yl) pyridin-2-yl) benzamides
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.69(d,J=1.6Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),8.05(s,1H),7.82(dd,J=7.4,1.6Hz,1H),7.63(d,J=7.6Hz,1H),7.58(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.37(dd,J=4.6,0.6Hz,2H),7.32-7.21(m,1H),5.60(t,J=5.0Hz,1H),5.41(t,J=5.1Hz,1H),5.15(td,J=7.0,0.6Hz,1H),4.00(s,3H),3.68-3.44(m,4H),3.43-3.27(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.61-2.42(m,2H).MS(ESI,m/z):642.2[M+1]+.
Example 114: synthesis of the Compound JL-111: 2-chloro-3- ((1S) -1 ((3-chloro-6-methoxy-5- (((5-oxopyrrolidin-3-yl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((5-oxopyrrolidin-3-yl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78-7.69(m,2H),7.65-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),7.23-7.09(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.20(dd,J=12.4,8.8Hz,1H),4.12-3.87(m,6H),3.54-3.28(m,6H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.67-2.34(m,7H),2.22-2.05(m,1H).MS(ESI,m/z):730.2[M+1]+.
Example 115: synthesis of Compound JL-112: 2-chloro-3- ((S) -1- ((3-chloro-5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.72(dd,J=7.5,1.4Hz,1H),7.69(s,1H),7.64-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.31-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),4.19(hd,J=7.0,1.0Hz,2H),4.00-3.84(m,5H),3.84-3.69(m,3H),3.56(d,J=7.0Hz,1H),3.39-3.21(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.65(m,7H),2.56-2.37(m,2H),1.99-1.71(m,2H),1.71-1.54(m,2H).MS(ESI,m/z):704.2[M+1]+.
Example 116: synthesis of Compound JL-113: 2-chloro-3- ((S) -1- ((3-chloro-5- ((((1R, 2S) -2-hydroxycyclopentyl) amino) methyl) -6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((((1R, 2S) -2-hydroxycyclopentyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(d,J=7.6Hz,2H),7.69-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.51(d,J=5.7Hz,1H),4.45(d,J=5.7Hz,1H),4.22(dd,J=12.4,9.1Hz,1H),4.12-3.95(m,3H),3.95-3.78(m,5H),3.36-3.23(m,1H),3.22-3.08(m,2H),3.08-2.92(m,2H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.43(m,2H),1.92-1.38(m,12H).MS(ESI,m/z):732.3[M+1]+.
Example 117: synthesis of Compound JL-114: 2-chloro-3- (S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.81-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.62(d,J=2.8Hz,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.25-3.95(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.91(dddd,J=12.6,7.6,6.9,0.6Hz,2H),2.85-2.69(m,3H),2.56-2.41(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):758.3[M+1]+.
Example 118: synthesis of Compound JL-115: (S) -2-chloro-3- (1- ((3-chloro-6-methoxy-5- ((6-oxo-2, 5-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((6-oxo-2, 5-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.65-7.56(m,2H),7.55-7.43(m,3H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.06-3.77(m,7H),3.48-3.28(m,8H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.44(m,2H),2.36(t,J=7.1Hz,4H),1.95(td,J=7.2,1.8Hz,2H),1.92-1.78(m,2H).MS(ESI,m/z):782.3[M+1]+.
Example 119: synthesis of Compound JL-116: (S) -2-chloro-3- (1- ((3-chloro-6-methoxy-5- ((7-oxo-2, 6-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((7-oxo-2, 6-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.57-7.44(m,3H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.91(d,J=6.5Hz,4H),3.87-3.76(m,3H),3.52-3.42(m,4H),3.16-2.95(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.44(m,4H),2.43(d,J=0.6Hz,2H).MS(ESI,m/z):782.3[M+1]+.
Example 120: synthesis of Compound JL-117: 2-chloro-3- ((1S) -1- ((3-chloro-6-methoxy-5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.63-7.60(m,1H),7.60-7.57(m,1H),7.55-7.43(m,3H),7.43-7.32(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.84(d,J=6.6Hz,2H),3.80-3.65(m,2H),3.46-3.24(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.88-2.37(m,15H),1.93-1.63(m,4H).MS(ESI,m/z):810.3[M+1]+.
Example 121: synthesis of Compound JL-118: 3- ((S) -1- ((5- (((R) -3- (1H-tetrazol-5-yl) pyrrolidin-1-yl) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((R) -3- (1H-tetrazol-5-yl) pyrrolidin-1-yl) methyl) pyridin-2-yl) -2-chlorobenzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),12.62(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.10-3.83(m,7H),3.77(d,J=3.4Hz,2H),3.55-3.40(m,2H),3.18(ddd,J=11.9,6.7,0.7Hz,2H),3.09-2.87(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.32(m,4H),2.30-2.09(m,4H).MS(ESI,m/z):808.3[M+1]+.
Example 122: synthesis of Compound JL-119: (S) -2-chloro-3- (1- ((3-chloro-6-methoxy-5- ((1-oxo-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((1-oxo-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.51-7.42(m,3H),7.40-7.32(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.93(d,J=8.8Hz,5H),3.78(s,2H),3.42(dd,J=5.9,0.5Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.93-2.57(m,9H),2.49(q,J=7.0Hz,2H),2.04-1.85(m,8H).MS(ESI,m/z):810.3[M+1]+.
Example 123: synthesis of Compound JL-120: (S) -2-chloro-3- (1- ((3-chloro-6-methoxy-5- ((3-oxo-2, 8-diazaspiro [4.5] decan-8-yl) methyl ] pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-oxo-2, 8-diazaspiro [4.5] deca-N-8-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.63-7.56(m,4H),7.47(t,J=7.4Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(d,J=3.3Hz,5H),3.78(s,2H),3.44(d,J=5.3Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.89-2.72(m,5H),2.66(dtd,J=12.4,7.1,4.4Hz,4H),2.55-2.43(m,2H),2.40(d,J=0.7Hz,4H),1.90-1.70(m,8H).MS(ESI,m/z):838.3[M+1]+.
Example 124: synthesis of Compound JL-121: (S) -2-chloro-3- (1- ((3-chloro-6-methoxy-5- ((1-oxo-2, 9-diazaspiro [5.5] undecan-9-yl) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((1-oxo-2, 9-diazaspiro [5.5] undecan-9-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.77(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.64-7.60(m,1H),7.60-7.58(m,1H),7.51-7.43(m,3H),7.43-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.95(s,2H),3.92(s,3H),3.78(s,2H),3.23(td,J=6.9,5.9Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.91-2.60(m,9H),2.53-2.44(m,2H),2.12(dq,J=12.4,7.1Hz,4H),1.95(dtd,J=12.4,7.1,1.0Hz,4H),1.81-1.70(m,3H),1.70-1.54(m,5H).MS(ESI,m/z):866.3[M+1]+.
Example 125: synthesis of Compound JL-122: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (6- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-3-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.54(d,J=1.6Hz,1H),7.92(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.76-7.70(m,2H),7.68(d,J=8.2Hz,1H),7.62(dd,J=7.5,1.6Hz,1H),7.58-7.46(m,2H),7.45-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.70(p,J=8.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.21-3.97(m,4H),3.91(s,3H),3.83-3.65(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.99-2.86(m,2H),2.85-2.69(m,3H),2.58-2.42(m,2H),2.37-2.20(m,4H),2.07-1.86(m,2H),1.85-1.69(m,2H).MS(ESI,m/z):758.3[M+1]+.
Example 126: synthesis of Compound JL-123: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (4- ((((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) benzamide
The synthesis was as in example 4.1HNMR(400MHz,DMSO-d6)δ9.14(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.79-7.74(m,3H),7.69(dd,J=8.2,4.6Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.77(tt,J=8.3,7.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.99-3.82(m,5H),3.74(tp,J=8.2,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,2H),2.84-2.67(m,3H),2.59-2.40(m,2H),2.29(t,J=6.9Hz,4H),2.07-1.88(m,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):757.3[M+1]+.
Example 127: synthesis of Compound JL-124: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrimidin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.46(s,2H),7.87(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.69(dd,J=8.2,7.3Hz,2H),7.60(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.99-6.84(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.27(d,J=9.9Hz,2H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.72(dpd,J=8.2,7.0,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.69(m,3H),2.53-2.43(m,2H),2.36-2.21(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):759.2[M+1]+.
Example 128: synthesis of Compound JL-125: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrazin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.39(s,1H),7.98(s,1H),7.87-7.74(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.78-6.63(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.13(qdd,J=12.4,11.4,9.2Hz,4H),3.91(s,3H),3.85-3.64(m,2H),3.11-2.86(m,3H),2.86-2.69(m,3H),2.56-2.41(m,2H),2.36-2.17(m,4H),2.10-1.86(m,2H),1.86-1.68(m,2H).MS(ESI,m/z):759.2[M+1]+.
Example 129: synthesis of Compound JL-126: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (6- ((((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridazin-3-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.82-7.74(m,3H),7.72-7.65(m,3H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.80-6.64(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.13(qdd,J=12.4,11.4,9.2Hz,4H),3.91(s,3H),3.83-3.65(m,2H),3.14-2.86(m,3H),2.86-2.67(m,3H),2.58-2.41(m,2H),2.36-2.18(m,4H),2.08-1.87(m,2H),1.85-1.69(m,2H).MS(ESI,m/z):759.2[M+1]+.
Example 130: synthesis of Compound JL-127: 2-chloro-N- (6-chloro-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) -3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),7.93-7.80(m,3H),7.78(s,1H),7.69(dd,J=8.2,4.6Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.05(tt,J=9.0,7.6Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.38-4.02(m,4H),3.91(s,3H),3.72(dpd,J=8.2,7.0,3.0Hz,2H),3.12-2.59(m,6H),2.54-2.41(m,2H),2.34-2.20(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):792.2[M+1]+.
Example 131: synthesis of Compound JL-128: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.72(d,J=7.5Hz,1H),7.69(s,1H),7.67(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,3H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.02(tt,J=9.1,7.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.29-4.01(m,4H),3.92(d,J=1.5Hz,6H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,2H),2.83-2.68(m,3H),2.57-2.43(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.05-1.86(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):788.3[M+1]+.
Example 132: synthesis of Compound JL-129: n- (6-bromo-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) -2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.83-7.76(m,3H),7.76-7.71(m,2H),7.69(d,J=8.2Hz,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.37(m,1H),7.34(dd,J=7.5,1.9Hz,1H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.03(tt,J=8.8,7.6Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.27-4.02(m,4H),3.91(s,3H),3.72(dpd,J=8.2,6.9,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.69(m,5H),2.56-2.42(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):836.2[M+1]+.
Example 133: synthesis of Compound JL-130: n- (6- (benzyloxy) -5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) -2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.78(d,J=6.5Hz,2H),7.74-7.69(m,2H),7.67(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.48(d,J=7.4Hz,1H),7.45-7.42(m,1H),7.42-7.31(m,6H),7.31-7.23(m,2H),7.02(tt,J=9.1,7.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.24(qt,J=12.4,1.0Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.22-4.00(m,4H),3.91(s,3H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.83(m,2H),2.83-2.69(m,3H),2.59-2.43(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.07-1.88(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):864.3[M+1]+.
Example 134: synthesis of Compound JL-131: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methylpyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.85-8.75(m,1H),8.73-8.65(m,1H),8.13(t,J=1.5Hz,1H),7.80-7.72(m,3H),7.69(d,J=8.2Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.37(m,1H),7.37-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.02(tt,J=9.1,7.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.37-5.19(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.25-4.00(m,4H),3.91(s,3H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.86(m,2H),2.83-2.70(m,3H),2.57-2.42(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.05-1.89(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):890.3[M+1]+.
Example 135: synthesis of Compound JL-132: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (3-methyl-4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.69(dd,J=8.2,4.6Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.30(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.12(dt,J=7.4,1.0Hz,1H),6.88(dtt,J=12.3,8.6,7.7Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.90-3.78(m,2H),3.77-3.66(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.55-2.45(m,2H),2.39-2.12(m,7H),2.06-1.87(m,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):771.3[M+1]+.
Example 136: synthesis of Compound JL-133: 2-chloro-N- (3-chloro-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-indenpyridin-4-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74-7.65(m,3H),7.62(dd,J=7.5,1.5Hz,1H),7.51-7.32(m,5H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.00-6.83(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),4.04-3.88(m,5H),3.72(dpd,J=8.1,6.9,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.55-2.43(m,2H),2.39-2.18(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):791.2[M+1]+.
Example 137: synthesis of Compound JL-134: n- (3-bromo-4- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) -2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),7.80(dd,J=7.3,1.6Hz,2H),7.77(s,1H),7.70(dd,J=8.2,5.0Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.52-7.44(m,2H),7.44-7.37(m,1H),7.37-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.19(q,J=7.8Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.22-4.05(m,2H),4.05-3.88(m,5H),3.73(dpd,J=7.8,7.0,0.8Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.68(m,5H),2.59-2.42(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.06-1.88(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):835.2[M+1]+.
Example 138: synthesis of Compound JL-135: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (3-cyano-4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.99(d,J=1.5Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.75-7.65(m,3H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,3H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.06-6.82(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),4.03-3.84(m,5H),3.72(dpd,J=8.1,6.9,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.58-2.42(m,2H),2.40-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):782.3[M+1]+.
Example 139: synthesis of Compound JL-136: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (3-methoxy-4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.69(dd,J=8.2,7.3Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.25(m,5H),7.20(d,J=1.4Hz,1H),6.88(dtt,J=10.6,8.3,7.7Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.96-3.80(m,8H),3.72(dpd,J=8.1,7.0,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.56-2.42(m,2H),2.39-2.17(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):787.3[M+1]+.
Example 140: synthesis of Compound JL-137: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (3, 5-dimethoxy-4- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) phenyl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.69(s,1H),7.67(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.52-7.32(m,4H),7.28(ddd,J=7.0,2.1,0.6Hz,1H),6.96(s,2H),6.96-6.82(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.28-3.94(m,4H),3.91(s,3H),3.90(s,6H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,2H),2.83-2.68(m,3H),2.56-2.40(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.09-1.86(m,2H),1.77(dq,J=12.3,7.0Hz,2H).MS(ESI,m/z):817.3[M+1]+.
Example 141: synthesis of Compound JL-138: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (2-oxo-6- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1, 2-dihydropyridin-3-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),9.58(s,1H),7.81-7.75(m,2H),7.74(d,J=8.1Hz,1H),7.68(d,J=8.2Hz,1H),7.61(dd,J=7.5,1.5Hz,1H),7.49(dd,J=7.7,1.6Hz,2H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.38(dt,J=8.0,1.0Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.64(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.67(m,5H),2.57-2.38(m,3H),2.29(td,J=7.1,1.7Hz,4H),2.08-1.90(m,2H),1.77(dddd,J=14.3,12.5,7.0,4.7Hz,2H).MS(ESI,m/z):774.2[M+1]+.
Example 142: synthesis of Compound JL-139: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (6-oxo-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) -1, 6-dihydropyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.43(s,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.69(s,1H),7.67(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.19(dt,J=6.8,1.0Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.23(d,J=6.8Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83-3.64(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.83(m,2H),2.82-2.65(m,4H),2.57-2.41(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.08-1.87(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):774.2[M+1]+.
Example 143: synthesis of Compound JL-140: 2-bromo-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.3,1.6Hz,1H),7.82-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.65-7.57(m,2H),7.52(t,J=7.4Hz,1H),7.43(t,J=7.4Hz,1H),7.35(dd,J=7.5,1.8Hz,1H),7.28(ddd,J=7.2,1.7,0.5Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.23-3.98(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.70(m,3H),2.49(q,J=7.1Hz,2H),2.36-2.20(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):802.2[M+1]+.
Example 144: synthesis of Compound JL-141: 3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-cyano-N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.15(d,J=1.6Hz,1H),7.95(dd,J=6.9,2.1Hz,1H),7.80-7.73(m,2H),7.73-7.64(m,4H),7.61(d,J=7.6Hz,1H),7.51(dd,J=7.4,1.6Hz,1H),7.41(t,J=7.4Hz,1H),7.31(ddd,J=7.5,1.6,0.6Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.32-4.01(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.04(dt,J=12.3,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.68(m,3H),2.49(q,J=6.8Hz,2H),2.40-2.20(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):749.3[M+1]+.
Example 145: synthesis of Compound JL-142: 3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methyl-N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.15(d,J=1.6Hz,1H),7.85-7.73(m,4H),7.69(dd,J=8.2,7.3Hz,2H),7.61(d,J=7.5Hz,1H),7.54-7.43(m,2H),7.33(t,J=7.4Hz,1H),7.26(ddd,J=7.5,1.6,0.6Hz,1H),7.00-6.71(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.31-4.01(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.03(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.68(m,3H),2.59-2.41(m,5H),2.39-2.14(m,4H),1.97(dq,J=12.4,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):738.3[M+1]+.
Example 146: synthesis of Compound JL-143: 3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methyl-N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.15(d,J=1.5Hz,1H),8.09(t,J=1.5Hz,1H),7.93(dt,J=7.4,1.5Hz,1H),7.81-7.74(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.62(t,J=7.4Hz,2H),7.56-7.45(m,2H),7.34(t,J=7.4Hz,1H),7.28(ddd,J=7.6,1.7,0.6Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.32-4.00(m,4H),3.92(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.02(dt,J=12.3,7.1Hz,1H),2.96-2.86(m,2H),2.85-2.70(m,3H),2.56-2.38(m,2H),2.37-2.20(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.85-1.66(m,2H).MS(ESI,m/z):724.3[M+1]+.
Example 147: synthesis of Compound JL-144: 3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methoxy-N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.15(d,J=1.6Hz,1H),7.98(dd,J=7.5,1.5Hz,1H),7.83-7.64(m,5H),7.60(d,J=7.5Hz,1H),7.52-7.38(m,2H),7.32(t,J=7.4Hz,1H),7.22(ddd,J=7.5,1.6,0.6Hz,1H),6.99-6.69(m,2H),5.14(td,J=7.0,0.7Hz,1H),4.23-4.00(m,4H),3.91(s,3H),3.84-3.63(m,5H),3.11-2.66(m,6H),2.53-2.42(m,2H),2.40-2.21(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):754.3[M+1]+.
Example 148: synthesis of Compound JL-145: 3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-hydroxy-N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzene
Carboxamides
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.41(s,1H),8.15(d,J=1.5Hz,1H),7.91(dd,J=7.5,1.5Hz,1H),7.77(d,J=7.5Hz,2H),7.73-7.57(m,4H),7.48(dd,J=7.4,1.6Hz,1H),7.35(t,J=7.5Hz,2H),7.24(ddd,J=7.5,1.6,0.7Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.14(td,J=7.0,0.7Hz,1H),4.31-4.01(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.07(dt,J=12.4,7.1Hz,1H),2.97-2.67(m,5H),2.55-2.43(m,2H),2.38-2.21(m,4H),1.97(dq,J=12.4,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):740.3[M+1]+.
Example 149: synthesis of Compound JL-146: (S) -4- (((5- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-2-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.42(s,1H),8.54(d,J=1.6Hz,
1H),8.26(p,J=8.7Hz,1H),8.06-7.84(m,2H),7.77(s,1H),7.73(dd,J=7.4,1.6Hz,1H),7.62(dd,J=7.5,1.6Hz,1H),7.56-7.44(m,2H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.32-3.98(m,6H),3.92(s,3H),3.20-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.54-2.32(m,6H).MS(ESI,m/z):768.2[M+1]+.
Example 150: synthesis of Compound JL-147: (S) -4- ((4- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) benzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.14(s,1H),8.22(tt,J=8.6,7.9Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.76(d,J=7.6Hz,3H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.28-3.99(m,4H),3.92(s,3H),3.89-3.66(m,2H),3.13-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.27(m,6H).MS(ESI,m/z):767.2[M+1]+.
Example 151: synthesis of Compound JL-148: (S) -4- (((2- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) -2-chlorobenzamido) pyrimidin-5-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.20(s,1H),8.44(s,2H),8.07-7.83(m,3H),7.77(s,1H),7.60(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.5Hz,2H),4.43-4.18(m,2H),4.18-4.11(m,1H),4.11-4.00(m,3H),3.92(s,3H),3.19-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.28(m,6H).MS(ESI,m/z):769.2[M+1]+.
Example 152: synthesis of Compound JL-149: (S) -4- (((5- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyrazin-2-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.84(s,1H),8.39(s,1H),8.18(p,J=9.1Hz,1H),8.01(s,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84-7.74(m,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.38-3.99(m,6H),3.92(s,3H),3.20-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.61-2.30(m,6H).MS(ESI,m/z):769.2[M+1]+.
Example 153: synthesis of Compound JL-150: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) -2-chlorobenzamido) pyridazin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.81(s,1H),8.18(p,J=9.1Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.83-7.72(m,3H),7.68(d,J=7.5Hz,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.35-3.94(m,6H),3.92(s,3H),3.20-2.90(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H).MS(ESI,m/z):769.2[M+1]+.
Example 154: synthesis of Compound JL-151: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) -2-chloropyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.73(s,1H),8.25(tt,J=9.2,8.0Hz,1H),8.01-7.85(m,2H),7.82(dt,J=7.5,0.8Hz,2H),7.77(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.5Hz,2H),4.29-3.96(m,6H),3.91(s,3H),3.17-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.29(m,6H).MS(ESI,m/z):802.2[M+1]+.
Example 155: synthesis of Compound JL-152: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) -2-chlorobenzamido) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),7.92(ttd,J=9.1,8.0,5.2Hz,2H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.72(d,J=7.5Hz,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.30(m,3H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.25-3.95(m,6H),3.92(d,J=1.3Hz,6H),3.18-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.25(m,6H).MS(ESI,m/z):798.2[M+1]+.
Example 156: synthesis of Compound JL-153: (S) -4- (((6- (((S) -4- (3- ((6-bromo-5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),8.23(tt,J=8.9,7.9Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.85-7.77(m,2H),7.73(d,J=7.4Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.5Hz,2H),4.31-3.99(m,6H),3.91(s,3H),3.15-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.33(m,6H).MS(ESI,m/z):846.1[M+1]+.
Example 157: synthesis of Compound JL-154: (S) -4- (((6- (((S) -4- (3- ((6- (benzyloxy) -5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),7.92(ttd,J=9.1,8.0,5.2Hz,2H),7.79(dd,J=7.5,1.5Hz,1H),7.78-7.68(m,2H),7.61(dd,J=7.5,1.6Hz,1H),7.52-7.21(m,10H),5.24(qt,J=12.4,1.0Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.20-3.94(m,6H),3.91(s,3H),3.19-2.87(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.26(m,6H).MS(ESI,m/z):874.3[M+1]+.
Example 158: synthesis of Compound JL-155: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) -2- ((5-cyanopyridin-3-yl) methoxy) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),8.80-8.76(m,1H),8.75-8.69(m,1H),8.13(t,J=1.5Hz,1H),7.92(ttd,J=9.1,8.0,5.2Hz,2H),7.79(dd,J=7.5,1.5Hz,1H),7.76-7.71(m,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.37(m,1H),7.37-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.40-5.19(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.21-4.11(m,1H),4.11-4.02(m,3H),4.02-3.95(m,1H),3.91(s,3H),3.73(dd,J=12.4,9.2Hz,1H),3.17-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.65-2.32(m,6H).MS(ESI,m/z):900.2[M+1]+.
Example 159: synthesis of Compound JL-156: (S) -4- ((4- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) -2-methylbenzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.23(s,1H),8.07(tt,J=8.7,7.9Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.12(dt,J=7.4,1.0Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(d,J=1.4Hz,1H),4.74(d,J=1.4Hz,1H),4.21-3.98(m,4H),3.92(s,3H),3.82(qdd,J=12.4,8.7,1.1Hz,2H),3.15-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.54-2.31(m,6H),2.22(d,J=0.5Hz,3H).MS(ESI,m/z):781.2[M+1]+.
Example 160: synthesis of Compound JL-157: (S) -4- ((4- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) -2-chlorobenzyl) amino) -3-hydroxybutyric acid
Synthesis methodAs in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.10(s,1H),8.32-8.13(m,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.67(d,J=1.4Hz,1H),7.62(dd,J=7.5,1.5Hz,1H),7.53-7.31(m,5H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.19-4.11(m,2H),4.11-4.01(m,3H),3.97(ddd,J=12.4,8.5,1.0Hz,1H),3.91(s,3H),3.16-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H).MS(ESI,m/z):801.2[M+1]+.
Example 161: synthesis of Compound JL-158: (S) -4- (((6- (((S) -4- (3- ((3-bromo-4- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) phenyl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.52(s,1H),8.21(p,J=8.0Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.3,1.5Hz,2H),7.75(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.52-7.44(m,2H),7.43-7.32(m,3H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.30-3.94(m,6H),3.91(s,3H),3.15-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H).MS(ESI,m/z):845.1[M+1]+.
Example 162: synthesis of Compound JL-159: (S) -4- ((4- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) -2-cyanobenzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),8.31(s,1H),8.16(p,J=8.0Hz,1H),7.98(d,J=1.4Hz,1H),7.97-7.86(m,1H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.72(dd,J=7.5,1.5Hz,1H),7.62(dd,J=7.5,1.5Hz,1H),7.53-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.22-4.00(m,5H),4.00-3.84(m,4H),3.16-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.30(m,6H).MS(ESI,m/z):792.2[M+1]+.
Example 163: synthesis of Compound JL-160: (S) -4- ((4- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) -2-methoxybenzyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.39(s,1H),8.01-7.91(m,1H),7.91-7.85(m,1H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.24(m,5H),7.20(d,J=1.4Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.20-4.11(m,1H),4.11-4.01(m,3H),3.95-3.76(m,8H),3.16-2.88(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.32(m,6H).MS(ESI,m/z):797.2[M+1]+.
Example 164: synthesis of Compound JL-161: (S) -4- (((6- (((S) -4- (3- ((4- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3, 5-dimethoxyphenyl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.71(s,1H),8.08-7.97(m,1H),7.97-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.49(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=7.1,1.8,0.5Hz,1H),6.96(s,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.24-3.94(m,6H),3.91(d,J=4.2Hz,9H),3.21-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.33(m,6H).MS(ESI,m/z):827.2[M+1]+.
Example 165: synthesis of Compound JL-162: (S) -4- (((6- (((S) -4- (3- ((6- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -2-oxo-1, 2-dihydropyridin-3-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.05(s,1H),9.58(s,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82-7.74(m,2H),7.61(dd,J=7.5,1.5Hz,1H),7.54-7.44(m,2H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.38(dt,J=8.2,1.0Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.74(d,J=1.4Hz,2H),4.27-4.01(m,4H),3.92(s,3H),3.89-3.78(m,1H),3.78-3.63(m,2H),3.18-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.30(m,6H).MS(ESI,m/z):784.2[M+1]+.
Example 166: synthesis of Compound JL-163: (S) -4- (((6- (3- ((S) -1- ((5- ((((S)
-3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoyl) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.80(s,1H),9.43(s,1H),7.93(tt,J=9.3,8.0Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.19(dt,J=6.9,0.9Hz,1H),6.23(d,J=6.8Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.19-3.99(m,4H),3.92(s,3H),3.90-3.80(m,2H),3.79-3.68(m,1H),3.19-2.85(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.29(m,6H).MS(ESI,m/z):784.2[M+1]+.
Example 167: synthesis of Compound JL-164: (S) -4- (((6- (((S) -4- (2-bromo-3- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.64(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.4Hz,1H),8.04-7.87(m,1H),7.85(dd,J=7.3,1.6Hz,1H),7.81-7.72(m,2H),7.67-7.57(m,2H),7.52(t,J=7.4Hz,1H),7.43(t,J=7.4Hz,1H),7.35(dd,J=7.5,1.8Hz,1H),7.28(ddd,J=7.3,1.8,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.31-3.98(m,6H),3.91(s,3H),3.18-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.28(m,6H).MS(ESI,m/z):812.2[M+1]+.
Example 168: synthesis of Compound JL-165: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-cyanobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.57(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.03-7.85(m,2H),7.80-7.74(m,2H),7.74-7.64(m,2H),7.61(d,J=7.6Hz,1H),7.51(dd,J=7.4,1.6Hz,1H),7.41(t,J=7.4Hz,1H),7.31(ddd,J=7.5,1.6,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.26-3.99(m,6H),3.92(s,3H),3.14-2.92(m,5H),2.77(ddd,J=12.4,7.3,6.7Hz,1H),2.60-2.32(m,6H).MS(ESI,m/z):759.2[M+1]+.
Example 169: synthesis of Compound JL-166: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) -2-methylbenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.59(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.81-7.71(m,4H),7.61(d,J=7.5Hz,1H),7.53-7.42(m,2H),7.33(t,J=7.4Hz,1H),7.26(ddd,J=7.5,1.6,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.33-3.99(m,6H),3.92(s,3H),3.22-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.20(m,9H).MS(ESI,m/z):748.3[M+1]+.
Example 170: synthesis of Compound JL-167: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) benzamide) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.44(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.4Hz,1H),8.09(t,J=1.5Hz,1H),8.01-7.85(m,2H),7.81-7.72(m,2H),7.62(t,J=7.4Hz,2H),7.57-7.47(m,2H),7.34(t,J=7.4Hz,1H),7.28(ddd,J=7.6,1.7,0.6Hz,1H),5.13(td,J=6.9,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.34-3.97(m,6H),3.92(s,3H),3.17-2.88(m,5H),2.79(ddd,J=12.3,7.4,6.8Hz,1H),2.63-2.25(m,6H).MS(ESI,m/z):734.3[M+1]+.
Example 171: synthesis of Compound JL-168: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-methoxybenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.48(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.6Hz,1H),8.03-7.85(m,2H),7.79-7.71(m,2H),7.69(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.52-7.38(m,2H),7.32(t,J=7.4Hz,1H),7.22(ddd,J=7.5,1.6,0.6Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,2H),4.23-3.98(m,6H),3.92(s,3H),3.80(s,3H),3.15-2.92(m,5H),2.79(ddd,J=12.3,7.4,6.8Hz,1H),2.55-2.32(m,6H).MS(ESI,m/z):764.3[M+1]+.
Example 172: synthesis of Compound JL-169: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) -2-hydroxybenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 4.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.68(s,1H),10.41(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.02-7.84(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64(dd,J=7.6,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.48(dd,J=7.5,1.6Hz,1H),7.35(td,J=7.5,1.5Hz,2H),7.24(ddd,J=7.5,1.6,0.6Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,2H),4.28-3.98(m,6H),3.92(s,3H),3.16-2.92(m,5H),2.80(ddd,J=12.3,7.3,6.7Hz,1H),2.56-2.27(m,6H).MS(ESI,m/z):750.2[M+1]+.
Example 173: synthesis of Compound JL-171: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.88(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.70(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.21-3.98(m,5H),3.92(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.14-2.95(m,3H),2.95-2.71(m,3H),2.56-2.24(m,6H),1.97(dq,J=12.6,7.0Hz,1H),1.78(ddd,J=12.4,7.4,6.2Hz,1H).MS(ESI,m/z):763.2[M+1]+.
Example 174: synthesis of Compound JL-172: (S) -4- (((6- (((S) -4- (3- ((5- ((((S) -2-carboxy-1-hydroxypropan-2-yl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dioxo-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.80-7.72(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.03(t,J=9.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(dd,J=7.2,6.8Hz,2H),4.21-3.99(m,5H),3.96-3.71(m,5H),3.20-2.91(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.62-2.04(m,4H),1.52(s,3H).MS(ESI,m/z):768.2[M+1]+.
Example 175: synthesis of Compound JL-173: (S) -4- (((6- (((S) -4- (3- ((5- ((((R) -2-carboxy-1-hydroxypropan-2-yl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.00-7.83(m,2H),7.80-7.72(m,2H),7.69-7.53(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.03(t,J=9.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(dd,J=7.2,6.8Hz,2H),4.24-3.98(m,5H),3.95-3.76(m,5H),3.19-2.91(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.30(m,4H),1.52(s,3H).MS(ESI,m/z):768.2[M+1]+.
Example 176: synthesis of Compound JL-174: (S) -4- (((6- (((S) -4- (3- ((5- (((2-carboxypropan-2-yl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.92(s,1H),10.61(s,1H),8.17(d,J=1.5Hz,1H),8.01-7.88(m,1H),7.86(dd,J=7.4,1.6Hz,1H),7.80-7.73(m,2H),7.62(d,J=2.7Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.36(t,J=10.2Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.42-4.18(m,2H),4.18-3.98(m,3H),3.92(s,3H),3.18-2.92(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.30(m,4H),1.54(s,3H),1.49(s,3H).MS(ESI,m/z):752.2[M+1]+.
Example 177: synthesis of Compound JL-175: (S) -4- (((6- (((S) -4- (3- ((5- (((carboxymethyl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),12.24(s,1H),10.61(s,1H),8.18(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,1H),4.39-4.20(m,2H),4.19-4.00(m,3H),3.96-3.78(m,4H),3.64-3.35(m,2H),3.23-2.86(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.63-2.31(m,4H).MS(ESI,m/z):724.2[M+1]+.
Example 178: synthesis of Compound JL-176: 3- (((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) amino) -3-methylbutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.85(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.82(m,2H),7.79-7.73(m,2H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.53(t,J=9.6Hz,1H),4.31-3.98(m,5H),3.92(s,3H),3.14-2.88(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.64-2.30(m,6H),1.42(s,3H),1.37(s,3H).MS(ESI,m/z):766.2[M+1]+.
Example 179: synthesis of Compound JL-177: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.95(m,4H),3.95-3.76(m,5H),3.20-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.27(m,4H),2.12(q,J=7.0Hz,2H).MS(ESI,m/z):750.2[M+1]+.
Example 180: synthesis of Compound JL-178: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.01-7.82(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.28-3.96(m,4H),3.94-3.78(m,5H),3.21-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.31(m,4H),2.26-1.98(m,2H).MS(ESI,m/z):750.2[M+1]+.
Example 181: synthesis of Compound JL-179: 1- ((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) azetidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.89(m,1H),7.86(dd,J=7.4,1.6Hz,1H),7.79-7.70(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.28-3.99(m,3H),3.92(s,3H),3.86(s,2H),3.38(dd,J=7.0,0.9Hz,4H),3.18-2.86(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.32(m,4H).MS(ESI,m/z):750.2[M+1]+.
Example 182: synthesis of Compound JL-180: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.81(m,2H),7.80-7.70(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.98(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.19-2.89(m,7H),2.84-2.72(m,2H),2.54-2.31(m,4H),2.01-1.72(m,2H).MS(ESI,m/z):764.2[M+1]+.
Example 183: synthesis of Compound JL-181: (S) -1- ((6- (3- ((S) -1- ((5- ((((S) -3-)
Carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.03-7.82(m,2H),7.80-7.70(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.99(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.17-2.66(m,9H),2.55-2.31(m,4H),1.97-1.74(m,2H).MS(ESI,m/z):764.2[M+1]+.
Example 184: synthesis of Compound JL-182: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.79(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.22-3.99(m,3H),3.92(s,3H),3.78(d,J=3.0Hz,2H),3.14-2.91(m,5H),2.78(dddd,J=12.4,7.4,6.7,2.8Hz,2H),2.59-2.29(m,5H),2.08-1.84(m,2H),1.28(s,3H).MS(ESI,m/z):778.2[M+1]+.
Example 185: synthesis of Compound JL-183: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.79(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.98(m,3H),3.92(s,3H),3.78(d,J=3.0Hz,2H),3.16-2.90(m,5H),2.84-2.67(m,2H),2.58-2.29(m,5H),2.00-1.82(m,2H),1.28(s,3H).MS(ESI,m/z):778.2[M+1]+.
Example 186: synthesis of Compound JL-184: (2S, 4S) -1- ((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -4-hydroxypyrrolidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.05(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.78-7.72(m,2H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.29-4.18(m,2H),4.18-4.01(m,3H),3.96-3.78(m,5H),3.65(td,J=7.0,0.6Hz,1H),3.34-3.21(m,1H),3.16-2.89(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.26(m,5H),2.07-1.88(m,1H).MS(ESI,m/z):780.2[M+1]+.
Example 187: synthesis of Compound JL-185: (3R, 4R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -4-isopropylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.31-3.98(m,3H),3.91(s,3H),3.86-3.70(m,2H),3.28-3.14(m,1H),3.13-2.89(m,4H),2.84-2.55(m,4H),2.54-2.33(m,4H),2.07(dtdt,J=8.6,7.0,5.5,1.5Hz,1H),1.74(dpd,J=13.7,6.8,0.7Hz,1H),0.94(dd,J=6.8,1.5Hz,3H),0.89(dd,J=6.8,1.4Hz,3H).MS(ESI,m/z):806.3[M+1]+.
Example 188: synthesis of Compound JL-186: (3R, 4R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.81(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.99(m,3H),3.92(s,3H),3.86-3.70(m,2H),3.26-3.14(m,1H),3.14-2.91(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.69-2.33(m,7H),2.21(dt,J=13.8,6.9Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):778.3[M+1]+.
Example 189: synthesis of Compound JL-187: (3S, 4S) -1- ((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.83(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.65-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.32-3.97(m,3H),3.92(s,3H),3.86-3.70(m,2H),3.13-2.94(m,4H),2.94-2.85(m,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.68-2.32(m,7H),2.21(dt,J=13.8,6.9Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):778.3[M+1]+.
Example 190: synthesis of Compound JL-188: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.81(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-3.98(m,3H),3.92(s,3H),3.90-3.76(m,2H),3.19-2.96(m,4H),2.96-2.70(m,3H),2.58-2.29(m,4H),1.91-1.43(m,6H).MS(ESI,m/z):778.3[M+1]+.
Example 191: synthesis of Compound JL-189: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.00-7.82(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.66-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.27-3.99(m,3H),3.92(s,3H),3.90-3.77(m,2H),3.21-2.91(m,4H),2.90-2.69(m,3H),2.56-2.28(m,4H),1.82-1.40(m,6H).MS(ESI,m/z):778.3[M+1]+.
Example 192: synthesis of Compound JL-190: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.03-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.32-4.00(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.15-2.86(m,5H),2.83-2.61(m,3H),2.60-2.33(m,5H),1.92-1.26(m,4H).MS(ESI,m/z):778.3[M+1]+.
Example 193: synthesis of Compound JL-191: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.03-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.28-3.99(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.14-2.94(m,4H),2.93-2.62(m,4H),2.61-2.30(m,5H),1.87-1.53(m,4H).MS(ESI,m/z):778.3[M+1]+.
Example 194: synthesis of Compound JL-192: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.82(m,2H),7.76(d,J=7.3Hz,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.31-4.00(m,3H),3.92(s,3H),3.77(d,J=3.1Hz,2H),3.16-2.92(m,4H),2.91-2.72(m,3H),2.71-2.58(m,1H),2.54-2.28(m,4H),1.95-1.63(m,4H),1.16(s,3H).MS(ESI,m/z):792.2[M+1]+.
Example 195: synthesis of Compound JL-193: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.82(m,2H),7.76(d,J=7.3Hz,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.99(m,3H),3.92(s,3H),3.77(d,J=3.1Hz,2H),3.15-2.88(m,5H),2.85-2.62(m,3H),2.56-2.31(m,4H),1.97-1.62(m,4H),1.16(s,3H).MS(ESI,m/z):792.2[M+1]+.
Example 196: synthesis of Compound JL-194: (S) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.81(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.75(d,J=7.6Hz,1H),4.19-3.98(m,3H),3.92(s,3H),3.88-3.73(m,2H),3.16-2.92(m,5H),2.90-2.63(m,3H),2.56-2.29(m,4H),2.06-1.71(m,4H).MS(ESI,m/z):794.2[M+1]+.
Example 197: synthesis of Compound JL-195: (R) -1- ((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.75(d,J=7.6Hz,1H),4.25-3.97(m,3H),3.92(s,3H),3.87-3.67(m,2H),3.17-2.91(m,5H),2.90-2.66(m,3H),2.51-2.27(m,4H),2.02-1.74(m,4H).MS(ESI,m/z):794.2[M+1]+.
Example 198: synthesis of Compound JL-196: (2S, 3S) -1- ((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) -2-methylpiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.86(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.00-7.82(m,2H),7.80-7.72(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.20-3.97(m,3H),3.92(s,3H),3.84-3.64(m,2H),3.14-2.88(m,4H),2.85-2.66(m,3H),2.64-2.31(m,5H),1.98-1.60(m,4H),1.17(d,J=6.8Hz,3H).MS(ESI,m/z):792.2[M+1]+.
Example 199: synthesis of Compound JL-197: 2- ((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-methoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) -2-azabicyclo [2.2.2] octane-4-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.90(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.73(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.98(m,3H),3.91(s,3H),3.80(s,2H),3.36-3.12(m,2H),3.12-2.92(m,3H),2.84-2.71(m,2H),2.60-2.27(m,4H),2.09-1.34(m,8H).MS(ESI,m/z):804.2[M+1]+.
Example 200: synthesis of Compound JL-198: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((dimethylamino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.96-7.71(m,4H),7.62(d,J=1.8Hz,1H),7.59(d,J=1.8Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.32-7.21(m,1H),5.13(td,J=7.0,0.7Hz,1H),4.76(d,J=7.6Hz,1H),4.24-3.99(m,3H),3.92(s,3H),3.85-3.66(m,2H),3.15-2.93(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.31(m,10H).MS(ESI,m/z):694.2[M+1]+.
Example 201: synthesis of Compound JL-199: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- (((2-hydroxyethyl) amino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,7.9Hz,1H),7.86-7.75(m,3H),7.73(dd,J=7.5,1.5Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,1H),4.53(t,J=6.3Hz,1H),4.34-4.16(m,2H),4.16-3.99(m,3H),3.92(s,3H),3.81-3.56(m,2H),3.15-2.94(m,3H),2.94-2.70(m,3H),2.56-2.30(m,4H).MS(ESI,m/z):710.2[M+1]+.
Example 202: synthesis of Compound JL-200: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3-methylazepin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-3.99(m,3H),3.92(s,3H),3.82(s,2H),3.13-2.93(m,7H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.29(m,4H),2.15-1.93(m,J=6.9Hz,1H),0.99(d,J=6.8Hz,3H).MS(ESI,m/z):720.2[M+1]+.
Example 203: synthesis of Compound JL-201: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.94(m,4H),3.92(s,3H),3.89-3.77(m,2H),3.75(d,J=7.1Hz,1H),3.15(dd,J=12.4,6.9Hz,2H),3.10-2.94(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.63-2.30(m,4H).MS(ESI,m/z):722.2[M+1]+.
Example 204: synthesis of Compound JL-202: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3-hydroxy-3-methylpyrrolidin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.54(s,1H),4.25-3.99(m,3H),3.92(s,3H),3.86(s,2H),3.38-3.21(m,4H),3.13-2.93(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.32(m,4H),1.34(s,3H).MS(ESI,m/z):736.2[M+1]+.
Example 205: synthesis of Compound JL-203: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3-methoxypyridin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.19-3.94(m,4H),3.92(s,3H),3.89-3.74(m,2H),3.25-3.15(m,5H),3.13-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.33(m,4H).MS(ESI,m/z):736.2[M+1]+.
Example 206: synthesis of Compound JL-204: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3- (hydroxymethyl) -3-methylazepin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25(t,J=6.4Hz,1H),4.19-3.99(m,3H),3.92(s,3H),3.83(s,2H),3.50(d,J=6.4Hz,2H),3.19(d,J=12.4Hz,2H),3.13-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.61-2.33(m,4H),1.07(s,3H).MS(ESI,m/z):750.2[M+1]+.
Example 207: synthesis of Compound JL-205: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.72(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.21-3.97(m,3H),3.92(s,3H),3.82(s,2H),3.69-3.46(m,2H),3.17(t,J=6.0Hz,1H),3.14-2.92(m,7H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.32(m,4H),2.19(p,J=7.0Hz,1H).MS(ESI,m/z):736.2[M+1]+.
Example 208: synthesis of Compound JL-206: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- (((((1R, 3R) -3-hydroxycyclobutyl) methyl) amino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.82(m,2H),7.80-7.70(m,2H),7.67-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.50(tt,J=9.4,7.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.99(m,6H),3.92(s,3H),3.79(hd,J=7.0,2.9Hz,1H),3.20-2.92(m,3H),2.87-2.57(m,3H),2.55-2.32(m,4H),2.16-1.78(m,5H).MS(ESI,m/z):750.2[M+1]+.
Example 209: synthesis of Compound JL-208: (3S) -4- (((5-chloro-6- (((1S) -4- (2-chloro-3- ((5- (((5-oxopyrrolidin-3-yl) amino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.82(m,2H),7.78-7.70(m,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.22-7.12(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.93(m,5H),3.92(s,3H),3.54-3.26(m,3H),3.13-2.91(m,3H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.67-2.33(m,6H),2.20-2.06(m,1H).MS(ESI,m/z):749.2[M+1]+.
Example 210: synthesis of Compound JL-209: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.32-3.98(m,4H),3.92(s,3H),3.77(d,J=3.6Hz,2H),3.57(d,J=7.1Hz,1H),3.38-3.22(m,1H),3.15-2.93(m,3H),2.89-2.65(m,4H),2.56-2.28(m,4H),2.01-1.71(m,1H),1.69-1.55(m,1H).MS(ESI,m/z):736.2[M+1]+.
Example 211: synthesis of Compound JL-210: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((((1R, 2S) -2-hydroxycyclopentyl) amino) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.02-7.83(m,2H),7.80-7.71(m,2H),7.67-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.45(d,J=5.7Hz,1H),4.24-3.93(m,5H),3.92(s,3H),3.90-3.82(m,1H),3.20-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.28(m,4H),1.88-1.54(m,6H).MS(ESI,m/z):750.2[M+1]+.
Example 212: synthesis of Compound JL-211: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((6-oxo-2, 5-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.83(m,2H),7.80-7.68(m,2H),7.65-7.56(m,2H),7.53-7.43(m,2H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.21-3.99(m,3H),3.92(s,3H),3.84(s,2H),3.45-3.24(m,4H),3.15-2.92(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H),1.92(dt,J=19.6,7.1Hz,2H).MS(ESI,m/z):775.2[M+1]+.
Example 213: synthesis of Compound JL-212: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((7-oxo-2, 6-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.03-7.83(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.58(m,2H),7.55(t,J=5.0Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.34-3.99(m,3H),3.92(s,3H),3.83(s,2H),3.60-3.39(m,2H),3.20-2.87(m,7H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.25(m,6H).MS(ESI,m/z):775.2[M+1]+.
Example 214: synthesis of Compound JL-213: (3S) -4- (((5-chloro-6- (((1S) -4- (2-chloro-3- ((5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.14(d,J=1.5Hz,1H),8.01-7.81(m,2H),7.79-7.72(m,2H),7.68-7.57(m,2H),7.54-7.44(m,2H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.99(m,3H),3.92(s,3H),3.75(d,J=2.6Hz,2H),3.52-3.21(m,2H),3.14-2.93(m,3H),2.85-2.57(m,6H),2.55-2.33(m,5H),1.89-1.69(m,2H).MS(ESI,m/z):789.2[M+1]+.
Example 215: synthesis of Compound JL-214: (S) -4- (((6- (((S) -4- (3- ((5- (((R) -3- (1H-tetrazol-5-yl) pyrrolidin-1-yl) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.81(m,2H),7.77(s,2H),7.67-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.45-7.29(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.92(m,4H),3.92(s,3H),3.77(d,J=3.4Hz,2H),3.53-3.33(m,1H),3.18(ddd,J=12.4,7.2,0.7Hz,1H),3.13-2.86(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.33(m,5H),2.31-2.09(m,2H).MS(ESI,m/z):788.2[M+1]+.
Example 216: synthesis of Compound JL-215: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((1-oxo-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.81(m,2H),7.76(d,J=7.3Hz,2H),7.68-7.57(m,2H),7.53-7.42(m,2H),7.42-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.27-3.99(m,3H),3.92(s,3H),3.78(s,2H),3.42(d,J=5.9Hz,2H),3.21-2.89(m,3H),2.85-2.59(m,5H),2.56-2.34(m,4H),1.95(td,J=7.1,5.3Hz,4H).MS(ESI,m/z):789.2[M+1]+.
Example 217: synthesis of Compound JL-216: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((3-oxo-2, 8-diazaspiro [4.5] decan-8-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.66-7.54(m,3H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-3.98(m,3H),3.91(s,3H),3.78(s,2H),3.43(dt,J=5.5,0.6Hz,2H),3.15-2.92(m,3H),2.85-2.72(m,3H),2.65(dt,J=12.4,7.1Hz,2H),2.55-2.28(m,6H),1.79(t,J=7.1Hz,4H).MS(ESI,m/z):803.3[M+1]+.
Example 218: synthesis of Compound JL-217: (S) -4- (((5-chloro-6- (((S) -4- (2-chloro-3- ((5- ((1-oxo-2, 9-diazaspiro [5.5] undecan-9-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxypyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.73(m,2H),7.62-7.56(m,2H),7.53-7.43(m,2H),7.44-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.29-3.99(m,3H),3.91(s,3H),3.78(s,2H),3.23(td,J=6.9,5.9Hz,2H),3.14-2.93(m,3H),2.86-2.73(m,3H),2.67(dt,J=12.4,7.1Hz,2H),2.57-2.31(m,4H),2.10(dt,J=12.4,7.1Hz,2H),1.95(dt,J=12.4,7.1Hz,2H),1.80-1.69(m,2H),1.67-1.50(m,2H).MS(ESI,m/z):817.3[M+1]+.
Example 219: synthesis of Compound JL-218: (R) -4- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(d,J=9.0Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.31-4.00(m,5H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.12-2.84(m,4H),2.83-2.68(m,2H),2.57-2.19(m,6H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.68(m,1H).MS(ESI,m/z):763.2[M+1]+.
Example 220: synthesis of Compound JL-219: (S) -4- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(d,J=9.0Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-4.00(m,5H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.15-2.85(m,4H),2.83-2.66(m,2H),2.56-2.18(m,6H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.62(m,1H).MS(ESI,m/z):763.2[M+1]+.
Example 221: synthesis of Compound JL-220: (S) -2- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropanoic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77(d,J=6.1Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.28-5.84(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(t,J=6.9Hz,1H),4.10(qdd,J=12.4,9.4,7.7Hz,4H),3.95-3.79(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.39(m,2H),2.35-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.3,6.2Hz,1H),1.52(s,3H).MS(ESI,m/z):763.2[M+1]+.
Example 222: synthesis of Compound JL-221: (R) -2- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropanoic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77(d,J=6.1Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.12-5.82(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(t,J=6.9Hz,1H),4.10(qdd,J=12.4,9.4,7.7Hz,4H),3.95-3.79(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.41(m,2H),2.40-2.13(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.3,6.2Hz,1H),1.52(s,3H).MS(ESI,m/z):763.2[M+1]+.
Example 223: synthesis of Compound JL-222: 2- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -2-methylpropanoic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.61(s,1H),8.17(d,J=1.5Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.81-7.71(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.45-7.29(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.36(t,J=10.2Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.42-4.00(m,4H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.83(m,1H),2.85-2.67(m,2H),2.56-2.42(m,2H),2.39-2.20(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.66(m,1H),1.54(s,3H),1.49(s,3H).MS(ESI,m/z):747.2[M+1]+.
Example 224: synthesis of Compound JL-223: ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) glycine
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),10.61(s,1H),8.18(d,J=1.6Hz,1H),7.83-7.76(m,2H),7.75-7.65(m,2H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.41-4.21(m,2H),4.12(qd,J=12.4,9.2Hz,2H),3.98-3.80(m,4H),3.73(dp,J=8.2,7.0Hz,1H),3.61-3.38(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.66(m,2H),2.62-2.43(m,2H),2.37-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.69(m,1H).MS(ESI,m/z):719.2[M+1]+.
Example 225: synthesis of Compound JL-224: 3- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -3-methylbutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.30(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.53(t,J=9.6Hz,1H),4.32-3.99(m,4H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.62-2.42(m,4H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.69(m,1H),1.42(s,3H),1.37(s,3H).MS(ESI,m/z):761.3[M+1]+.
Example 226: synthesis of Compound JL-225: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.99(td,J=7.0,0.7Hz,1H),3.94-3.80(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.18-2.98(m,3H),2.96-2.85(m,1H),2.84-2.68(m,2H),2.55-2.42(m,2H),2.38-2.21(m,2H),2.12(q,J=7.1Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.67(m,1H).MS(ESI,m/z):745.2[M+1]+.
Example 227: synthesis of Compound JL-226: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) azetidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.99(td,J=7.0,0.9Hz,1H),3.94-3.81(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.20-2.97(m,3H),2.96-2.85(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.58-2.42(m,2H),2.39-2.23(m,2H),2.23-2.04(m,2H),2.04-1.89(m,1H),1.86-1.68(m,1H).MS(ESI,m/z):745.2[M+1]+.
Example 228: synthesis of Compound JL-227: 1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methylazetidin-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.38(dd,J=7.0,0.9Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.85(m,2H),2.83-2.68(m,2H),2.57-2.39(m,2H),2.37-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.87-1.67(m,1H).MS(ESI,m/z):745.2[M+1]+.
Example 229: synthesis of Compound JL-228: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.87-7.82(m,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.85-3.63(m,3H),3.20-2.85(m,6H),2.84-2.69(m,3H),2.57-2.41(m,2H),2.37-2.21(m,2H),2.10-1.67(m,4H).MS(ESI,m/z):759.2[M+1]+.
Example 230: synthesis of Compound JL-229: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.63(m,3H),3.14-2.84(m,6H),2.84-2.68(m,3H),2.55-2.43(m,2H),2.38-2.20(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.91-1.68(m,3H).MS(ESI,m/z):759.2[M+1]+.
Example 231: synthesis of Compound JL-230: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) benzamide) pyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.85-3.57(m,3H),3.13-2.96(m,3H),2.96-2.85(m,1H),2.84-2.66(m,3H),2.55-2.39(m,3H),2.29(td,J=7.1,1.7Hz,2H),2.07-1.86(m,3H),1.84-1.68(m,1H),1.28(s,3H).MS(ESI,m/z):773.3[M+1]+.
Example 232: synthesis of Compound JL-231: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) benzamide) pyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.85-3.64(m,3H),3.18-2.85(m,4H),2.83-2.68(m,3H),2.58-2.41(m,3H),2.29(td,J=7.1,1.7Hz,2H),2.05-1.88(m,3H),1.85-1.59(m,1H),1.28(s,3H).MS(ESI,m/z):773.3[M+1]+.
Example 233: synthesis of Compound JL-232: (2S, 4S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -4-hydroxypyrrolidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.34-4.02(m,4H),3.97-3.80(m,5H),3.79-3.58(m,2H),3.31-3.21(m,1H),3.11-2.84(m,3H),2.84-2.68(m,2H),2.55-2.43(m,2H),2.41-2.20(m,3H),2.06-1.89(m,2H),1.84-1.70(m,1H).MS(ESI,m/z):775.2[M+1]+.
Example 234: synthesis of Compound JL-233: (3R, 4R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -4-isopropylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.63-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.61(m,3H),3.26-3.15(m,1H),3.10-2.84(m,3H),2.83-2.55(m,5H),2.54-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.17-1.88(m,2H),1.86-1.63(m,2H),0.91(ddd,J=14.9,6.8,1.5Hz,6H).MS(ESI,m/z):801.3[M+1]+.
Example 235: synthesis of Compound JL-234: (3R, 4R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.64(m,3H),3.33-3.14(m,1H),3.10-2.85(m,3H),2.76(dddd,J=12.4,9.7,7.5,6.9Hz,2H),2.67-2.40(m,5H),2.36-2.12(m,3H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.67(m,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):773.3[M+1]+.
Example 236: synthesis of Compound JL-235: (3S, 4S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.63(m,3H),3.11-2.98(m,2H),2.97-2.84(m,2H),2.76(dddd,J=12.4,9.7,7.5,6.9Hz,2H),2.67-2.41(m,5H),2.38-2.12(m,3H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.69(m,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):773.3[M+1]+.
Example 237: synthesis of Compound JL-236: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzamide) pyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.90-3.79(m,2H),3.73(dp,J=8.2,7.0Hz,1H),3.12(t,J=6.9Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.95-2.64(m,5H),2.54-2.41(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.43(m,7H).MS(ESI,m/z):773.3[M+1]+.
Example 238: synthesis of Compound JL-237: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-indenyl-4-yl) benzamide) pyridin-3-yl) methyl) piperidine-2-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.59(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.98-3.61(m,6H),3.12(t,J=6.9Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.62(m,5H),2.56-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.45(m,7H).MS(ESI,m/z):773.3[M+1]+.
Example 239: synthesis of Compound JL-238: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.62(m,3H),3.15-2.84(m,4H),2.84-2.62(m,4H),2.60-2.42(m,3H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.54(m,5H).MS(ESI,m/z):773.3[M+1]+.
Example 240: synthesis of Compound JL-239: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) piperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.88-3.63(m,3H),3.12-2.84(m,4H),2.83-2.64(m,4H),2.62-2.42(m,3H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.50(m,5H).MS(ESI,m/z):773.3[M+1]+.
Example 241: synthesis of Compound JL-240: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.63(m,3H),3.15-2.57(m,8H),2.54-2.42(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.90-1.64(m,5H),1.16(s,3H).MS(ESI,m/z):787.3[M+1]+.
Example 242: synthesis of Compound JL-241: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -3-methylpiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.62(m,3H),3.14-2.97(m,2H),2.97-2.84(m,2H),2.84-2.64(m,4H),2.56-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.90-1.66(m,5H),1.16(s,3H).MS(ESI,m/z):787.3[M+1]+.
Example 243: synthesis of Compound JL-242: (S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.88-3.62(m,3H),3.16-2.98(m,3H),2.97-2.65(m,5H),2.55-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.08-1.66(m,6H).MS(ESI,m/z):788.3[M+1]+.
Example 244: synthesis of Compound JL-243: (R) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -3-hydroxypiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.89-3.60(m,3H),3.15-2.98(m,3H),2.96-2.85(m,1H),2.85-2.67(m,4H),2.49(q,J=7.3Hz,2H),2.29(td,J=7.1,1.7Hz,2H),2.08-1.59(m,6H).MS(ESI,m/z):788.3[M+1]+.
Example 245: synthesis of Compound JL-244: (2S, 3S) -1- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -2-methylpiperidine-3-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.73(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.84-3.65(m,3H),3.11-2.97(m,2H),2.95-2.85(m,1H),2.82-2.67(m,4H),2.58(q,J=6.9Hz,1H),2.49(q,J=7.2Hz,2H),2.29(td,J=7.1,1.7Hz,2H),2.07-1.60(m,6H),1.17(d,J=6.8Hz,3H).MS(ESI,m/z):787.3[M+1]+.
Example 246: synthesis of Compound JL-245: 2- ((6- (2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) -2-azabicyclo [2.2.2] octane-4-carboxylic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.75(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.62(m,3H),3.36-3.12(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.68(m,3H),2.55-2.41(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.09-1.66(m,10H).MS(ESI,m/z):799.3[M+1]+.
Example 247: synthesis of Compound JL-246: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((dimethylamino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84-7.71(m,3H),7.65(d,J=8.2Hz,1H),7.60(dd,J=7.5,1.8Hz,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.31-7.22(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.87-3.62(m,3H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.43(m,2H),2.38(s,6H),2.34-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.67(m,1H).MS(ESI,m/z):689.2[M+1]+.
Example 248: synthesis of Compound JL-247: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl)) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((((((2-hydroxyphenyl) amino) methyl) -2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.88-7.75(m,3H),7.72(dd,J=7.5,1.5Hz,1H),7.68-7.56(m,3H),7.47(t,J=7.5Hz,1H),7.42-7.34(m,2H),7.32-7.22(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.53(t,J=6.3Hz,1H),4.39-4.00(m,4H),3.92(s,3H),3.83-3.57(m,3H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.66(m,5H),2.49(q,J=7.3Hz,2H),2.37-2.16(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.62(m,1H).MS(ESI,m/z):705.2[M+1]+.
Example 249: synthesis of Compound JL-248: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((S) -5-oxopyrrolidin-2-yl)) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-methylaza-1-yl) methyl) -2-pyridinyl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.82(s,2H),3.71(dq,J=8.2,7.0Hz,1H),3.13-2.96(m,5H),2.96-2.85(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.55-2.39(m,2H),2.38-2.19(m,2H),2.14-1.87(m,2H),1.85-1.69(m,1H),0.99(d,J=6.8Hz,3H).MS(ESI,m/z):715.2[M+1]+.
Example 250: synthesis of Compound JL-249: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.21-3.89(m,6H),3.89-3.65(m,4H),3.15(dd,J=12.4,6.9Hz,2H),3.05(dd,J=12.4,7.0Hz,3H),2.97-2.85(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.49(q,J=7.3Hz,2H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.69(m,1H).MS(ESI,m/z):717.2[M+1]+.
Example 251: synthesis of Compound JL-250: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-hydroxy-3-methylpyrrolidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.54(s,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.86(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.41-3.19(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.85(m,1H),2.83-2.69(m,2H),2.53-2.44(m,2H),2.37-2.20(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.3,6.2Hz,1H),1.34(s,3H).MS(ESI,m/z):731.2[M+1]+.
Example 252: synthesis of Compound JL-251: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-methoxyazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),4.03-3.89(m,4H),3.88-3.77(m,2H),3.77-3.66(m,1H),3.25-3.15(m,5H),3.13-2.97(m,3H),2.96-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.59-2.38(m,2H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.68(m,1H).MS(ESI,m/z):731.2[M+1]+.
Example 253: synthesis of Compound JL-252: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.25(t,J=6.4Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.50(d,J=6.4Hz,2H),3.19(d,J=12.4Hz,2H),3.09-2.96(m,3H),2.96-2.85(m,1H),2.84-2.67(m,2H),2.54-2.42(m,2H),2.35-2.17(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.4,6.2Hz,1H),1.07(s,3H).MS(ESI,m/z):745.3[M+1]+.
Example 254: synthesis of Compound JL-253: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.81-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.82(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.65-3.42(m,2H),3.17(t,J=6.0Hz,1H),3.14-2.97(m,5H),2.97-2.85(m,1H),2.84-2.68(m,2H),2.55-2.43(m,2H),2.38-2.24(m,2H),2.17(dq,J=14.0,7.0Hz,1H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.65(m,1H).MS(ESI,m/z):731.2[M+1]+.
Example 255: synthesis of Compound JL-254: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((((((((1R, 3R) -3-hydroxycyclobutyl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.81-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.50(tt,J=9.4,7.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.26-4.00(m,5H),3.91(s,3H),3.87-3.64(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.84-2.57(m,4H),2.54-2.42(m,2H),2.38-2.21(m,2H),2.15-1.69(m,7H).MS(ESI,m/z):745.3[M+1]+.
Example 256: synthesis of Compound JL-255: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (4, 5-dihydro-1H-imidazol-2-yl) pyridin-2-yl) benzamide
The synthesis was as in example 6.1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.69(d,J=1.6Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.70-7.57(m,3H),7.47(t,J=7.4Hz,1H),7.43-7.33(m,2H),7.31-7.22(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.60(t,J=5.0Hz,1H),5.12(td,J=7.0,0.7Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.57-3.44(m,2H),3.41-3.26(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.84-2.67(m,2H),2.59-2.41(m,2H),2.37-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.65(m,1H).MS(ESI,m/z):700.2[M+1]+.
Example 257: synthesis of Compound JL-256: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((5-oxopyrrolidin-3-yl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.22-7.10(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.25-4.06(m,2H),4.06-3.93(m,2H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.54-3.28(m,3H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.84-2.69(m,2H),2.67-2.41(m,4H),2.38-2.21(m,2H),2.21-2.06(m,1H),1.97(dq,J=12.4,7.0Hz,1H),1.87-1.69(m,1H).MS(ESI,m/z):744.2[M+1]+.
Example 258: synthesis of Compound JL-257: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.37-4.01(m,3H),3.92(s,3H),3.86-3.64(m,3H),3.57(d,J=7.2Hz,1H),3.38-3.25(m,1H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.66(m,6H),2.55-2.43(m,2H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.70(m,2H),1.70-1.57(m,1H).MS(ESI,m/z):731.2[M+1]+.
Example 259: synthesis of Compound JL-258: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((1R, 2S) -2-hydroxycyclopentyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.76(d,J=9.0Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.45(d,J=5.7Hz,1H),4.25-4.05(m,2H),4.05-3.96(m,2H),3.95-3.82(m,4H),3.73(dp,J=8.2,7.0Hz,1H),3.20-2.85(m,4H),2.83-2.68(m,2H),2.54-2.42(m,2H),2.38-2.17(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.56(m,7H).MS(ESI,m/z):745.3[M+1]+.
Example 260: synthesis of Compound JL-259: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((6-oxo-2, 5-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.75(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.53-7.44(m,2H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.84(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.47-3.26(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.68(m,2H),2.53-2.43(m,2H),2.41-2.22(m,4H),2.07-1.85(m,3H),1.84-1.69(m,1H).MS(ESI,m/z):770.3[M+1]+.
Example 261: synthesis of Compound JL-260: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((7-oxo-2, 6-diazaspiro [3.4] octan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.63-7.58(m,2H),7.55(t,J=5.0Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.52-3.42(m,2H),3.14-2.97(m,5H),2.96-2.84(m,1H),2.84-2.65(m,2H),2.55-2.45(m,2H),2.43(d,J=0.6Hz,2H),2.36-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.68(m,1H).MS(ESI,m/z):770.3[M+1]+.
Example 262: synthesis of Compound JL-261: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.73(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.55-7.44(m,2H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83-3.62(m,3H),3.47-3.24(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.64(m,5H),2.64-2.41(m,5H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.88-1.69(m,3H).MS(ESI,m/z):784.3[M+1]+.
Example 263: synthesis of Compound JL-262: n- (5- (((R) -3- (1H-tetrazol-5-yl) pyrrolidin-1-yl) methyl) pyridin-2-yl) -2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.22-4.04(m,2H),4.04-3.93(m,1H),3.91(s,3H),3.84-3.75(m,2H),3.75-3.64(m,1H),3.55-3.43(m,1H),3.18(ddd,J=12.4,7.2,0.7Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.85(m,2H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.36(m,3H),2.36-2.09(m,4H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.68(m,1H).MS(ESI,m/z):783.3[M+1]+.
Example 264: synthesis of Compound JL-263: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((1-oxo-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,2H),7.52-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83-3.62(m,3H),3.42(d,J=5.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.83-2.59(m,6H),2.54-2.44(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.95(td,J=7.1,5.3Hz,5H),1.85-1.64(m,1H).MS(ESI,m/z):784.3[M+1]+.
Example 265: synthesis of Compound JL-264: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((3-oxo-2, 8-diazaspiro [4.5] decan-8-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.71(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,3H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.64(m,3H),3.43(dt,J=5.5,0.6Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.84(m,1H),2.84-2.60(m,6H),2.53-2.43(m,2H),2.40(d,J=0.6Hz,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.88-1.67(m,5H).MS(ESI,m/z):798.3[M+1]+.
Example 266: synthesis of Compound JL-265: 2-chloro-3- ((S) -1- ((3-chloro-6-methoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((1-oxo-2, 9-diazaspiro [5.5] undecan-9-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.77(d,J=7.5Hz,2H),7.68(d,J=8.2Hz,1H),7.63-7.56(m,2H),7.52-7.43(m,2H),7.43-7.32(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.84-3.62(m,3H),3.23(td,J=6.9,5.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.85-2.61(m,6H),2.53-2.44(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.10(dt,J=12.4,7.1Hz,2H),1.96(ddt,J=12.4,10.4,7.0Hz,3H),1.85-1.67(m,3H),1.67-1.54(m,2H).MS(ESI,m/z):812.3[M+1]+.
Example 267: synthesis of Compound JL-266: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6-ethoxypyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.18-8.04(m,2H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.71(m,2H),7.66-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.26(qd,J=8.0,1.6Hz,2H),4.19-3.99(m,6H),3.14-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.53-2.33(m,6H),1.45(t,J=8.0Hz,3H).MS(ESI,m/z):782.2[M+1]+.
Example 268: synthesis of Compound JL-267: (S) -4- (((6- (3- ((S) -1- ((6- (allyloxy) -5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloropyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.18-8.01(m,2H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.68(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.00(ddt,J=16.1,10.4,6.1Hz,1H),5.43-5.26(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.82-4.66(m,4H),4.30-3.97(m,6H),3.15-2.91(m,5H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.56-2.30(m,6H).MS(ESI,m/z):794.2[M+1]+.
Example 269: synthesis of Compound JL-268: (S) -4- (((6- (3- ((S) -1- ((6- (benzyloxy) -5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloropyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzamido) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.18-8.03(m,2H),7.86-7.69(m,3H),7.66-7.56(m,2H),7.53-7.31(m,7H),7.31-7.22(m,2H),5.32-5.17(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.32-3.97(m,6H),3.14-2.89(m,5H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.55-2.33(m,6H).MS(ESI,m/z):844.2[M+1]+.
Example 270: synthesis of Compound JL-269: (S) -4- (((6- (3- ((S) -1- ((5- (((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6- (((5-cyanopyridin-3-yl) methoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.80-8.75(m,1H),8.71(d,J=1.5Hz,1H),8.24(tt,J=9.3,7.9Hz,1H),8.16-8.10(m,2H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.72(m,2H),7.61(dd,J=7.5,1.5Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.30(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.36-5.18(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.31-3.96(m,6H),3.17-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.31(m,6H).MS(ESI,m/z):870.2[M+1]+.
Example 271: synthesis of Compound JL-270: (S) -4- (((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -3-chloro-6- (((5- (methylsulfonyl) pyridin-3-yl) methoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylaminopyridin-3-yl) methyl) amino) -3-
Hydroxy butyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.72(d,J=1.5Hz,1H),8.65-8.57(m,1H),8.36-8.21(m,1H),8.19(t,J=1.5Hz,1H),8.15(d,J=1.4Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.72(m,2H),7.61(dd,J=7.5,1.5Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.41-5.24(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.25-3.95(m,6H),3.26(s,3H),3.15-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.32(m,6H).MS(ESI,m/z):923.2[M+1]+.
Example 272: synthesis of Compound JL-271: 2-chloro-3- ((S) -1- ((3-chloro-6-ethoxy-5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.81-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.97-6.72(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.26(qd,J=8.0,1.6Hz,2H),4.20-4.03(m,4H),3.73(dpd,J=8.0,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.91(dtt,J=12.4,7.5,0.6Hz,2H),2.86-2.69(m,3H),2.58-2.43(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H),1.45(t,J=8.0Hz,3H).MS(ESI,m/z):772.3[M+1]+.
Example 273: synthesis of Compound JL-272: 3- ((S) -1- ((6- (allyloxy) -3-chloro-5- ((((((S)
-5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chloro-N- (5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.81-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.65-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.84(dtt,J=33.2,9.2,7.6Hz,2H),6.00(ddt,J=16.1,10.4,6.1Hz,1H),5.47-5.23(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.77(dt,J=6.1,1.0Hz,2H),4.44-3.94(m,4H),3.73(dpd,J=8.1,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.65(m,5H),2.56-2.40(m,2H),2.39-2.17(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):784.3[M+1]+.
Example 274: synthesis of Compound JL-273: 3- ((S) -1- ((6- (benzyloxy) -3-chloro-5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chloro-N- (5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzyl
Amides of carboxylic acids
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.4Hz,1H),7.84-7.75(m,3H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.51-7.31(m,7H),7.31-7.23(m,2H),6.84(dtt,J=33.2,9.2,7.6Hz,2H),5.33-5.16(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.25-3.98(m,4H),3.73(dpd,J=8.1,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.67(m,5H),2.49(q,J=7.0Hz,2H),2.37-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):834.3[M+1]+.
Example 275: synthesis of Compound JL-274: 2-chloro-3- ((S) -1- ((3-chloro-6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.80-8.76(m,1H),8.74-8.60(m,1H),8.19-8.06(m,2H),7.82(dd,J=7.4,1.6Hz,1H),7.80-7.75(m,2H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.02-6.69(m,2H),5.39-5.20(m,2H),5.13(td,6Hz,1H),4.24-4.00(m,4H),J=7.0,0.3.73(dpd,J=8.0,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.70(m,5H),2.60-2.44(m,2H),2.37-2.15(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):860.3[M+1]+.
Example 276: synthesis of Compound JL-275: 2-chloro-3- ((S) -1- ((3-chloro-6- ((5- (methylsulfonyl) pyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.72(d,J=1.7Hz,1H),8.66-8.58(m,1H),8.19(t,J=1.5Hz,1H),8.15(d,J=1.4Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.80-7.75(m,2H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.42-5.22(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.32-3.96(m,4H),3.73(dpd,J=8.0,7.0,1.1Hz,2H),3.26(s,3H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.69(m,5H),2.55-2.42(m,2H),2.38-2.20(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):913.3[M+1]+.
Example 277: synthesis of Compound JL-277: 3- ((S) -1- ((3-bromo-6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chloro-N- (5- (((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 7.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.85-8.74(m,1H),8.73-8.65(m,1H),8.22-8.06(m,2H),7.85-7.76(m,3H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.0,2.0,0.7Hz,1H),6.84(dtt,J=33.2,9.2,7.6Hz,2H),5.37-5.18(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.23-3.99(m,4H),3.73(dpd,J=8.1,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.70(m,5H),2.59-2.41(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):904.2[M+1]+.
Example 278: synthesis of Compound JL-278: (S) -4- (((6- (3- ((S) -1- ((5- ((((S) -3-carboxy-2-hydroxypropyl) amino) methyl) -6- ((5-cyanopyridin-3-yl) methoxy) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorobenzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.80-8.75(m,1H),8.74-8.67(m,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.11(t,J=1.5Hz,1H),7.91(tt,J=9.2,7.9Hz,1H),7.79(ddd,J=9.8,7.5,1.6Hz,2H),7.71(d,J=7.5Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.9,2.2,0.7Hz,1H),6.56(d,J=7.5Hz,1H),5.35-5.18(m,2H),5.11(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.28-3.91(m,6H),3.17-2.92(m,5H),2.79(dt,J=12.3,6.9Hz,1H),2.53-2.33(m,6H).MS(ESI,m/z):836.3[M+1]+.
Example 279: synthesis of Compound JL-279: 2-chloro-3- ((S) -1- ((6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.86-8.75(m,1H),8.74-8.63(m,1H),8.15(d,J=1.5Hz,1H),8.11(t,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78(dd,J=7.5,1.4Hz,1H),7.74-7.65(m,3H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.29(ddd,J=6.9,2.2,0.7Hz,1H),6.83(dtt,J=27.7,9.2,7.6Hz,2H),6.56(d,J=7.5Hz,1H),5.36-5.19(m,2H),5.11(td,J=7.0,0.6Hz,1H),4.08(dd,J=21.0,9.1Hz,3H),3.83-3.55(m,3H),3.06(dt,J=12.4,7.1Hz,1H),2.98-2.72(m,5H),2.46(q,J=6.9Hz,2H),2.36-2.16(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):826.3[M+1]+.
Example 280: synthesis of Compound JL-280: (3S) -4- (((5-chloro-6- (((1S) -4- (2-chloro-3- ((5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) carbamoyl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2- ((5-cyanopyridin-3-yl) methoxy) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.79-8.76(m,1H),8.71(d,J=1.4Hz,1H),8.13(q,J=1.4Hz,2H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.71(m,2H),7.63-7.57(m,2H),7.54-7.43(m,2H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.44-5.19(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.97(m,3H),3.75(d,J=2.6Hz,2H),3.43-3.24(m,2H),3.15-2.90(m,3H),2.85-2.63(m,5H),2.61-2.32(m,6H),1.79(td,J=7.1,0.7Hz,2H).MS(ESI,m/z):891.3[M+1]+.
Example 281: synthesis of Compound JL-281: 2-chloro-3- ((S) -1- ((3-chloro-6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) -N- (5- ((8-oxo-2, 7-diazaspiro [4.4] nonan-2-yl) methyl) pyridin-2-yl) benzamide
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.82-8.75(m,1H),8.71(d,J=1.4Hz,1H),8.13(q,J=1.4Hz,2H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.73(m,2H),7.69(d,J=8.1Hz,1H),7.64-7.57(m,2H),7.54-7.44(m,2H),7.44-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.36-5.18(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.11(qd,J=12.4,9.2Hz,2H),3.84-3.61(m,3H),3.49-3.25(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.84-2.63(m,6H),2.61-2.42(m,4H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.88-1.67(m,3H).MS(ESI,m/z):886.3[M+1]+.
Example 282: synthesis of Compound JL-282: (S) -4- (((6- (((S) -4- (3- ((5- ((((S) -2-carboxy-1-hydroxypropan-2-yl) amino) methyl) pyridin-2-yl) carbamoyl) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2- ((5-cyanopyridin-3-yl) methoxy) pyridin-3-yl) methyl) amino) -3-hydroxybutyric acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.97(s,1H),10.61(s,1H),8.82-8.74(m,1H),8.74-8.64(m,1H),8.18(d,J=1.5Hz,1H),8.13(t,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.03(t,J=9.7Hz,1H),5.42-5.20(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(dd,J=7.2,6.8Hz,2H),4.20-3.98(m,5H),3.97-3.74(m,2H),3.23-2.87(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.29(m,4H),1.52(s,3H).MS(ESI,m/z):870.2[M+1]+.
Example 283: synthesis of Compound JL-283: (S) -2- (((6- (2-chloro-3- ((S) -1- ((3-chloro-6- ((5-cyanopyridin-3-yl) methoxy) -5- ((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) oxy) -2, 3-dihydro-1H-inden-4-yl) benzoylamino) pyridin-3-yl) methyl) amino) -3-hydroxy-2-methylpropionic acid
The synthesis was as in example 5.1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.61(s,1H),8.85-8.76(m,1H),8.73-8.62(m,1H),8.18(d,J=1.5Hz,1H),8.13(t,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.73(m,2H),7.69(d,J=8.1Hz,1H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.03(t,J=9.7Hz,1H),5.42-5.17(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(t,J=6.9Hz,1H),4.10(qdd,J=12.4,9.5,6.9Hz,4H),3.96-3.79(m,2H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.77(ddt,J=12.2,7.5,6.8Hz,2H),2.56-2.42(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.69(m,1H),1.52(s,3H).MS(ESI,m/z):865.3[M+1]+.
Experimental example 1 determination of inhibitory Activity of PD1/PD-L1
(I) Experimental Equipment and reagent
(II) procedure of experiment
1. 1 × modified TR-FRET assay buffer is prepared.
2. Preparation of compound concentration gradient: test compound concentrations were 10000nM starting, 3-fold dilution, 10 concentration points, single well assay. The solution was diluted to 100-fold final concentration in 384-well plates and then 200nL was transferred to 384 reaction plates using Ech0550 for future use. 200nL of 100% DMSO was added to each of the negative and positive control wells.
3. PD-L1-Biotin solution was prepared at 4-fold final concentration using a1 Xmodified TR-FRET assay buffer.
4. Add 5. mu.L of PD-L1-Biotin solution with 4 times final concentration to the compound well and the positive control well, respectively; mu.L of 1 × modified TR-FRET assay buffer was added to the negative control wells.
5.1000rpm for 30 seconds, and after shaking and mixing, incubating at room temperature for 15 minutes.
6. A mixed solution of PD-1-Eu of 4 times final concentration and Dye labeled acceptor of 2 times final concentration was prepared using 1 Xmodified TR-FRET assay buffer.
7. mu.L of a mixed solution of PD-1-Eu and Dye labeled receptor (containing 5. mu.L of PD-1-Eu at 4-fold final concentration and 10. mu.L of Dye labeled receptor at 2-fold final concentration) was added.
8.1000rpm for 30 seconds, and after shaking and mixing, incubating at room temperature for 90 minutes.
9. The 384 well plate was centrifuged at 1000rpm for 30 seconds, after shaking and mixing, fluorescence intensities at 665nm and 620nm were read by EnVision, and TR-FRET ratio (665nm emission/620nm emission) was calculated.
(III) data analysis
Calculating the formula:
wherein: ratio (R)sampleIs the ratio of sample wells; ratiomin: negative control well ratio mean, representing the reading of wells without the PD-1/PD-L1 interaction; ratio (R)max: positive control wells are averaged, representing readings from wells without compound inhibition. Fitting a dose-response curve:
the log values of the concentrations were taken as the X-axis and the percent inhibition as the Y-axis, and the log (inhibitor) vs. response-Variable slope of the analytical software GraphPad Prism 5 was used to fit the dose-effect curves to obtain the IC50 values of each compound for enzyme activity.
(IV) results of the experiment
The results of the PD1/PD-L1 inhibitory activity assay are shown in the following table, C: IC (integrated circuit)50>100nM;B:IC50=100nM-10nM;A:IC50<10nM;
Compound numbering | IC50(nM) | Compound numbering | IC50(nM) |
JL-1 | B | JL-143 | B |
JL-2 | A | JL-144 | B |
JL-3 | A | JL-145 | A |
JL-4 | B | JL-146 | A |
JL-5 | B | JL-147 | A |
JL-6 | A | JL-148 | A |
JL-7 | B | JL-149 | A |
JL-8 | A | JL-150 | B |
JL-9 | A | JL-151 | C |
JL-10 | B | JL-152 | B |
JL-11 | A | JL-153 | C |
JL-12 | A | JL-154 | B |
JL-13 | A | JL-155 | B |
JL-14 | A | JL-156 | B |
JL-15 | B | JL-157 | B |
JL-16 | A | JL-158 | C |
JL-17 | A | JL-159 | B |
JL-18 | A | JL-160 | B |
JL-19 | A | JL-161 | B |
Claims (11)
1. A benzamide compound having the structure shown in formula I:
wherein ring a and ring B are independently an aromatic ring or an aromatic heterocycle;
l is a bond, -CH2O-、-OCH2-、-CH2CH2-、-NH(C=O)-、-(C=O)NH-、-(S=O)2NH-、-NH(S=O)2-, -O (C ═ O) -, - (C ═ O) O-, or two adjacent R —4And the two atoms of the phenyl ring to which they are attached together form a 5-7 membered substituted or unsubstituted carbocyclic oxy group, substituted or unsubstituted carbocyclic oxy group;
R1independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R2independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
R3independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl;
R4independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkyl;
m is 1 or 2;
n is 1 or 2;
p is 1, 2 or 3.
2. The benzamide compound of the structure shown in the formula I according to claim 1, which is characterized in that:
R1when said substituted alkyl or said substituted alkoxy is present, the substituent is one or more of the following substituents: halogen, C1-C4 alkyl, hydroxy,Benzyl, benzyl with cyano substituent, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; the substituents in said substituted hydroxy or said substituted amino are one or more of the following substituents: C1-C4 alkyl, benzyl, cyano-substituted benzyl, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; when the number of the substituents is plural, the substituents may be the same or different;
R2when said substituted alkyl or said substituted alkoxy is present, the substituent is one or more of the following substituents: halogen, C1-C4 alkyl, hydroxy,Benzyl, cyano-substitutedBenzyl, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester or C1-C4 amide groups; the substituents in said substituted hydroxy or said substituted amino are one or more of the following substituents: C1-C4 alkyl, benzyl, cyano-substituted benzyl, C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amido; when the number of the substituents is plural, the substituents may be the same or different;
in, R5And R6Independently hydrogen, substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl or aminoalkyl groups; or R5、R6Together with the nitrogen atom to which they are attached form a 5-7 membered substituted or unsubstituted carbon heterocyclic ring; in the carbon heterocycle, the heteroatom is nitrogen or nitrogen and oxygen, and the number of the heteroatoms is 1-4;
R5or R6Wherein the substituents in said substituted alkyl are one or more of the following groups: halogen, C1-C4 alkyl, hydroxy,C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; r5、R6And the nitrogen atom to which they are attached, form a 5-to 7-membered substituted carbon heterocyclic ring. The substituents in the substituted carbon heterocycle are one or more of the following groups: halogen, C1-C4 alkyl, hydroxy,C1-C4 alkoxy, C1-C4 carboxyl, C1-C4 ester group or C1-C4 amide group; when the number of the substituents is plural, the substituents may be the same or different;in, R7And R8Independently hydrogen or C1-C4 alkyl.
3. The benzamide compound of the structure shown in the formula I according to claim 1, which is characterized in that: the aromatic ring is a C6-C14 aromatic ring; the hetero atom number of the hetero aromatic ring is 1-4 and is nitrogen, oxygen or sulfur.
7. the benzamide compound of the structure shown in the formula I according to any one of claims 1 to 6, characterized in that: the compound also comprises pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof.
8. A pharmaceutical composition, which comprises a therapeutically effective amount of one or more benzamide compounds as shown in formula I in any one of claims 1-7, and a pharmaceutically acceptable carrier or adjuvant.
9. The process for preparing benzamide compounds of formula I according to any one of claims 1-7, characterized in that: the method comprises the following steps:
(1) carrying out condensation reaction on the compound of the formula II and the compound of the formula III to obtain a compound of a formula IV;
(2) carrying out Suzuki reaction on the compound of the formula IV and the compound of the formula V to obtain a compound of a formula VI;
(3) deprotection reaction catalyzed by tetrabutyl ammonium fluorideCoupling the compound of formula VI with-OPg1Is converted into-OH;
(4) carrying out hydroxyl selective oxidation reaction on the compound of the formula VII to obtain a compound of a formula VIII;
(5) carrying out reductive amination reaction on the compound shown in the formula VIII to obtain a compound shown in the formula IX;
(6) carrying out Suzuki reaction on the compound of the formula X and the compound of the formula XI to obtain a compound of a formula XII;
(7) carrying out reductive amination reaction on the compound shown in the formula XII to obtain a compound shown in the formula XIII;
(8) the compound of formula XIV and the compound of formula XV undergo a reductive amination reaction to give the compound of formula XVI.
10. Use of the benzamide compound as shown in the formula I in any one of claims 1-7 in the preparation of an immune checkpoint inhibitor, an inhibitor with the inhibitory activity of PD-1/PD-L1 signal channel, an antitumor drug and an anti-infective drug.
11. Use of the pharmaceutical composition of claim 8 for the preparation of an inhibitor as an immune checkpoint inhibitor, an inhibitor with inhibitory activity of the PD-1/PD-L1 signaling pathway, an antineoplastic agent, an anti-infective agent.
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WO2017202274A1 (en) * | 2016-05-23 | 2017-11-30 | 中国医学科学院药物研究所 | Nicotinyl alcohol ether derivative, preparation method therefor, and pharmaceutical composition and uses thereof |
WO2018006795A1 (en) * | 2016-07-05 | 2018-01-11 | 广州再极医药科技有限公司 | Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof |
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