Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis

Abstract

We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.

INTRODUCTION

The amide-bond formation plays a central role in organic synthesis, chemical biology, and pharmaceutical research.¹ According to a recent survey, N-acylation of amines represents the most frequently employed reaction in drug discovery.² Thus, it is not surprising that amide synthesis has been extensively used for assembly of small-molecule libraries designed to deliver pharmacological probes and drugs.³ While early work in this area has relied almost exclusively on solid-phase synthesis,⁴ much of the recent effort has shifted to generating nonpeptide small-molecule libraries in solution.⁵ The most attractive feature of solution-based methods is the high efficiency of monitoring and optimizing chemical reactions. Indeed, many innovative strategies have been developed to enable high-throughput organic synthesis in solution, including the use of soluble polymeric supports,⁶ phase-separation tags,⁷ scavenging agents,⁸ or automated preparative LCMS methods.⁹ Another attractive purification tactic is a liquid–liquid extraction, which takes advantage of the differences in aqueous solubility of reagents, reactants, and products under either basic or acidic conditions. This method is particularly well suited for amide-bond formation and can completely avoid chromatographic purification, use of scavenging agents or attachment of phase-separation tags. Boger and co-workers were the first to recognize the value of parallel solution-phase amide synthesis followed by a simple liquid–liquid extraction, and employed this strategy for preparation of several amide-containing libraries.^10,11 While small libraries were produced as individual compounds,¹⁰ larger libraries were typically generated as compound mixtures presumably due to the manual nature of the assembly process.¹¹

As the amide-bond formation continues to play a dominant role in organic, bioorganic, and medicinal chemistry, the automation of this important process could greatly improve its efficiency, enabling rapid access to large nonpeptide amide-containing libraries of individual, pure compounds. Herein, we report the development of a fully automated, chromatography-free protocol for parallel amide synthesis in solution, which was employed for the preparation of four representative heterocyclic libraries. The first stage of the assembly process entailed the synthesis of a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. To further expand heterocyclic diversity, we developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides to afford a wide range of bicyclic and tricyclic dienamides. The final stage of the parallel assembly process entailed diversification of the initially produced heterocyclic cores via a solution-phase amide synthesis, which was readily performed by a conventional liquid-handling robot. This automation platform delivered 1872 new heterocyclic compounds, which were obtained with high efficiency and excellent chemical purity without chromatographic purification.

RESULTS AND DISCUSSION

Library Design

Our previous work demonstrated that reactions of vinylogous carbamates with maleic anhydride delivered a library of functionalized pyrrolidinones, which yielded two noncompetitive inhibitors of facilitative glucose transport.^12a,b While this library was produced using a short and efficient reaction sequence, chromatographic purification of all final compounds was required in order to ensure their high chemical purity prior to the biological evaluation.^12a,b Building on this precedent, the objectives of our present study were 2-fold. First, we aimed to increase the size and skeletal diversity of newly designed heterocyclic libraries based on five- and six-membered lactams. Second, we set out to develop a fully automated protocol for solution-phase amide synthesis that could be efficiently employed for final-stage diversification of such libraries. Such an automation platform would deliver a large number of individual compounds in high purity without chromatographic purification.

Our general synthetic strategy is depicted in Figure 1. The assembly process begins with a condensation of primary amines 1 and ketoesters 2 to deliver the corresponding vinylogous carbamates 3. Subsequent reaction of 3 with maleic anhydride 4 would afford pyrrolidinones 7.¹² A similar transformation employing itaconic anhydride 5 is expected to give ring-expanded piperidinones 8.¹³ Structural diversity can be readily introduced into 7 and 8 by selecting a variety of amines 1 and ketoesters 2. The use of alkyne-containing primary amines (R¹ = propargyl) could further expand skeletal diversity of lactams 7 and 8 via a transition-metal-catalyzed enyne cycloisomerization¹⁴ to deliver tetrahydro-oxindolizines 9 and hexahydrooxoquinolizines 10. The final stage of the synthesis would rely on the development of an automated amide-bond forming protocol that would convert the initial set of core structures 7–10 to the final amide-containing libraries 12–15, which would be produced on 10–20 mg scale and subjected to rigorous purity analysis. The use of cheminformatics methods would facilitate selection of the appropriate building blocks at each stage of the diversification process in order to produce all final compounds with favorable physicochemical properties en route to subsequent identification of new pharmacological probes.

Figure 1.

General Synthetic Strategy to Skeletally Diverse Heterocyclic Libraries. The assembly process is divided into two stages. First, a number of skeletally diverse lactams 7–10 are produced starting with readily available primary amines 1, ketoesters 2 and unsaturated anhydrides 4 or 5. Second, each of the lactams 7–10 is coupled to amines 11 in a fully automated fashion to deliver the resulting amide-containing heterocyclic libraries 12–15.

Automation of the Solution-Phase Amide Synthesis

Our initial objective was to develop a general protocol for efficient, automated amide synthesis in solution that would employ readily available amide-coupling agents followed by a simple liquid–liquid extraction to purify final amide products (Figure 2). Such an automation platform was expected to possess excellent throughput capabilities by avoiding chromatographic purification using scavenging agents or attaching and detaching tags for phase separation. For purification, we intended to employ a single extraction step that would entail partitioning the reaction mixture between an organic phase and an acidic aqueous solution. This procedure would efficiently separate the amide-containing product, which would be collected in the organic phase, from an excess of starting amine, amide-coupling reagent and other coproducts, which would all partition into the acidic aqueous layer. In order to develop and validate this protocol, we prepared several pyrrolidinone-containing carboxylic acids 7 by reaction of amines 1 with ketoesters 2, followed by cyclization with maleic anhydride 4 (Figure 2A). Evaluation of a number of existing amide-coupling protocols revealed that 1,1′-carbonyldiimidazole (CDI, 16) served as the best reagent not only to promote efficient N-acylation but also to afford highest purity of the resulting amides following a single liquid–liquid extraction step. During the optimization studies, the efficiency of the initial acyl imidazole formation was conveniently monitored by ¹H NMR spectroscopy. This transformation proceeded to completion typically within 2–4 h at 20 °C in chloroform using a slight excess of CDI (1.05 equiv). The resulting acyl imidazole 17 was next treated with 3 equiv of either primary or secondary amines 11. The excess of amine ensured complete conversion of acyl imidazole 17 to the corresponding amide 12. The final reaction mixture was treated with a 1.2 M solution of hydrochloric acid. The two phases were thoroughly mixed and allowed to separate. Retrieval of the chloroform layer and evaporation produced several representative amide-containing products 12a–d (Figure 2B) in high efficiency. High chemical purity of each of the products was established independently by LCMS analysis and 500 MHz ¹H NMR spectroscopy. We found that amide-bond formation and liquid–liquid extraction could be readily performed using a typical robotic liquid handler, followed by parallel evaporation. The use of this protocol can yield 1–100 mg of individual final products depending on the amount of carboxylic acid used for the amide-coupling step.

Figure 2.

Development of an automation platform for solution-phase amide synthesis and liquid–liquid extraction. (A) Synthetic scheme used for the development of automated amide synthesis and extractive purification. Carboxylic acids 7 were manually prepared from primary amines 1, ketoesters 2, and anhydride 4 as previously described.¹² Automated amide synthesis entailed activation of each carboxylic acid 7 with 1,1′-carbonyldiimidazole (CDI, 16), followed by treatment of the resulting acyl imidazole 17 with 3 equivalents of amines 11 for 48 h at 20 °C and washing the resulting chloroform solution with 1.2 M aqueous solution of HCl. (B) Structures and isolated yields of four representative amides, which were prepared by the above protocol following solvent evaporation. The purity of each compound was established by LCMS analysis and confirmed by ¹H NMR spectroscopy.

Synthesis of a Pyrrolidinone Library

Having developed an automated amide-coupling protocol, we next examined its first application to a larger set of pyrrolidinone-containing compounds. Our goal was to prepare a 216-membered library 12 on 20 mg scale starting from 3 primary amines 1, 3 ketoesters 2, and 24 amines 11 (Figure 3). We wanted to ensure that all reactions would produce final products 12 in high chemical purity without chromatographic purification of any of the final compounds. Selection of each of the building blocks shown in Figure 3B–D was guided by Accelrys Pipeline Pilot, which enabled virtual enumeration of the target library and estimation of various molecular properties in silico. Specifically, during the design process, we applied appropriate filters in order to select building blocks that would produce the target library 12 with molecular weight below 600 and calculated logarithmic value of n-octanol/water partition coefficient (cLogP) within a range of 1–5.¹⁵ The distribution of both parameters for this library is shown in the Supporting Information (Figure S1).¹⁶

Figure 3.

Synthesis of a 216-membered library of bicyclic pyrrolidinones. (A) Two-stage assembly process entailed preparation of nine carboxylic acids 7 starting with 3 amines 1 and 3 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 3 amines 1. (C) Structures of 3 ketoesters 2. (D) Structures of 24 amines 11.

The synthesis began with condensations of three primary amines 1 (Figure 3B) with three ketoesters 2 (Figure 3C), followed by reactions of the resulting vinylogous carbamates 3 with maleic anhydride 4 to afford nine pyrrolidinone-containing carboxylic acids 7. Each of the acids 7 was obtained as a single diastereomer approximately on a 500 mg scale in a single-flask operation starting with the corresponding amines 1 and ketoesters 2. In order to ensure their high chemical purity, all pyrrolidinone-containing carboxylic acids 7 were purified by conventional chromatography. The second stage of the assembly process entailed a fully automated synthesis of the target library 12 using a set of 24 amines 11 (Figure 3D). To this end, each acid 7 was first treated with a slight excess of CDI (16) in chloroform at room temperature and divided into 24 equal batches. Upon completion of the acyl imidazole formation, each batch was treated for 48 h with a solution of amine 11 in chloroform at the same temperature, followed by addition of a 1.2 M aqueous solution of HCl. The organic and aqueous layers were thoroughly mixed and allowed to separate. The amides 12 were obtained by removal of the chloroform layer and parallel solvent evaporation. We determined the yields of all final compounds by automated weighing, which established that 216 N-acylations proceeded with high efficiency with an average isolated yield of 87.2 ± 7.2%. The high purity of each library member was established using LCMS.¹⁶ In addition, we acquired 500 MHz ¹H NMR spectra of 18 randomly selected amides, which independently confirmed their high diastereomeric and chemical purities.¹⁶

Synthesis of a Piperidinone Library

The reactions of vinylogous carbamates with maleic anhydride provided efficient and fully diastereoselective entry into the 2-pyrrolidinone core 7 (Figure 3) via a tandem reaction sequence including conjugate addition and anhydride opening. We next examined the construction of ring-expanded 2-piperidinones 8 (Table 1) via the corresponding reaction of vinylogous carbamates 3 with itaconic anhydride 5. A representative reaction of amine 1a with ketoester 2a cleanly afforded enamine 3, which was subsequently treated with anhydride 5 to give piperidinone 8a with high efficiency and diastereoselectivity (Table 1, entry 1). The structure of 8a was determined by X-ray crystallography.¹⁶ Investigation of the scope of this transformation revealed that both six- and seven-membered ketoesters 2b and 2c efficiently afforded the corresponding pyrrolidinones 8b and 8c (Table 1, entries 2 and 3). The use of furan-containing primary amine 1d was also tolerated (Table 1, entry 4). High diastereoselectivity was observed in all cases. Interestingly, the opposite stereochemical outcome was observed during the formation of six-membered lactams 8 compared to the corresponding cyclizations leading to five-membered 2-pyrrolidiones 7.

Table 1.

Synthesis of Bicyclic 2-Piperidinones

^aYields refer to those of isolated compounds following chromatographic purification.

^bDiastereomeric ratios (dr) were determined by ¹H NMR analysis of unpurified reaction mixtures.

The high level of diastereoselectivity of both reactions can be rationalized by examining conjugate addition and anhydride-opening steps (Figure 4). The two initial transition states A and E have one common feature: they both entail the approach of unsaturated anhydride, which facilitates subsequent lactam formation by placing the imine moiety in close spatial proximity to the carbonyl group of the anhydride for its subsequent opening. In the case of maleic anhydride, this process predicts the formation of intermediates B and C and explains the observed stereochemistry of the product 7. For itaconic anhydride, similar logic predicts the intermediacy of anhydride F and N-acyliminium ion G en route to the observed six-membered lactam 8.

Figure 4.

Proposed explanation of the diastereoselective formation of 2-pyrrolidinones 7 and 2-piperidinones 8. In both cases, the tandem reaction sequence entails a conjugate addition of the enamine to unsaturated anhydride followed by a ring-opening and a proton transfer. Initial approach of each anhydride facilitates subsequent lactam formation by placing the reactive imine and carbonyl moieties in close spatial proximity, as shown in intermediates B and F.

Because a number of 2-piperidinones 8 were prepared with good efficiency and high diastereoselectivity (Table 1), we next employed this process for generating a 768-membered library 13 starting with 8 primary amines 1, 4 ketoesters 2, and 24 amines 11 (Figure 5). Analysis of the enumerated library in silico identified structures of 8 commercially available amines 1 (Figure 5B), 4 ketoesters 2 (Figure 5C), and the same set of 24 amines 11 (Figure 5D), which would deliver this chemical library with favorable molecular weight and a narrow cLogP distribution (Figure S2 in the Supporting Information). The synthesis began with parallel reactions of 8 amines 1 with each of the four ketoesters 2. The resulting vinylogous carbamates 3 were not isolated but directly reacted with itaconic anhydride 5 to give 32 piperidinone-containing carboxylic acids 8. Following this one-flask protocol, each of the acids 8 was obtained approximately on a 500 mg scale as a single diastereomer with good efficiency following conventional chromatographic purification in order to ensure their high purity. The final stage entailed CDI-promoted coupling of each of the 32 carboxylic acids 8 with 24 amines 11. This operation was fully automated and conducted under the same conditions used for generating library of 2-pyrrolidinones 12. This process delivered 768 amides 13, which were prepared on a 15–20 mg scale. Parallel LCMS analysis of all library members established their high chemical purity, which was independently confirmed by obtaining 500 MHz ¹H NMR spectra of 64 randomly selected compounds.¹⁶

Figure 5.

Synthesis of a 768-membered library of bicyclic piperidinones. (A) Two-stage assembly process entailed preparation of 32 carboxylic acids 8 starting with 8 amines 1 and 4 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 8 amines 1. (C) Structures of 4 ketoesters 2. (D) Structures of 24 amines 11.

Synthesis of a Library of Fused Dihydropyrans and Piperidinones

Assembly of pyrrolidinones 12 and 2-piperidinones 13 thus far relied on the use of readily available carbocyclic ketoesters 2, which limited the extent of their skeletal diversification. We next examined the ability of tetrahydropyran-containing ketoesters to participate in such lactam-forming reactions. This process would enable fusion of oxygen- and nitrogen-containing heterocyclic platforms, expanding both the skeletal and heteroatom diversity of the resulting libraries while maintaining their favorable physico-chemical properties. Our previously developed Prins cyclization of β-hydroxy dioxinones enabled efficient assembly of a range of highly functionalized tetrahydropyranones.¹⁷ Validated through several applications in the synthesis of complex polyketide natural products,¹⁸ this method could afford a variety of 3-carbomethoxy-4-tetrahydropyranones 24 diversified at both the C(2) and the C(6) positions (Table 2).

Table 2.

Synthesis of Carbomethoxytetrahydropyranones

Entry	R1	R2	Ketoester	Yield, % (3 steps)a	drb
1	t-Bu	Me	24a	60	>95:5
2		Me	24b	57	>95:5
3	i-Pr		24c	60	85:15c
4		Me	24d	53	>95:5

^aYields refer to those of isolated compounds following chromatographic purification.

^bDiastereomeric ratios (dr) were determined by ¹H NMR analysis of unpurified reaction mixtures.

^cMajor diastereomer was obtained in diastereomerically pure form after chromatographic purification.

The synthesis began with the Mukaiyama aldol reaction of silyl dienol ether 19 with aldehyde 20 to give β-hydroxy dioxinones 21. The next step entailed the Lewis acid promoted Prins cyclization of dioxinones 21 with aldehydes 22, which proceeded efficiently in all cases. Finally, treatment of dihydropyrans 23 with methanol at 150 °C afforded four requisite 3-carbomethoxy-4-tetrahydropyranones 24 with high diastereoselectivity. Erosion of diastereoselectivity in the final product was observed only in one case at the final methanolysis stage (Table 2, entry 3). However, the major diastereomer 24c was readily obtained in good overall yield and high diastereomeric purity by chromatographic purification.

We next examined reactions of vinylogous carbamates 25 derived from tetrahydopyran-containing ketoesters 24 with unsaturated anhydrides 4 and 5. While the reaction of maleic anhydride 4 with 25 proved low yielding, the corresponding condensation with itaconic anhydride successfully delivered the expected piperidinone-containing products 26. The results of the initial scope study of this transformation are summarized in Table 3. The four ketoesters 24a–d afforded the corresponding oxabicyclic piperidinones 26a–d with high efficiency as single observed diastereomers. Excellent diastereoselectivity of this transformation, which affords products containing four stereogenic centers, is particularly noteworthy. Stereochemistry of the final products was determined by extensive NMR analysis and can be explained by considering a transition state model E (Figure 4) with the approach of itaconic anhydride 5 expected to occur opposite to the R² substituent, corresponding to a sterically more accessible face of the pyran moiety.

Table 3.

Synthesis of Pyrrolidinones Fused to Dihydropyrans

^aYields refer to those of isolated compounds following chromatographic purification.

^bDiastereomeric ratios (dr) were determined by ¹H NMR analysis of unpurified reaction mixtures.

Having established efficient and fully diastereoselective access to dihydropyrans fused with piperidinones, we next examined the possibility of generating a large library of such heterocyclic compounds from four tetrahydropyran-containing ketoesters 24a–d and the same two sets of amines 1 and 11, which were used to prepare library 13. This process would produce 768 compounds starting with 4 ketoesters 24, 8 primary amines 1, and 24 primary and secondary amines 11 (Figure 6). Analysis of the enumerated library in silico revealed that such compounds would display favorable molecular properties, including molecular weight and cLogP (Figure S3 in the Supporting Information).

Figure 6.

Synthesis of a 768-membered library of 2-piperidinones fused to dihydropyrans. (A) Assembly process entailed preparation of 32 carboxylic acids 26 starting with 8 amines 1 and 4 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 8 amines 1. (C) Structures of 4 ketoesters 2. (D) Structures of 24 amines 11.

The synthesis began with reactions of 8 amines 1 with each of the 4 ketoesters 24, followed by treatment of the resulting vinylogous carbamates with itaconic anhydride 5. This one-flask operation successfully delivered 32 expected carboxylic acids 26, which were obtained with good efficiency and high purity following a single parallel chromatographic purification. Using the same automated liquid-handling platform employed for syntheses of libraries 12 and 13, each of the acids 26 was activated using CDI (16) and coupled to 24 amines 11, followed by liquid–liquid extraction and solvent evaporation. This process successfully delivered the target 768-membered library 27 on 15–20 mg scale in high efficiency and excellent purity, which was determined by LCMS.¹⁶ The NMR analysis of 64 randomly selected compounds once again confirmed their high chemical and diastereomeric purity.¹⁶

Development of Au-Catalyzed Enynamide Cycloisomerization

The efficient access to a series of structurally diverse bicyclic lactams prompted us to further expand their skeletal diversity by examining the ability of such compounds to participate in enyne cycloisomerizations in the presence of an appropriate metal catalyst. Among transition metals that catalyze enyne cycloisomerizations, Au- and Pt-based complexes are particularly noteworthy for their ability to chemoselectively activate the alkyne moiety and provide access to various reaction topologies depending on the structure of the starting enyne.¹⁴ Such reactions typically proceed under mild conditions, tolerate a wide variety of commonly used functional groups, and provide powerful methods for structural diversification in organic synthesis. Despite significant advances in Au- and Pt-catalyzed cycloisomerizations of 1,5-enynes, the vast majority of such reactions typically afford carbocyclic products.^14b Only a few examples of Au-catalyzed syntheses of nitrogen heterocycles are known. Indeed, we reported a series of Au(I)-catalyzed double cyclizations that produced a number of oxygen and nitrogen heterocycles.¹⁹ While such reactions efficiently proceeded under mild conditions, they were limited to the synthesis of several unique heterobicyclic products.¹⁹ Recently, Schaus and co-workers described Au(III)-catalyzed cycloisomerizations of alkyne-tethered dihydropyrimidones.²⁰ While this new catalytic process yielded a number of pyridopyrimidones, such reactions were conducted at high temperatures presumably due to the requirement for the initial isomerization of a vinylogous imide. Furthermore, only internal alkynes participated in such cycloisomerizations.²⁰

Prompted by the lack of general studies of transition-metal-catalyzed cycloisomerizations of enynes containing stable enamide fragments, we prepared several potential cyclization substrates 28a–c by reactions of the corresponding primary propargyl amines 27a–c with ketoester 2a, followed by treatment of the resulting vinylogous carbamates with itaconic anhydride 5 (Table 4). Having examined several commonly employed transition metal complexes, we found that treatment of phenyl-substituted enyne 28a with 5 mol % of PPh₃AuCl in the presence of a number of Ag-based additives produced cycloisomerization product 29a (Table 1, entries 1–3). The reaction efficiency considerably decreased in the absence of PPh₃AuCl (Table 4, entry 4). Initially, the best results were obtained by combining PPh₃AuCl with AgSbF₅ in either dichloromethane or chloroform (Table 4, entries 1 and 5). The use of acetonitrile as a reaction solvent resulted in a further increase in efficiency and enabled nearly quantitative conversion of 28a to 29a (Table 4, entry 6). However, this set of conditions did not give successful results when applied to enamide 28b containing a terminal alkyne. Indeed, the conversion level dropped to 20% (Table 4, entry 7). We next examined the effect of the various phosphine ligands on the reaction outcome. While electron deficient phosphines did not provide much improvement (Table 4, entry 8), the use of sterically hindered or electron-rich phosphines substantially improved the efficiency of cycloisomerization of 28b to 29b (Table 4, entries 9–12). Interestingly, a similar trend was recently attributed to a more efficient protodemetalation step in the presence of bulky or electron rich phosphines when this step became turnover limiting.²¹ Continuing to explore this trend, we evaluated a number of cationic gold complexes 30, 31 and 32 containing bulky carbene or phosphine ligands (Table 4, entries 13–15). The best results were obtained using either 31 or 32. In both cases, cycloisomerization of 28b proceeded with quantitative efficiency. In addition, complex 31 proved superb at promoting cyclizations of 28a and 28c (Table 4, entries 16 and 17).

Table 4.

Discovery and Optimization of Enyne Cycloisomerization

entry	R1	enyne	catalyst(s), (mol %)	solvent	product	yielda (%)
1	Ph	28a	Ph3PAuCl (5), AgSbF6 (10)	CH2Cl2	29a	85
2	Ph	28a	Ph3PAuCl (5),AgBF4(10)	CH2Cl2	29a	75
3	Ph	28a	Ph3PAuCl (5),AgOTf (10)	CH2Cl2	29a	60
4	Ph	28a	AuSbF6 (10)	CH2CL2	29a	45
5	Ph	28a	Ph3PAuCL (5),AgSbF6(10)	CHCl3	29a	85
6	Ph	28a	Ph3PAuCl (5), AgSbF6 (10)	CH3CN	29a	95
7	H	28b	Ph3PAuCl (5),AgSbF6(10)	CH3CN	29b	20
8	H	28b	(p-CF3Ph)3PAuCl (5), AgSbF6 (10)	CH3CN	29b	30
9	H	28b	Cy3PAuCl (5), AgSbF6 (10)	CH3CN	29b	95
10	H	28b	t-Bu3PAuCl (5), AgSbF6 (10)	CH3CN	29b	95
11	H	28b	Ph (Me)2PAuCl (5), AgSbF6 (10)	CH3CN	29b	87
12	H	28b	Et3PAuCl (5), AgSbF6 (10)	CH3CN	29b	98
13	H	28b	complex 30 (3)	CH3CN	29b	95
14	H	28b	complex 31 (3)	CH3CN	29b	100
15	H	28b	complex 32 (3)	CH3CN	29b	100
16	Ph	28a	complex 31 (3)	CH3CN	29a	100
17	Me	28c	complex 31 (3)	CH3CN	29c	100

^aYields were determined by 500 MHz 1H NMR analysis of unpurified reaction mixtures using an internal standard. Each of the products 29 was subsequently isolated and fully characterized.

The high efficiency of this catalytic system, which operates at low catalyst loadings at room temperature to promote cyclizations of enamides containing both terminal and internal alkynes is highly noteworthy. Furthermore, this reaction tolerates a number of functional groups present in cycloisomerization substrates 28, including unprotected carboxylic acids. The latter feature of the reaction is particularly important in maximizing synthetic efficiency of subsequent elaboration of of cycloisomerization products (vide infra) despite the known reactivity of carboxylic acids in a number of other Au-catalyzed reactions.²²

We next examined the utility of cationic gold-phosphine complex 31 in promoting cycloisomerizations of other structurally diverse alkyne-containing enamides 33, which originated from propargyl amines 27, ketoesters 2, and itaconic anhydride 5 (Table 5). We found that enynes 33a and 33b successfully underwent cycloisomerizations to deliver the corresponding dienamides 34a and 34b in high yields (Table 5, entries 1 and 2). Such transformations further expanded the skeletal diversity of the tricyclic products that can be efficiently prepared by this approach. Furthermore, acyclic ketoesters 2e or 2f could be efficiently converted to the corresponding enynes 33c and 33d, which upon treatment with Au complex 31 afforded bicylic dienamides 34c and 34d (Table 5, entries 3 and 4).

Table 5.

Au-Catalyzed Cycloisomerizations of Enyne-Containing 2-Piperidinones

Entry	Ketoester	R1	Enyne	Yield, %	Product	Yield, %a	drb
1		H	33a	98		98	>95:5
2		Ph	33b	75		75	>95:5
3		Ph	33c	90		90	>95:5
4		H	33d	100		100	>95:5

^aYields were determined by 500 MHz ¹H NMR analysis of unpurified reaction mixtures using an internal standard. Each of the products 34 was subsequently isolated and fully characterized.

While all enyne cycloisomerization products obtained thus far contained six-membered 2-piperidinones, we next examined the ability of this reaction to produce 1,3-dienamides incorporating five-membered lactams 36 (Table 6). The requisite alkyne-containing enamides 35 were prepared by the same one-pot procedure starting with propargyl amines 27, ketoesters 2, and maleic anhydride 4. Subjections of enynes 35a and 35b to the general cycloisomerization protocol cleanly afforded the expected products 36a and 36b with quantitative efficiency (Table 6, entries 1 and 2). Similarly, cycloisomerizations of enynes 35c and 35d, which were derived from a seven-membered ketoester 2c, successfully afforded dienamides 36c and 36d (Table 6, entries 3 and 4). The structure of tricylic lactam 36d was confirmed by X-ray crystallography.¹⁶

Table 6.

Au-Catalyzed Cycloisomerizations of Enyne-Containing 2-Pyrrolidinones

Entry	Ketoester	R1	Enyne	Yield, %	Product	Yield, %a	drb
1		H	35a	100		100	>95:5
2		Ph	35b	100		100	>95:5
3		H	35c	72		72	>95:5
4		Ph	35d	77		77	>95:5

^aYields were determined by 500 MHz ¹H NMR analysis of unpurified reaction mixtures using an internal standard. Each of the products 36 was subsequently isolated and fully characterized.

Having established synthetic access to a variety of five- and six-membered lactams 34 and 36, we next examined the preparation of a skeletally diverse chemical library using this newly uncovered enyne cycloisomerization and our previously developed automated amide synthesis protocol. Our initial studies established that chemical stability of the dienamide moiety found in 34 and 36 proved to be inadequate. Slow degradation of such compounds was observed upon their dissolution in either DMSO or MeOH. We found that this problem can be solved by partial hydrogenatation of the dienamide fragment. We next subjected five enynes shown in Figure 7A to Au-catalyzed cycloisomerization, followed by immediate heterogeneous hydrogenation (H₂, Pd/C, EtOH). This one-pot operation efficiently delivered the corresponding tricyclic lactams 37–41 (Figure 7B) as a result of chemo-selective hydrogenation of disubstituted alkenes. The structure of 38 was established by X-ray crystallography.¹⁶ Such partially hydrogenated lactams proved to be stable and were next diversified by coupling each of them with the same set of 24 amines 11 (Figure 7C), which were employed for synthesis of other libraries discussed above. This fully automated process delivered a 120-membered amide-containing library containing five heterotryclic cores (Figure 7D) with favorable distributions of molecular weight and cLogP (Figure S4 in the Supporting Information). The library was produced on a 15–20 mg scale with good efficiency and excellent chemical purity, which was established by LCMS analysis.¹⁶ Diastereomeric purity of 10 randomly selected compounds was further confirmed by ¹H NMR.¹⁶

Figure 7.

Synthesis of a 120-Membered Library of Tetrahydro-oxo-indolizines and Hexahydro-oxo-quinolizines. (A) Structures of five enamides employed for the Au-catalyzed cycloisomerization, followed by alkene hydrogenation. (B) Structures of tetrahydro-oxo-indolizines 37, 38 and 39 and hexahydro-oxo-quinolizines 40 and 41. (C) Structures of 24 amines 11 used for automated amide syntheis. (D) Final amide-containing library incorporating five skeletally diverse lactams.

CONCLUSIONS

We have described a unified strategy for efficient synthesis of four new heterocyclic libraries. The first stage of the process entailed creation of a range of skeletally diverse pyrrolidinones or piperidinones in a single-flask operation starting with readily available amines, ketoesters and unsaturated anhydrides. In the course of this investigation, we employed our Lewis acid-promoted Prins cyclization protocol for efficient fusion of pyran and piperidinone cores and developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides to provide access into a wide range of bicyclic and tricyclic dienamides. Such catalytic processes substantially expanded heterocyclic diversity of the resulting libraries. For final diversification of each library, we developed a fully automated, chromatography-free protocol for parallel amide synthesis, which was applied to prepare 1870 heterocyclic products with favorable physicochemical properties. Because of the prominent role played by the amide-bond formation in high-throughput synthesis, chemical biology, and medicinal chemistry, the development of this automation platform represents an important and enabling synthetic advance that will facilitate access to a variety of new amide-containing libraries for subsequent biomedical applications. Results of the expansion of this automation platform to other commonly employed reactions, as well as the broad biological evaluation of the four new heterocyclic libraries will be reported in due course.²³

EXPERIMENTAL PROCEDURES

General Procedure A: Synthesis of Pyrrolidinones and Piperidinones

A solution of ketoester (2 or 24, 5.0 mmol) in CHCl₃ (8.0 mL) was treated with primary amine (1 or 27, 5.0 mmol) and 4 Å molecular sieves. The reaction mixture was stirred at 70 °C. The completion of the reaction monitored by ¹H NMR spectroscopy, which typically required 12–18 h. The resulting mixture was treated with anhydrous MgSO₄, filtered, and concentrated under reduced pressure to a 20 mL volume. The resulting solution was then treated with either maleic anhydride (4, 1.1 equiv) or itaconic anhydride (5, 1.1 equiv) and stirred overnight at room temperature. The removal of the solvent under reduced pressure followed by silica gel chromatographic purification afforded pyrrolidinones (7 or 35) or piperidinones (8, 26, 28, or 34).

Pyrrolidinone-Containing Carboxylic Acid 7a (2-((3SR,3aRS)-1-Allyl-3a-(ethoxycarbonyl)-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-3-yl)acetic Acid)

Compound 7a was prepared according to general procedure A from primary amine 1a, ketoester 2a, and maleic anhydride 4: yield 661 mg, 43%; ¹H NMR (500 MHz, CDCl₃) δ 10.18 (s, 1H), 4.94 (dddd, J = 17.5, 10.3, 6.1, 5.1 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H), 4.37 (d, J = 10.4 Hz, 1H), 4.26 (t, J = 3.8 Hz, 1H), 3.53–3.45 (m, 1H), 3.40–3.28 (m, 2H), 3.15 (dd, J = 16.1, 6.1 Hz, 1H), 2.28 (dd, J = 8.5, 5.7 Hz, 1H), 2.10 (ddd, J = 17.5, 5.7, 1.0 Hz, 1H), 1.79 (dd, J = 9.5, 3.6 Hz, 1H), 1.53 (ddd, J = 17.5, 8.5, 1.0 Hz, 1H), 1.45–1.36 (m, 1H), 1.36–1.27 (m, 1H), 1.08–0.98 (m, 1H), 0.76–0.63 (m, 2H), 0.43 (t, J = 7.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5, 173.5, 171.4, 138.2, 131.4, 117.9, 102.2, 61.7, 52.2, 47.5, 43.1, 31.7, 30.6, 22.9, 19.7, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₁₆H₂₂NO₅ 308.1498, found 308.1498.

Pyrrolidinone-Containing Carboxylic Acid 7b

Compound 7b was prepared according to general procedure A from primary amine 1b, ketoester 2a, and maleic anhydride 4: yield 1259 mg, 70%; ¹H NMR (500 MHz, CDCl₃) δ 7.27–7.22 (m, 1H), 6.88–6.83 (m, 1H), 5.06 (t, J = 3.7 Hz, 1H), 4.79 (d, J = 15.2 Hz, 1H), 4.48 (d, J = 15.1 Hz, 1H), 4.12 (dq, J = 10.8, 7.1 Hz, 1H), 4.03 (dq, J = 10.8, 7.1 Hz, 1H), 3.79 (s, 2H), 3.01 (dd, J = 8.4, 5.8 Hz, 1H), 2.80 (dd, J = 16.5, 8.5 Hz, 1H), 2.59 (dt, J = 12.2, 2.9 Hz, 1H), 2.47 (dd, J = 16.5, 5.9 Hz, 1H), 2.20–2.12 (m, 1H), 2.12–2.03 (m, 1H), 1.83 (ddd, J = 14.6, 6.6, 3.6 Hz, 1H), 1.58–1.40 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.8, 173.9, 171.3, 159.1, 138.2, 129.2, 127.9, 113.9, 102.2, 61.6, 55.4, 52.1, 47.5, 43.9, 31.6, 30.6, 22.8, 19.6, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₁H₂₆NO₆ 388.1760, found 388.1753.

Pyrrolidinone-Containing Carboxylic Acid 7c

Compound 7c was prepared according to general procedure A from primary amine 1c, ketoester 2a, and maleic anhydride 4: yield 1319 mg, 50%; ¹H NMR (500 MHz, CDCl₃) δ 11.21 (s, 1H), 7.24–7.18 (m, 2H), 7.17–7.10 (m, 2H), 5.02 (t, J = 3.7 Hz, 1H), 4.15–4.02 (m, 2H), 3.85 (ddd, J = 13.7, 10.6, 6.4 Hz, 1H), 3.38 (ddd, J = 13.8, 10.5, 5.1 Hz, 1H), 2.99 (dd, J = 8.4, 5.8 Hz, 1H), 2.90–2.81 (m, 2H), 2.77 (ddd, J = 13.6, 10.5, 6.4 Hz, 1H), 2.60–2.53 (m, 1H), 2.30 (dd, J = 17.4, 8.4 Hz, 1H), 2.20 (ddd, J = 17.8, 6.6, 4.0 Hz, 1H), 2.14–2.03 (m, 1H), 1.86–1.76 (m, 1H), 1.52–1.41 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.0, 173.0, 171.3, 164.1, 138.0, 136.9, 132.2, 130.0, 128.6, 101.1, 77.4, 61.4, 52.2, 47.2, 41.3, 32.0, 31.2, 30.5, 22.7, 19.5, 14.0; MS (ESI) calcd for C₂₁H₂₄ClNO₅ 405.13 (M⁺), found 406.19 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7d

Compound 7d was prepared according to general procedure A from primary amine 1a, ketoester 2b, and maleic anhydride 4: yield 1076 mg, 65%; ¹H NMR (500 MHz, CDCl₃) δ 6.41–6.31 (m, 1H), 5.69 (ddt, J = 17.2, 10.3, 5.1 Hz, 1H), 5.25–5.12 (m, 3H), 4.20 (ddt, J = 16.3, 4.9, 1.8 Hz, 1H), 4.03 (ddt, J = 16.4, 5.0, 1.8 Hz, 1H), 3.69 (s, 3H), 3.06 (t, J = 6.9 Hz, 1H), 2.78 (dd, J = 17.0, 6.8 Hz, 1H), 2.53–2.44 (m, 1H), 2.37 (dd, J = 17.0, 7.0 Hz, 1H), 2.26–2.15 (m, 1H), 1.96–1.84 (m, 2H), 1.76–1.62 (m, 2H), 1.62–1.52 (m, 1H), 1.37–1.27 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.7, 173.3, 171.3, 142.7, 130.9, 130.2, 117.2, 105.9, 55.5, 52.3, 48.3, 42.9, 36.1, 32.1, 27.7, 27.4, 26.1; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₁₆H₂₂NO₅ 308.1498, found 308.1496.

Pyrrolidinone-Containing Carboxylic Acid 7e

Compound 7e was prepared according to general procedure A from primary amine 1b, ketoester 2b, and maleic anhydride 4: yield 1588 mg, 82%; ¹H NMR (500 MHz, CDCl₃) δ 7.21–7.14 (m, 2H), 6.89–6.81 (m, 2H), 5.20 (dd, J = 8.8, 4.4 Hz, 1H), 4.78 (d, J = 15.4 Hz, 1H), 4.55 (d, J = 15.4 Hz, 1H), 3.80 (d, J = 1.2 Hz, 3H), 3.66 (s, 3H), 3.04 (dd, J = 9.3, 4.8 Hz, 1H), 2.71 (ddd, J = 16.2, 9.3, 1.2 Hz, 1H), 2.56–2.41 (m, 2H), 2.22–2.09 (m, 1H), 1.95–1.79 (m, 2H), 1.79–1.64 (m, 2H), 1.62–1.52 (m, 1H), 1.34–1.21 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 175.6, 173.8, 171.3, 158.9, 142.5, 128.4, 127.6, 114.0, 106.3, 55.4, 55.3, 52.3, 48.4, 43.8, 36.0, 32.0, 27.6, 27.4, 26.1; MS (ESI) calcd for C₂₁H₂₆NO₆ 388.1760 (M + H), found 388.1768.

Pyrrolidinone-Containing Carboxylic Acid 7f

Compound 7f was prepared according to general procedure A from primary amine 1c, ketoester 2b, and maleic anhydride 4: yield 1766 mg, 79%; ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.24 (m, 2H), 7.20–7.14 (m, 2H), 5.22 (dd, J = 8.9, 4.4 Hz, 1H), 3.79 (ddd, J = 13.8, 9.8, 6.4 Hz, 1H), 3.70 (s, 3H), 3.56 (ddd, J = 13.8, 9.8, 5.6 Hz, 1H), 3.01 (t, J = 6.9 Hz, 1H), 2.86 (ddd, J = 13.5, 9.8, 5.6 Hz, 1H), 2.82–2.72 (m, 2H), 2.49 (ddd, J = 13.6, 4.7, 2.6 Hz, 1H), 2.35 (dd, J = 17.2, 7.2 Hz, 1H), 2.31–2.22 (m, 1H), 2.01–1.89 (m, 2H), 1.80–1.64 (m, 2H), 1.61–1.53 (m, 1H), 1.37–1.26 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 173.1, 171.3, 142.7, 136.8, 132.5, 130.3, 128.7, 104.9, 55.5, 52.3, 48.2, 41.6, 36.1, 32.1, 31.7, 27.7, 27.4, 26.1; MS (ESI) calcd for C₂₁H₂₄ClNO₅ 405.13 (M⁺), found 406.23 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7g

Compound 7g was prepared according to general procedure A from primary amine 1a, ketoester 2c, and maleic anhydride 4: yield 838 mg, 65%; ¹H NMR (500 MHz, CDCl₃) δ 5.74–5.64 (m, 1H), 5.22–5.11 (m, 2H), 4.89–4.79 (m, 1H), 4.22–4.10 (m, 4H), 3.02 (t, J = 7.0 Hz, 1H), 2.87–2.77 (m, 1H), 2.62–2.51 (m, 1H), 2.40 (dd, J = 16.9, 7.3 Hz, 1H), 2.10–2.00 (m, 1H), 2.00–1.86 (m, 1H), 1.76–1.61 (m, 2H), 1.61–1.49 (m, 3H), 1.48–1.30 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 173.5, 171.4, 140.5, 130.7, 117.1, 104.0, 61.7, 53.9, 48.2, 42.8, 39.5, 32.8, 27.9, 26.1, 23.1, 22.7, 14.1; MS (ESI) calcd for C₁₈H₂₅NO₅ 335.17 (M⁺), found 336.33 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7h

Compound 7h was prepared according to general procedure A from primary amine 1b, ketoester 2c, and maleic anhydride 4: yield 1641 mg, 87%; ¹H NMR (500 MHz, CDCl₃) δ 7.12 (dd, J = 8.4, 1.5 Hz, 2H), 6.85–6.78 (m, 2H), 4.85–4.73 (m, 1H), 4.66 (s, 2H), 4.21–4.05 (m, 2H), 3.76 (s, 3H), 3.08 (t, J = 7.0 Hz, 1H), 2.89 (dd, J = 16.9, 6.5 Hz, 1H), 2.57 (dd, J = 12.9, 6.6 Hz, 1H), 2.49–2.40 (m, 1H), 2.01–1.84 (m, 2H), 1.73–1.62 (m, 1H), 1.61–1.42 (m, 3H), 1.35–1.23 (m, 1H), 1.23–1.15 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5, 173.8, 171.3, 158.9, 140.3, 128.2, 127.5, 114.0, 104.5, 61.6, 55.3, 53.9, 48.2, 43.6, 39.3, 32.8, 27.8, 25.8, 23.0, 22.6, 14.0; MS (ESI) calcd for C₂₃H₂₉NO₆ 415.20 (M⁺), found 416.29 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7i

Compound 7i was prepared according to general procedure A from primary amine 1c, ketoester 2c, and maleic anhydride 4: yield 1519 mg, 70%; ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.23 (m, 2H), 7.19–7.11 (m, 2H), 4.88 (dd, J = 10.6, 7.7 Hz, 1H), 4.23–4.14 (m, 2H), 3.79–3.66 (m, 2H), 2.94 (t, J = 7.0 Hz, 1H), 2.84 (t, J = 7.6 Hz, 2H), 2.77 (dd, J = 16.9, 6.7 Hz, 1H), 2.57 (dd, J = 13.1, 6.2 Hz, 1H), 2.37 (dd, J = 16.9, 7.2 Hz, 1H), 2.15–2.06 (m, 1H), 2.04–1.93 (m, 1H), 1.76–1.64 (m, 3H), 1.64–1.49 (m, 3H), 1.48–1.38 (m, 1H), 1.37–1.29 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5, 173.4, 171.4, 140.7, 136.7, 132.6, 130.3, 128.8, 103.0, 61.7, 54.0, 48.1, 41.6, 39.7, 32.8, 31.8, 27.9, 26.0, 23.1, 22.6, 14.1; MS (ESI) calcd for C₂₃H₂₈ClNO₅ 433.17 (M⁺), found 434.24 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8a (2-((3RS,4aSR)-1-(3,4-Dimethoxyphenethyl)-4a-(ethoxycarbonyl)-2-oxo-2,3,4,4a,5,6-hexahydro-1H-cyclopenta[b]pyridin-3-yl)acetic Acid)

Compound 8a (1.59 g, 55%) was obtained according to general procedure A. ¹H NMR (500 MHz, CDCl₃) δ 6.77 (m, 3H), 5.11 (t, J = 2.5 Hz, 1H), 4.15 (m, 2H), 3.95 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.68 (m, 1H), 2.79 (m, 4H), 2.67 (m, 1H), 2.50 (m, 2H), 2.34 (m, 2H), 1.86 (dt, J = 12.8, 9.3 Hz, 1H), 1.69 (t, J = 12.8 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 173.9, 169.7, 149.0, 147.7, 140.9, 131.5, 120.7, 112.2, 111.4, 106.8, 61.5, 56.0, 56.0, 54.4, 46.0, 36.9, 36.7, 36.4, 35.7, 32.3, 29.0, 14.2; MS (ESI) calcd for C₂₃H₂₉NO₇ 431.2 (M⁺), found 414.3 (M – OH)⁺, 432.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8b

Compound 8b (1.12 g, 51%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 5.42 (m, 1H), 5.32 (dd, J = 5.1, 2.8 Hz, 1H), 4.14 (m, 2H), 3.82 (m, 1H), 3.70 (m, 1H), 2.77 (dd, J = 16.2, 6.9 Hz, 1H), 2.67 (m, 1H), 2.52 (dd, J = 16.2, 4.9 Hz, 1H), 2.32 (dd, J = 13.0, 5.7 Hz, 1H), 2.25 (m, 3H), 2.14 (m, 1H), 2.05 (m, 1H), 1.95 (m, 5H), 1.68 (m, 1H), 1.58 (m, 3H), 1.50 (m, 4H), 1.37 (m, 1H), 1.27 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.3, 173.9, 170.3, 135.8, 135.2, 122.7, 108.1, 61.7, 46.4, 43.2, 37.5, 36.8, 36.1, 34.9, 34.8, 28.6, 25.3, 24.5, 22.9, 22.4, 18.6, 14.3; MS (ESI) calcd for C₂₂H₃₁NO₅ 389.2 (M⁺), found 372.3 (M – OH)⁺, 390.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8c

Compound 8c (814 mg, 37%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 7.29 (m, 2H), 7.20 (m, 1H), 7.14 (d, J = 6.7 Hz, 2H), 5.42 (t, J = 7.0 Hz, 1H), 5.17 (d, J = 16.0 Hz, 1H), 4.75 (d, J = 16.1 Hz, 1H), 3.77 (s, 3H), 2.84 (m, 2H), 2.62 (m, 1H), 2.15 (dd, J = 13.2, 4.1 Hz, 1H), 2.05 (m, 2H), 1.93 (m, 2H), 1.69 (m, 3H), 1.57 (m, 1H), 1.24 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 174.2, 171.1, 140.6, 137.3, 128.6, 126.8, 126.4, 116.1, 52.6, 51.6, 49.5, 39.5, 36.6, 35.6, 35.6, 26.3, 25.3, 24.8; MS (ESI) calcd for C₂₁H₂₅NO₅ 371.2 (M⁺), found 354.2 (M – OH)⁺, 372.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8d

Compound 8b (582 mg, 57%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 7.33 (dd, J = 1.7, 0.8 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 5.51 (t, J = 4.1 Hz, 1H), 5.28 (d, J = 15.8 Hz, 1H), 4.57 (d, J = 15.8 Hz, 1H), 3.65 (s, 3H), 2.77 (dd, J = 16.3, 7.5 Hz, 1H), 2.63 (m, 2H), 2.28 (dd, J = 12.9, 5.7 Hz, 1H), 2.22 (d, J = 13.6 Hz, 1H), 2.00 (d, J = 4.1 Hz, 2H), 1.69 (t, J = 12.9 Hz, 1H), 1.43 (d, J = 13.6 Hz, 1H), 0.97 (s, 3H), 0.83 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.1, 174.8, 170.6, 150.8, 141.7, 135.6, 110.7, 109.3, 108.3, 52.8, 47.2, 45.6, 42.6, 38.8, 38.7, 37.3, 36.0, 31.7, 28.7, 25.3; MS (ESI) calcd for C₂₀H₂₅NO₆ 375.2 (M⁺), found 358.2 (M – OH)⁺, 376.2 (M + H)⁺, 398.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8e

Compound 8e was prepared according to general procedure A from primary amine 1d, ketoester 2d, and itaconic anhydride 5: yield 1144 mg, 63%; ¹H NMR (500 MHz, CDCl₃) δ 5.04 (s, 1H), 4.13 (m, 2H), 3.79 (m, 1H), 3.42 (m, 1H), 2.77 (m, 2H), 2.61 (m, 1H), 2.50 (dd, J = 12.6, 5.2 Hz, 1H), 2.43 (dd, J = 16.1, 9.3 Hz, 1H), 2.31 (dd, J = 12.7, 7.4 Hz, 2H), 1.82 (dt, J = 12.8, 9.2 Hz, 1H), 1.64 (t, J = 12.7 Hz, 1H), 1.53 (m, 2H), 1.21 (m, 15H), 0.83 (t, J = 6.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 174.0, 169.9, 140.9, 107.1, 61.5, 54.3, 44.2, 36.9, 36.9, 36.4, 35.9, 31.9, 29.4, 29.3, 29.0, 27.1, 26.5, 22.7, 14.2, 14.2, 14.2; MS (ESI) calcd for C₂₁H₃₃NO₅ 379.2 (M⁺), found 362.3 (M – OH)⁺, 380.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8f

Compound 8f was prepared according to general procedure A from primary amine 1e, ketoester 2d, and itaconic anhydride 5: yield 626 mg, 55%; ¹H NMR (500 MHz, CDCl₃) δ 7.25 (m, 5H), 5.00 (m, 2H), 4.84 (m, 1H), 4.14 (m, 2H), 2.91 (m, 2H), 2.81 (m, 1H), 2.56 (dd, J = 12.9, 5.8 Hz, 1H), 2.36 (m, 2H), 2.26 (m, 1H), 1.85 (m, 2H), 1.19 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 174.1, 170.2, 141.2, 136.7, 128.4, 127.0, 126.9, 108.2, 61.5, 54.4, 54.4, 47.9, 36.9, 36.5, 36.4, 35.5, 29.0, 14.2, 14.1; MS (ESI) calcd for C₂₀H₂₃NO₅ 357.2 (M⁺), found 340.2 (M – OH)⁺, 358.2 (M + H)⁺, 380.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8g

Compound 8g was prepared according to general procedure A from primary amine 1f, ketoester 2d, and itaconic anhydride 5: yield 855 mg, 55%; ¹H NMR (500 MHz, CDCl₃) δ 6.74 (m, 3H), 5.91 (s, 2H), 5.06 (dd, J = 3.2, 1.8 Hz, 1H), 4.81 (m, 2H), 4.14 (m, 2H), 2.92 (dq, J = 12.8, 5.6 Hz, 1H), 2.81 (dd, J = 5.6, 1.6 Hz, 2H), 2.55 (dd, J = 12.7, 5.6 Hz, 1H), 2.33 (m, 3H), 1.83 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.5, 174.0, 170.4, 147.9, 146.7, 141.2, 130.6, 120.5, 108.4, 108.3, 107.8, 101.1, 61.6, 54.5, 47.7, 37.0, 36.6, 36.6, 35.8, 29.1, 14.2; MS (ESI) calcd for C₂₁H₂₃NO₇ 401.1 (M⁺), found 402.2 (M + H)⁺, 424.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8h

Compound 8h was prepared according to general procedure A from primary amine 1g, ketoester 2d, and itaconic anhydride 5: yield 705 mg, 42%; ¹H NMR (500 MHz, CDCl₃) δ 7.32 (dd, J = 1.8, 0.9 Hz, 1H), 6.28 (m, 1H), 5.27 (t, J = 2.5 Hz, 1H), 4.92 (m, 1H), 4.81 (m, 1H), 4.12 (m, 2H), 2.90 (m, 1H), 2.81 (m, 1H), 2.70 (m, 1H), 2.54 (dd, J = 12.7, 5.6 Hz, 1H), 2.46 (m, 1H), 2.34 (m, 2H), 1.86 (dt, J = 13.2, 9.2 Hz, 1H), 1.71 (t, J = 12.8 Hz, 1H), 1.18 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.0, 173.9, 170.3, 150.2, 141.9, 140.9, 110.6, 108.4, 108.3, 61.6, 54.5, 41.2, 37.0, 36.9, 36.5, 35.9, 29.2, 14.2; MS (ESI) calcd for C₁₈H₂₁NO₆ 347.1 (M⁺), found 330.2 (M – OH)⁺, 348.2 (M + H)⁺, 370.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8i

Compound 8i was prepared according to general procedure A from primary amine 1h, ketoester 2d, and itaconic anhydride 5: yield 571 mg, 47%; ¹H NMR (500 MHz, CDCl₃) δ 5.41 (t, J = 3.4 Hz, 1H), 5.10 (t, J = 2.4 Hz, 1H), 4.14 (m, 2H), 3.82 (m, 1H), 3.59 (m, 1H), 2.80 (m, 2H), 2.60 (m, 1H), 2.52 (dd, J = 12.3, 5.4 Hz, 1H), 2.46 (m, 1H), 2.34 (m, 2H), 2.19 (m, 1H), 2.11 (m, 1H), 1.95 (m, 4H), 1.85 (dt, J = 12.6, 9.3 Hz, 1H), 1.65 (m, 1H), 1.59 (m, 2H), 1.52 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.5, 173.9, 169.9, 140.8, 135.0, 122.9, 107.1, 61.5, 54.3, 43.2, 37.1, 37.0, 36.4, 35.9, 34.6, 29.0, 28.5, 25.3, 23.0, 22.4, 14.2; MS (ESI) calcd for C₂₁H₂₉NO₅ 375.2 (M⁺), found 358.3 (M – OH)⁺, 376.3 (M + H)⁺, 398.3 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8j

Compound 8j was prepared according to general procedure A from primary amine 1j, ketoester 2d, and itaconic anhydride 5: yield 1277 mg, 49%; ¹H NMR (500 MHz, CDCl₃) δ 7.98 (m, 2H), 7.87 (m, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.7 Hz, 1H), 7.49 (td, J = 8.6, 6.9, 1.5 Hz, 1H), 7.35 (d, J = 7.0 Hz, 1H), 5.48 (d, J = 16.4 Hz, 1H), 5.36 (d, J = 16.1 Hz, 1H), 4.87 (dd, J = 3.2, 1.6 Hz, 1H), 4.23 (m, 2H), 4.14 (m, 1H), 3.01 (m, 2H), 2.83 (dd, J = 16.8, 3.9 Hz, 1H), 2.63 (dd, J = 12.7, 5.4 Hz, 1H), 2.36 (m, 2H), 2.22 (m, 1H), 1.95 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 174.2, 170.3, 141.3, 133.7, 130.8, 130.8, 128.9, 127.4, 126.1, 125.6, 125.5, 122.9, 122.5, 108.6, 61.5, 54.5, 45.9, 37.0, 36.6, 36.2, 35.5, 28.9, 14.2; MS (ESI) calcd for C₂₄H₂₅NO₅ 407.2 (M⁺), found 390.2 (M – OH)⁺, 408.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8k

Compound 8k was prepared according to general procedure A from primary amine 1k, ketoester 2d, and itaconic anhydride 5: yield 568 mg, 35%; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 1.9 Hz, 1H), 7.16 (m, 2H), 5.01 (d, J = 16.9 Hz, 1H), 4.86 (d, J = 16.9 Hz, 2H), 4.20 (m, 2H), 2.98 (dd, J = 17.4, 5.3 Hz, 1H), 2.91 (m, 1H), 2.76 (dd, J = 17.0, 4.4 Hz, 1H), 2.56 (dd, J = 12.7, 5.5 Hz, 1H), 2.37 (m, 2H), 2.26 (m, 1H), 1.91 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.6, 174.1, 170.2, 141.0, 133.3, 133.2, 132.4, 129.2, 128.4, 127.4, 108.3, 61.7, 54.5, 45.4, 37.1, 36.5, 36.0, 35.4, 29.0, 14.3; MS (ESI) calcd for C₂₀H₂₁Cl₂NO₅ 425.1 (M⁺), found 408.2 (M – OH)⁺, 426.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8l

Compound 8l was prepared according to general procedure A from primary amine 1d, ketoester 2a, and itaconic anhydride 5: yield 1018 mg, 88%; ¹H NMR (500 MHz, CDCl₃) δ 5.25 (dd, J = 5.2, 2.8 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 2.76 (dd, J = 16.3, 6.1 Hz, 1H), 2.66 (dq, J = 11.9, 5.8 Hz, 3H), 2.52 (dd, J = 16.3, 5.6 Hz, 1H), 2.30 (dd, J = 12.9, 5.7 Hz, 1H), 2.22 (m, 2H), 2.12 (m, 1H), 1.65 (m, 1H), 1.55 (t, J = 13.0 Hz, 1H), 1.46 (m, 2H), 1.34 (m, 1H), 1.24 (m, 12H), 1.18 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 6.9 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 173.9, 169.9, 135.9, 107.8, 61.5, 46.3, 44.0, 37.2, 36.6, 36.1, 34.9, 31.8, 29.3, 29.3, 27.1, 26.7, 24.4, 22.6, 18.5, 14.2, 14.1; MS (ESI) calcd for C₂₂H₃₅NO₅ 393.3 (M⁺), found 376.3 (M –OH)⁺, 394.3 (M + H)⁺, 416.3 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8m

Compound 8m was prepared according to general procedure A from primary amine 1e, ketoester 2a, and itaconic anhydride 5: yield 858 mg, 79%; ¹H NMR (500 MHz, CDCl₃) δ 7.30 (m, 2H), 7.21 (m, 3H), 5.39 (d, J = 16.0 Hz, 1H), 5.21 (dd, J = 5.2, 2.8 Hz, 1H), 4.55 (d, J = 16.0 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.47 (s, 1H), 2.81 (m, 3H), 2.40 (m, 1H), 2.27 (dt, J = 12.9, 3.4 Hz, 1H), 2.15 (m, 1H), 2.04 (m, 1H), 1.81 (t, J = 12.8 Hz, 1H), 1.66 (m, 1H), 1.52 (td, J = 13.6, 13.2, 2.8 Hz, 1H), 1.37 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 174.2, 170.4, 137.4, 136.9, 128.6, 128.5, 126.7, 126.2, 109.1, 61.6, 48.9, 46.6, 36.5, 36.4, 36.3, 34.8, 24.2, 18.5, 14.3; MS (ESI) calcd for C₂₁H₂₅NO₅ 371.2 (M⁺), found 354.2 (M – OH)⁺, 372.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8n

Compound 8n was prepared according to general procedure A from primary amine 1f, ketoester 2a, and itaconic anhydride 5: yield 1014 mg, 83%; ¹H NMR (500 MHz, CDCl₃) δ 6.69 (m, 3H), 5.89 (s, 2H), 5.22 (m, 2H), 4.47 (d, J = 15.8 Hz, 1H), 4.16 (m, 2H), 2.78 (m, 3H), 2.36 (dd, J = 12.9, 5.5 Hz, 1H), 2.25 (dt, J = 13.1, 3.3 Hz, 1H), 2.14 (m, 1H), 2.05 (m, 1H), 1.79 (t, J = 13.0 Hz, 1H), 1.64 (dd, J = 14.0, 5.2 Hz, 1H), 1.50 (td, J = 13.6, 13.1, 2.8 Hz, 1H), 1.36 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 174.2, 170.3, 147.9, 146.4, 136.8, 131.3, 119.4, 109.0, 108.3, 107.1, 100.9, 61.6, 48.5, 46.6, 36.5, 36.4, 36.3, 34.8, 24.3, 18.5, 14.3; MS (ESI) calcd for C₂₂H₂₅NO₇ 415.2 (M⁺), found 398.2 (M – OH)⁺, 416.3 (M + H)⁺, 438.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8o

Compound 8o was prepared according to general procedure A from primary amine 1g, ketoester 2a, and itaconic anhydride 5: yield 583 mg, 55%; ¹H NMR (500 MHz, CDCl₃) δ 7.31 (m, 1H), 6.27 (m, 2H), 5.51 (dd, J = 5.2, 2.8 Hz, 1H), 5.24 (d, J = 15.8 Hz, 1H), 4.54 (d, J = 15.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.82 (dd, J = 16.1, 5.8 Hz, 1H), 2.75 (dq, J = 12.9, 5.6 Hz, 1H), 2.65 (dd, J = 16.1, 5.3 Hz, 1H), 2.37 (dd, J = 13.0, 5.7 Hz, 1H), 2.25 (m, 2H), 2.13 (m, 1H), 1.66 (m, 2H), 1.50 (td, J = 13.6, 13.1, 2.6 Hz, 1H), 1.38 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.2, 174.0, 170.2, 150.9, 141.6, 136.7, 110.6, 109.0, 108.0, 61.7, 46.6, 42.2, 37.0, 36.7, 36.2, 34.9, 24.4, 18.6, 14.3; MS (ESI) calcd for C₁₉H₂₃NO₆ 361.2 (M⁺), found 344.2 (M – OH)⁺, 362.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8p

Compound 8p was prepared according to general procedure A from primary amine 1i, ketoester 2a, and itaconic anhydride 5: yield 914 mg, 58%; ¹H NMR (500 MHz, CDCl₃) δ 6.76 (m, 3H), 5.33 (dd, J = 5.2, 2.8 Hz, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.86 (m, 2H), 3.84 (s, 4H), 3.81 (s, 3H), 2.85 (m, 1H), 2.76 (dd, J = 16.0, 5.7 Hz, 1H), 2.69 (m, 2H), 2.62 (dd, J = 16.1, 5.6 Hz, 1H), 2.32 (dd, J = 13.0, 5.6 Hz, 1H), 2.25 (m, 2H), 2.14 (m, 1H), 1.67 (m, 1H), 1.61 (t, J = 12.8 Hz, 1H), 1.48 (td, J = 13.4, 12.9, 2.6 Hz, 1H), 1.38 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 173.9, 169.8, 148.9, 147.5, 135.9, 131.7, 120.5, 112.1, 111.3, 107.6, 61.5, 55.9, 55.9, 46.4, 45.6, 36.8, 36.4, 36.1, 34.8, 32.4, 24.4, 18.5, 14.2; MS (ESI) calcd for C₂₄H₃₁NO₇ 445.2 (M⁺), found 428.3 (M – OH)⁺, 446.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8q

Compound 8q was prepared according to general procedure A from primary amine 1j, ketoester 2a, and itaconic anhydride 5: 1040 mg, 84%; ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J = 8.2 Hz, 1H), 7.88 (m, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.51 (m, 3H), 7.33 (d, J = 7.1 Hz, 1H), 5.90 (d, J = 16.7 Hz, 1H), 5.07 (dd, J = 5.1, 2.9 Hz, 1H), 5.02 (d, J = 16.7 Hz, 1H), 4.25 (m, 2H), 3.03 (dd, J = 16.6, 5.1 Hz, 1H), 2.85 (m, 2H), 2.47 (dd, J = 12.9, 5.4 Hz, 1H), 2.31 (dt, J = 13.3, 3.3 Hz, 1H), 2.03 (m, 3H), 1.66 (m, 1H), 1.58 (td, J = 13.5, 2.8 Hz, 1H), 1.40 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.1, 174.2, 170.1, 137.0, 133.6, 131.3, 130.3, 128.8, 127.1, 125.9, 125.7, 125.5, 122.4, 122.4, 109.1, 61.6, 47.4, 46.7, 36.3, 36.2, 36.1, 34.7, 24.1, 18.5, 14.3; MS (ESI) calcd for C₂₅H₂₇NO₅ 421.2 (M⁺), found 404.3 (M – OH)⁺, 422.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8r

Compound 8r was prepared according to general procedure A from primary amine 1k, ketoester 2a, and itaconic anhydride 5: yield 861 mg, 67%; ¹H NMR (500 MHz, CDCl₃) δ 7.32 (s, 1H), 7.13 (m, 2H), 5.26 (d, J = 17.1 Hz, 1H), 4.91 (dd, J = 5.1, 2.8 Hz, 1H), 4.56 (d, J = 17.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.00 (dd, J = 16.9, 5.1 Hz, 1H), 2.69 (m, 2H), 2.35 (dd, J = 12.9, 5.6 Hz, 1H), 2.25 (dt, J = 13.2, 3.2 Hz, 1H), 2.11 (m, 1H), 2.00 (m, 1H), 1.90 (t, J = 12.9 Hz, 1H), 1.64 (m, 1H), 1.51 (td, J = 13.7, 2.8 Hz, 1H), 1.34 (m, 1H), 1.24 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 174.2, 170.3, 136.7, 133.0, 133.0, 132.7, 129.1, 128.3, 127.4, 109.0, 61.8, 46.8, 46.8, 36.2, 36.1, 35.8, 34.8, 24.2, 18.5, 14.4; MS (ESI) calcd for C₂₁H₂₃Cl₂NO₅ 439.1 (M⁺), found 422.2 (M – OH)⁺, 440.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8s

Compound 8s was prepared according to general procedure A from primary amine 1d, ketoester 2b, and itaconic anhydride 5: yield 443 mg, 38%; ¹H NMR (500 MHz, CDCl₃) δ 5.54 (t, J = 7.1 Hz, 1H), 3.76 (s, 4H), 3.60 (m, 1H), 2.80 (dd, J = 16.1, 7.5 Hz, 1H), 2.70 (m, 1H), 2.40 (dd, J = 16.1, 5.1 Hz, 1H), 2.23 (m, 1H), 2.05 (m, 3H), 1.79 (m, 1H), 1.70 (m, 4H), 1.56 (m, 2H), 1.40 (m, 1H), 1.26 (m, 11H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.3, 174.1, 171.3, 140.3, 115.1, 52.7, 51.6, 51.6, 45.5, 40.0, 37.0, 36.6, 35.6, 31.9, 29.4, 29.4, 27.1, 26.9, 26.5, 25.5, 25.0, 22.8, 14.2; MS (ESI) calcd for C₂₂H₃₅NO₅ 393.3 (M⁺), found 376.3 (M – OH)⁺, 394.4 (M + H)⁺, 416.4 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8t

Compound 8t was prepared according to general procedure A from primary amine 1f, ketoester 2b, and itaconic anhydride 5: yield 595 mg, 33%; ¹H NMR (500 MHz, CDCl₃) δ 6.74 (d, J = 7.9 Hz, 1H), 6.64 (d, J = 1.7 Hz, 1H), 6.62 (dd, J = 8.0, 1.8 Hz, 1H), 5.92 (d, J = 1.7 Hz, 2H), 5.46 (t, J = 7.0 Hz, 1H), 5.04 (d, J = 15.8 Hz, 1H), 4.69 (d, J = 15.8 Hz, 1H), 3.77 (s, 3H), 2.88–2.76 (m, 2H), 2.63–2.56 (m, 1H), 2.19–2.07 (m, 2H), 2.07–2.00 (m, 1H), 2.00–1.92 (m, 1H), 1.88 (t, J = 13.2 Hz, 1H), 1.78–1.54 (m, 4H), 1.33–1.23 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 174.2, 171.3, 148.0, 146.5, 140.6, 131.2, 119.6, 116.2, 108.4, 107.1, 101.0, 52.7, 51.6, 49.4, 39.6, 36.7, 35.9, 35.6, 26.3, 25.3, 24.9; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₂H₂₆NO₇ 416.1709, found 416.1714.

Piperidinone-Containing Carboxylic Acid 8u

Compound 8u was prepared according to general procedure A from primary amine 1g, ketoester 2b, and itaconic anhydride 5: yield 452 mg, 28%; ¹H NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 1.7, 0.9 Hz, 1H), 6.28 (dd, J = 3.1, 1.8 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 5.68 (t, J = 7.1 Hz, 1H), 5.08 (d, J = 15.9 Hz, 1H), 4.69 (d, J = 15.9 Hz, 1H), 3.74 (s, 3H), 2.86 (dd, J = 16.7, 6.0 Hz, 1H), 2.76 (dt, J = 6.8, 4.4 Hz, 1H), 2.48 (dd, J = 16.7, 6.4 Hz, 1H), 2.17 (m, 1H), 2.11 (dd, J = 13.2, 4.4 Hz, 1H), 2.00 (m, 2H), 1.78 (m, 2H), 1.64 (m, 2H), 1.27 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 174.1, 171.0, 150.8, 141.5, 140.5, 116.3, 110.5, 108.1, 52.6, 51.8, 42.9, 39.5, 36.6, 35.6, 35.6, 26.4, 25.3, 24.9; MS (ESI) calcd for C₁₉H₂₃NO₆ 361.2 (M⁺), found 344.2 (M – OH)⁺, 362.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8v

Compound 8v was prepared according to general procedure A from primary amine 1h, ketoester 2b, and itaconic anhydride 5: yield 438 mg, 38%; ¹H NMR (500 MHz, CDCl₃) δ 5.54 (t, J = 7.2 Hz, 3H), 5.39 (m, 3H), 3.98 (m, 3H), 3.74 (s, 9H), 3.60 (m, 3H), 2.80 (dd, J = 16.3, 6.9 Hz, 3H), 2.68 (m, 3H), 2.37 (dd, J = 16.3, 5.7 Hz, 3H), 2.19 (m, 9H), 2.03 (m, 9H), 1.95 (m, 13H), 1.79 (m, 3H), 1.68 (m, 13H), 1.57 (m, 6H), 1.50 (m, 6H), 1.36 (m, 2H), 1.23 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 174.1, 171.1, 140.2, 135.0, 123.0, 114.9, 52.6, 51.6, 43.3, 39.7, 37.0, 36.2, 35.5, 34.8, 28.4, 26.8, 25.6, 25.3, 25.0, 22.9, 22.4; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₂H₃₂NO₅ 390.2280, found 390.2280.

Piperidinone-Containing Carboxylic Acid 8w

Compound 8w was prepared according to general procedure A from primary amine 1i, ketoester 2b, and itaconic anhydride 5: yield 1090 mg, 42%; ¹H NMR (500 MHz, CDCl₃) δ 6.77 (m, 3H), 5.64 (t, J = 7.2 Hz, 1H), 4.06 (m, 1H), 3.88 (s, 3H), 3.85 (s, 4H), 3.76 (s, 3H), 2.85 (dt, J = 9.4, 5.6 Hz, 2H), 2.78 (dd, J = 16.4, 7.1 Hz, 1H), 2.72 (dt, J = 12.6, 6.0 Hz, 1H), 2.40 (dd, J = 15.9, 4.8 Hz, 1H), 2.26 (m, 1H), 2.05 (m, 3H), 1.80 (m, 1H), 1.67 (m, 3H), 1.60 (t, J = 13.3 Hz, 1H), 1.39 (m, 1H), 1.24 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 174.0, 170.8, 148.8, 147.5, 140.4, 131.3, 120.6, 114.6, 112.0, 111.2, 77.4, 77.2, 76.9, 55.9, 52.5, 51.5, 46.1, 39.4, 36.7, 35.6, 35.5, 32.4, 26.6, 25.5, 24.9; MS (ESI) calcd for C₂₄H₃₁NO₇ 445.2 (M⁺), found 428.2 (M – OH)⁺, 446.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8x

Compound 8x was prepared according to general procedure A from primary amine 1j, ketoester 2b, and itaconic anhydride 5: yield 791 mg, 32%; ¹H NMR (500 MHz, CDCl₃) δ 7.94 (d, J = 8.3 Hz, 1H), 7.88 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.52 (m, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 5.56 (d, J = 16.4 Hz, 1H), 5.36 (t, J = 7.0 Hz, 1H), 5.27 (d, J = 16.6 Hz, 1H), 3.81 (s, 3H), 2.89 (m, 2H), 2.71 (m, 1H), 2.20 (dd, J = 13.2, 4.2 Hz, 1H), 2.03 (m, 3H), 1.89 (m, 1H), 1.69 (m, 3H), 1.57 (m, 1H), 1.24 (m, 1H); MS (ESI) calcd for C₂₅H₂₇NO₅ 421.2 (M⁺), found 404.3 (M – OH)⁺, 422.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8y

Compound 8y was prepared according to general procedure A from primary amine 1k, ketoester 2b, and itaconic anhydride 5: yield 1118 mg, 46%; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.4, 2.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.18 (t, J = 6.9 Hz, 1H), 4.98 (d, J = 17.2 Hz, 1H), 4.86 (d, J = 17.0 Hz, 1H), 3.79 (s, 3H), 2.77 (m, 3H), 2.11 (m, 3H), 1.98 (m, 2H), 1.80 (m, 2H), 1.63 (m, 2H), 1.34 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.0, 174.2, 170.8, 140.8, 133.1, 133.0, 129.2, 128.3, 127.5, 115.4, 52.8, 51.7, 47.9, 39.2, 36.9, 35.6, 35.3, 26.1, 25.3, 24.9; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₁H₂₄Cl₂NO₅ 440.1032, found 440.1037.

Piperidinone-Containing Carboxylic Acid 8z

Compound 8z was prepared according to general procedure A from primary amine 1d, ketoester 2e, and itaconic anhydride 5: yield 479 mg, 41%; ¹H NMR (500 MHz, CDCl₃) δ 5.19 (t, J = 4.1 Hz, 1H), 3.66 (m, 2H), 3.61 (s, 3H), 2.70 (m, 1H), 2.53 (m, 2H), 2.19 (m, 2H), 1.97 (d, J = 4.1 Hz, 2H), 1.59 (m, 2H), 1.47 (m, 1H), 1.38 (d, J = 13.7 Hz, 1H), 1.23 (m, 11H), 0.92 (s, 3H), 0.82 (t, J = 6.7 Hz, 3H), 0.79 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.6, 175.1, 169.8, 134.9, 107.4, 52.4, 47.2, 45.3, 44.5, 38.7, 38.4, 37.1, 35.9, 31.8, 31.6, 29.3, 29.3, 28.5, 27.2, 26.7, 25.3, 22.6, 14.1, 14.1; MS (ESI) calcd for C₂₃H₃₇NO₅ 407.3 (M⁺), found 390.3 (M – OH)⁺, 408.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8aa

Compound 8aa was prepared according to general procedure A from primary amine 1e, ketoester 2e, and itaconic anhydride 5: yield 474 mg, 76%; ¹H NMR (500 MHz, CDCl₃) δ 7.30 (m, 2H), 7.22 (m, 3H), 5.50 (d, J = 16.1 Hz, 1H), 5.14 (t, J = 4.1 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 3.67 (s, 3H), 2.90 (m, 1H), 2.74 (dd, J = 17.0, 5.2 Hz, 1H), 2.63 (dt, J = 18.5, 5.4 Hz, 1H), 2.29 (dd, J = 12.8, 5.8 Hz, 1H), 2.22 (d, J = 13.5 Hz, 1H), 1.88 (m, 3H), 1.46 (d, J = 13.6 Hz, 1H), 0.94 (s, 3H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.5, 175.4, 170.3, 137.5, 137.5, 136.0, 128.6, 126.8, 126.3, 108.8, 52.6, 49.5, 47.2, 45.6, 38.6, 38.3, 36.5, 36.1, 31.7, 28.6, 25.4; MS (ESI) calcd for C₂₂H₂₇NO₅ 385.2 (M⁺), found 368.2 (M – OH)⁺, 386.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8ab

Compound 8ab was prepared according to general procedure A from primary amine 1f, ketoester 2e, and itaconic anhydride 5: yield 890 mg, 76%; ¹H NMR (500 MHz, CDCl₃) δ 7.26 (s, 1H), 6.74 (m, 2H), 6.69 (m, 1H), 5.92 (d, J = 1.8 Hz, 2H), 5.34 (d, J = 15.8 Hz, 1H), 5.19 (m, 1H), 4.45 (dd, J = 15.7, 3.4 Hz, 1H), 3.67 (s, 3H), 2.82 (m, 1H), 2.74 (m, 1H), 2.63 (dt, J = 13.1, 5.5 Hz, 1H), 2.28 (dd, J = 12.8, 5.8 Hz, 1H), 2.22 (d, J = 13.6 Hz, 1H), 1.91 (t, J = 3.0 Hz, 2H), 1.82 (td, J = 13.0, 3.0 Hz, 1H), 1.44 (d, J = 13.6 Hz, 1H), 0.94 (s, 3H), 0.81 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.0, 175.4, 170.4, 147.9, 146.4, 136.0, 131.4, 119.6, 108.8, 108.4, 107.2, 101.0, 66.0, 52.6, 49.2, 47.2, 45.6, 38.7, 38.3, 36.6, 36.1, 31.7, 28.6, 25.5, 15.3; MS (ESI) calcd for C₂₃H₂₇NO₇ 429.2 (M⁺), found 412.2 (M – OH)⁺, 430.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8ac

Compound 8ac was prepared according to general procedure A from primary amine 1h, ketoester 2e, and itaconic anhydride 5: yield 420 mg, 38%; ¹H NMR (500 MHz, CDCl₃) δ 5.46 (m, 1H), 5.32 (m, 1H), 3.90 (m, 1H), 3.72 (m, 1H), 3.67 (s, 3H), 2.74 (dd, J = 15.7, 7.3 Hz, 1H), 2.53 (m, 2H), 2.31 (td, J = 12.3, 11.6, 5.6 Hz, 1H), 2.23 (m, 2H), 2.11 (m, 1H), 2.00 (m, 7H), 1.61 (m, 3H), 1.55 (m, 2H), 1.43 (d, J = 13.7 Hz, 1H), 1.21 (m, 1H), 0.97 (s, 3H), 0.84 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.3, 175.1, 170.2, 135.2, 134.9, 122.6, 107.7, 52.6, 47.2, 45.3, 43.8, 38.8, 38.5, 37.4, 35.9, 34.8, 31.7, 28.6, 28.6, 25.4, 25.3, 22.9, 22.4; MS (ESI) calcd for C₂₃H₃₃NO₅ 403.2 (M⁺), found 386.2 (M – OH)⁺, 404.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8ad

Compound 8ad was prepared according to general procedure A from primary amine 1i, ketoester 2e, and itaconic anhydride 5: yield 570 mg, 46%; ¹H NMR (500 MHz, CDCl₃) δ 6.80 (m, 3H), 5.39 (dd, J = 5.0, 3.2 Hz, 1H), 3.96 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.68 (s, 3H), 2.94 (m, 1H), 2.77 (m, 2H), 2.62 (m, 1H), 2.53 (dd, J = 16.0, 3.4 Hz, 1H), 2.26 (m, 2H), 2.06 (m, 2H), 1.63 (t, J = 13.0 Hz, 1H), 1.45 (d, J = 13.6 Hz, 1H), 1.00 (s, 3H), 0.87 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.7, 175.1, 169.8, 148.9, 147.5, 135.0, 131.8, 120.6, 112.1, 111.3, 107.4, 55.9, 55.9, 52.4, 47.1, 46.2, 45.3, 38.7, 38.2, 36.8, 35.9, 32.5, 31.6, 28.5, 25.3; MS (ESI) calcd for C₂₅H₃₃NO₇ 459.2 (M⁺), found 442.3 (M – OH)⁺, 460.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8ae

Compound 8ae was prepared according to general procedure A from primary amine 1j, ketoester 2e, and itaconic anhydride 5: yield 715 mg, 60%; ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.3 Hz, 1H), 7.88 (dd, J = 8.0, 1.5 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.53 (m, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 5.99 (d, J = 16.7 Hz, 1H), 5.03 (dd, J = 5.1, 2.9 Hz, 1H), 4.93 (d, J = 16.7 Hz, 1H), 3.74 (s, 3H), 3.05 (m, 1H), 2.73 (m, 2H), 2.36 (dd, J = 12.8, 5.6 Hz, 1H), 2.27 (dd, J = 13.7, 1.9 Hz, 1H), 2.05 (m, 1H), 1.85 (m, 2H), 1.52 (d, J = 13.7 Hz, 1H), 0.95 (s, 3H), 0.85 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.8, 175.6, 170.2, 136.3, 133.8, 131.6, 130.4, 128.9, 127.3, 126.1, 125.8, 125.6, 122.7, 122.6, 109.0, 77.4, 77.2, 76.9, 52.7, 48.3, 47.2, 45.7, 38.5, 38.3, 36.3, 36.2, 31.7, 28.6, 25.4; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₆H₃₀NO₅ 436.2124, found 436.2120.

Piperidinone-Containing Carboxylic Acid 8af

Compound 8af was prepared according to general procedure A from primary amine 1k, ketoester 2e, and itaconic anhydride 5: yield 944 mg, 77%; ¹H NMR (500 MHz, CDCl₃) δ 7.35 (d, J = 1.9 Hz, 1H), 7.15 (m, 2H), 5.41 (d, J = 17.2 Hz, 1H), 4.89 (dd, J = 4.8, 3.2 Hz, 1H), 4.49 (d, J = 17.1 Hz, 1H), 3.71 (s, 3H), 3.09 (dd, J = 17.2, 4.9 Hz, 1H), 2.60 (m, 2H), 2.25 (m, 2H), 1.98 (t, J = 13.0 Hz, 1H), 1.89 (t, J = 4.1 Hz, 2H), 1.48 (d, J = 13.7 Hz, 1H), 0.94 (s, 3H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 175.4, 170.1, 136.0, 133.2, 133.0, 132.7, 129.1, 128.3, 127.4, 108.5, 52.7, 47.6, 47.1, 45.6, 38.5, 37.9, 36.1, 35.7, 31.7, 28.6, 25.4; MS (ESI) calcd for C₂₂H₂₅Cl₂NO₅ 453.1 (M⁺), found 436.2 (M – OH)⁺, 454.2 (M + H)⁺.

Carbomethoxytetrahydropyranone 24a ((2RS,6RS)-Methyl 6-tert-Butyl-2-methyl-4-oxotetrahydro-2H-pyran-3-carboxy-late)

Compound 24a was prepared according to reported procedures:^{17 1}H NMR (500 MHz, CDCl₃) δ 3.96 (dd, J = 10.4, 6.0 Hz, 1H), 3.77 (s, 3H), 3.31 (dd, J = 11.8, 2.3 Hz, 1H), 3.17 (dd, J = 10.4, 0.7 Hz, 1H), 2.45 (dd, J = 13.9, 2.3 Hz, 1H), 2.29 (ddd, J = 13.9, 11.9, 0.9 Hz, 1H), 1.32 (d, J = 6.0 Hz, 3H), 0.93 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 203.8, 168.9, 84.4, 75.0, 64.6, 52.2, 42.2, 34.4, 25.6, 20.9; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₂₀O₄Na 251.1259, found 251.1267.

Carbomethoxytetrahydropyranone 24b

Compound 24b was prepared according to reported procedures:^{17 1}H NMR (500 MHz, CDCl₃) δ 3.97 (dq, J = 10.4, 6.0 Hz, 1H), 3.76 (s, 3H), 3.43 (ddd, J = 11.5, 7.9, 2.3 Hz, 1H), 3.19 (dd, J = 10.4, 0.8 Hz, 1H), 2.50 (dd, J = 14.2, 2.3 Hz, 1H), 2.27 (ddd, J = 14.2, 11.6, 0.9 Hz, 1H), 1.97 (q, J = 8.3 Hz, 1H), 1.87–1.81 (m, 1H), 1.69–1.51 (m, 6H), 1.45–1.40 (m, 1H), 1.32 (d, J = 6.0 Hz, 3H), 1.21–1.14 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 202.8, 168.8, 81.2, 75.0, 64.6, 52.3, 46.2, 45.5, 29.3, 28.6, 25.62, 25.43, 21.0; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₀O₄Na 263.1259, found 263.1266.

Carbomethoxytetrahydropyranone 24c

Compound 24c was prepared according to reported procedures:^{17 1}H NMR (500 MHz, CDCl₃) δ 3.76 (s, 3H), 3.39–3.33 (m, 2H), 3.33–3.27 (m, 1H), 2.46 (dd, J = 14.3, 2.3 Hz, 1H), 2.27–2.22 (m, 1H), 1.79 (dq, J = 13.4, 6.7 Hz, 1H), 0.99–0.93 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.57–0.49 (m, 2H), 0.48–0.43 (m, 1H), 0.40–0.35 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 203.1, 168.8, 81.6, 81.4, 63.9, 52.2, 44.3, 33.4, 18.5, 18.1, 15.7, 2.9, 2.1; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₀O₄Na 263.1259, found 263.1258.

Carbomethoxytetrahydropyranone 24d

Compound 24d was prepared according to reported procedures:^{17 1}H NMR (500 MHz, CDCl₃) δ 7.37–7.28 (m, 5H), 4.60 (q, J = 9.9 Hz, 2H), 4.04 (dq, J = 10.5, 6.0 Hz, 1H), 3.94–3.89 (m, 1H), 3.77 (s, 3H), 3.60–3.53 (m, 2H), 3.23 (dd, J = 10.5, 0.7 Hz, 1H), 2.53–2.41 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 202.1, 168.6, 137.8, 128.6, 127.95, 127.85, 76.1, 75.2, 73.6, 71.9, 64.3, 52.3, 43.4, 20.9; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₆H₂₀O₅Na 315.1208, found 315.1211.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26a (2-((3SR,4aRS,5RS,7RS)-1-Benzyl-7-tert-butyl-4a-(methoxycarbonyl)-5-methyl-2-oxo-2,3,4,4a,5,7-hexahydro-1H-pyrano[4,3-b]pyridin-3-yl)acetic Acid)

Compound 26a (428 mg, 82%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 7.34–7.28 (m, 1H), 7.25–7.20 (m, 1H), 5.43 (s, 1H), 5.27 (d, J = 15.5 Hz, 1H), 4.47 (d, J = 15.5 Hz, 1H), 3.84 (q, J = 6.4 Hz, 1H), 3.72 (s, 1H), 3.59 (s, 3H), 3.14–3.06 (m, 1H), 3.00 (dd, J = 17.0, 5.3 Hz, 1H), 2.78 (dd, J = 17.0, 5.2 Hz, 1H), 2.47 (dd, J = 12.6, 7.4 Hz, 1H), 1.79 (t, J = 12.6 Hz, 1H), 1.18 (d, J = 6.3 Hz, 3H), 0.73 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 176.4, 172.7, 170.9, 138.3, 137.4, 128.7, 127.2, 127.0, 111.6, 82.1, 74.6, 52.8, 51.4, 49.4, 37.5, 36.5, 34.7, 28.8, 25.5, 16.2; MS (ESI) calcd for C₂₄H₃₁NO₆ 429.2 (M⁺), found 412.2 (M – OH)⁺, 430.2 (M + H)⁺, 452.2 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26b

Compound 26b (366 mg, 74%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 5.43 (s, 1H), 5.41–5.38 (m, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.98 (q, J = 6.6 Hz, 1H), 3.82–3.72 (m, 1H), 3.67 (s, 2H), 3.64–3.55 (m, 1H), 3.02–2.91 (m, 1H), 2.75 (dd, J = 16.8, 5.9 Hz, 1H), 2.71–2.63 (m, 1H), 2.38 (dd, J = 12.8, 7.2 Hz, 1H), 2.30–2.20 (m, 1H), 2.06–1.99 (m, 1H), 1.99–1.92 (m, 5H), 1.77–1.66 (m, 2H), 1.66–1.56 (m, 5H), 1.56–1.47 (m, 4H), 1.44–1.34 (m, 1H), 1.34–1.24 (m, 1H), 1.19 (dd, J = 6.6, 2.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 172.6, 170.5, 170.5, 136.4, 135.0, 123.0, 111.0, 78.1, 74.5, 52.9, 51.3, 44.8, 43.4, 37.9, 37.9, 36.3, 34.9, 29.3, 28.7, 28.6, 28.5, 25.9, 25.8, 25.4, 23.0, 22.4, 16.6; MS (ESI) calcd for C₂₆H₃₇NO₆ 459.3 (M⁺), found 460.4 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26c

Compound 26c (609 mg, 81%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 6.77–6.68 (m, 3H), 5.27 (d, J = 1.9 Hz, 1H), 3.91 (dd, J = 6.2, 1.8 Hz, 1H), 3.89–3.82 (m, 1H), 3.81 (s, 3H), 3.81–3.76 (m, 4H), 3.78–3.72 (m, 1H), 3.62 (s, 3H), 3.30 (d, J = 8.0 Hz, 1H), 3.02–2.91 (m, 1H), 2.84–2.71 (m, 4H), 2.48 (dd, J = 12.8, 6.7 Hz, 1H), 1.85 (t, J = 12.1 Hz, 1H), 1.83–1.72 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.48 (d, J = 8.3 Hz, 2H), 0.45–0.36 (m, 1H), 0.18–0.11 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 172.7, 170.3, 148.9, 147.5, 136.2, 131.5, 120.6, 111.9, 111.3, 108.9, 81.5, 78.7, 55.8, 55.8, 52.7, 51.6, 45.8, 37.1, 36.4, 33.2, 32.5, 29.8, 18.3, 18.0, 11.7, 3.5, 2.4; MS (ESI) calcd for C₂₈H₃₇NO₈ 515.3 (M⁺), found 498.4 (M – OH)⁺, 516.4 (M + H)⁺, 538.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26d

Compound 26d (293 mg, 54%) was obtained according to general procedure A: ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 6.30 (dd, J = 3.3, 1.8 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 5.58 (d, J = 1.7 Hz, 1H), 4.91 (d, J = 15.7 Hz, 1H), 4.75 (d, J = 15.7 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.48 (td, J = 6.0, 1.7 Hz, 1H), 4.07 (q, J = 6.5 Hz, 1H), 3.61 (s, 2H), 3.54 (dd, J = 9.9, 6.5 Hz, 1H), 3.40 (dd, J = 9.8, 5.6 Hz, 1H), 3.05–2.95 (m, 1H), 2.80 (dd, J = 16.9, 5.4 Hz, 1H), 2.72 (dd, J = 16.9, 6.2 Hz, 1H), 2.39 (dd, J = 12.8, 6.7 Hz, 1H), 1.71 (t, J = 12.1 Hz, 1H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 172.4, 170.3, 150.1, 141.8, 138.1, 136.6, 128.5, 128.5, 127.8, 127.8, 127.8, 110.6, 108.8, 108.7, 74.4, 73.5, 73.3, 72.7, 53.0, 51.2, 51.2, 41.0, 37.2, 36.4, 29.2, 16.8; MS (ESI) calcd for C₂₆H₂₉NO₈ 483.2 (M⁺), found 484.3 (M + H)⁺, 506.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26e

Compound 26e was prepared according to general procedure A from primary amine 1d, ketoester 24a, and itaconic anhydride 5: yield 454 mg, 93%; ¹H NMR (500 MHz, CDCl₃) δ 5.46 (s, 1H), 3.88 (q, J = 6.4 Hz, 1H), 3.82 (s, 1H), 3.76–3.68 (m, 1H), 3.65 (s, 3H), 3.48–3.39 (m, 1H), 3.06–2.97 (m, 1H), 2.78 (dd, J = 16.9, 6.0 Hz, 1H), 2.67 (dd, J = 16.9, 5.2 Hz, 1H), 2.41 (dd, J = 12.7, 7.7 Hz, 1H), 1.60 (dd, J = 12.6, 10.7 Hz, 2H), 1.48–1.38 (m, 1H), 1.33–1.18 (m, 12H), 1.15 (d, J = 6.5 Hz, 3H), 0.91–0.81 (m, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 176.8, 172.6, 170.4, 138.0, 110.0, 82.2, 74.6, 52.7, 51.4, 44.5, 37.8, 36.3, 34.7, 31.9, 29.3, 29.3, 28.6, 27.2, 26.8, 25.6, 22.7, 16.2, 14.2; MS (ESI) calcd for C₂₅H₄₁NO₆ 451.3 (M⁺), found 434.4 (M – OH)⁺, 452.4 (M + H)⁺, 474.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26f

Compound 26f was prepared according to general procedure A from primary amine 1f, ketoester 24a, and itaconic anhydride 5: yield 431 mg, 77%; ¹H NMR (500 MHz, CDCl₃) δ 6.77–6.72 (m, 2H), 6.70 (dd, J = 7.8, 1.8 Hz, 1H), 5.94–5.90 (m, 2H), 5.49 (d, J = 1.6 Hz, 1H), 5.06 (d, J = 15.3 Hz, 1H), 4.48 (d, J = 15.3 Hz, 1H), 3.85 (q, J = 6.4 Hz, 1H), 3.74 (d, J = 1.5 Hz, 1H), 3.61 (s, 3H), 3.12–3.05 (m, 1H), 2.96 (dd, J = 17.0, 5.4 Hz, 1H), 2.75 (dd, J = 17.0, 5.3 Hz, 1H), 2.45 (dd, J = 12.6, 7.4 Hz, 1H), 1.76 (dd, J = 12.7, 11.1 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H), 0.78 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 176.0, 172.6, 170.9, 148.0, 146.7, 138.3, 131.2, 120.4, 111.5, 108.3, 107.9, 101.1, 82.1, 77.4, 77.4, 77.2, 76.9, 74.6, 52.8, 51.4, 49.0, 37.4, 36.5, 34.7, 28.7, 25.6, 16.2; MS (ESI) calcd for C₂₅H₃₁NO₈ 473.2 (M⁺), found 474.2 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26g

Compound 26g was prepared according to general procedure A from primary amine 1g, ketoester 24a, and itaconic anhydride 5: yield 219 mg, 46%; ¹H NMR (500 MHz, CDCl₃) δ 7.31 (dd, J = 1.7, 0.9 Hz, 1H), 6.30 (dd, J = 3.1, 1.8 Hz, 1H), 6.23 (d, J = 3.1 Hz, 1H), 5.69 (d, J = 1.5 Hz, 1H), 5.07 (d, J = 15.6 Hz, 1H), 4.47 (d, J = 15.6 Hz, 1H), 3.85 (q, J = 6.3 Hz, 1H), 3.79 (d, J = 1.6 Hz, 1H), 3.61 (s, 3H), 3.07–2.99 (m, 1H), 2.86 (dd, J = 17.0, 6.1 Hz, 1H), 2.70 (dd, J = 17.0, 4.6 Hz, 1H), 2.43 (dd, J = 12.7, 7.5 Hz, 1H), 1.66 (dd, J = 12.7, 10.9 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H), 0.83 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 177.0, 172.7, 170.4, 150.6, 141.7, 138.1, 111.1, 110.7, 108.6, 82.1, 74.5, 52.8, 51.3, 42.2, 37.4, 36.4, 34.7, 28.5, 25.5, 16.1; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₂H₃₀NO₇ 420.2022, found 420.2000.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26h

Compound 26h was prepared according to general procedure A from primary amine 1h, ketoester 24a, and itaconic anhydride 5: yield 363 mg, 71%; ¹H NMR (500 MHz, CDCl₃) δ 5.54 (s, 1H), 5.47 (s, 1H), 3.90 (q, J = 6.5 Hz, 1H), 3.84 (s, 1H), 3.77 (ddd, J = 13.4, 11.3, 5.0 Hz, 1H), 3.68 (s, 3H), 3.62 (ddd, J = 13.5, 11.1, 5.5 Hz, 1H), 3.09–3.01 (m, 1H), 2.77–2.67 (m, 2H), 2.45 (dd, J = 12.7, 7.6 Hz, 1H), 2.31 (td, J = 12.3, 11.3, 5.4 Hz, 1H), 2.07–1.92 (m, 5H), 1.66–1.59 (m, 3H), 1.58–1.51 (m, 2H), 1.19 (d, J = 6.5 Hz, 3H), 0.91 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 175.1, 172.5, 170.9, 137.9, 135.0, 123.1, 110.4, 82.2, 74.7, 52.8, 51.4, 44.0, 38.2, 36.3, 35.2, 34.8, 29.1, 28.6, 25.7, 25.4, 23.0, 22.4, 16.2; MS (ESI) calcd for C₂₅H₃₇NO₆ 447.3 (M⁺), found 448.3 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26i

Compound 26i was prepared according to general procedure A from primary amine 1i, ketoester 24a, and itaconic anhydride 5: yield 460 mg, 80%; ¹H NMR (500 MHz, CDCl₃) δ 6.78 (d, J = 7.9 Hz, 1H), 6.76–6.71 (m, 2H), 5.42 (d, J = 1.5 Hz, 1H), 3.88 (q, J = 6.4 Hz, 2H), 3.86–3.80 (m, 7H), 3.80–3.72 (m, 1H), 3.62 (s, 3H), 3.07–3.00 (m, 1H), 2.90–2.81 (m, 2H), 2.79–2.72 (m, 1H), 2.69 (dd, J = 16.9, 4.9 Hz, 1H), 2.44 (dd, J = 12.7, 7.6 Hz, 1H), 1.63 (dd, J = 12.6, 10.5 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H), 0.85 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 176.9, 172.5, 170.4, 149.0, 147.6, 138.3, 131.7, 120.6, 111.9, 111.4, 110.3, 82.1, 74.5, 55.9, 55.9, 52.7, 51.4, 47.2, 37.6, 36.4, 34.6, 32.8, 28.5, 25.5, 16.1; MS (ESI) calcd for C₂₇H₃₇NO₈ 503.3 (M⁺), found 486.4 (M – OH)⁺, 504.4 (M + H)⁺, 526.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26j

Compound 26j was prepared according to general procedure A from primary amine 1j, ketoester 24a, and itaconic anhydride 5: yield 395 mg, 72%; ¹H NMR (500 MHz, CDCl₃) δ 8.04–7.98 (m, 1H), 7.89–7.83 (m, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.56–7.51 (m, 1H), 7.48 (ddd, J = 8.0, 6.7, 1.2 Hz, 1H), 7.43 (dd, J = 8.2, 7.1 Hz, 1H), 7.36 (dd, J = 7.2, 1.3 Hz, 1H), 5.50 (d, J = 1.4 Hz, 1H), 5.46 (d, J = 16.0 Hz, 1H), 5.26 (d, J = 16.0 Hz, 1H), 3.82 (q, J = 6.4 Hz, 1H), 3.72 (d, J = 1.5 Hz, 1H), 3.28 (s, 3H), 3.21–3.13 (m, 2H), 2.85–2.78 (m, 1H), 2.49 (dd, J = 12.6, 7.2 Hz, 1H), 1.92 (dd, J = 12.7, 10.8 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.77 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 177.7, 172.7, 170.4, 138.1, 133.8, 131.5, 131.0, 128.8, 127.8, 126.3, 125.7, 125.4, 125.4, 123.2, 111.8, 82.0, 74.5, 52.4, 51.4, 47.0, 37.0, 36.5, 34.6, 28.4, 25.5, 16.1; MS (ESI) calcd for C₂₈H₃₃NO₆ 479.2 (M⁺), found 480.4 (M + H)⁺, 502.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26k

Compound 26k was prepared according to general procedure A from primary amine 1k, ketoester 24a, and itaconic anhydride 5: yield 468 mg, 82%; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 2.0 Hz, 1H), 7.24–7.14 (m, 2H), 5.26 (d, J = 1.5 Hz, 1H), 5.23 (d, J = 16.8 Hz, 1H), 4.48 (d, J = 16.8 Hz, 1H), 3.83 (q, J = 6.4 Hz, 1H), 3.71 (d, J = 1.5 Hz, 1H), 3.68 (s, 3H), 3.22 (dd, J = 17.7, 5.2 Hz, 1H), 3.01 (ddt, J = 11.9, 7.3, 4.6 Hz, 1H), 2.69 (dd, J = 17.7, 4.2 Hz, 1H), 2.43 (dd, J = 12.6, 7.2 Hz, 1H), 1.91 (t, J = 12.1 Hz, 1H), 1.20 (d, J = 6.4 Hz, 3H), 0.75 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 178.1, 172.7, 170.4, 138.4, 133.3, 133.0, 132.8, 129.2, 129.1, 127.2, 111.2, 82.0, 74.6, 52.9, 51.4, 47.4, 36.3, 36.2, 34.7, 28.1, 25.5, 16.1; MS (ESI) calcd for C₂₄H₂₉Cl₂NO₆ 497.1 (M⁺), found 480.3 (M – OH)⁺, 498.3 (M + H)⁺, 520.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26l

Compound 26l was prepared according to general procedure A from primary amine 1d, ketoester 24b, and itaconic anhydride 5: yield 357 mg, 76%; ¹H NMR (500 MHz, CDCl₃) δ 5.37 (d, J = 1.7 Hz, 1H), 4.06 (dd, J = 7.5, 1.6 Hz, 1H), 3.97 (q, J = 6.5 Hz, 1H), 3.77 (ddd, J = 13.6, 10.2, 6.1 Hz, 1H), 3.67 (s, 3H), 3.50–3.40 (m, 1H), 3.00 (ddt, J = 11.1, 7.2, 5.7 Hz, 1H), 2.75 (dd, J = 16.8, 5.7 Hz, 1H), 2.69 (dd, J = 16.9, 6.1 Hz, 1H), 2.39 (dd, J = 12.7, 7.2 Hz, 1H), 2.02–1.92 (m, 1H), 1.78–1.34 (m, 12H), 1.33–1.21 (m, 12H), 1.19 (d, J = 6.5 Hz, 3H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 172.6, 170.5, 136.5, 111.1, 78.2, 74.6, 52.8, 51.3, 44.7, 44.0, 37.8, 36.3, 31.9, 29.4, 29.3, 29.1, 28.6, 28.4, 27.2, 26.7, 25.9, 25.8, 22.7, 16.5, 14.2; MS (ESI) calcd for C₂₆H₄₁NO₆ 463.3 (M⁺), found 446.4 (M – OH)⁺, 464.4 (M + H)⁺, 486.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26m

Compound 26m was prepared according to general procedure A from primary amine 1e, ketoester 24b, and itaconic anhydride 5: yield 368 mg, 68%; ¹H NMR (500 MHz, CDCl₃) δ 7.34–7.28 (m, 2H), 7.26–7.20 (m, 3H), 5.35 (d, J = 1.6 Hz, 1H), 5.15 (d, J = 15.5 Hz, 1H), 4.63 (d, J = 15.5 Hz, 1H), 4.00–3.93 (m, 2H), 3.59 (s, 3H), 3.10–3.03 (m, 1H), 2.90 (dd, J = 16.9, 5.3 Hz, 1H), 2.81 (dd, J = 17.0, 5.7 Hz, 1H), 2.43 (dd, J = 12.7, 6.9 Hz, 1H), 1.92–1.85 (m, 1H), 1.81 (dd, J = 12.7, 11.6 Hz, 1H), 1.69–1.60 (m, 1H), 1.55–1.37 (m, 5H), 1.32–1.23 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.18–1.11 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 172.7, 170.9, 137.1, 136.7, 128.7, 127.3, 127.1, 112.2, 77.9, 74.5, 52.9, 51.3, 48.6, 44.5, 37.4, 36.4, 29.2, 28.6, 28.2, 25.9, 25.8, 16.6.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26n

Compound 26n was prepared according to general procedure A from primary amine 1f, ketoester 24b, and itaconic anhydride 5: yield 353 mg, 68%; ¹H NMR (500 MHz, CDCl₃) δ 6.77–6.66 (m, 3H), 5.93 (s, 2H), 5.39 (d, J = 1.6 Hz, 1H), 4.97 (d, J = 15.3 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 3.99 (dd, J = 7.3, 1.6 Hz, 1H), 3.96 (q, J = 6.8 Hz, 1H), 3.61 (s, 3H), 3.09–3.01 (m, 1H), 2.88 (dd, J = 17.0, 5.3 Hz, 1H), 2.79 (dd, J = 16.9, 5.8 Hz, 1H), 2.41 (dd, J = 12.6, 6.9 Hz, 1H), 1.96–1.87 (m, 1H), 1.79 (dd, J = 12.7, 11.6 Hz, 1H), 1.72–1.62 (m, 1H), 1.61–1.41 (m, 5H), 1.34–1.25 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 172.7, 171.0, 148.0, 146.8, 136.7, 131.0, 120.5, 112.2, 108.3, 107.9, 101.1, 78.0, 74.5, 52.9, 51.3, 48.3, 44.5, 37.4, 36.4, 29.2, 28.6, 28.3, 25.9, 25.8, 16.6; MS (ESI) calcd for C₂₆H₃₁NO₈ 485.2 (M⁺), found 486.2 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26o

Compound 26o was prepared according to general procedure A from primary amine 1g, ketoester 24b, and itaconic anhydride 5: yield 283 mg, 60%; ¹H NMR (500 MHz, CDCl₃) δ 7.29 (dd, J = 1.7, 0.9 Hz, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 5.56 (d, J = 1.6 Hz, 1H), 4.98 (d, J = 15.6 Hz, 1H), 4.58 (d, J = 15.7 Hz, 1H), 4.03 (d, J = 7.3 Hz, 1H), 3.93 (q, J = 6.5 Hz, 1H), 3.59 (s, 2H), 3.03–2.95 (m, 1H), 2.80 (dd, J = 17.0, 6.2 Hz, 1H), 2.73 (dd, J = 17.1, 4.9 Hz, 1H), 2.39 (dd, J = 12.6, 7.1 Hz, 1H), 1.99–1.90 (m, 1H), 1.69 (dd, J = 12.7, 11.1 Hz, 3H), 1.58–1.41 (m, 4H), 1.38–1.20 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.9, 172.6, 170.3, 150.3, 141.6, 136.7, 111.8, 110.6, 108.5, 78.0, 74.4, 52.8, 51.2, 44.4, 41.5, 37.2, 36.3, 28.8, 28.5, 28.1, 25.8, 25.8, 16.4; MS (ESI) calcd for C₂₃H₂₉NO₇ 431.2 (M⁺), found 414.3 (M – OH)⁺, 432.3 (M + H)⁺, 454.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26p

Compound 26p was prepared according to general procedure A from primary amine 1i, ketoester 24b and itaconic anhydride 5: yield 457 mg, 73%; ¹H NMR (500 MHz, CDCl₃) δ 6.78 (d, J = 7.9 Hz, 1H), 6.76–6.72 (m, 2H), 5.35 (d, J = 1.6 Hz, 1H), 4.05 (d, J = 7.4 Hz, 1H), 3.98 (q, J = 6.5 Hz, 1H), 3.84 (d, J = 10.2 Hz, 7H), 3.73 (ddd, J = 13.5, 10.4, 5.0 Hz, 1H), 3.64 (s, 3H), 2.98 (dt, J = 12.0, 6.0 Hz, 1H), 2.88–2.81 (m, 1H), 2.80–2.70 (m, 2H), 2.40 (dd, J = 12.7, 7.1 Hz, 1H), 1.97–1.89 (m, 1H), 1.76–1.63 (m, 2H), 1.63–1.47 (m, 3H), 1.41–1.34 (m, 1H), 1.32–1.23 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 172.6, 170.3, 149.0, 147.6, 136.7, 131.6, 120.6, 111.9, 111.3, 111.0, 78.0, 74.5, 55.9, 55.9, 52.8, 51.3, 46.3, 44.7, 37.5, 36.4, 32.6, 28.9, 28.6, 28.4, 25.8, 25.7, 16.5; MS (ESI) calcd for C₂₈H₃₇NO₈ 515.3 (M⁺), found 516.4 (M + H)⁺, 538.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26q

Compound 26q was prepared according to general procedure A from primary amine 1j, ketoester 24b, and itaconic anhydride 5: yield 379 mg, 63%; ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.57–7.49 (m, 1H), 7.48 (ddd, J = 8.0, 6.7, 1.2 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.1 Hz, 1H), 5.40 (d, J = 16.1 Hz, 1H), 5.36 (d, J = 1.4 Hz, 1H), 5.33 (d, J = 16.0 Hz, 1H), 4.01 (dd, J = 6.6, 1.5 Hz, 1H), 3.91 (q, J = 6.5 Hz, 1H), 3.29 (s, 3H), 3.12 (dt, J = 17.6, 4.0 Hz, 1H), 3.07 (d, J = 5.9 Hz, 1H), 2.85 (dd, J = 16.9, 4.3 Hz, 1H), 2.46 (dd, J = 12.6, 6.8 Hz, 1H), 1.98–1.86 (m, 2H), 1.67–1.58 (m, 1H), 1.53–1.38 (m, 5H), 1.31–1.22 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.4, 172.7, 170.4, 136.8, 133.8, 131.3, 131.1, 128.8, 127.8, 126.3, 125.7, 125.4, 125.2, 123.1, 112.6, 77.7, 74.5, 52.5, 51.3, 46.4, 44.3, 37.0, 36.5, 28.8, 28.2, 28.1, 25.9, 25.8, 16.4; MS (ESI) calcd for C₂₉H₃₃NO₆ 491.2 (M⁺), found 492.4 (M + H)⁺, 514.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26r

Compound 26r was prepared according to general procedure A from primary amine 1k, ketoester 24b, and itaconic anhydride 5: yield 360 mg, 56%; ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.33 (m, 1H), 7.16 (s, 2H), 5.16 (d, J = 16.8 Hz, 1H), 5.13 (d, J = 1.7 Hz, 1H), 4.60 (d, J = 16.7 Hz, 1H), 4.00–3.92 (m, 2H), 3.68 (s, 3H), 3.11 (dd, J = 17.5, 5.5 Hz, 1H), 3.01–2.91 (m, 1H), 2.72 (dd, J = 17.5, 4.4 Hz, 1H), 2.38 (dd, J = 12.7, 6.7 Hz, 1H), 1.93 (t, J = 12.3 Hz, 1H), 1.92–1.82 (m, 1H), 1.66–1.56 (m, 1H), 1.55–1.46 (m, 2H), 1.46–1.38 (m, 4H), 1.32–1.23 (m, 2H), 1.21 (d, J = 6.5 Hz, 3H), 1.19–1.13 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.6, 172.8, 170.3, 136.6, 133.3, 132.9, 132.8, 129.1, 129.1, 129.0, 127.3, 111.5, 77.6, 77.4, 74.4, 53.0, 51.3, 46.4, 44.4, 36.3, 36.2, 28.6, 28.3, 28.1, 25.9, 25.8, 16.6; MS (ESI) calcd for C₂₅H₂₉Cl₂NO₆ 509.1 (M⁺), found 492.3 (M – OH)⁺, 510.3 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26s

Compound 26s was prepared according to general procedure A from primary amine 1d, ketoester 24c, and itaconic anhydride 5: yield 461 mg, 73%; ¹H NMR (500 MHz, CDCl₃) δ 5.30 (d, J = 1.8 Hz, 1H), 3.93 (dd, J = 6.1, 1.7 Hz, 1H), 3.80–3.70 (m, 1H), 3.64 (s, 2H), 3.50–3.40 (m, 1H), 3.31 (d, J = 7.9 Hz, 1H), 3.02–2.92 (m, 1H), 2.73 (dd, J = 16.9, 5.2 Hz, 1H), 2.67 (dd, J = 16.9, 6.4 Hz, 1H), 2.48 (dd, J = 12.8, 6.8 Hz, 1H), 1.87–1.76 (m, 2H), 1.57–1.48 (m, 1H), 1.47–1.39 (m, 1H), 1.27–1.17 (m, 9H), 1.15 (t, J = 7.1 Hz, 1H), 0.90 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.82 (t, J = 6.9 Hz, 3H), 0.52–0.45 (m, 2H), 0.44–0.36 (m, 1H), 0.18–0.11 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 172.8, 170.3, 136.2, 108.9, 81.6, 78.8, 52.7, 51.6, 43.5, 37.4, 36.3, 33.2, 31.8, 29.9, 29.3, 29.2, 27.1, 26.5, 22.6, 18.3, 18.0, 14.1, 11.8, 3.4, 2.4; MS (ESI) calcd for C₂₆H₄₁NO₆ 463.3 (M⁺), found 446.5 (M – OH)⁺, 464.5 (M + H)⁺, 486.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26t

Compound 26t was prepared according to general procedure A from primary amine 1e, ketoester 24c, and itaconic anhydride 5: yield 343 mg, 68%; ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.23 (m, 2H), 7.23–7.16 (m, 3H), 5.28 (d, J = 1.8 Hz, 1H), 5.15 (d, J = 15.7 Hz, 1H), 4.66 (d, J = 15.7 Hz, 1H), 3.83 (dd, J = 6.4, 1.8 Hz, 1H), 3.59 (s, 3H), 3.30 (d, J = 8.1 Hz, 1H), 3.09–2.99 (m, 1H), 2.92 (dd, J = 17.1, 6.1 Hz, 1H), 2.81 (dd, J = 17.1, 4.9 Hz, 1H), 2.50 (dd, J = 12.9, 6.4 Hz, 1H), 2.06 (t, J = 12.4 Hz, 1H), 1.75–1.65 (m, 1H), 0.88–0.83 (m, 1H), 0.81 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H), 0.57–0.50 (m, 1H), 0.50–0.44 (m, 1H), 0.44–0.37 (m, 1H), 0.22–0.13 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.2, 172.9, 170.6, 137.0, 136.0, 128.5, 127.1, 126.8, 109.9, 81.6, 78.6, 52.8, 51.6, 47.9, 36.8, 36.4, 33.2, 29.9, 18.1, 11.9, 3.9, 2.5; MS (ESI) calcd for C₂₅H₃₁NO₆ 441.2 (M⁺), found 424.4 (M – OH)⁺, 442.4 (M + H)⁺, 464.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26u

Compound 26u was prepared according to general procedure A from primary amine 1f, ketoester 24c, and itaconic anhydride 5: yield 361 mg, 66%; ¹H NMR (500 MHz, CDCl₃) δ 6.74–6.64 (m, 3H), 5.89 (s, 2H), 5.32 (d, J = 1.9 Hz, 1H), 4.94 (d, J = 15.5 Hz, 1H), 4.67 (d, J = 15.5 Hz, 1H), 3.85 (dd, J = 6.4, 1.9 Hz, 1H), 3.61 (s, 3H), 3.31 (d, J = 8.2 Hz, 1H), 3.07–2.97 (m, 1H), 2.89 (dd, J = 17.1, 6.0 Hz, 1H), 2.79 (dd, J = 17.1, 4.9 Hz, 1H), 2.48 (dd, J = 12.9, 6.5 Hz, 1H), 2.02 (t, J = 12.4 Hz, 1H), 1.81–1.68 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.57–0.44 (m, 2H), 0.44–0.37 (m, 1H), 0.22–0.13 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.0, 172.9, 170.7, 147.9, 146.6, 136.0, 130.9, 120.2, 109.8, 108.2, 107.6, 101.0, 81.6, 78.7, 52.8, 51.6, 47.5, 36.8, 36.4, 33.2, 29.9, 18.3, 18.2, 11.9, 3.9, 2.5; MS (ESI) calcd for C₂₆H₃₁NO₈ 485.2 (M⁺), found 486.4 (M + H)⁺, 508.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26v

Compound 26v was prepared according to general procedure A from primary amine 1g, ketoester 24c, and itaconic anhydride 5: yield 373 mg, 63%; ¹H NMR (500 MHz, CDCl₃) δ 7.29–7.28 (m, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 5.52 (d, J = 1.7 Hz, 1H), 5.00 (d, J = 15.8 Hz, 1H), 4.64 (d, J = 15.8 Hz, 1H), 3.91 (dd, J = 6.0, 1.8 Hz, 1H), 3.61 (s, 3H), 3.30 (d, J = 8.0 Hz, 1H), 3.02 (dq, J = 11.9, 6.0 Hz, 1H), 2.77 (d, J = 5.7 Hz, 2H), 2.51 (dd, J = 12.9, 6.8 Hz, 1H), 1.90 (t, J = 12.2 Hz, 1H), 1.80 (h, J = 6.7 Hz, 1H), 0.89 (d, J = 6.8 Hz, 4H), 0.84 (d, J = 6.6 Hz, 4H), 0.50 (dq, J = 7.6, 4.7 Hz, 2H), 0.44–0.37 (m, 1H), 0.19–0.12 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.8, 172.8, 170.4, 150.4, 141.6, 136.2, 110.6, 109.9, 108.3, 81.5, 78.8, 52.8, 51.6, 41.0, 37.0, 36.4, 33.2, 29.8, 18.1, 18.1, 11.7, 3.5, 2.5; MS (ESI) calcd for C₂₃H₂₉NO₇ 431.2 (M⁺), found 432.4 (M + H)⁺, 454.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26w

Compound 26w was prepared according to general procedure A from primary amine 1h, ketoester 24c, and itaconic anhydride 5: yield 520 mg, 77%; ¹H NMR (500 MHz, CDCl₃) δ 5.39 (s, 1H), 5.33 (s, 1H), 3.91 (dd, J = 6.0, 1.8 Hz, 1H), 3.74 (ddd, J = 13.0, 10.6, 5.4 Hz, 1H), 3.64 (s, 3H), 3.30 (d, J = 8.0 Hz, 1H), 2.97–2.87 (m, 1H), 2.74 (dd, J = 16.8, 5.4 Hz, 1H), 2.64 (dd, J = 16.8, 6.3 Hz, 1H), 2.44 (dd, J = 12.9, 6.6 Hz, 1H), 2.23–2.13 (m, 1H), 2.06–1.97 (m, 1H), 1.95–1.88 (m, 4H), 1.87–1.78 (m, 2H), 1.59–1.52 (m, 2H), 1.52–1.45 (m, 2H), 0.91 (d, J = 6.7 Hz, 4H), 0.88 (d, J = 6.7 Hz, 4H), 0.51–0.46 (m, 2H), 0.44–0.37 (m, 1H), 0.20–0.12 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.5, 172.8, 170.2, 135.9, 134.9, 122.9, 108.5, 81.6, 78.7, 52.7, 51.6, 42.7, 37.2, 36.3, 34.7, 33.3, 29.9, 28.4, 25.2, 22.9, 22.3, 18.4, 18.1, 11.9, 3.7, 2.4; MS (ESI) calcd for C₂₆H₃₇NO₆ 459.3 (M⁺), found 460.4 (M + H)⁺, 482.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26x

Compound 26x was prepared according to general procedure A from primary amine 1j, ketoester 24c, and itaconic anhydride 5: yield 436 mg, 61%; ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.48 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.45–7.38 (m, 1H), 7.32 (d, J = 7.0 Hz, 1H), 5.42 (d, J = 16.1 Hz, 1H), 5.36 (d, J = 16.0 Hz, 1H), 5.31 (d, J = 1.8 Hz, 1H), 3.86 (dd, J = 5.9, 1.8 Hz, 1H), 3.32 (s, 3H), 3.29 (d, J = 7.8 Hz, 1H), 3.23–3.13 (m, 1H), 3.04 (dd, J = 17.1, 5.9 Hz, 1H), 2.87 (dd, J = 17.2, 4.8 Hz, 1H), 2.60 (dd, J = 12.9, 6.8 Hz, 1H), 2.12 (t, J = 12.3 Hz, 1H), 1.77–1.66 (m, 1H), 0.95–0.86 (m, 1H), 0.82 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H), 0.55–0.45 (m, 2H), 0.47–0.38 (m, 1H), 0.18–0.11 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 172.8, 170.6, 136.3, 133.8, 131.3, 131.1, 128.9, 127.8, 126.4, 125.8, 125.4, 125.0, 123.0, 110.9, 81.5, 78.8, 52.5, 51.7, 45.8, 37.0, 36.6, 33.1, 29.9, 18.2, 17.8, 11.7, 3.3, 2.5; MS (ESI) calcd for C₂₉H₃₃NO₆ 491.2 (M⁺), found 492.4 (M + H)⁺, 514.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26y

Compound 26y was prepared according to general procedure A from primary amine 1k, ketoester 24c, and itaconic anhydride 5: yield 450 mg, 60%; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.14–5.08 (m, 2H), 4.75 (d, J = 16.8 Hz, 1H), 3.82 (dd, J = 6.6, 1.9 Hz, 1H), 3.70 (s, 3H), 3.34 (d, J = 8.1 Hz, 1H), 3.04 (dd, J = 17.1, 5.6 Hz, 1H), 3.01–2.93 (m, 1H), 2.77 (dd, J = 17.1, 4.2 Hz, 1H), 2.47 (dd, J = 12.9, 6.0 Hz, 1H), 2.16 (t, J = 12.5 Hz, 1H), 1.79–1.69 (m, 1H), 0.96–0.87 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.61–0.49 (m, 2H), 0.49–0.41 (m, 1H), 0.27–0.18 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.6, 173.0, 170.5, 135.8, 133.4, 133.0, 132.7, 129.2, 128.8, 127.4, 109.5, 81.5, 78.5, 53.0, 51.7, 45.5, 36.3, 36.1, 33.3, 29.7, 18.4, 18.3, 12.0, 4.1, 2.5; MS (ESI) calcd for C₂₅H₂₉Cl₂NO₆ 509.1 (M⁺), found 492.3 (M – OH)⁺, 510.3 (M + H)⁺, 532.3 (M + Na)⁺.

Tetrahydropyran-fused Piperidinone-Containing Carboxylic Acid 26z

Compound 26z was prepared according to general procedure A from primary amine 1d, ketoester 24d, and itaconic anhydride 5: yield 351 mg, 65%; ¹H NMR (500 MHz, CDCl₃) δ 7.36–7.23 (m, 5H), 5.34 (d, J = 1.8 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.49 (td, J = 6.0, 1.7 Hz, 1H), 4.08 (q, J = 6.6 Hz, 1H), 3.85–3.75 (m, 1H), 3.67 (s, 3H), 3.54 (dd, J = 9.8, 6.4 Hz, 1H), 3.47–3.37 (m, 2H), 3.01–2.91 (m, 1H), 2.76 (dd, J = 16.8, 5.5 Hz, 1H), 2.64 (dd, J = 16.8, 6.2 Hz, 1H), 2.36 (dd, J = 12.7, 6.8 Hz, 1H), 1.64 (t, J = 12.1 Hz, 1H), 1.60–1.51 (m, 1H), 1.49–1.39 (m, 1H), 1.28–1.18 (m, 13H), 0.85 (t, J = 6.9 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 172.4, 170.2, 137.9, 136.4, 128.5, 127.8, 127.8, 107.6, 74.4, 73.5, 73.3, 72.6, 52.9, 51.1, 43.6, 37.5, 36.2, 31.8, 29.3, 29.3, 29.2, 27.1, 26.5, 22.7, 16.8, 14.2; MS (ESI) calcd for C₂₉H₄₁NO₇ 515.3 (M⁺), found 516.4 (M + H)⁺, 538.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26aa

Compound 26aa was prepared according to general procedure A from primary amine 1e, ketoester 24d, and itaconic anhydride 5: yield 257 mg, 63%; ¹H NMR (500 MHz, CDCl₃) δ 7.36–7.27 (m, 5H), 7.25–7.19 (m, 5H), 5.39 (s, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.41 (td, J = 6.1, 1.8 Hz, 1H), 4.10 (q, J = 6.4 Hz, 1H), 3.58 (s, 3H), 3.48 (dd, J = 9.7, 6.3 Hz, 1H), 3.29 (dd, J = 9.8, 5.8 Hz, 1H), 3.09–2.99 (m, 1H), 2.85–2.78 (m, 2H), 2.40 (dd, J = 12.8, 6.5 Hz, 1H), 1.80 (t, J = 12.0 Hz, 1H), 1.20 (d, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.4, 172.6, 170.6, 138.0, 136.8, 136.4, 128.6, 128.5, 128.5, 127.8, 127.8, 127.2, 127.1, 126.6, 108.5, 74.3, 73.5, 73.0, 72.7, 52.9, 51.3, 47.8, 37.0, 36.4, 29.4, 17.0; MS (ESI) calcd for C₂₈H₃₁NO₇ 493.2 (M⁺), found 494.3 (M + H)⁺, 516.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26ab

Compound 26ab was prepared according to general procedure A from primary amine 1f, ketoester 24d, and itaconic anhydride 5: yield 393 mg, 68%; ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.23 (m, 5H), 6.75–6.65 (m, 3H), 5.90 (d, J = 1.4 Hz, 1H), 5.90 (d, J = 1.4 Hz, 1H), 5.37 (d, J = 1.9 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.74 (d, J = 15.5 Hz, 1H), 4.51 (q, J = 12.1 Hz, 2H), 4.42 (td, J = 6.1, 1.8 Hz, 1H), 4.10 (q, J = 6.4 Hz, 1H), 3.62 (s, 3H), 3.49 (dd, J = 9.8, 6.4 Hz, 1H), 3.32 (dd, J = 9.8, 5.7 Hz, 1H), 3.05–2.95 (m, 1H), 2.81 (dd, J = 5.7, 2.1 Hz, 2H), 2.37 (dd, J = 12.7, 6.5 Hz, 1H), 1.80 (t, J = 12.3 Hz, 1H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 172.5, 170.6, 147.9, 146.7, 138.0, 136.4, 130.6, 128.5, 128.5, 127.8, 127.8, 127.8, 120.4, 108.5, 108.3, 107.8, 101.1, 74.3, 73.5, 73.1, 72.7, 53.0, 51.2, 47.5, 37.0, 36.4, 29.3, 17.0; MS (ESI) calcd for C₂₉H₃₁NO₉ 537.2 (M⁺), found 538.3 (M + H)⁺, 560.2 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26ac

Compound 26ac was prepared according to general procedure A from primary amine 1h, ketoester 24d, and itaconic anhydride 5: yield 555 mg, 70%; ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.31 (m, 4H), 7.31–7.27 (m, 1H), 5.45–5.41 (m, 1H), 5.40 (d, J = 1.9 Hz, 1H), 4.61 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.50 (td, J = 6.1, 1.7 Hz, 1H), 4.11 (q, J = 6.5 Hz, 1H), 3.82 (ddd, J = 13.5, 10.5, 5.2 Hz, 1H), 3.70 (s, 3H), 3.67–3.59 (m, 1H), 3.57 (dd, J = 9.7, 6.4 Hz, 1H), 3.43 (dd, J = 9.7, 5.8 Hz, 1H), 2.99–2.89 (m, 1H), 2.78 (dd, J = 16.7, 6.1 Hz, 1H), 2.63 (dd, J = 16.7, 5.8 Hz, 1H), 2.36 (dd, J = 12.7, 6.7 Hz, 1H), 2.28–2.17 (m, 1H), 2.10–2.00 (m, 1H), 1.99–1.92 (m, 4H), 1.64 (t, J = 11.5 Hz, 1H), 1.61–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.22 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 172.4, 170.3, 138.0, 136.2, 134.9, 128.6, 127.9, 127.9, 123.0, 107.6, 74.4, 73.5, 73.2, 72.7, 53.0, 51.2, 42.9, 37.6, 36.3, 34.7, 29.5, 28.6, 25.3, 23.0, 22.4, 17.0; MS (ESI) calcd for C₂₉H₃₇NO₇ 511.3 (M⁺), found 512.3 (M + H)⁺, 534.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26ad

Compound 26ad was prepared according to general procedure A from primary amine 1i, ketoester 24d, and itaconic anhydride 5: yield 339 mg, 53%; ¹H NMR (500 MHz, CDCl₃) δ 7.34–7.28 (m, 4H), 7.28–7.23 (m, 1H), 6.77–6.68 (m, 3H), 5.37 (d, J = 1.9 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.50 (td, J = 6.2, 1.9 Hz, 1H), 4.09 (q, J = 6.5 Hz, 1H), 3.97–3.87 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78–3.68 (m, 1H), 3.65 (s, 3H), 3.53 (dd, J = 9.7, 6.4 Hz, 1H), 3.38 (dd, J = 9.7, 5.9 Hz, 1H), 3.01–2.91 (m, 1H), 2.88–2.77 (m, 1H), 2.77–2.70 (m, 2H), 2.70–2.64 (m, 1H), 2.37 (dd, J = 12.7, 6.7 Hz, 1H), 1.68 (t, J = 12.1 Hz, 1H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 172.4, 170.1, 149.0, 147.6, 137.9, 136.5, 131.4, 128.5, 127.8, 127.8, 120.6, 112.0, 111.3, 107.7, 74.4, 73.5, 73.2, 72.6, 55.9, 55.9, 52.9, 51.2, 45.7, 37.2, 36.3, 32.4, 29.2, 16.8; MS (ESI) calcd for C₃₁H₃₇NO₉ 567.2 (M⁺), found 568.4 (M + H)⁺, 590.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26ae

Compound 26ae was prepared according to general procedure A from primary amine 1j, ketoester 24d, and itaconic anhydride 5: yield 277 mg, 46%; ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 7.8, 1.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.56–7.45 (m, 2H), 7.42–7.35 (m, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.25–7.20 (m, 3H), 7.17–7.11 (m, 2H), 5.45 (d, J = 16.2 Hz, 1H), 5.34 (d, J = 1.8 Hz, 1H), 5.28 (d, J = 16.1 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.37 (td, J = 5.5, 3.0 Hz, 1H), 4.04 (q, J = 6.4, 5.8 Hz, 1H), 3.45 (dd, J = 9.8, 6.4 Hz, 1H), 3.29 (s, 3H), 3.28–3.24 (m, 1H), 3.14–3.04 (m, 1H), 2.92 (dd, J = 17.0, 5.7 Hz, 1H), 2.84 (dd, J = 17.0, 5.2 Hz, 1H), 2.42 (dd, J = 12.8, 6.6 Hz, 1H), 1.91 (t, J = 12.3 Hz, 1H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.8, 172.4, 170.3, 137.8, 136.4, 133.8, 131.0, 130.9, 128.8, 128.3, 127.8, 127.7, 127.7, 126.3, 125.7, 125.4, 124.8, 123.0, 108.8, 74.3, 73.3, 73.1, 72.5, 52.5, 51.2, 45.7, 36.7, 36.4, 29.1, 16.8; MS (ESI) calcd for C₃₂H₃₃NO₇ 543.2 (M⁺), found 544.4 (M + H)⁺, 566.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carboxylic Acid 26af

Compound 26af was prepared according to general procedure A from primary amine 1k, ketoester 24d, and itaconic anhydride 5: yield 392 mg, 62%; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 2.1 Hz, 1H), 7.34–7.26 (m, 3H), 7.23–7.20 (m, 2H), 7.16 (dd, J = 8.4, 2.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.15 (d, J = 1.9 Hz, 1H), 5.08 (d, J = 16.9 Hz, 1H), 4.74 (d, J = 16.9 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.38 (td, J = 5.9, 1.9 Hz, 1H), 4.13 (q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.47 (dd, J = 9.7, 6.4 Hz, 1H), 3.30 (dd, J = 9.7, 5.6 Hz, 1H), 3.03–2.89 (m, 2H), 2.76 (dd, J = 16.8, 4.0 Hz, 1H), 2.36 (dd, J = 12.7, 5.8 Hz, 1H), 1.94 (t, J = 12.3 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.9, 172.7, 170.3, 137.9, 136.2, 133.4, 133.1, 132.4, 129.3, 128.7, 128.5, 127.8, 127.8, 127.8, 127.4, 108.0, 74.3, 73.5, 72.9, 72.6, 53.1, 51.2, 45.9, 36.4, 36.2, 29.2, 17.1; MS (ESI) calcd for C₂₈H₂₉Cl₂NO₇ 561.1 (M⁺), found 562.4 (M + H)⁺, 584.3 (M + Na)⁺.

Enynamide 28a (2-((3RS,4aSR)-4a-(Ethoxycarbonyl)-2-oxo-1-(3-phenylprop-2-yn-1-yl)-1,2,3,4,4a,5,6,7-octahydroquinolin-3-yl)acetic Acid)

Compound 28a was prepared according to general procedure A from primary amine 27a, ketoester 2a, and itaconic anhydride 5 (3.16 g, 80%): ¹H NMR (CDCl₃, 500 MHz) δ 7.35 (2H, m), 7.22–7.19 (3H, m), 5.59 (1H, dd, J = 4.5, 2.5 Hz), 5.02 (1H, d, J = 17.0 Hz), 4.27 (1H, d, J = 17.5 Hz), 4.09 (2H, 7.0 Hz), 2.83 (1H, dd, J = 16.0, 6.0 Hz), 2.71 (1H, m), 2.48 (1H, dd, J = 16.5, 5.5 Hz), 2.29–2.10 (3H, m), 1.65 (1H, br), 1.59 (1H, t, J = 13.0 Hz), 1.47 (1H, dt, J = 14.0, 2.5 Hz), 1.37 (1H, m), 1.15 (3H, t, J = 6.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.6, 173.7, 169.9, 136.0, 131.8, 128.3, 128.2, 122.8, 109.3, 84.3, 83.4, 61.6, 46.4, 37.0, 36.7, 36.2, 35.2, 34.6, 24.3, 18.5, 14.1; HRMS-ESI m/z [M + H]⁺ calcd for C₂₃H₂₅NO₅ 396.1811, found 396.1818.

Enynamide 28b

Compound 28b was prepared according to general procedure A from primary amine 27b, ketoester 2a and itaconic anhydride 5 (3.19 g, quant): ¹H NMR (CDCl₃, 500 MHz) δ 5.47 (1H, dd, J = 5.0, 3.0 Hz), 4.80 (1H, dd, J = 17.0, 2.0 Hz), 4.10 (2H, q, J = 7.0 Hz), 4.05 (1H, dd, J = 17.5, 2.5 Hz), 2.81 (1H, dd, J = 16.5, 6.0 Hz), 2.69 (1H, m), 2.53 (1H, dd, J = 6.0 Hz), 2.33 (1H, dd, J = 13.0, 6.0 Hz), 2.27–2.09 (5H, m), 1.65 (1H, br), 1.59 (1H, t, J = 13.0 Hz), 1.47 (1H, dt, J = 14.0, 2.5 Hz), 1.39–1.29 (1H, m), 1.17(3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.1, 173.7, 169.6, 136.0, 108.8, 78.8, 71.7, 61.6, 46.4, 36.7, 36.6, 36.1, 34.6, 34.2, 24.2, 18.5, 14.1; HRMS-ESI m/z [M + H]⁺ calcd for C₁₇H₂₂NO₅ 320.1498, found 320.1497.

Enynamide 28c

Compound 28c was prepared according to general procedure A from primary amine 27c, ketoester 2a and itaconic anhydride 5 (2.40 g, 72%): ¹H NMR (DMSO-d₆, 500 MHz) δ 5.40 (1H, dd, J = 4.5, 3.0 Hz), 4.66 (1H, dd, J = 17.0, 2.5 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.03 (1H, dd, J = 17.0, 2.0 Hz), 2.65 (1H, dd, J = 16.5, 4.5 Hz), 2.50 (1H, m), 2.42 (1H, dd, J = 16.5, 7.0 Hz), 2.23–2.12 (4H, m), 1.17 (3H, s), 1.70 (1H, s, J = 13.0 Hz), 1.65 (1H, m), 1.51 (1H, dt, J = 13.5, 2.0 Hz), 1.26 (1H, m), 1.15 (3H, t, J = 7.0 Hz); ¹³C NMR (DMSO-d₆, 125 MHz) δ 173.4, 172.7, 168.3, 136.2, 106.5, 78.4, 75.2, 60.8, 45.9, 36.0, 35.8, 35.7, 33.9, 33.5, 23.7, 18.2, 13.9, 3.1; HRMS-EI m/z [M]⁺ calcd for C₁₈H₂₃NO₅ 333.1576, found 333.1569

Enynamide 33a (2-((3RS,4aSR)-4a-(Ethoxycarbonyl)-2-oxo-1-(prop-2-yn-1-yl)-2,3,4,4a,5,6-hexahydro-1H-cyclopenta[b]-pyridin-3-yl)acetic Acid)

Compound 33a was prepared according to general procedure A from primary amine 27b, ketoester 2d, and itaconic anhydride 5 (1.71 g, 56%): ¹H NMR (CDCl₃, 500 MHz) δ 5.28 (1H, s), 4.60 (1H, dd, J = 17.5, 2.5 Hz), 4.36 (1H, dd, J = 17.5, 2.5 Hz), 4.18 (2H, m), 2.91–2.81 (2H, m), 2.70 (1H, dd, J = 6.0, 16.5 Hz), 2.59–2.50 (2H, m), 2.43–2.36 (2H, m), 2.21 (1H, t, J = 2.0 Hz), 1.91 (1H, m), 1.73 (1H, t, J = 12.5 Hz), 1.25 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.7, 173.7, 169.3, 140.3, 107.9, 77.9, 71.5, 61.5, 54.2, 36.8, 36.4, 36.3, 35.6, 33.4, 29.0, 14.1; HRMS-ESI m/z [M + H]⁺ calcd for C₁₆H₂₀NO₅ 306.1341, found 306.1339.

Enynamide 33b

Compound 33b was prepared according to general procedure A from primary amine 27a, ketoester 2b and itaconic anhydride 5 (1.62 g, 41%): ¹H NMR (CDCl₃, 500 MHz) δ 7.35 (2H, m), 7.22 (3H, m), 5.78 (1H, t, J = 7.0 Hz), 4.86 (1H, d, J = 17.5 Hz), 4.45 (1H, d, J = 17.5 Hz), 3.70 (3H, s), 2.83 (1H, dd, J = 16.5, 6.5 Hz), 2.71 (1H, m), 2.38 (1H, dd, J = 16.5, 6.0 Hz), 2.23 (1H, m), 2.10–1.98 (4H, m), 1.76–1.61 (5H, m), 1.42–1.34 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 173.9, 170.7, 139.8, 131.8, 128.3, 128.2, 122.7, 116.3, 84.4, 83.4, 52.6, 51.6, 39.5, 36.5, 36.0, 35.7, 35.5, 26.3, 25.3, 24.9; HRMS-EI m/z [M]⁺ calcd for C₂₃H₂₅NO₅ 395.1733, found 395.1734.

Enynamide 33c

Compound 33c was prepared according to general procedure A from primary amine 27a, ketoester 2e, and itaconic anhydride 5 (1.85 g, 50%): ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (2H, m), 7.21 (3H, m), 4.95 (1H, d, J = 2.5 Hz), 4.87 (1H, d, J = 17.0 Hz), 4.62 (1H, d, J = 2.5 Hz), 4.53 (1H, d, J = 17.0 Hz), 4.07 (2H, q, J = 7.5 Hz), 2.98 (1H, m), 2.81 (1H, dd, J = 17.0, 5.5 Hz), 2.53 (1H, dd, J = 17.0, 6.5 Hz), 2.29 (1H, dd, J = 13.5, 6.0 Hz), 1.61 (1H, t, J = 13.0 Hz), 1.43 (3H, s), 1.14 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.3, 173.6, 170.3, 146.0, 131.8, 128.3, 128.1, 122.7, 96.2, 83.9, 83.4, 61.6, 46.5, 36.5, 36.4, 36.1, 35.4, 24.8, 14.0; HRMS-ESI m/z [M + H]⁺ calcd for C₂₁H₂₄NO₅ 370.1654, found 370.1652.

Enynamide 33d

Compound 33d was prepared according to general procedure A from primary amine 27b, ketoester 2f, and itaconic anhydride 5 (1.47 g, 50%): ¹H NMR (CDCl₃, 500 MHz) δ 5.01 (1H, d, J = 2.0 Hz), 4.76 (1H, d, J = 2.0 Hz), 4.62 (1H, dd, J = 17.5, 1.5 Hz), 4.35 (1H, dd, J = 17.5, 1.5 Hz), 4.20 (2H, m), 4.14 (2H, q, J = 7.0 Hz), 3.14 (1H, m), 2.90 (1H, dd, J = 17.0, 5.5 Hz), 2.61 (1H, dd, J = 17.0, 6.5 Hz), 2.41–2.25 (5H, m), 2.18–2.12 (1H, m), 1.62 (1H, t, J = 13.0 Hz), 1.27 (3H, dt, J = 7.0, 1.0 Hz), 1.26 (3H, dt, J = 7.0, 1.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 172.7, 172.6, 170.4, 144.4, 97.6, 78.2, 72.0, 72.0, 61.8, 60.7, 49.7, 35.8, 35.7, 34.7, 33.0, 32.9, 29.5, 14.2, 14.0; HRMS-EI m/z [M]⁺ calcd for C₁₉H₂₅NO₇ 379.1631, found 379.1623.

Enynamide 35a (2-((3SR,3aRS)-3a-(Ethoxycarbonyl)-2-oxo-1-(prop-2-yn-1-yl)-2,3,3a,4,5,6-hexahydro-1H-indol-3-yl)acetic Acid)

Compound 35a was prepared according to general procedure A from primary amine 27b, ketoester 2a, and maleic anhydride 4 (2.53 g, 83%): ¹H NMR (CDCl₃, 500 MHz) δ 5.19 (1H, t, J = 7.5 Hz), 4.23 (2H, dq, J = 17.5, 2.5 Hz), 4.13–4.03 (2H, m), 2.96 (1H, t, J = 7.0 Hz), 2.80 (1H, dd, J = 17.5, 6.5 Hz), 2.54 (1H, m), 2.29 (1H, dd, J = 17.5, 8.0 Hz), 2.22–2.07 (3H, m), 1.81 (1H, m), 1.55–1.42 (2H, m), 1.17 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 172.5, 171.1, 137.3, 102.4, 76.8, 71.7, 61.5, 52.0, 47.3, 31.2, 30.3, 29.6, 22.7, 19.5, 14.0; HRMS-ESI m/z [M + H]⁺ calcd for C₁₆H₂₀NO₅ 306.1341, found 306.1339.

Enynamide 35b

Compound 35b was prepared according to general procedure A from primary amine 27a, ketoester 2a, and maleic anhydride 4 (1.95 g, 51%): ¹H NMR (CDCl₃, 500 MHz) δ 7.33 (2H, m), 7.25–7.19 (3H, m), 5.28 (1H, t, J = 3.5 Hz), 4.45 (2H, q, J = 11.5 Hz), 4.05 (2H, m), 2.98 (1H, t, J = 7.0 Hz), 2.79 (1H, dd, J = 17.0, 6.5 Hz), 2.53 (1H, m), 2.31 (1H, dd, J = 17.5, 7.5 Hz), 2.22–2.08 (2H, m), 1.80 (1H, m), 1.56–1.42 (2H, m), 1.13 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.5, 172.8, 171.1, 137.4, 131.8, 128.5, 128.2, 122.5, 102.7, 83.4, 82.3, 61.5, 52.0, 47.4, 31.3, 30.6, 30.2, 22.8, 19.5, 14.0; HRMS-ESI m/z [M + H]⁺ calcd for C₂₂H₂₄NO₅ 382.1654, found 382.1647.

Enynamide 35c

Compound 35c was prepared according to general procedure A from primary amine 27b, ketoester 2b, and maleic anhydride 4 (2.63 g, 86%):¹H NMR (CDCl₃, 500 MHz) δ 5.40 (1H, dd, J = 9.0, 4.5 Hz), 4.40 (1H, d, J = 17.0 Hz), 4.20 (1H, d, J = 17.0 Hz), 3.71 (3H, s), 3.09 (1H, t, J = 6.5 Hz), 2.80 (1H, dd, J = 17.0, 6.5 Hz), 2.50 (1H, d, J = 11.5 Hz), 2.40–2.27 (2H, m), 2.21 (1H, s), 2.01–1.94 (2H, m), 1.78–1.60 (3H, m), 1.38 (1H, q, J = 12.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 172.4, 171.1, 141.7, 106.2, 76.8, 71.6, 55.4, 52.3, 48.1, 35.6, 31.6, 30.0, 27.5, 27.2, 26.1; HRMS-EI m/z [M – H]⁺ calcd for C₁₆H₁₈NO₅ 304.1185, found 304.1179.

Enynamide 35d

Compound 35d was prepared according to general procedure A from primary amine 27a, ketoester 2b, and maleic anhydride 4 (1.95 g, 51%): ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (2H, m), 7.23 (3H, m), 5.42 (1H, dd, J = 8.5 4.0 Hz), 4.55 (1H, d, J = 17.5 Hz), 4.32 (1H, d, J = 17.5 Hz), 3.61 (3H, s), 3.02 (1H, t, J = 7.0 Hz), 2.66 (1H, dd, J = 17.0, 7.5 Hz), 2.41 (1H, d, J = 15.0 Hz), 2.34 (1H, dd, J = 17.0, 6.5 Hz), 2.24 (1H, m), 1.94–1.84 (2H, m), 1.67 (2H, m), 1.55 (1H, t, J = 13.5 Hz), 1.29 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.1, 172.8, 171.0, 141.6, 131.7, 128.4, 128.3, 122.4, 106.7, 83.4, 82.1, 55.4, 52.3, 48.2, 35.5, 31.6, 30.9, 27.4, 27.2, 26.1; HRMS-ESI m/z [M + H]⁺ calcd for C₂₂H₂₄NO₅ 382.1654, found 382.1653.

General Procedure B: Au-Catalyzed Enynamide Cycloisomerization

A solution of enyne-containing piperidinones (28 or 33, 5.00 mmol) or pyrrolidinones (35, 5.00 mmol) in CH₃CN (8.2 mL) was treated with JohnPhos-Au-NCMe·SbF₆ (31, 0.15 mmol, 3 mol %). The resulting solution was stirred overnight at room temperature under inert nitrogen atmosphere. Removal of solvent under reduced pressure afforded crude dienamides (29, 34, or 36), which were used for subsequent hydrogenation without purification.

Cycloisomerization product 29a (2-((2RS,10aSR)-10a-(Ethoxycarbonyl) - 3 - oxo-7-phenyl - 1, 2, 3, 5, 8, 9, 10, 10a-octahydropyrido[3,2,1-ij]quinolin-2-yl)acetic Acid)

Compound 29a was prepared according to general procedure B from enynamide 28a (quantative yield by ¹H NMR using mesitylene as an internal standard): ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (3H, m), 7.20 (2H, m), 5.66 (1H, dd, J = 6.0, 2.5 Hz), 5.22 (1H, dd, J = 17.5, 6.0 Hz), 4.24 (2H, m), 3.88 (1H, d, J = 17.5 Hz), 2.98 (1H, dd, J = 16.5, 6.5 Hz), 2.60 (1H, dd, J = 16.5, 6.0 Hz), 2.34 (1H, d, J = 13.0 Hz), 2.15 (1H, m), 1.89 (1H, dd, J = 18.0, 4.5 Hz), 1.70 (2H, m), 1.55–1.42 (2H, m), 1.30 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.6, 173.9, 169.3, 139.0, 138.7, 131.3, 128.4, 128.0, 127.3, 118.9, 116.8, 61.8, 46.5, 41.3, 37.3, 36.5, 36.1, 34.3, 27.0, 19.0, 14.2; HRMS-ESI m/z [M + H]⁺ calcd for C₂₃H₂₄NO₅ 395.1733, found 395.1724.

Cycloisomerization Product 29b

Compound 29b was prepared according to general procedure B from enynamide 28b (quantative yield by ¹H NMR using mesitylene as an internal standard): ¹H NMR (CDCl₃, 500 MHz) δ 5.70 (2H, m), 5.03 (1H, dd, J = 18.0, 5.5 Hz), 4.20 (2H, m), 3.85 (1H, d, J = 18.0 Hz), 2.89 (1H, dd, J = 16.0, 6.0 Hz), 2.77 (1H, m), 2.54 (1H, dd, J = 16.5, 6.5 Hz), 2.39 (1H, dd, J = 13.0, 6.0 Hz), 2.30 (1H, m), 2.19 (2H, m), 1.70 (1H, m), 1.61 (1H, t, J = 13.0 Hz), 1.47 (2H, m), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 173.9, 169.1, 129.8, 125.5, 120.4, 115.1, 61.7, 45.7, 42.2, 37.0, 36.0, 35.9, 34.4, 27.3, 18.8, 14.2; HRMS-ESI m/z [M + H]⁺ calcd for C₁₇H₂₂NO₅ 320.1498, found 320.1506.

Cycloisomerization Product 29c

Compound 29c was prepared according to general procedure B from enynamide 28c (90% yield by ¹H NMR using mesitylene as an internal standard): ¹H NMR (CDCl₃, 500 MHz) δ 5.49 (1H, m), 5.01 (1H, dd, J = 17.0, 6.0 Hz), 4.21 (2H, m), 3.70 (1H, dq, J = 17.5, 2.5 Hz), 2.89 (1H, dd, J = 16.5, 7.0 Hz), 2.78 (1H, m), 2.50 (1H, dd, J = 16.0, 5.0 Hz), 2.43 (1H, dd, J = 6.0, 13.0 Hz), 2.33–2.29 (2H, m), 2.23–2.16 (1H, m), 1.86–1.77 (1H, m), 1.77 (3H, m), 1.60 (1H, t, J = 12.5 Hz), 1.50–1.41 (2H, m), 1.27 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 174.8, 173.9, 169.4, 129.0, 117.8, 61.5, 46.0, 40.9, 37.7, 37.0, 35.6, 34.6, 29.7, 27.9, 21.6, 18.9, 14.2; HRMS-EI m/z [M]⁺ calcd for C₁₈H₂₃NO₅ 333.1576, found 333.1569.

Cycloisomerization Product 34a (2-((2RS,9aSR)-9a-(Ethoxy-carbonyl)-3-oxo-2,3,5,8,9,9a-hexahydro-1H-cyclopenta[ij]-quinolizin-2-yl)acetic Acid)

Compound 34a (98% yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 5.94 (1H, dt, J = 2.0, 10.0 Hz), 5.60 (1H, m), 4.85 (1H, dd, J = 19.5, 4.5), 4.16–4.28 (3H, m), 2.89 (2H, m), 2.60 (3H, m), 2.37 (2H, m), 1.89 (1H, dt, J = 18.5, 9.0 Hz), 1.67 (1H, t, J = 12.5 Hz), 1.28 (3H, t, J = 6.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.3, 173.7, 168.5, 134.6, 121.2, 120.5, 116.0, 61.6, 53.0, 44.1, 36.6, 36.4, 36.3, 35.0, 29.8, 14.2; HRMS-ESI m/z [M + H]⁺ calcd for C₁₆H₂₀NO₅ 306.1341, found 306.1343.

Cycloisomerization Product 34b

Compound 34b (75% yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 7.37–7.29 (3H, m), 7.18 (2H, m), 5.71 (1H, dd, J = 5.5, 4.5 Hz), 4.86 (1H, dd, J = 15.5, 5.5 Hz), 4.00 (1H, dd, J = 15.5, 4.0 Hz), 3.87 (3H, s), 2.97–2.86 (2H, m), 2.45 (1H, dd, J = 16.0, 6.0 Hz), 2.20 (3H, m), 2.02 (1H, m), 1.86–1.66 (5H, m), 1.35 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 176.0, 174.0, 171.1, 142.2, 139.1, 136.3, 128.2, 128.1, 127.3, 126.0, 117.2, 52.7, 51.9, 40.2, 40.0, 36.6, 35.7, 35.5, 29.5, 26.6, 25.6; HRMS-EI m/z [M]⁺ calcd for C₂₃H₂₅NO₅ 395.1733, found 395.1736.

Cycloisomerization Product 34c

Compound 34c (90% yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 7.42–7.29 (5H, m), 5.88 (1H, m), 5.74 (1H, d, J = 1.5 Hz), 5.05 (1H, dd, J = 18.0, 5.5 Hz), 4.31–4.20 (3H, m), 3.09 (1H, m), 2.95 (1H, dd, J = 16.5, 6.0 Hz), 2.60 (1H, dd, J = 17.0, 6.5 Hz), 2.43 (1H, dd, J = 13.5, 6.0 Hz), 1.73 (1H, t, J = 13.0 Hz), 1.58 (3H, s), 1.29 (3H, t, J = 7.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.3, 173.6, 169.7, 139.4, 138.5, 134.2, 128.6, 127.7, 125.5, 115.8, 106.7, 61.8, 45.9, 42.8, 36.6, 36.2, 36.2, 24.0, 14.1; HRMS-ESI m/z [M]⁺ calcd for C₂₁H₂₃NO₅ 369.1576, found 369.1585.

Cycloisomerization Product 34d

Compound 34d (quantitative yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 5.95 (1H, m), 5.68 (1H, m), 5.48 (1H, d, J = 5.5 Hz), 4.55 (1H, dd, J = 17.5, 4.0 Hz), 4.40 (1H, d, J = 17.5 Hz), 4.22 (2H, m), 4.15 (2H, q, J = 7.0 Hz), 3.13 (1H, m), 2.90 (1H, dd, J = 17.0, 6.5 Hz), 2.54 (1H, dd, J = 16.5, 6.0 Hz), 2.39 (2H, t, J = 8.0 Hz), 2.31 (2H, m), 2.16–2.10 (1H, m), 1.58 (1H, t, J = 13.0 Hz), 1.30–1.25 (6H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 172.7, 172.6, 170.5, 136.8, 122.2, 120.5, 107.3, 61.9, 60.8, 48.9, 41.6, 36.1, 35.8, 32.9, 32.8, 29.6, 14.2, 14.0; HRMS-EI m/z [M – H]⁺ calcd for C₁₉H₂₄NO₇ 378.1553, found 378.1558.

Cycloisomerization Product 36a (2-((1SR,9aRS)-9a-(Ethoxy-carbonyl)-2-oxo-2,4,7,8,9,9a-hexahydro-1H-pyrrolo[3,2,1-ij]-quinolin-1-yl)acetic Acid)

Compound 36a (quantitative yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 5.81 (1H, dq, J = 10.0, 1.5 Hz), 5.51 (1H, ddd, J = 9.5, 5.0, 2.0 Hz), 4.72 (1H, dd, J = 17.5, 5.0 Hz), 4.2 (2H, m), 4.1 (1H, d, J = 17.5), 3.01–2.93 (2H, m), 2.65 (1H, dt, J = 12.5, 3.0 Hz), 2.37 (1H, dd, J = 17.0, 8.0 Hz), 2.22 (1H, dd, J = 17.5, 6.5 Hz), 2.07 (1H, m), 1.92 (1H, m), 1.57 (1H, m), 1.46 (1H, td, J = 13.0, 2.5 Hz), 1.28 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.6, 173.0, 170.7, 133.5, 124.8, 117.9, 109.0, 61.5, 51.8, 47.3, 41.3, 31.3, 30.2, 24.3, 19.8, 13.9; HRMS-ESI m/z [M – H]⁺ calcd for C₁₆H₁₈NO₅ 304.1185, found 304.1186.

Cycloisomerization Product 36b

Compound 36b (quantitative yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 7.38–7.30 (3H, m), 7.21 (2H, m), 5.41 (1H, dd, J = 5.0, 2.5 Hz), 4.83 (1H, dd, J = 17.5, 5.5 Hz), 4.84 (3H, m), 3.08 (1H, t, J = 7.5 Hz), 2.96 (1H, dd, J = 17.0, 6.5 Hz), 2.65 (1H, d, J = 10.5 Hz), 2.43 (1H, dd, J = 17.5, 8.0 Hz), 2.09 (1H, dd, J = 16.5, 6.0 Hz), 1.89 (2H, m), 1.51 (2H, m), 1.32 (3H, 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.4, 173.1, 170.8, 138.9, 138.2, 134.1, 128.3, 128.0, 127.3, 116.8, 109.8, 61.8, 52.5, 47.4, 41.2, 31.5, 29.9, 23.9, 20.2, 14.1; HRMS-ESI m/z [M – H]⁺ calcd for C₂₂H₂₂NO₅ 380.1498, found 380.1494.

Cycloisomerization Product 36c

Compound 36c (72% yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 5.76 (1H, dt, J = 10.0, 2.0 Hz), 5.46 (1H, m), 4.56 (1H, dd, J = 18.0, 4.5 Hz), 4.22 (1H, dq, J = 18.0 2.5 Hz), 3.76 (3H, s), 3.05 (1H, t, J = 6.5 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 2.52 (1H, m), 2.40 (1H, dd, J = 17.5, 7.0 Hz), 2.21–2.10 (2H, m), 1.94 –1.91 (1H, m), 1.79–1.74 (1H, m), 1.60–1.70 (2H, m), 1.36–1.45 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.3, 173.1, 170.9, 136.2, 128.2, 116.7, 113.1, 55.8, 52.5, 47.5, 42.0, 35.7, 31.9, 31.9, 27.3, 26.9; HRMS-EI m/z [M – H]⁺ calcd for C₁₆H₁₈NO₅ 304.1185, found 304.1187.

Cycloisomerization Product 36d

Compound 36d (77% yield determined by ¹H NMR using mesitylene as an internal standard) was prepared according to the general procedure B: ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (3H, m), 7.18 (2H, m), 5.40 (1H, dd, J = 5.0, 2.5 Hz), 4.71 (1H, dd, J = 17.5, 5.5 Hz), 4.24 (1H, d, J = 17.0 Hz), 3.79 (3H, s), 3.16 (1H, t, J = 6.5 Hz), 2.84 (1H, dd, J = 17.0, 7.0 Hz), 2.56 (1H, m), 2.43 (1H, 17.0, 7.0 Hz), 2.18 (1H, dd, J = 15.5, 6.5 Hz), 1.94–1.66 (5H, m), 1.40 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.5, 173.1, 171.0, 140.3, 139.8, 138.4, 128.2, 127.3, 115.6, 114.2, 56.3, 52.5, 47.8, 41.5, 35.3, 31.8, 28.2, 27.3, 26.7; HRMS-ESI m/z [M – H]⁺ calcd for C₂₂H₂₂NO₅ 380.1498, found 380.1505.

General Procedure C: Diene Hydrogenations

To a round-bottom flask was added 10% Pd/C (0.30 mmol, 0.10 equiv) and the corresponding crude acid solution (prepared from general procedure B, 3.00 mmol, 1.00 equiv) in EtOH (30.0 mL). The mixture was stirred overnight at room temperature under H₂ atmosphere (1 atm). The mixture was filtered over Celite and concentrated under reduced pressure. The product was isolated after purification by Combi-flash column chromatography (DCM: (EtOAc + 1% HCOOH) = 95:5 to 30:70).

Tricyclic Carboxylic Acid 37 (2-((2RS,10aSR)-10a-(ethoxycarbonyl)-3-oxo-1,2,3,5,6,7,8,9,10,10a-decahydropyrido[3,2,1-ij]-quinolin-2-yl)acetic Acid)

Compound 37 (771 mg, 80%) was prepared according to the general procedure C: ¹H NMR (CDCl₃, 500 MHz) δ 4.62 (1H, dt, J = 13.0, 3.5 Hz), 4.24–4.13 (2H, m), 2.97 (1H, dt, J = 12.0, 2.5 Hz), 2.82 (1H, dd, J = 16.0, 7.5), 2.36 (1H, dd, J = 13.0, 5.5 Hz), 2.27 (1H, m), 2.20–2.13 (1H, m), 2.09 (2H, m), 2.01–1.90 (2H, m), 1.80–1.71 (2H, m), 1.61 (1H, t, J = 13.0 Hz), 1.54–1.39 (2H, m), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.1, 173.9, 169.4, 132.1, 130.1, 118.0, 116.2, 61.7, 46.1, 41.4, 37.5, 36.5, 35.9, 34.1, 25.2, 18.8, 18.1, 14.2; HRMS-ESI m/z [M]⁺ calcd for C₁₇H₂₃NO₅ 321.1576, found 321.1584.

Tricyclic Carboxylic Acid 38

Compound 38 (645 mg, 70%) was prepared according to the general procedure C: ¹H NMR (CD₃CN, 500 MHz) δ 4.18–4.08 (2H, m), 3.85 (1H, m), 3.56 (1H, br), 3.31–3.26 (1H, m), 2.73–2.65 (2H, m), 2.57–2.52 (1H, m), 2.48–2.41 (2H, m), 2.29–2.22 (2H, m), 2.09 (2H, m), 1.97 (1H, quintet, J = 2.5 Hz), 1.88–1.78 (3H, m), 1.69 (1H, t, J = 12.5 Hz), 1.21 (3H, t, J = 7.0 Hz); ¹³C NMR (CD₃CN, 125 MHz) δ 174.8, 174.0, 168.6, 133.5, 118.8, 61.3, 53.4, 40.1, 36.4, 35.6, 35.3, 35.2, 32.1, 22.4, 21.3, 13.4; HRMS-ESI m/z [M + H]⁺ calcd for C₁₆H₂₂NO₅ 308.1498, found 308.1503.

Tricyclic Carboxylic Acid 39

compound 39 (882 mg, 77%) was prepared according to the general procedure C: ¹H NMR (CDCl₃, 500 MHz) δ 5.19 (1H, t, J = 4.0 Hz), 4.23–4.13 (4H, m), 3.87 (1H, m), 3.65 (1H, m), 3.08 (1H, m), 2.85 (1H, dd, J = 16.0, 7.0 Hz), 2.56 (1H, dd, J = 16.0, 5.0 Hz), 2.38–2.24 (4H, m), 2.19 (2H, m), 2.14–2.08 (1H, m), 1.81 (2H, m), 1.59 (1H, t, J = 13.0 Hz), 1.28 (6H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.3, 173.0, 172.7, 170.1, 135.8, 109.1, 61.7, 60.8, 48.6, 41.1, 36.8, 35.5, 33.2, 32.3, 29.4, 22.6, 21.5, 14.2, 14.1; HRMS-ESI m/z [M + H]⁺ calcd for C₁₉H₂₈NO₇ 382.1866, found 382.1864.

Tricyclic Carboxylic Acid 40

Compound 40 (600 mg, 65%) was prepared according to the general procedure C: ¹H NMR (CDCl₃, 500 MHz) δ 4.22–4.11 (2H, m), 3.90 (1H, m), 3.31 (1H, dt, J = 10.5, 3.5 Hz), 2.96 (1H, t, J = 7.5 Hz), 2.84 (1H, dd, J = 17.0, 7.5 Hz), 2.61 (1H, t, J = 12.0, 2.5 Hz), 2.42 (1H, dd, J = 16.5, 6.5 Hz), 2.21–1.87 (6H, m), 1.71–1.80 (1H, m), 1.61–1.44 (2H, m), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 174.6, 172.5, 171.3, 131.4, 111.2, 61.4, 51.4, 48.0, 38.9, 32.0, 30.5, 26.8, 25.4, 20.9, 19.9, 14.1; HRMSESI m/z [M + H]⁺ calcd for C₁₆H₂₂NO₅ 308.1498, found 308.1507.

Tricyclic Carboxylic Acid 41

Compound 41 (645 mg, 70%) was prepared according to the general procedure C: ¹H NMR (CDCl₃, 500 MHz) δ 3.79 (1H, m), 3.73 (3H, s), 3.30 (1H, m), 2.98 (1H, dd, J = 9.0, 5.5 Hz), 2.68 (1H, dd, J = 16.5, 9.0 Hz), 2.50–2.42 (2H, m), 2.20–2.08 (3H, m), 2.00 (1H, m), 1.93–1.88 (2H, m), 1.78–1.69 (3H, m), 1.59 (1H, dt, J = 13.0, 3.5 Hz), 1.38 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 173.6, 172.4, 171.2, 134.2, 116.8, 55.4, 52.3, 48.2, 38.8, 35.5, 33.2, 32.4, 29.2, 27.3, 26.7, 20.5; HRMS-ESI m/z [M]⁺ calcd for C₁₆H₂₁NO₅ 307.1420, found 307.1422.

General Procedure D: Automated Library Synthesis

A of solution of a carboxylic acid (7, 8, 26, or 36, 1.25 mmol) in 25 mL of CDCl₃ was treated with CDI (16, 212.8 mg, 1.31 mmol, 1.05 equiv). The reaction was stirred at room temperature until NMR indicated complete conversion of the carboxylic acid to the corresponding acylimidazole, which typically took 2–4 h. Using a Perkin-Elmer Multiprobe II liquid handler, the resulting solution was distributed into 24 1-dram glass vials, delivering 0.95 mL of the above solution into each vial. For reactions involving the coupling with secondary amines, the glass vials were precharged with imidazole hydrochloride (9.9 mg, 0.095 mmol, 2 equiv). For each vial, a solution of one of the 24 amines 11 (2 M, 2.7 equiv) in 0.065 mL of chloroform was added. The resulting reaction mixtures were capped and agitated on an orbital shaker at room temperature for 48 h. The vials were then returned to the deck of the liquid handler and treated with 1.9 mL of 1.2 N HCl solution followed by eight cycles of rapid aspiration and dispensing to ensure thorough mixing. After complete phase separation, which can be accelerated by centrifugation for 10 min at 500 g (versus ~2 h without centrifugation), the bottom layers were retrieved by the liquid hander and transferred to 24 empty barcoded, preweighed one-dram vials. The vials containing the product solutions were placed in a GeneVac centrifugal evaporator to remove solvent, and were weighed using an automated Mettler Toledo weigher to determine the yield of each final product. Each of the tips used for the above material transfer was then washed in another vial containing 0.5 mL of MeOH in order to dissolve the residual material present on the tip, which provided sufficient amount of material for purity analysis of each final compound using LC–MS equipped with an autosampler.

Pyrrolidinone-Containing Amide 12a ((3SR,3aRS)-Ethyl 1-(4-Methoxybenzyl)-2-oxo-3-(2-oxo-2-(prop-2-yn-1-ylamino)-ethyl)-2,3,3a,4,5,6-hexahydro-1H-indole-3a-carboxylate)

Compound 12a (18.85 mg, 93%) was prepared according to the general procedure D: 93% yield; ¹H NMR (500 MHz, CDCl₃) δ 7.25–7.17 (m, 2H), 6.87–6.78 (m, 2H), 4.99 (t, J = 3.7 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H), 4.44 (d, J = 15.1 Hz, 1H), 4.12–3.95 (m, 3H), 3.78 (s, 3H), 2.99 (dd, J = 7.8, 5.6 Hz, 1H), 2.65 (dd, J = 15.1, 7.8 Hz, 1H), 2.56 (dt, J = 12.4, 3.1 Hz, 1H), 2.26–2.17 (m, 2H), 2.17–2.00 (m, 2H), 1.85–1.74 (m, 1H), 1.57–1.36 (m, 2H), 1.12 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 171.4, 170.6, 159.1, 138.2, 129.2, 128.1, 113.9, 102.0, 79.7, 71.5, 61.4, 55.4, 52.3, 48.5, 43.8, 33.4, 30.3, 29.4, 22.9, 19.5, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₄H₂₉N₂O₅ 425.2076, found 425.2066.

Pyrrolidinone-Containing Amide 12b

Compound 12b (18.02 mg, 85%) was prepared according to the general procedure D: ¹H NMR (500 MHz, CDCl₃) δ 7.20–7.11 (m, 2H), 6.87–6.81 (m, 2H), 6.76 (t, J = 5.7 Hz, 1H), 5.08 (dd, J = 8.6, 4.4 Hz, 1H), 4.73 (d, J = 15.4 Hz, 1H), 4.52 (d, J = 15.4 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 3.33–3.17 (m, 2H), 3.07 (dd, J = 8.2, 4.8 Hz, 1H), 2.56 (dd, J = 15.0, 8.2 Hz, 1H), 2.50–2.43 (m, 1H), 2.20–2.07 (m, 2H), 1.92–1.82 (m, 1H), 1.82–1.70 (m, 1H), 1.70–1.61 (m, 1H), 1.61–1.45 (m, 3H), 1.41–1.21 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 171.5, 170.6, 158.9, 142.5, 128.5, 127.9, 113.9, 105.8, 55.7, 55.4, 52.1, 49.3, 43.8, 39.6, 35.2, 33.9, 31.7, 27.4, 27.2, 26.2, 20.2, 13.9; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₅H₃₅N₂O₅ 443.2546, found 443.2538.

Pyrrolidinone-Containing Amide 12c

Compound 12c (19.75 mg, 88%) was prepared according to the general procedure D: ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.22 (m, 3H), 7.19–7.14 (m, 2H), 7.08 (t, J = 6.2 Hz, 1H), 5.15 (dd, J = 8.7, 4.4 Hz, 1H), 3.76 (ddd, J = 13.6, 10.0, 6.3 Hz, 1H), 3.70 (s, 3H), 3.54 (ddd, J = 13.7, 9.9, 5.5 Hz, 1H), 3.48–3.29 (m, 4H), 3.27–3.15 (m, 2H), 3.14–3.08 (m, 1H), 2.85 (ddd, J = 13.5, 10.1, 5.6 Hz, 1H), 2.77 (ddd, J = 13.5, 10.0, 6.3 Hz, 1H), 2.53 (dd, J = 15.4, 7.3 Hz, 1H), 2.50–2.44 (m, 1H), 2.41 (t, J = 8.1 Hz, 2H), 2.30–2.18 (m, 1H), 2.12 (dd, J = 15.4, 6.2 Hz, 1H), 2.09–2.00 (m, 2H), 1.99–1.84 (m, 2H), 1.82–1.63 (m, 5H), 1.56 (ddd, J = 13.7, 12.2, 3.4 Hz, 1H), 1.38–1.25 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 173.7, 171.5, 170.5, 142.9, 137.2, 132.4, 130.3, 128.7, 103.9, 55.5, 52.3, 48.7, 47.5, 41.5, 39.8, 36.2, 35.5, 33.7, 31.7, 31.1, 27.5, 27.4, 26.6, 26.2, 18.1. MS (ESI) calcd for C₂₈H₃₆ClN₃O₅ 529.23 (M⁺), found 530.18 (M + H)⁺.

Pyrrolidinone-Containing Amide 12d

Compound 12d (22.01 mg, 72%) was prepared according to the general procedure D: ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.20 (m, 6H), 5.71 (ddt, J = 17.3, 10.3, 5.1 Hz, 1H), 5.22–5.15 (m, 3H), 4.86 (t, J = 9.2 Hz, 1H), 4.48 (dd, J = 14.8, 5.9 Hz, 1H), 4.41 (dd, J = 14.8, 5.5 Hz, 2H), 4.19–4.10 (m, 3H), 3.04 (dd, J = 8.4, 4.6 Hz, 1H), 2.71 (dd, J = 15.3, 8.4 Hz, 1H), 2.61 (ddd, J = 14.4, 6.4, 2.2 Hz, 1H), 2.22 (dd, J = 15.3, 4.6 Hz, 1H), 2.07 (ddd, J = 9.1, 6.8, 3.5 Hz, 2H), 1.77–1.57 (m, 5H), 1.54–1.38 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 171.6, 170.6, 140.4, 138.4, 131.0, 128.7, 127.9, 127.4, 117.0, 104.1, 61.5, 54.7, 48.0, 43.9, 42.8, 34.7, 27.8, 26.5, 23.1, 22.6, 14.2; MS (ESI) calcd for C₂₅H₃₂N₂O₄ 424.24 (M⁺), found 425.34 (M + H)⁺.

Pyrrolidinone-Containing Amide 12e

Compound 12e was prepared according to the general procedure D from carboxylic acid 7b and amine 11x: ¹H NMR (500 MHz, CDCl₃) δ 7.33 (td, J = 7.5, 1.5 Hz, 2H), 7.29–7.18 (m, 5H), 6.89–6.82 (m, 2H), 4.98 (d, J = 3.8 Hz, 1H), 4.81 (dd, J = 15.2, 2.9 Hz, 2H), 4.47 (dd, J = 15.2, 7.9 Hz, 1H), 4.16–3.90 (m, 2H), 3.80 (s, 3H), 3.40 (dd, J = 8.6, 4.2 Hz, 1H), 3.22–3.10 (m, 1H), 3.01 (m, 1H), 2.81–2.59 (m, 2H), 2.33 (ddd, J = 17.0, 8.7, 2.4 Hz, 1H), 2.19–2.01 (m, 2H), 1.96–1.86 (m, 1H), 1.86–1.75 (m, 1H), 1.75–1.43 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 174.4, 172.1, 172.0, 168.6, 168.6, 158.9, 145.4, 145.3, 138.7, 129.2, 129.1, 128.7, 128.5, 126.9, 126.6, 113.9, 113.9, 101.2, 61.1, 61.1, 55.4, 52.5, 52.4, 47.9, 47.9, 46.3, 46.2, 43.7, 43.0, 43.0, 43.0, 43.0, 33.8, 33.7, 33.0, 33.0, 31.0, 30.2, 30.1, 22.9, 22.9, 19.8, 19.8, 14.3, 14.3. MS (ESI) calcd for C₃₂H₃₈N₂O₅ 530.28 (M⁺), found 531.48 (M + H)⁺.

Pyrrolidinone-Containing Amide 12f

Compound 12f was prepared according to the general procedure D from carboxylic acid 7e and amine 11u. ¹H NMR (500 MHz, CDCl₃) δ 7.20–7.14 (m, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.05 (dd, J = 8.9, 4.3 Hz, 1H), 4.73 (d, J = 15.6 Hz, 1H), 4.55 (d, J = 15.5 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 3.62–3.57 (m, 1H), 3.57–3.50 (m, 1H), 3.45–3.33 (m, 2H), 2.91 (dd, J = 16.7, 4.6 Hz, 1H), 2.64–2.56 (m, 1H), 2.31 (dd, J = 16.7, 7.3 Hz, 1H), 2.15–2.05 (m, 1H), 1.92–1.79 (m, 2H), 1.70–1.51 (m, 7H), 1.30–1.18 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 172.0, 168.2, 158.7, 143.1, 128.4, 128.3, 128.1, 113.9, 113.8, 104.9, 55.7, 55.2, 51.9, 48.5, 46.5, 43.6, 43.2, 35.8, 30.3, 27.6, 27.4, 26.3, 26.1, 25.5, 24.6; MS (ESI) calcd for C₂₆H₃₄N₂O₅ 454.25 (M⁺), found 455.41 (M + H)⁺.

Pyrrolidinone-Containing Amide 12g

Compound 12g was prepared according to the general procedure D from carboxylic acid 7a and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 6.73 (t, J = 5.5 Hz, 1H), 5.81–5.69 (m, 1H), 5.27 (d, J = 17.2 Hz, 1H), 5.19 (dd, J = 10.3, 1.5 Hz, 1H), 5.02 (t, J = 3.7 Hz, 1H), 4.28 (dd, J = 15.9, 5.3 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.00–3.89 (m, 1H), 3.33–3.18 (m, 2H), 2.97 (dd, J = 7.6, 5.8 Hz, 1H), 2.63–2.52 (m, 2H), 2.27–2.06 (m, 3H), 1.89–1.79 (m, 1H), 1.69–1.58 (m, 1H), 1.57–1.36 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H), 0.91 (d, J = 6.6 Hz, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.6, 170.7, 138.3, 131.6, 117.7, 101.7, 61.4, 52.4, 48.6, 43.0, 38.4, 38.2, 33.6, 30.2, 26.0, 22.9, 22.6, 22.6, 19.6, 14.3; MS (ESI) calcd for C₂₁H₃₂N₂O₄ 376.24 (M⁺), found 377.39 (M + H)⁺.

Pyrrolidinone-Containing Amide 12h

Compound 12h was prepared according to the general procedure D from carboxylic acid 7a and amine 11e: ¹H NMR (500 MHz, CDCl₃) δ 7.25–7.17 (m, 2H), 6.97 (dd, J = 3.4, 1.2 Hz, 1H), 6.93 (dd, J = 5.1, 3.4 Hz, 1H), 5.78–5.68 (m, 1H), 5.25 (d, J = 17.2 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H), 5.01 (t, J = 3.7 Hz, 1H), 4.67–4.53 (m, 2H), 4.26 (dd, J = 15.8, 5.3 Hz, 1H), 4.14–4.06 (m, 2H), 3.97–3.89 (m, 1H), 2.98 (dd, J = 7.6, 5.8 Hz, 1H), 2.63 (dd, J = 15.1, 7.7 Hz, 1H), 2.55 (dt, J = 12.5, 3.0 Hz, 1H), 2.24–2.15 (m, 1H), 2.15–2.05 (m, 1H), 1.87–1.78 (m, 1H), 1.58–1.39 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.9, 171.5, 170.5, 141.1, 138.2, 131.6, 126.9, 126.0, 125.1, 117.7, 101.8, 61.5, 52.4, 48.4, 43.0, 38.5, 33.5, 30.3, 22.9, 19.6, 14.2; MS(ESI) calcd for C₂₁H₂₆N₂O₄S 402.16 (M⁺), found 403.33 (M + H)⁺.

Pyrrolidinone-Containing Amide 12i

Compound 12i was prepared according to the general procedure D from carboxylic acid 7h and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 7.15–7.08 (m, 3H), 6.90–6.77 (m, 5H), 4.80 (dd, J = 10.1, 8.2 Hz, 1H), 4.67 (d, J = 15.5 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.15–4.01 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H), 3.08 (dd, J = 8.4, 4.6 Hz, 1H), 2.72 (dd, J = 15.2, 8.4 Hz, 1H), 2.58 (ddd, J = 14.6, 6.7, 2.3 Hz, 1H), 2.22 (dd, J = 15.2, 4.6 Hz, 1H), 2.05–1.91 (m, 2H), 1.77–1.49 (m, 3H), 1.39–1.23 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 171.5, 170.5, 158.9, 149.2, 148.4, 140.2, 131.1, 128.3, 127.7, 120.1, 114.0, 111.3, 111.2, 104.6, 61.5, 56.0, 56.0, 55.4, 54.6, 48.0, 43.7, 43.6, 37.5, 34.8, 27.8, 26.4, 23.1, 22.5, 14.2; MS (ESI) calcd for C₃₂H₄₀N₂O₇ 564.28 (M⁺), found 565.4 (M + H)⁺.

Pyrrolidinone-Containing Amide 12j

Compound 12j was prepared according to the general procedure D from carboxylic acid 7h and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (t, J = 5.9 Hz, 1H), 7.57–7.48 (m, 3H), 7.47–7.41 (m, 1H), 7.16–7.10 (m, 2H), 6.86–6.79 (m, 2H), 4.83 (dd, J = 10.3, 8.1 Hz, 1H), 4.69 (d, J = 15.4 Hz, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.54 (dd, J = 15.2, 6.0 Hz, 1H), 4.46 (dd, J = 15.2, 5.8 Hz, 1H), 4.17–4.02 (m, 2H), 3.78 (s, 3H), 3.04 (dd, J = 8.8, 4.1 Hz, 1H), 2.77 (dd, J = 15.2, 8.8 Hz, 1H), 2.58 (ddd, J = 14.7, 6.3, 2.9 Hz, 1H), 2.25 (dd, J = 15.2, 4.1 Hz, 1H), 2.08–1.93 (m, 2H), 1.76–1.49 (m, 5H), 1.43–1.23 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.7, 171.4, 171.0, 159.0, 140.0, 139.7, 131.2 (q, 4JC–F = 1.3 Hz), 129.2, 128.3, 127.6, 131.0 (q, ²J_C–F = 32.2 Hz), 124.4 (q, ³J_C–F = 3.8 Hz), 124.2 (q, ³J_C–F = 3.8 Hz), 124.2 (q, ¹J_C–F = 273.4 Hz), 114.0, 105.0, 61.5, 55.4, 54.8, 47.9, 43.6, 43.3, 37.1, 34.7, 27.7, 26.5, 23.1, 22.5, 14.2; MS(ESI) calcd for C₃₁H₃₅F₃N₂O₅ 572.25 (M⁺), found 573.37 (M + H)⁺.

Pyrrolidinone-Containing Amide 12k

Compound 12k was prepared according to the general procedure D from carboxylic acid 7i and amine 11r: ¹H NMR (500 MHz, CDCl₃) δ 7.51 (dd, J = 1.8, 0.9 Hz, 1H), 7.29–7.23 (m, 2H), 7.22–7.15 (m, 2H), 7.07 (dd, J = 3.5, 0.9 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.86 (dd, J = 10.7, 7.5 Hz, 1H), 4.23–4.07 (m, 2H), 3.94–3.63 (m, 7H), 3.61–3.48 (m, 2H), 3.48–3.41 (m, 1H), 3.18 (dd, J = 8.3, 4.7 Hz, 1H), 2.92–2.79 (m, 2H), 2.75–2.63 (m, 2H), 2.34 (dd, J = 16.6, 8.4 Hz, 1H), 2.15–2.07 (m, 1H), 2.05–1.94 (m, 1H), 1.81–1.72 (m, 1H), 1.72–1.50 (m, 4H), 1.50–1.39 (m, 1H), 1.40–1.30 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.9, 172.2, 169.2, 159.3, 147.7, 144.1, 141.4, 136.8, 132.5, 130.6, 128.7, 117.3, 111.6, 102.2, 61.3, 54.2, 48.7, 45.5, 42.1, 41.3, 39.5, 31.9, 31.8, 28.4, 25.9, 23.2, 23.0, 14.3; MS (ESI) calcd for C₃₂H₃₈ClN₃O₆ 595.24 (M⁺), found 596.34 (M + H)⁺.

Pyrrolidinone-Containing Amide 12l

Compound 12l was prepared according to the general procedure D from carboxylic acid 7i and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.23 (m, 2H), 7.19–7.13 (m, 2H), 6.87 (t, J = 5.5 Hz, 1H), 6.11 (d, J = 3.1 Hz, 1H), 5.90 (dd, J = 3.1, 1.3 Hz, 1H), 4.86 (dd, J = 10.0, 8.3 Hz, 1H), 4.43 (dd, J = 15.4, 5.8 Hz, 1H), 4.36–4.28 (m, 1H), 4.20–4.07 (m, 2H), 3.76 (dt, J = 13.9, 8.0 Hz, 1H), 3.66 (dt, J = 14.1, 7.1 Hz, 1H), 2.96 (dd, J = 8.0, 5.2 Hz, 1H), 2.83 (t, J = 7.7 Hz, 2H), 2.64–2.53 (m, 2H), 2.27 (s, 3H), 2.18–2.03 (m, 3H), 1.71–1.58 (m, 5H), 1.48–1.37 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.6, 170.3, 151.9, 149.5, 140.7, 136.9, 132.6, 130.4, 128.8, 108.3, 106.4, 103.0, 61.5, 54.7, 47.9, 41.5, 37.8, 37.0, 34.6, 31.8, 27.9, 26.5, 23.1, 22.6, 14.2, 13.7; MS(ESI) calcd for C₂₉H₃₅ClN₂O₅ 526.22 (M⁺), found 527.33 (M + H)⁺.

Pyrrolidinone-Containing Amide 12m

Compound 12m was prepared according to the general procedure D from carboxylic acid 7g and amine 11m: ¹H NMR (500 MHz, CDCl₃) δ 7.25–7.18 (m, 1H), 7.14 (dd, J = 7.4, 1.8 Hz, 1H), 6.92–6.82 (m, 3H), 6.72 (t, J = 5.5 Hz, 1H), 5.72 (ddt, J = 17.2, 10.2, 5.0 Hz, 1H), 5.22–5.14 (m, 2H), 4.84 (dd, J = 10.0, 8.4 Hz, 1H), 4.21–3.99 (m, 3H), 3.83 (s, 4H), 3.60– 3.38 (m, 2H), 3.00 (dd, J = 7.4, 5.7 Hz, 1H), 2.92–2.76 (m, 3H), 2.70–2.53 (m, 2H), 2.16–1.97 (m, 3H), 1.74–1.53 (m, 5H), 1.52–1.37 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 171.7, 170.4, 157.6, 140.6, 131.0, 130.8, 127.9, 127.5, 120.7, 116.9, 110.5, 103.7, 61.4, 55.4, 54.6, 48.0, 42.7, 40.0, 34.7, 30.3, 27.9, 26.4, 23.1, 22.6, 14.2; MS (ESI) calcd for C₂₇H₃₆N₂O₅ 468.26 (M⁺), found 469.38 (M + H)⁺.

Pyrrolidinone-Containing Amide 12n

Compound 12n was prepared according to the general procedure D from carboxylic acid 7f and amine 11b: ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.23 (m, 3H), 7.22–7.13 (m, 2H), 6.82 (t, J = 5.9 Hz, 1H), 5.18 (dd, J = 8.6, 4.4 Hz, 1H), 3.85–3.71 (m, 1H), 3.68 (s, 3H), 3.60–3.49 (m, 1H), 3.21–3.10 (m, 1H), 3.09–3.01 (m, 1H), 2.98–2.92 (m, 1H), 2.91–2.82 (m, 1H), 2.81–2.74 (m, 1H), 2.54–2.45 (m, 2H), 2.33–2.19 (m, 1H), 2.14 (dd, J = 15.0, 4.8 Hz, 1H), 2.03–1.84 (m, 2H), 1.84–1.60 (m, 11H), 1.56 (ddd, J = 14.1, 12.3, 3.5 Hz, 1H), 1.51–1.41 (m, 1H), 1.40–1.28 (m, 1H), 1.28–1.09 (m, 4H), 1.00–0.86 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.0, 171.4, 170.6, 142.6, 137.0, 132.5, 130.3, 128.8, 104.5, 55.9, 52.2, 49.1, 46.2, 41.6, 38.0, 35.2, 33.8, 31.7, 31.0, 27.4, 27.2, 26.6, 26.2, 26.0; MS(ESI) calcd for C₂₈H₃₇ClN₂O₄ 500.24 (M⁺), found 501.14 (M + H)⁺.

Pyrrolidinone-Containing Amide 12o

Compound 12o was prepared according to the general procedure D from carboxylic acid 7d and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 6.97–6.88 (m, 1H), 5.70 (ddt, J = 17.3, 10.3, 5.1 Hz, 1H), 5.21 (ddd, J = 17.3, 1.6 Hz, 1H), 5.16 (ddd, J = 10.3, 1.5 Hz, 1H), 5.12 (dd, J = 8.6, 4.4 Hz, 1H), 4.19 (ddt, J = 16.4, 5.1, 1.8 Hz, 1H), 4.04 (ddt, J = 16.2, 5.2, 1.7 Hz, 1H), 3.67 (s, 3H), 3.02–2.95 (m, 2H), 2.88 (dd, J = 13.4, 6.0 Hz, 1H), 2.54 (dd, J = 15.0, 8.4 Hz, 1H), 2.51–2.45 (m, 1H), 2.25–2.12 (m, 2H), 1.99–1.92 (m, 4H), 1.92–1.83 (m, 1H), 1.82–1.64 (m, 6H), 1.64 (s, 0H), 1.50–1.45 (m, 7H), 1.37–1.24 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.4, 170.8, 142.6, 131.2, 117.1, 105.4, 55.7, 52.2, 51.5, 49.3, 42.9, 40.3, 37.1, 35.2, 33.8, 33.8, 28.4, 27.4, 27.2, 26.1; MS(ESI) calcd for C₂₇H₃₈N₂O₄ 454.28 (M⁺), found 455.36 (M + H)⁺.

Pyrrolidinone-Containing Amide 12p

Compound 12p was prepared according to the general procedure D from carboxylic acid 7d and amine 11q: ¹H NMR (500 MHz, CDCl₃) δ 5.69 (ddt, J = 17.2, 10.3, 5.0 Hz, 1H), 5.20 (ddd, J = 17.3, 1.6 Hz, 1H), 5.17–5.09 (m, 2H), 4.20–4.13 (m, 1H), 4.09–4.00 (m, 1H), 3.78–3.59 (m, 9H), 3.58–3.37 (m, 1H), 3.29 (dd, J = 7.0, 5.0 Hz, 1H), 2.83 (dd, J = 16.5, 5.1 Hz, 1H), 2.55 (dd, J = 11.3, 5.0 Hz, 1H), 2.30 (dd, J = 16.5, 6.9 Hz, 1H), 2.24–2.14 (m, 1H), 1.96–1.84 (m, 3H), 1.75–1.65 (m, 3H), 1.65–1.54 (m, 2H), 1.35–1.24 (m, 1H), 1.01–0.95 (m, 2H), 0.81–0.73 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 173.4, 172.4, 172.2, 171.9, 171.1, 169.0, 142.9, 131.2, 116.7, 105.6, 104.8, 55.6, 52.0, 48.5, 48.2, 45.2, 42.7, 41.9, 41.7, 36.1, 30.1, 27.6, 27.4, 26.1, 11.0, 7.6; MS(ESI) calcd for C₂₄H₃₃N₃O₅ 443.24 (M⁺), found 444.35 (M + H)⁺.

Pyrrolidinone-Containing Amide 12q

Compound 12q was prepared according to the general procedure D from carboxylic acid 7c and amine 11v: ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.22 (m, 3H), 7.17 (dq, J = 9.1, 4.0, 3.3 Hz, 3H), 5.01 (t, J = 3.7 Hz, 1H), 4.13–4.05 (m, 2H), 3.94–3.82 (m, 2H), 3.72 (q, J = 4.0 Hz, 2H), 3.42 (ddd, J = 13.8, 10.4, 4.9 Hz, 1H), 3.28 (dd, J = 8.6, 4.4 Hz, 1H), 2.93–2.72 (m, 3H), 2.66–2.53 (m, 7H), 2.28–2.08 (m, 3H), 1.88–1.80 (m, 1H), 1.60–1.43 (m, 2H), 1.34–1.22 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.6, 172.2, 168.8, 138.6, 137.2, 132.4, 130.2, 128.8, 100.6, 61.2, 52.7, 48.4, 47.7, 45.0, 41.4, 32.2, 31.0, 30.2, 27.7, 27.5, 23.0, 19.9, 14.4; MS (ESI) calcd for C₂₅H₃₁ClN₂O₄S 490.17 (M⁺), found 491.28 (M + H)⁺.

Pyrrolidinone-Containing Amide 12r

Compound 12r was prepared according to the general procedure D from carboxylic acid 7c and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.23 (m, 5H), 7.22–7.13 (m, 7H), 6.77 (t, J = 5.7 Hz, 1H), 5.05 (t, J = 3.7 Hz, 1H), 4.17–4.06 (m, 2H), 3.88 (ddd, J = 13.8, 10.7, 6.3 Hz, 1H), 3.44 (ddd, J = 13.8, 10.6, 5.2 Hz, 1H), 3.35–3.19 (m, 3H), 2.98–2.76 (m, 3H), 2.68–2.51 (m, 5H), 2.31–2.20 (m, 1H), 2.21–2.08 (m, 2H), 1.87 (ddt, J = 13.6, 6.5, 3.3 Hz, 1H), 1.74–1.63 (m, 2H), 1.62–1.50 (m, 3H), 1.46 (ddd, J = 15.4, 10.1, 2.9 Hz, 1H), 1.35–1.25 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.5, 170.8, 142.3, 138.2, 137.1, 132.5, 130.2, 128.8, 128.5, 128.4, 125.9, 101.0, 61.5, 52.6, 48.5, 41.5, 39.7, 35.6, 33.5, 32.2, 30.2, 29.2, 28.8, 23.0, 19.7, 14.3; MS (ESI) calcd for C₃₁H₃₇ClN₂O₄ 536.24 (M⁺), found 537.47 (M + H)⁺.

Piperidinone-Containing Amide 13a ((3RS,4aSR)-Ethyl 1-Benzyl-3-(2-(4-(furan-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-oxo-2,3,4,4a,5,6-hexahydro-1H-cyclopenta[b]pyridine-4a-carboxylate)

Compound 13a was prepared according to the general procedure D from carboxylic acid 8f and amine 11r: ¹H NMR (500 MHz, CDCl₃) δ 7.50 (dd, J = 1.7, 0.8 Hz, 1H), 7.29 (d, J = 4.3 Hz, 4H), 7.24–7.18 (m, 1H), 7.04 (dd, J = 3.5, 0.9 Hz, 1H), 6.49 (dd, J = 3.5, 1.8 Hz, 1H), 5.00 (dd, J = 3.2, 1.8 Hz, 1H), 4.95 (d, J = 15.5 Hz, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.19–4.05 (m, 2H), 3.81 (s, 4H), 3.74–3.63 (m, 2H), 3.57 (t, J = 5.2 Hz, 2H), 2.99–2.90 (m, 2H), 2.79–2.73 (m, 1H), 2.54 (dd, J = 12.7, 5.1 Hz, 1H), 2.44–2.35 (m, 1H), 2.32 (dd, J = 12.7, 7.0 Hz, 1H), 2.25 (ddd, J = 15.4, 8.6, 3.2 Hz, 1H), 2.05–1.98 (m, 1H), 1.91–1.81 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 170.7, 169.6, 159.3, 147.7, 144.1, 141.5, 137.2, 128.5, 127.1, 127.0, 127.0, 119.4, 117.2, 111.6, 107.8, 61.4, 54.5, 47.8, 45.5, 43.8, 41.8, 37.0, 36.8, 35.9, 35.1, 29.1, 14.3; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₉H₃₄N₃O₆ 520.2448, found 520.2452.

Piperidinone-Containing Amide 13b

Compound 13b was prepared according to the general procedure D from carboxylic acid 8f and amine 11m: ¹H NMR (500 MHz, CDCl₃) δ 7.32–7.27 (m, 2H), 7.25–7.19 (m, 3H), 7.18 (dd, J = 6.8, 1.4 Hz, 1H), 7.11 (dd, J = 7.4, 1.8 Hz, 1H), 6.90–6.82 (m, 2H), 6.08 (t, J = 5.6 Hz, 1H), 4.98 (dd, J = 3.2, 1.7 Hz, 1H), 4.92–4.86 (m, 2H), 4.19–4.07 (m, 2H), 3.82 (s, 3H), 3.53–3.37 (m, 2H), 2.92–2.85 (m, 1H), 2.78 (t, J = 6.9 Hz, 2H), 2.68 (dd, J = 14.7, 5.6 Hz, 1H), 2.59–2.48 (m, 2H), 2.42–2.29 (m, 2H), 2.24 (ddd, J = 14.9, 8.6, 3.2 Hz, 1H), 1.90–1.82 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 170.9, 170.7, 157.6, 141.5, 136.9, 130.7, 128.5, 127.9, 127.5, 127.1, 127.0, 120.7, 110.5, 107.8, 61.4, 55.4, 54.6, 47.8, 39.8, 38.5, 37.5, 37.0, 35.7, 30.4, 29.0, 14.3; MS(ESI) calcd for C₂₉H₃₄N₂O₅ 490.25 (M⁺), found 491.28 (M + H)⁺, 513.24 (M + Na)⁺.

Piperidinone-Containing Amide 13c

Compound 13c was prepared according to the general procedure D from carboxylic acid 8g and amine 11e: ¹H NMR (500 MHz, CDCl₃) δ 7.19 (dd, J = 4.8, 1.5 Hz, 1H), 6.95–6.89 (m, 2H), 6.76–6.69 (m, 3H), 5.91 (s, 2H), 5.03 (t, J = 2.3 Hz, 1H), 4.83 (d, J = 15.4 Hz, 1H), 4.70 (d, J = 15.3 Hz, 1H), 4.57 (d, J = 5.5 Hz, 2H), 4.19–4.07 (m, 2H), 3.47 (s, 1H), 2.91 (dq, J = 13.1, 5.4 Hz, 1H), 2.81 (dd, J = 14.6, 5.0 Hz, 1H), 2.56 (ddd, J = 14.4, 7.8, 5.5 Hz, 2H), 2.46–2.31 (m, 2H), 2.27 (ddd, J = 15.3, 8.7, 3.3 Hz, 1H), 1.93–1.81 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 170.9, 170.8, 147.9, 146.7, 141.2, 141.1, 130.7, 127.0, 126.0, 125.2, 120.4, 108.2, 107.7, 101.1, 61.5, 54.6, 47.5, 38.4, 38.2, 37.6, 37.0, 35.7, 29.1, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₆H₂₉N₂O₆S 497.1746, found 497.1740.

Piperidinone-Containing Amide 13d

Compound 13d was prepared according to the general procedure D from carboxylic acid 8g and amine 11k: ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.26 (m, 2H), 7.24 (td, J = 6.5, 1.7 Hz, 3H), 6.76–6.69 (m, 3H), 5.89 (s, 2H), 5.03 (dd, J = 3.2, 1.8 Hz, 1H), 4.81 (d, J = 15.3 Hz, 1H), 4.69 (d, J = 15.3 Hz, 1H), 4.40 (d, J = 5.6 Hz, 2H), 4.18–4.08 (m, 2H), 3.46 (s, 1H), 2.95–2.88 (m, 1H), 2.83 (dd, J = 14.7, 5.0 Hz, 1H), 2.57 (ddd, J = 14.7, 5.5, 2.6 Hz, 2H), 2.45–2.36 (m, 1H), 2.33 (dd, J = 12.7, 7.0 Hz, 1H), 2.27 (ddd, J = 15.3, 8.7, 3.2 Hz, 1H), 1.92–1.82 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.2, 170.9, 147.9, 146.7, 141.2, 138.4, 130.6, 128.8, 127.8, 127.5, 120.4, 108.3, 108.2, 107.7, 101.1, 61.5, 54.5, 47.6, 43.7, 38.2, 37.6, 37.0, 35.7, 29.1, 14.2; MS(ESI) calcd for C₂₈H₃₀N₂O₆ 490.21 (M⁺), found 491.22 (M + H)⁺, 513.21 (M + Na)⁺.

Piperidinone-Containing Amide 13e

Compound 13e was prepared according to the general procedure D from carboxylic acid 8h and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 7.33 (d, J = 0.9 Hz, 1H), 6.37 (s, 1H), 6.32–6.29 (m, 1H), 6.28–6.25 (m, 1H), 5.23 (t, J = 2.4 Hz, 1H), 4.94 (d, J = 15.5 Hz, 1H), 4.78 (d, J = 15.7 Hz, 1H), 4.17–4.08 (m, 2H), 4.05–3.97 (m, 1H), 3.96–3.87 (m, 1H), 3.48 (s, 1H), 2.90–2.82 (m, 1H), 2.75–2.68 (m, 1H), 2.58–2.51 (m, 2H), 2.49–2.40 (m, 1H), 2.38–2.28 (m, 2H), 2.21–2.17 (m, 1H), 1.91–1.82 (m, 1H), 1.77 (dd, J = 13.5, 12.5 Hz, 1H), 1.21–1.15 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 170.8, 170.4, 150.4, 141.9, 141.1, 110.5, 108.2, 108.0, 79.8, 71.5, 61.5, 54.6, 41.2, 38.3, 37.6, 36.9, 35.8, 29.2, 29.1, 14.2; MS(ESI) calcd for C₂₁H₂₄N₂O₅ 384.17 (M⁺), found 407.16 (M + Na)⁺.

Piperidinone-Containing Amide 13f

Compound 13f was prepared according to the general procedure D from carboxylic acid 8h and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.32–7.27 (m, 1H), 6.73 (s, 1H), 6.28 (dd, J = 3.1, 1.8 Hz, 1H), 6.25 (dd, J = 3.3, 1.0 Hz, 1H), 5.16 (dd, J = 3.2, 1.8 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.15–4.05 (m, 2H), 3.46 (s, 1H), 3.36 (t, J = 7.1 Hz, 2H), 3.31 (t, J = 6.4 Hz, 2H), 3.21–3.07 (m, 2H), 2.90–2.81 (m, 1H), 2.66–2.55 (m, 2H), 2.49 (dd, J = 12.8, 5.7 Hz, 1H), 2.46–2.35 (m, 5H), 2.34–2.24 (m, 2H), 2.09–1.96 (m, 2H), 1.88–1.73 (m, 2H), 1.69–1.59 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 174.2, 171.1, 170.2, 150.7, 141.7, 141.3, 110.5, 107.9, 107.3, 61.4, 54.6, 47.5, 41.1, 39.9, 38.5, 37.2, 37.0, 36.0, 35.9, 31.1, 29.1, 26.7, 18.1, 14.2; MS(ESI) calcd for C₂₅H₃₃N₃O₆ 471.24 (M⁺), found 472.25 (M + H)⁺, 494.24 (M + Na)⁺.

Piperidinone-Containing Amide 13g

Compound 13g was prepared according to the general procedure D from carboxylic acid 8i and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 6.85–6.74 (m, 3H), 5.42–5.37 (m, 1H), 5.06 (t, J = 2.4 Hz, 1H), 4.40 (dd, J = 14.4, 6.0 Hz, 1H), 4.27 (dd, J = 14.6, 5.4 Hz, 1H), 4.19–4.09 (m, 2H), 3.91–3.81 (m, 7H), 3.77 (ddd, J = 13.2, 10.6, 5.8 Hz, 1H), 3.47 (ddd, J = 13.2, 10.7, 5.3 Hz, 1H), 2.85–2.77 (m, 1H), 2.69 (dd, J = 14.6, 4.8 Hz, 1H), 2.61–2.41 (m, 3H), 2.38–2.27 (m, 2H), 2.09 (m, 2H), 2.00–1.89 (m, 4H), 1.85 (dt, J = 13.0, 9.4 Hz, 1H), 1.74 (t, J = 13.0 Hz, 1H), 1.64–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.1, 170.1, 149.2, 148.4, 141.0, 135.0, 131.2, 122.8, 120.1, 111.2, 111.1, 106.8, 61.5, 56.0, 56.0, 54.4, 43.5, 43.1, 38.7, 37.6, 37.0, 35.9, 34.5, 29.1, 28.6, 25.4, 23.0, 22.4, 14.3; MS(ESI) calcd for C₃₀H₄₀N₂O₆ 524.29 (M⁺), found 525.29 (M + H)⁺.

Piperidinone-Containing Amide 13h

Compound 13h was prepared according to the general procedure D from carboxylic acid 8i and amine 11s: ¹H NMR (500 MHz, CDCl₃) δ 5.43 (dd, J = 3.3, 1.8 Hz, 1H), 5.07 (t, J = 2.3 Hz, 1H), 4.21–4.08 (m, 4H), 3.88 (ddd, J = 13.3, 10.7, 5.6 Hz, 1H), 3.66–3.31 (m, 9H), 2.85–2.70 (m, 3H), 2.55–2.41 (m, 2H), 2.39–2.26 (m, 3H), 2.25–2.08 (m, 2H), 2.05–1.92 (m, 4H), 1.91–1.77 (m, 2H), 1.66–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.32–1.18 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 169.7, 169.4, 155.3, 141.1, 135.1, 122.5, 106.0, 61.6, 61.2, 54.2, 45.1, 43.5, 43.0, 41.3, 37.5, 36.9, 36.5, 35.8, 35.2, 34.4, 28.9, 28.4, 25.2, 22.9, 22.3, 14.6, 14.2; MS(ESI) calcd for C₂₈H₄₁N₃O₆ 515.30 (M⁺), found 516.32 (M + H)⁺, 538.3 (M + Na)⁺.

Piperidinone-Containing Amide 13i

Compound 13i was prepared according to the general procedure D from carboxylic acid 8a and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.24 (m, 2H), 7.14 (m, 3H), 6.79 (m, 3H), 6.03 (s, 1H), 5.09 (t, J = 2.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.01 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.64 (m, 1H), 3.23 (m, 2H), 2.79 (m, 3H), 2.66 (m, 1H), 2.60 (t, J = 7.6 Hz, 2H), 2.55 (dd, J = 13.0, 5.8 Hz, 1H), 2.48 (dd, J = 14.5, 5.3 Hz, 2H), 2.35 (m, 2H), 1.87 (m, 1H), 1.78 (t, J = 13.0 Hz, 1H), 1.60 (m, 2H), 1.50 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 171.0, 170.2, 149.1, 147.8, 142.2, 141.1, 131.7, 128.5, 128.4, 125.9, 120.8, 112.3, 111.5, 106.6, 61.5, 56.1, 56.1, 54.5, 45.9, 39.4, 38.5, 37.6, 36.9, 35.8, 35.6, 32.5, 29.4, 29.0, 28.7, 14.3; MS(ESI) calcd for C₃₃H₄₂N₂O₆ 562.30 (M⁺), found 563.37 (M + H)⁺.

Piperidinone-Containing Amide 13j

Compound 13j was prepared according to the general procedure D from carboxylic acid 8a and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 6.80 (m, 3H), 5.09 (t, J = 2.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.00 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.71 (m, 1H), 3.42 (m, 4H), 2.82 (m, 4H), 2.61 (dd, J = 15.9, 2.9 Hz, 1H), 2.49 (m, 2H), 2.35 (m, 2H), 1.90 (m, 6H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 170.5, 169.2, 149.0, 147.6, 141.5, 132.1, 120.7, 112.3, 111.4, 105.8, 61.3, 56.0, 56.0, 54.5, 46.6, 45.9, 45.7, 37.0, 36.6, 36.5, 36.0, 32.4, 29.1, 26.2, 24.5, 14.3; MS(ESI) calcd for C₂₇H₃₆N₂O₆ 484.26 (M⁺), found 485.32 (M + H)⁺, 507.31 (M + Na)⁺.

Piperidinone-Containing Amide 13k

Compound 13k was prepared according to the general procedure D from carboxylic acid 8j and amine : ¹H NMR (500 MHz, CDCl₃) δ 8.03–7.94 (m, 1H), 7.92–7.77 (m, 4H), 7.71 (d, J = 8.1 Hz, 1H), 7.59–7.32 (m, 7H), 7.25–7.20 (m, 1H), 6.29 (t, J = 5.1 Hz, 1H), 5.10 (d, J = 16.5 Hz, 1H), 5.03 (dd, J = 14.4, 6.5 Hz, 1H), 4.75 (d, J = 16.4 Hz, 1H), 4.72–4.65 (m, 2H), 4.18 (dq, J = 11.0, 7.2 Hz, 1H), 4.10 (dq, J = 10.8, 7.1 Hz, 1H), 3.02–2.89 (m, 2H), 2.65 (dd, J = 13.0, 5.5 Hz, 1H), 2.51 (dd, J = 14.0, 4.6 Hz, 1H), 2.39–2.28 (m, 2H), 2.25–2.16 (m, 1H), 2.01 (t, J = 13.0 Hz, 1H), 1.96–1.85 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 170.7, 170.5, 140.9, 134.1, 134.0, 133.8, 131.5, 130.9, 130.9, 129.0, 128.8, 128.6, 127.5, 127.0, 126.7, 126.1, 126.1, 125.7, 125.6, 125.6, 123.9, 122.8, 122.6, 108.3, 61.5, 54.5, 45.1, 41.6, 38.3, 38.0, 37.1, 35.5, 29.0, 14.3; MS(ESI) calcd for C₃₅H₃₄N₂O₄ 546.25 (M⁺), found 547.28 (M + H)⁺.

Piperidinone-Containing Amide 13l

Compound 13l was prepared according to the general procedure D from carboxylic acid 8j and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.3 Hz, 1H), 7.90–7.84 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55–7.39 (m, 4H), 5.45 (d, J = 16.4 Hz, 1H), 5.38 (d, J = 16.4 Hz, 1H), 4.84 (dd, J = 3.4, 1.7 Hz, 1H), 4.23–4.15 (m, 1H), 4.14–4.05 (m, 1H), 3.57–3.48 (m, 1H), 3.47–3.38 (m, 3H), 3.03–2.93 (m, 2H), 2.69–2.60 (m, 1H), 2.57 (dd, J = 12.7, 5.4 Hz, 1H), 2.40–2.30 (m, 2H), 2.28–2.15 (m, 2H), 1.99–1.88 (m, 3H), 1.88–1.78 (m, 2H), 1.26–1.19 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.7, 171.2, 169.2, 141.8, 133.8, 131.4, 131.0, 128.9, 127.3, 126.0, 125.8, 125.5, 123.5, 122.7, 107.8, 61.3, 54.6, 46.6, 46.0, 45.7, 37.2, 36.8, 36.5, 36.0, 29.1, 26.2, 24.5, 14.3; MS(ESI) calcd for C₂₈H₃₂N₂O₄ 460.24 (M⁺), found 461.26 (M + H)⁺, 483.25 (M + Na)⁺.

Piperidinone-Containing Amide 13m

Compound 13m was prepared according to the general procedure D from carboxylic acid 8k and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.33 (m, 1H), 7.23–7.16 (m, 2H), 6.16 (t, J = 5.4 Hz, 1H), 4.99–4.90 (m, 2H), 4.85 (dd, J = 3.2, 1.7 Hz, 1H), 4.27–4.12 (m, 2H), 4.07–3.94 (m, 2H), 2.95–2.87 (m, 1H), 2.82 (dd, J = 15.1, 5.0 Hz, 1H), 2.60–2.50 (m, 2H), 2.42–2.32 (m, 2H), 2.29–2.21 (m, 1H), 2.20 (t, J = 2.5 Hz, 1H), 1.98 (t, J = 13.0 Hz, 1H), 1.94–1.85 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 170.8, 170.6, 141.1, 133.3, 133.3, 132.4, 129.2, 128.5, 127.4, 108.1, 79.6, 71.7, 61.6, 54.6, 45.3, 37.8, 37.4, 37.1, 35.6, 29.3, 29.0, 14.4; MS(ESI) calcd for C₂₃H₂₄Cl₂N₂O₄ 462.11 (M⁺), found 533.39 (M + H)⁺, 555.38 (M + Na)⁺.

Piperidinone-Containing Amide 13n

Compound 13n was prepared according to the general procedure D from carboxylic acid 8k and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.34 (d, J = 2.1 Hz, 1H), 7.27–7.23 (m, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.74 (t, J = 6.2 Hz, 1H), 4.96–4.88 (m, 2H), 4.79 (dd, J = 3.2, 1.7 Hz, 1H), 4.24–4.11 (m, 2H), 3.38–3.26 (m, 4H), 3.21–3.11 (m, 2H), 2.92–2.85 (m, 1H), 2.78 (dd, J = 15.4, 5.6 Hz, 1H), 2.58–2.47 (m, 2H), 2.41–2.30 (m, 4H), 2.25–2.17 (m, 1H), 2.06–1.95 (m, 3H), 1.91–1.82 (m, 1H), 1.67–1.59 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 174.2, 170.9, 170.8, 141.4, 133.2, 133.1, 132.8, 129.0, 128.8, 127.4, 107.3, 61.5, 54.6, 47.5, 45.2, 39.8, 37.9, 37.1, 37.0, 35.8, 35.8, 31.0, 29.0, 26.6, 18.1, 14.4; MS(ESI) calcd for C₂₇H₃₃Cl₂N₃O₅ 549.18 (M⁺), found 550.18 (M + H)⁺.

Piperidinone-Containing Amide 13o

Compound 13o was prepared according to the general procedure D from carboxylic acid 8l and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 6.69 (t, J = 5.4 Hz, 1H), 5.25 (dd, J = 5.3, 2.8 Hz, 1H), 4.16 (dd, J = 7.0, 2.0 Hz, 1H), 4.14 (dd, J = 7.1, 1.9 Hz, 1H), 4.05–3.94 (m, 2H), 3.71 (ddd, J = 13.6, 10.5, 5.2 Hz, 1H), 3.64 (ddd, J = 13.7, 10.7, 5.7 Hz, 1H), 2.68–2.59 (m, 2H), 2.56–2.49 (m, 1H), 2.34 (dd, J = 13.1, 5.4 Hz, 1H), 2.31–2.21 (m, 2H), 2.17 (t, J = 2.6 Hz, 1H), 2.16–2.09 (m, 1H), 1.72–1.58 (m, 3H), 1.55–1.45 (m, 2H), 1.43–1.35 (m, 1H), 1.34–1.20 (m, 13H), 0.87 (t, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 171.0, 170.0, 136.2, 107.3, 79.8, 71.4, 61.6, 46.6, 44.2, 38.8, 37.3, 36.7, 35.0, 32.0, 29.5, 29.4, 29.2, 27.3, 27.0, 24.5, 22.8, 18.7, 14.4, 14.2; MS(ESI) calcd for C₂₅H₃₈N₂O₄ 430.28 (M⁺), found 431.29 (M + H)⁺.

Piperidinone-Containing Amide 13p

Compound 13p was prepared according to the general procedure D from carboxylic acid 8l and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 6.46 (t, J = 5.7 Hz, 1H), 6.04 (d, J = 3.0 Hz, 1H), 5.85 (dd, J = 3.1, 1.3 Hz, 1H), 5.22 (dd, J = 5.3, 2.8 Hz, 1H), 4.35 (dd, J = 15.5, 5.6 Hz, 1H), 4.29 (dd, J = 15.4, 5.4 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.71–3.58 (m, 2H), 2.70–2.60 (m, 2H), 2.56–2.49 (m, 1H), 2.39–2.32 (m, 1H), 2.31–2.20 (m, 5H), 2.18–2.09 (m, 1H), 1.73–1.64 (m, 2H), 1.62–1.54 (m, 1H), 1.54–1.34 (m, 3H), 1.33–1.18 (m, 13H), 0.87 (t, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 170.9, 169.9, 151.8, 149.7, 136.3, 108.1, 107.1, 106.3, 61.5, 46.6, 44.1, 38.7, 37.4, 36.7, 36.5, 35.0, 32.0, 29.5, 27.3, 26.8, 24.5, 22.8, 18.7, 14.3, 14.2, 13.7; MS(ESI) calcd for C₂₈H₄₂N₂O₅486.31 (M⁺), found 487.32 (M + H)⁺, 509.3 (M + Na)⁺.

Piperidinone-Containing Amide 13q

Compound 13q was prepared according to the general procedure D from carboxylic acid 8m and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 8.2, 6.9 Hz, 2H), 7.23–7.17 (m, 3H), 6.38 (t, J = 5.7 Hz, 1H), 5.39 (d, J = 16.0 Hz, 1H), 5.13 (dd, J = 5.2, 2.8 Hz, 1H), 4.54 (d, J = 16.1 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.44–3.29 (m, 3H), 3.28 (s, 3H), 3.27–3.20 (m, 1H), 2.79–2.68 (m, 2H), 2.59–2.51 (m, 1H), 2.42 (dd, J = 13.1, 5.3 Hz, 1H), 2.29–2.22 (m, 1H), 2.17–2.08 (m, 1H), 2.06–1.95 (m, 1H), 1.91 (t, J = 13.0 Hz, 1H), 1.76–1.67 (m, 2H), 1.68–1.60 (m, 1H), 1.52 (td, J = 13.6, 2.7 Hz, 1H), 1.40–1.30 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 170.9, 170.7, 137.7, 137.2, 128.6, 126.8, 126.2, 108.5, 71.4, 61.5, 58.8, 48.8, 46.8, 38.6, 37.8, 37.6, 36.6, 34.9, 29.3, 24.4, 18.7, 14.4; MS(ESI) calcd for C₂₅H₃₄N₂O₅ 442.25 (M⁺), found 443.27 (M + H)⁺, 465.23 (M + Na)⁺.

Piperidinone-Containing Amide 13r

Compound 13r was prepared according to the general procedure D from carboxylic acid 8m and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 8.2, 6.9 Hz, 2H), 7.23–7.17 (m, 3H), 6.38 (t, J = 5.7 Hz, 1H), 5.39 (d, J = 16.0 Hz, 1H), 5.13 (dd, J = 5.2, 2.8 Hz, 1H), 4.54 (d, J = 16.1 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.44–3.29 (m, 3H), 3.28 (s, 3H), 3.27–3.20 (m, 1H), 2.79–2.68 (m, 2H), 2.59–2.51 (m, 1H), 2.42 (dd, J = 13.1, 5.3 Hz, 1H), 2.29–2.22 (m, 1H), 2.17–2.08 (m, 1H), 2.06–1.95 (m, 1H), 1.91 (t, J = 13.0 Hz, 1H), 1.76–1.67 (m, 2H), 1.68–1.60 (m, 1H), 1.52 (td, J = 13.6, 2.7 Hz, 1H), 1.40–1.30 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 170.9, 170.7, 137.7, 137.2, 128.6, 126.8, 126.2, 108.5, 71.4, 61.5, 58.8, 48.8, 46.8, 38.6, 37.8, 37.6, 36.6, 34.9, 29.3, 24.4, 18.7, 14.4; MS(ESI) calcd for C₂₈H₃₇N₃O₅ 495.27 (M⁺), found 496.28 (M + H)⁺.

Piperidinone-Containing Amide 13s

Compound 13s was prepared according to the general procedure D from carboxylic acid 8n and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 6.74 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.67 (dd, J = 7.9, 1.7 Hz, 1H), 6.23 (t, J = 6.3 Hz, 1H), 5.92 (s, 2H), 5.23–5.13 (m, 2H), 4.57 (d, J = 15.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.00 (dd, J = 13.4, 6.8 Hz, 1H), 2.87–2.67 (m, 3H), 2.56 (dd, J = 13.8, 4.5 Hz, 1H), 2.41 (dd, J = 13.2, 5.4 Hz, 1H), 2.30–2.22 (m, 1H), 2.15 (dt, J = 18.3, 5.4 Hz, 1H), 2.09–1.98 (m, 1H), 1.97–1.84 (m, 4H), 1.74–1.55 (m, 8H), 1.55–1.46 (m, 1H), 1.45–1.41 (m, 6H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.2, 170.9, 148.0, 146.5, 137.0, 131.5, 119.6, 108.7, 108.4, 107.3, 101.0, 61.6, 51.1, 48.3, 46.8, 40.3, 38.8, 37.8, 37.1, 36.6, 34.9, 33.7, 28.4, 24.4, 18.7, 14.4; MS(ESI) calcd for C₃₃H₄₂N₂O₆ 562.30 (M⁺), found 563.31 (M + H)⁺.

Piperidinone-Containing Amide 13t

Compound 13t was prepared according to the general procedure D from carboxylic acid 8n and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 6.85 (d, J = 1.6 Hz, 1H), 6.80–6.70 (m, 2H), 5.95–5.87 (m, 2H), 5.31 (d, J = 15.9 Hz, 1H), 5.17 (dd, J = 5.2, 2.7 Hz, 1H), 4.42 (d, J = 15.8 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.51 (dt, J = 13.0, 6.8 Hz, 1H), 3.41 (p, J = 6.9, 6.3 Hz, 3H), 2.90 (dd, J = 16.5, 6.2 Hz, 1H), 2.73 (dtd, J = 12.4, 5.9, 3.3 Hz, 1H), 2.62 (dd, J = 16.4, 3.3 Hz, 1H), 2.36 (dd, J = 12.8, 5.8 Hz, 1H), 2.28–2.18 (m, 1H), 2.18–1.97 (m, 3H), 1.97–1.89 (m, 2H), 1.87–1.78 (m, 2H), 1.67–1.58 (m, 1H), 1.52 (td, J = 13.6, 2.7 Hz, 1H), 1.42–1.30 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.8, 171.1, 169.1, 148.0, 146.3, 137.6, 132.2, 119.5, 108.3, 108.2, 107.5, 100.9, 61.5, 48.9, 46.8, 46.6, 45.8, 36.7, 36.6, 36.4, 35.1, 26.2, 24.5, 24.5, 18.8, 14.4; MS(ESI) calcd for C₂₆H₃₂N₂O₆ 468.23 (M⁺), found 469.23 (M + H)⁺, 491.22 (M + Na)⁺.

Piperidinone-Containing Amide 13u

Compound 13u was prepared according to the general procedure D from carboxylic acid 8o and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.52–7.45 (m, 2H), 7.42–7.37 (m, 2H), 7.27 (dd, J = 1.8, 0.8 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 6.27 (dd, J = 3.2, 1.8 Hz, 1H), 6.22 (d, J = 3.1 Hz, 1H), 5.50 (dd, J = 5.2, 2.8 Hz, 1H), 5.22 (d, J = 15.8 Hz, 1H), 4.51 (d, J = 15.9 Hz, 1H), 4.43 (dd, J = 15.3, 6.3 Hz, 1H), 4.34 (dd, J = 15.3, 5.8 Hz, 1H), 4.15 (qd, J = 7.1, 1.8 Hz, 2H), 2.81–2.69 (m, 2H), 2.59–2.52 (m, 1H), 2.40 (dd, J = 13.1, 5.4 Hz, 1H), 2.30–2.20 (m, 2H), 2.12 (dddd, J = 18.0, 11.1, 6.4, 2.9 Hz, 1H), 1.78–1.64 (m, 2H), 1.50 (td, J = 13.6, 13.2, 2.6 Hz, 1H), 1.44–1.31 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.3, 170.5, 151.2, 141.6, 139.8, 136.9, 131.0, 131.0, 129.1, 124.3 (q, 3JC–F = 3.6 Hz), 124.2 (q, 3JC–F = 3.5 Hz), 124.2 (q, 1JC–F = 272.8 Hz), 110.6, 108.8, 107.9, 61.6, 46.8, 43.0, 42.1, 38.7, 37.6, 36.6, 34.8, 24.5, 18.6, 14.3; MS(ESI) calcd for C₂₇H₂₉F₃N₂O₅ 518.20 (M⁺), found 519.21 (M + H)⁺, 541.21 (M + Na)⁺.

Piperidinone-Containing Amide 13v

Compound 13v was prepared according to the general procedure D from carboxylic acid 8o and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (d, J = 1.9 Hz, 1H), 6.71 (t, J = 6.0 Hz, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.25 (d, J = 3.1 Hz, 1H), 5.41 (dd, J = 5.1, 2.7 Hz, 1H), 5.24 (d, J = 15.9 Hz, 1H), 4.51 (d, J = 15.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.36 (t, J = 7.1 Hz, 2H), 3.30 (t, J = 6.5 Hz, 2H), 3.22–3.06 (m, 2H), 2.78–2.70 (m, 1H), 2.60 (d, J = 5.3 Hz, 2H), 2.41–2.32 (m, 3H), 2.28–2.18 (m, 2H), 2.14–1.97 (m, 3H), 1.79–1.71 (m, 1H), 1.69–1.60 (m, 3H), 1.50 (td, J = 13.6, 2.6 Hz, 1H), 1.42–1.31 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.8, 174.3, 171.0, 170.2, 151.4, 141.4, 137.2, 110.6, 108.1, 107.7, 61.5, 47.4, 46.7, 42.2, 39.9, 38.6, 37.1, 36.7, 36.1, 34.9, 31.1, 26.8, 24.5, 18.7, 18.1, 14.3; MS(ESI) calcd for C₂₆H₃₅N₃O₆ 485.25 (M⁺), found 486.26 (M + H)⁺, 508.24 (M + Na)⁺.

Piperidinone-Containing Amide 13w

Compound 13w was prepared according to the general procedure D from carboxylic acid 8p and amine 11r: ¹H NMR (500 MHz, CDCl₃) δ 7.51–7.46 (m, 1H), 7.04 (d, J = 3.4 Hz, 1H), 6.82–6.78 (m, 3H), 6.49 (dt, J = 3.3, 1.4 Hz, 1H), 5.35 (dd, J = 5.2, 2.7 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.95–3.87 (m, 2H), 3.87–3.83 (m, 7H), 3.83–3.76 (m, 2H), 3.75–3.67 (m, 1H), 3.67–3.60 (m, 1H), 3.58–3.52 (m, 2H), 3.51–3.42 (m, 1H), 2.96–2.86 (m, 1H), 2.85–2.68 (m, 4H), 2.37 (dd, J = 12.8, 5.4 Hz, 1H), 2.33–2.22 (m, 2H), 2.22–2.15 (m, 1H), 1.82 (t, J = 12.6 Hz, 1H), 1.73–1.65 (m, 1H), 1.54 (td, J = 13.5, 13.0, 2.6 Hz, 1H), 1.47–1.39 (m, 1H), 1.30–1.21 (m, 4H), 1.19 (t, J = 7.0 Hz, 3H), 0.90–0.81 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 169.9, 169.5, 159.3, 149.0, 147.6, 144.1, 136.5, 132.2, 120.7, 117.2, 112.2, 111.6, 111.4, 106.8, 66.0, 61.5, 56.0, 56.0, 46.6, 45.6, 41.8, 36.8, 36.6, 35.3, 35.2, 32.6, 31.7, 24.6, 22.8, 18.8, 15.4, 14.4, 14.2; MS(ESI) calcd for C₃₃H₄₁N₃O₈ 607.29 (M⁺), found 608.35 (M + H)⁺, 630.31 (M + Na)⁺.

Piperidinone-Containing Amide 13x

Compound 13x was prepared according to the general procedure D from carboxylic acid 8p and amine 11q: ¹H NMR (500 MHz, CDCl₃) δ 6.80 (d, J = 3.2 Hz, 4H), 5.35 (dd, J = 5.3, 2.7 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 3.95–3.88 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.75–3.55 (m, 6H), 3.53–3.41 (m, 2H), 2.96–2.86 (m, 1H), 2.85–2.66 (m, 4H), 2.40–2.22 (m, 2H), 2.22–2.12 (m, 1H), 1.81 (t, J = 12.6 Hz, 1H), 1.70 (dq, J = 13.5, 5.3, 4.5 Hz, 2H), 1.54 (td, J = 13.5, 12.9, 2.6 Hz, 1H), 1.46–1.38 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.03–0.96 (m, 2H), 0.83–0.75 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 172.4, 170.0, 169.5, 149.0, 147.6, 136.5, 132.1, 120.7, 112.2, 111.3, 106.9, 61.5, 56.0, 56.0, 46.6, 45.6, 45.3, 41.6, 36.8, 36.6, 35.3, 35.2, 32.6, 24.6, 18.8, 14.4, 11.1, 7.8; MS(ESI) calcd for C₃₂H₄₃N₃O₇ 581.31 (M⁺), found 582.37 (M + H)⁺, 604.34 (M + Na)⁺.

Piperidinone-Containing Amide 13y

Compound 13y was prepared according to the general procedure D from carboxylic acid 8q and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.56–7.40 (m, 4H), 5.85 (d, J = 16.6 Hz, 1H), 5.04 (dd, J = 5.1, 2.8 Hz, 1H), 4.97 (d, J = 16.6 Hz, 1H), 4.27–4.14 (m, 2H), 3.64 (ddt, J = 9.2, 6.9, 4.7 Hz, 6H), 3.47 (dd, J = 6.1, 3.6 Hz, 2H), 2.97 (dd, J = 16.2, 6.4 Hz, 1H), 2.87–2.80 (m, 1H), 2.75 (dd, J = 16.2, 3.2 Hz, 1H), 2.47 (dd, J = 12.8, 5.7 Hz, 1H), 2.29 (dt, J = 13.3, 3.3 Hz, 1H), 2.16 (t, J = 12.8 Hz, 1H), 2.06 (dt, J = 18.1, 5.5 Hz, 1H), 2.02–1.93 (m, 1H), 1.69–1.54 (m, 2H), 1.44–1.34 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.7, 170.7, 169.4, 137.7, 133.8, 132.0, 130.5, 128.9, 127.1, 126.0, 125.5, 123.0, 122.7, 108.8, 67.0, 66.6, 61.6, 47.8, 46.9, 45.9, 42.0, 36.9, 36.8, 35.1, 34.8, 24.4, 18.8, 14.5; MS(ESI) calcd for C₂₉H₃₄N₂O₅ 490.25 (M⁺), found 491.28 (M + H)⁺, 513.27 (M + Na)⁺.

Piperidinone-Containing Amide 13z

Compound 13z was prepared according to the general procedure D from carboxylic acid 8q and amine 11p: ¹H NMR (500 MHz, CDCl₃) δ 8.02–7.95 (m, 1H), 7.91–7.85 (m, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.58–7.47 (m, 2H), 7.42 (dd, J = 8.2, 7.1 Hz, 1H), 7.23 (dd, J = 7.1, 1.4 Hz, 1H), 6.38 (t, J = 5.5 Hz, 1H), 5.86 (d, J = 16.7 Hz, 1H), 5.01 (dd, J = 5.1, 2.8 Hz, 1H), 4.96 (d, J = 16.7 Hz, 1H), 4.26–4.19 (m, 2H), 3.45–3.36 (m, 3H), 3.31 (t, J = 6.6 Hz, 2H), 3.29–3.21 (m, 1H), 2.85–2.77 (m, 2H), 2.58–2.45 (m, 2H), 2.30 (dd, J = 13.2, 3.5 Hz, 1H), 2.11–2.01 (m, 2H), 2.01–1.92 (m, 1H), 1.78–1.62 (m, 4H), 1.58 (td, J = 13.6, 2.8 Hz, 1H), 1.53–1.45 (m, 2H), 1.42–1.33 (m, 1H), 1.30 (t, J = 7.1 Hz, 4H), 0.87 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 170.8, 170.6, 137.4, 133.8, 131.7, 130.5, 129.0, 127.2, 126.1, 125.8, 125.7, 122.6, 122.5, 108.8, 71.0, 69.5, 61.6, 47.5, 47.0, 38.4, 38.1, 37.7, 36.6, 34.9, 31.9, 29.4, 24.3, 19.5, 18.7, 14.5, 14.0; MS(ESI) calcd for C₂₉H₃₄N₂O₅ 490.25 (M⁺), found 491.28 (M + H)⁺, 513.27 (M + Na)⁺.

Piperidinone-Containing Amide 13aa

Compound 13aa was prepared according to the general procedure D from carboxylic acid 8r and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 1.7 Hz, 1H), 7.23–7.17 (m, 2H), 6.20 (t, J = 5.9 Hz, 1H), 5.26 (d, J = 17.2 Hz, 1H), 4.91 (dd, J = 5.2, 2.8 Hz, 1H), 4.61 (d, J = 17.2 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.46–3.37 (m, 2H), 3.37–3.23 (m, 6H), 2.82 (dd, J = 15.0, 5.4 Hz, 1H), 2.74–2.67 (m, 1H), 2.47 (dd, J = 15.0, 4.3 Hz, 1H), 2.39 (dd, J = 13.1, 5.7 Hz, 1H), 2.27 (dd, J = 13.0, 3.3 Hz, 1H), 2.13 (dt, J = 17.8, 5.6 Hz, 1H), 2.08–1.97 (m, 2H), 1.77–1.63 (m, 2H), 1.54 (td, J = 13.7, 2.8 Hz, 1H), 1.35 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 170.8, 170.7, 137.1, 133.3, 133.0, 132.8, 129.1, 128.6, 127.5, 108.4, 71.6, 61.6, 58.9, 46.9, 46.7, 38.0, 37.8, 37.2, 36.4, 34.9, 29.3, 24.3, 18.7, 14.4; MS(ESI) calcd for C₂₅H₃₂Cl₂N₂O₅ 510.17 (M⁺), found 511.19 (M + H)⁺, 533.18 (M + Na)⁺.

Piperidinone-Containing Amide 13ab

Compound 13ab was prepared according to the general procedure D from carboxylic acid 8r and amine 11q: ¹H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.20 (dd, J = 8.3, 2.2 Hz, 1H), 5.32 (d, J = 17.2 Hz, 1H), 4.95 (dd, J = 5.3, 2.7 Hz, 1H), 4.54 (d, J = 17.2 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.76–3.56 (m, 6H), 3.56–3.42 (m, 2H), 3.08 (dd, J = 16.5, 5.7 Hz, 1H), 2.77–2.68 (m, 1H), 2.61 (dd, J = 16.6, 3.2 Hz, 1H), 2.34 (dd, J = 12.8, 5.7 Hz, 1H), 2.30–2.22 (m, 1H), 2.20–2.10 (m, 2H), 2.07–1.97 (m, 1H), 1.76–1.62 (m, 2H), 1.55 (td, J = 13.6, 2.8 Hz, 1H), 1.44–1.33 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.04–0.96 (m, 2H), 0.84–0.75 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 172.5, 170.8, 169.4, 137.3, 133.6, 132.9, 132.7, 129.0, 127.5, 108.4, 61.6, 47.2, 46.9, 45.2, 41.9, 41.6, 36.6, 35.0, 34.6, 24.4, 18.7, 14.5, 11.2, 7.8; MS(ESI) calcd for C₂₉H₃₅Cl₂N₃O₅ 575.20 (M⁺), found 576.22 (M + H)⁺, 598.18 (M + Na)⁺.

Piperidinone-Containing Amide 13ac

Compound 13ac was prepared according to the general procedure D from carboxylic acid 8s and amine 11b: ¹H NMR (500 MHz, CDCl₃) δ 6.56 (t, J = 6.0 Hz, 1H), 5.49 (t, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.60 (ddd, J = 14.2, 10.0, 5.4 Hz, 1H), 3.06 (dt, J = 13.2, 6.6 Hz, 1H), 2.99 (dt, J = 13.1, 6.3 Hz, 1H), 2.65–2.58 (m, 1H), 2.50 (d, J = 5.4 Hz, 2H), 2.27–2.17 (m, 1H), 2.13 (dd, J = 13.5, 4.2 Hz, 1H), 2.08–1.95 (m, 1H), 1.77–1.60 (m, 10H), 1.60–1.49 (m, 1H), 1.49–1.34 (m, 1H), 1.34–1.08 (m, 18H), 0.95–0.83 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 171.0, 169.2, 141.1, 113.5, 52.5, 51.7, 46.6, 45.1, 42.9, 40.1, 37.0, 35.8, 34.3, 31.9, 29.5, 29.4, 27.2, 26.9, 26.6, 26.5, 25.7, 25.5, 25.2, 24.7, 22.8, 14.2; MS(ESI) calcd for C₂₉H₄₈N₂O₄ 488.36 (M⁺), found 489.38 (M + H)⁺.

Piperidinone-Containing Amide 13ad

Compound 13ad was prepared according to the general procedure D from carboxylic acid 8s and amine 11u: ¹H NMR (500 MHz, CDCl₃) δ 5.47 (t, J = 7.1 Hz, 1H), 3.84–3.68 (m, 4H), 3.65–3.53 (m, 1H), 3.47–3.38 (m, 2H), 3.38–3.29 (m, 1H), 2.99 (dd, J = 16.3, 3.8 Hz, 1H), 2.82–2.73 (m, 1H), 2.33 (dd, J = 16.4, 8.3 Hz, 1H), 2.26–2.14 (m, 2H), 2.08–1.99 (m, 2H), 1.81–1.44 (m, 14H), 1.45–1.33 (m, 1H), 1.33–1.18 (m, 10H), 0.87 (t, J = 6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 171.0, 169.2, 141.1, 113.5, 52.5, 51.7, 46.6, 45.1, 42.9, 40.1, 37.0, 35.8, 34.3, 31.9, 29.5, 29.4, 27.2, 26.9, 26.6, 26.5, 25.7, 25.5, 25.2, 24.7, 22.8, 14.2; MS(ESI) calcd for C₂₇H₄₄N₂O₄ 460.33 (M⁺), found 461.35 (M + H)⁺, 483.32 (M + Na)⁺.

Piperidinone-Containing Amide 13ae

Compound 13ae was prepared according to the general procedure D from carboxylic acid 8c and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 8.2, 6.9 Hz, 2H), 7.24–7.19 (m, 1H), 7.15–7.10 (m, 2H), 6.32 (d, J = 5.9 Hz, 1H), 5.40 (t, J = 7.1 Hz, 1H), 5.14 (d, J = 16.1 Hz, 1H), 4.79 (d, J = 16.1 Hz, 1H), 3.78 (s, 3H), 3.27–3.14 (m, 2H), 2.81–2.74 (m, 1H), 2.56 (d, J = 5.4 Hz, 2H), 2.21 (dd, J = 13.5, 4.4 Hz, 1H), 2.12–2.02 (m, 2H), 1.96–1.85 (m, 2H), 1.77–1.62 (m, 3H), 1.62–1.52 (m, 2H), 1.33 (q, J = 7.3 Hz, 2H), 1.25–1.15 (m, 1H), 0.95–0.84 (m, 7H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 171.7, 171.1, 140.9, 137.4, 128.7, 126.9, 126.3, 115.9, 52.7, 51.8, 49.4, 39.7, 38.5, 37.9, 37.8, 36.8, 36.8, 26.6, 26.0, 25.5, 24.9, 22.6, 22.6; MS(ESI) calcd for C₂₆H₃₆N₂O₄ 440.27 (M⁺), found 441.27 (M + H)⁺, 463.24 (M + Na)⁺.

Piperidinone-Containing Amide 13af

Compound 13af was prepared according to the general procedure D from carboxylic acid 8c and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.32–7.22 (m, 5H), 7.22–7.08 (m, 5H), 6.36 (s, 1H), 5.38 (t, J = 7.1 Hz, 1H), 5.08 (d, J = 16.1 Hz, 1H), 4.78 (d, J = 16.1 Hz, 1H), 3.76 (s, 3H), 3.25–3.16 (m, 2H), 2.77 (ddd, J = 10.8, 8.8, 4.9 Hz, 1H), 2.66–2.49 (m, 4H), 2.20 (dd, J = 13.5, 4.3 Hz, 1H), 2.12–1.98 (m, 2H), 1.95–1.84 (m, 2H), 1.78–1.52 (m, 8H), 1.51–1.43 (m, 2H), 1.26–1.14 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.7, 171.1, 142.3, 140.9, 137.4, 128.7, 128.5, 128.4, 126.9, 126.3, 125.9, 115.9, 52.7, 51.7, 49.4, 39.7, 39.4, 37.8, 36.8, 36.8, 35.6, 29.3, 28.8, 26.6, 25.5, 24.9; MS(ESI) calcd for C₃₁H₃₈N₂O₄ 502.28 (M⁺), found 503.28 (M + H)⁺, 505.3 (M + Na)⁺.

Piperidinone-Containing Amide 13ag

Compound 13ag was prepared according to the general procedure D from carboxylic acid 8u and amine 11j: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (dd, J = 1.8, 0.9 Hz, 1H), 6.33 (s, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.19 (d, J = 3.2 Hz, 1H), 5.67 (t, J = 7.1 Hz, 1H), 5.11 (d, J = 15.9 Hz, 1H), 4.69 (d, J = 15.9 Hz, 1H), 3.76 (s, 3H), 3.21–3.14 (m, 2H), 2.75–2.67 (m, 1H), 2.58–2.48 (m, 2H), 2.22–2.12 (m, 2H), 2.06–1.93 (m, 2H), 1.83–1.73 (m, 2H), 1.73–1.57 (m, 2H), 1.45–1.38 (m, 2H), 1.36–1.23 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.6, 171.1, 151.0, 141.6, 140.8, 116.1, 110.6, 108.0, 52.7, 51.8, 43.0, 39.6, 39.3, 37.7, 36.7, 36.6, 31.7, 26.6, 25.4, 24.9, 20.2, 13.9; MS(ESI) calcd for C₂₃H₃₂N₂O₅ 416.23 (M⁺), found 417.27 (M + H)⁺, 439.26 (M + Na)⁺.

Piperidinone-Containing Amide 13ah

Compound 13ah was prepared according to the general procedure D from carboxylic acid 8u and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (dd, J = 1.8, 0.9 Hz, 1H), 6.56 (s, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.19–6.16 (m, 1H), 6.05 (d, J = 3.1 Hz, 1H), 5.88–5.84 (m, 1H), 5.66 (t, J = 7.2 Hz, 1H), 5.06 (d, J = 16.0 Hz, 1H), 4.70 (d, J = 15.9 Hz, 1H), 4.34–4.29 (m, 2H), 3.76 (s, 3H), 2.78–2.71 (m, 1H), 2.60 (dd, J = 14.4, 6.1 Hz, 1H), 2.53 (dd, J = 14.4, 5.0 Hz, 1H), 2.27–2.21 (m, 3H), 2.21–2.12 (m, 2H), 2.06–1.92 (m, 2H), 1.83–1.72 (m, 2H), 1.72–1.57 (m, 3H), 1.31–1.22 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.5, 170.9, 151.8, 151.0, 149.7, 141.6, 140.8, 116.0, 110.6, 108.1, 108.0, 106.3, 52.7, 51.8, 43.0, 39.6, 37.5, 36.7, 36.7, 36.6, 26.6, 25.4, 25.0, 13.7; MS(ESI) calcd for C₂₅H₃₀N₂O₆ 454.21 (M⁺), found 455.26 (M + H)⁺, 477.24 (M + Na)⁺.

Piperidinone-Containing Amide 13ai

Compound 13ai was prepared according to the general procedure D from carboxylic acid 8v and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 6.85–6.72 (m, 4H), 5.54–5.47 (m, 1H), 5.42–5.36 (m, 1H), 4.36 (dd, J = 14.6, 5.8 Hz, 1H), 4.31 (dd, J = 14.6, 5.6 Hz, 1H), 3.94–3.81 (m, 7H), 3.76 (s, 3H), 3.63–3.54 (m, 1H), 2.72–2.64 (m, 1H), 2.56 (dd, J = 14.2, 6.8 Hz, 1H), 2.45 (dd, J = 14.1, 4.2 Hz, 1H), 2.27–2.18 (m, 1H), 2.16–2.08 (m, 2H), 2.08–2.01 (m, 1H), 1.97 (s, 8H), 1.81 (dd, J = 11.2, 5.9 Hz, 1H), 1.75–1.62 (m, 3H), 1.62–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.40–1.30 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.3, 171.2, 149.2, 148.3, 140.6, 135.1, 131.3, 122.9, 120.0, 114.4, 111.1, 111.1, 56.0, 56.0, 52.6, 51.7, 43.5, 43.4, 39.9, 38.0, 37.1, 36.6, 34.9, 28.5, 27.0, 25.7, 25.4, 25.1, 23.0, 22.5; MS(ESI) calcd for C₃₁H₄₂N₂O₆ 538.30 (M⁺), found 539.35 (M + H)⁺.

Piperidinone-Containing Amide 13aj

Compound 13aj was prepared according to the general procedure D from carboxylic acid 8v and amine 11m: ¹H NMR (500 MHz, CDCl₃) δ 7.19 (td, J = 7.8, 1.8 Hz, 1H), 7.11 (dd, J = 7.4, 1.8 Hz, 1H), 6.90–6.82 (m, 2H), 6.44 (s, 1H), 5.51 (dd, J = 8.2, 6.2 Hz, 1H), 5.42 (dd, J = 4.2, 2.4 Hz, 1H), 4.00–3.87 (m, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.60 (ddd, J = 14.2, 8.7, 5.9 Hz, 1H), 3.50–3.38 (m, 2H), 2.79 (t, J = 6.9 Hz, 2H), 2.67–2.59 (m, 1H), 2.56 (dd, J = 14.3, 6.3 Hz, 1H), 2.36–2.12 (m, 4H), 2.12–1.87 (m, 7H), 1.87–1.77 (m, 1H), 1.76–1.57 (m, 6H), 1.57–1.49 (m, 2H), 1.40–1.30 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.2, 171.2, 157.6, 140.7, 135.2, 130.7, 127.8, 127.5, 122.9, 120.7, 114.2, 110.4, 55.4, 52.6, 51.8, 43.4, 39.8, 39.7, 37.8, 37.1, 36.5, 35.0, 30.4, 28.5, 27.1, 25.7, 25.4, 25.1, 23.0, 22.5; MS(ESI) calcd for C₃₁H₄₂N₂O₅ 522.31 (M⁺), found 523.37 (M + H)⁺.

Piperidinone-Containing Amide 13ak

Compound 13ak was prepared according to the general procedure D from carboxylic acid 8w and amine 11x: ¹H NMR (500 MHz, CDCl₃) δ 7.36–7.27 (m, 2H), 7.25–7.12 (m, 3H), 6.83–6.74 (m, 3H), 5.59 (t, J = 7.1 Hz, 1H), 4.75 (d, J = 12.8 Hz, 1H), 4.11–3.96 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.81–3.74 (m, 3H), 3.16–2.95 (m, 2H), 2.92–2.79 (m, 3H), 2.77–2.57 (m, 2H), 2.45–2.35 (m, 1H), 2.32–2.21 (m, 1H), 2.18 (dd, J = 13.0, 4.4 Hz, 1H), 2.12–1.99 (m, 2H), 1.91–1.83 (m, 3H), 1.82– 1.75 (m, 1H), 1.75–1.54 (m, 6H), 1.46–1.38 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 171.2, 169.1, 149.0, 147.6, 145.3, 141.1, 131.9, 128.7, 126.8, 126.6, 120.8, 113.6, 112.2, 111.3, 56.0, 56.0, 52.6, 51.8, 46.5, 46.4, 46.2, 42.9, 42.8, 42.6, 42.5, 39.9, 36.9, 35.9, 34.2, 33.9, 33.1, 33.0, 32.7, 26.6, 25.5, 25.2; MS(ESI) calcd for C₃₅H₄₄N₂O₆ 588.32 (M⁺), found 589.39 (M + H)⁺.

Piperidinone-Containing Amide 13al

Compound 13al was prepared according to the general procedure D from carboxylic acid 8w and amine 11v: ¹H NMR (500 MHz, CDCl₃) δ 6.82–6.73 (m, 3H), 5.58 (t, J = 7.1 Hz, 1H), 4.10–4.02 (m, 1H), 4.01–3.93 (m, 1H), 3.86 (d, J = 10.6 Hz, 7H), 3.78 (s, 4H), 3.74–3.64 (m, 2H), 2.91 (dd, J = 16.3, 4.0 Hz, 1H), 2.88–2.83 (m, 2H), 2.82–2.76 (m, 1H), 2.69–2.53 (m, 4H), 2.32 (dd, J = 16.3, 7.7 Hz, 1H), 2.25 (q, J = 7.9, 7.3 Hz, 1H), 2.12 (dd, J = 13.0, 4.4 Hz, 1H), 2.09–1.97 (m, 2H), 1.82–1.75 (m, 1H), 1.75–1.60 (m, 4H), 1.45–1.37 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 171.0, 169.3, 149.0, 147.7, 141.0, 131.9, 120.8, 113.8, 112.2, 111.3, 56.1, 56.0, 52.6, 51.8, 48.2, 46.3, 44.5, 39.9, 36.9, 35.8, 34.2, 32.7, 27.9, 27.5, 26.6, 25.6, 25.2; MS(ESI) calcd for C₂₈H₃₈N₂O₆S 530.25 (M⁺), found 531.31 (M + H)⁺.

Piperidinone-Containing Amide 13am

Compound 13am was prepared according to the general procedure D from carboxylic acid 8x and amine 11x: ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.56–7.47 (m, 2H), 7.44 (t, J = 7.7 Hz, 1H), 7.36–7.26 (m, 3H), 7.24–7.13 (m, 3H), 5.58 (dd, J = 17.2, 6.7 Hz, 1H), 5.32 (t, J = 6.9 Hz, 1H), 5.26 (dd, J = 16.5, 8.5 Hz, 1H), 4.81 (d, J = 12.1 Hz, 1H), 4.06–3.99 (m, 1H), 3.83 (s, 3H), 3.16–3.06 (m, 1H), 3.05–2.93 (m, 2H), 2.77–2.58 (m, 3H), 2.34–2.27 (m, 1H), 2.14 (t, J = 13.1 Hz, 1H), 2.10–2.00 (m, 2H), 1.95–1.84 (m, 3H), 1.83–1.54 (m, 6H), 1.33–1.23 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.7, 171.3, 145.3, 141.4, 133.8, 132.0, 130.7, 128.9, 128.7, 127.2, 126.9, 126.6, 126.0, 125.9, 125.6, 123.6, 122.8, 115.3, 52.6, 51.9, 48.7, 46.2, 42.9, 42.7, 42.5, 40.0, 36.6, 36.1, 34.1, 33.8, 33.1, 26.1, 25.0; MS(ESI) calcd for C₃₆H₄₀N₂O₄ 564.30 (M⁺), found 565.3 (M + H)⁺.

Piperidinone-Containing Amide 13an

Compound 13an was prepared according to the general procedure D from carboxylic acid 8x and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 7.93 (dd, J = 8.3, 1.3 Hz, 1H), 7.90–7.85 (m, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.56–7.47 (m, 2H), 7.41 (dd, J = 8.3, 7.1 Hz, 1H), 7.14 (dd, J = 7.1, 1.3 Hz, 1H), 6.53 (s, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.85–5.82 (m, 1H), 5.45 (d, J = 16.4 Hz, 1H), 5.35–5.27 (m, 2H), 4.41–4.28 (m, 2H), 3.81 (s, 3H), 2.94–2.83 (m, 1H), 2.63 (d, J = 5.4 Hz, 2H), 2.30–2.23 (m, 1H), 2.22 (s, 3H), 2.10–1.98 (m, 3H), 1.91–1.83 (m, 1H), 1.78–1.62 (m, 3H), 1.62–1.52 (m, 1H), 1.26–1.15 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 171.4, 170.9, 151.8, 149.6, 141.1, 133.9, 131.5, 130.6, 129.0, 127.4, 126.1, 125.7, 123.2, 122.7, 116.0, 108.1, 106.3, 52.7, 51.8, 48.4, 39.6, 37.6, 36.9, 36.8, 36.8, 26.5, 25.4, 25.0, 13.7; MS(ESI) calcd for C₃₁H₃₄N₂O₅ 514.25 (M⁺), found 515.25 (M + H)⁺, 527.23 (M + Na)⁺.

Piperidinone-Containing Amide 13ao

Compound 13ao was prepared according to the general procedure D from carboxylic acid 8y and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.3, 2.2 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.05 (s, 1H), 5.16 (t, J = 7.0 Hz, 1H), 4.91 (s, 2H), 3.80 (s, 3H), 3.26–3.14 (m, 2H), 2.81–2.72 (m, 1H), 2.59 (dd, J = 14.6, 4.8 Hz, 1H), 2.52 (dd, J = 14.6, 5.7 Hz, 1H), 2.21 (dd, J = 13.4, 4.6 Hz, 1H), 2.14–1.99 (m, 3H), 1.97–1.87 (m, 1H), 1.82–1.72 (m, 2H), 1.72–1.52 (m, 3H), 1.37–1.23 (m, 3H), 0.89 (d, J = 3.4 Hz, 3H), 0.87 (d, J = 3.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.5, 170.8, 141.0, 133.1, 133.0, 133.0, 129.3, 128.3, 127.5, 115.2, 52.8, 51.8, 47.8, 39.5, 38.5, 38.0, 37.4, 37.0, 36.6, 26.4, 26.0, 25.4, 25.0, 22.6, 22.6; MS(ESI) calcd for C₂₆H₃₄Cl₂N₂O₄ 508.19 (M⁺), found 509.23 (M + H)⁺, 531.22 (M + Na)⁺.

Piperidinone-Containing Amide 13ap

Compound 13ap was prepared according to the general procedure D from carboxylic acid 8y and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 5.17 (t, J = 7.0 Hz, 1H), 5.01 (d, J = 17.1 Hz, 1H), 4.82 (d, J = 17.2 Hz, 1H), 3.80 (s, 3H), 2.94–2.84 (m, 2H), 2.82–2.72 (m, 1H), 2.64 (dd, J = 14.1, 4.5 Hz, 1H), 2.56 (dd, J = 14.4, 5.9 Hz, 1H), 2.22 (dd, J = 13.5, 4.5 Hz, 1H), 2.15–1.98 (m, 3H), 1.98–1.86 (m, 4H), 1.83–1.64 (m, 6H), 1.64–1.54 (m, 4H), 1.45–1.39 (m, 6H), 1.32–1.24 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 171.6, 171.1, 141.1, 133.1, 133.0, 132.9, 129.3, 128.3, 127.5, 115.2, 52.8, 51.8, 51.1, 47.8, 40.3, 39.5, 37.5, 37.1, 37.0, 36.7, 33.7, 28.3, 26.6, 25.5, 25.0; MS(ESI) calcd for C₃₂H₄₀Cl₂N₂O₄ 586.24 (M⁺), found 587.28 (M + H)⁺.

Piperidinone-Containing Amide 13aq

Compound 13aq was prepared according to the general procedure D from carboxylic acid 8z and amine 11v: ¹H NMR (500 MHz, CDCl₃) δ 5.20 (t, J = 4.1 Hz, 1H), 3.98–3.89 (m, 1H), 3.79–3.66 (m, 5H), 3.65 (s, 3H), 2.78–2.64 (m, 2H), 2.62–2.48 (m, 5H), 2.25 (dd, J = 12.6, 5.9 Hz, 1H), 2.19 (d, J = 13.6 Hz, 1H), 2.00 (d, J = 4.1 Hz, 2H), 1.80 (t, J = 12.7 Hz, 1H), 1.69–1.61 (m, 1H), 1.59–1.51 (m, 1H), 1.43 (d, J = 13.5 Hz, 1H), 1.35–1.21 (m, 10H), 0.95 (s, 3H), 0.87 (t, J = 6.9 Hz, 3H), 0.84 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.8, 169.8, 169.2, 135.6, 106.4, 52.4, 48.3, 47.5, 45.5, 44.5, 44.5, 38.9, 38.7, 36.5, 35.4, 32.0, 31.9, 29.5, 29.5, 28.7, 27.9, 27.5, 27.4, 26.9, 25.5, 22.8, 14.2; MS(ESI) calcd for C₂₇H₄₄N₂O₄S 492.30 (M⁺), found 493.42 (M + H)⁺, 515.4 (M + Na)⁺.

Piperidinone-Containing Amide 13ar

Comound 13ar was prepared according to the general procedure D from carboxylic acid 8z and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.23 (m, 3H), 7.21–7.13 (m, 3H), 6.29 (s, 1H), 5.16 (t, J = 4.1 Hz, 1H), 3.72–3.65 (m, 2H), 3.64 (s, 3H), 3.28–3.14 (m, 2H), 2.67–2.57 (m, 3H), 2.54–2.39 (m, 2H), 2.26 (dd, J = 12.9, 5.7 Hz, 1H), 2.19 (d, J = 13.7 Hz, 1H), 2.00–1.95 (m, 2H), 1.72 (t, J = 13.1 Hz, 1H), 1.68–1.56 (m, 3H), 1.55–1.45 (m, 2H), 1.42 (d, J = 13.6 Hz, 1H), 1.35–1.22 (m, 10H), 0.95 (s, 3H), 0.88 (t, J = 6.7 Hz, 3H), 0.83 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 171.1, 170.0, 142.3, 135.3, 128.5, 128.4, 125.9, 106.9, 52.5, 47.3, 45.5, 44.5, 39.4, 38.8, 38.4, 37.4, 35.6, 32.0, 31.8, 29.5, 29.5, 29.4, 28.7, 28.6, 27.4, 26.9, 25.4, 22.8, 14.2; MS(ESI) calcd for C₃₃H₅₀N₂O₄ 538.38 (M⁺), found 539.49 (M + H)⁺.

Piperidinone-Containing Amide 13as

Compound 13as was prepared according to the general procedure D from carboxylic acid 8aa and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.27 (m, 2H), 7.23–7.16 (m, 3H), 6.79–6.72 (m, 3H), 6.38 (s, 1H), 5.41 (d, J = 16.1 Hz, 1H), 5.09 (t, J = 4.1 Hz, 1H), 4.50 (d, J = 16.1 Hz, 1H), 4.42–4.34 (m, 1H), 4.25 (dd, J = 14.4, 5.3 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.66 (s, 3H), 2.77 (dd, J = 14.4, 5.0 Hz, 1H), 2.65 (dt, J = 18.4, 5.3 Hz, 1H), 2.50 (dd, J = 14.4, 4.9 Hz, 1H), 2.34 (dd, J = 12.9, 5.8 Hz, 1H), 2.26–2.19 (m, 1H), 2.03 (t, J = 13.2 Hz, 1H), 1.90–1.85 (m, 2H), 1.47 (d, J = 13.7 Hz, 1H), 0.93 (s, 3H), 0.81 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.6, 170.8, 170.5, 149.2, 148.4, 137.7, 136.2, 131.1, 128.6, 126.8, 126.3, 120.1, 111.2, 111.2, 108.3, 56.0, 55.9, 52.6, 49.2, 47.2, 45.7, 43.4, 38.7, 38.6, 38.5, 37.4, 31.8, 28.6, 25.4; MS(ESI) calcd for C₃₁H₃₈N₂O₆ 534.27 (M⁺), found 535.34 (M + H)⁺, 557.33 (M + Na)⁺.

Piperidinone-Containing Amide 13at

Compound 13at was prepared according to the general procedure D from carboxylic acid 8aa and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.51–7.44 (m, 2H), 7.42–7.34 (m, 2H), 7.31–7.26 (m, 2H), 7.22–7.17 (m, 3H), 6.77 (t, J = 6.1 Hz, 1H), 5.39 (d, J = 16.1 Hz, 1H), 5.12 (t, J = 4.1 Hz, 1H), 4.56–4.44 (m, 2H), 4.31 (dd, J = 15.2, 5.6 Hz, 1H), 3.66 (s, 3H), 2.79 (dd, J = 14.4, 4.8 Hz, 1H), 2.69–2.60 (m, 1H), 2.54 (dd, J = 14.4, 5.2 Hz, 1H), 2.35 (dd, J = 13.0, 5.8 Hz, 1H), 2.23 (d, J = 13.6 Hz, 2H), 1.99 (t, J = 13.2 Hz, 1H), 1.91–1.86 (m, 2H), 1.48 (d, J = 13.7 Hz, 1H), 0.94 (s, 3H), 0.81 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5, 171.2, 170.6, 139.7, 137.6, 136.2, 131.1, 131.0 (q, ²J_C–F = 31.5 Hz), 129.2, 128.6, 126.9, 126.3, 124.2 (q, ¹J_C–F = 272.2 Hz), 124.4 (q, ³J_C–F = 3.8 Hz), 124.2 (q, ³J_C–F = 3.8 Hz), 108.6, 52.6, 49.3, 47.2, 45.7, 43.0, 38.7, 38.6, 38.5, 37.5, 31.8, 28.6, 25.4; MS(ESI) calcd for C₃₀H₃₃F₃N₂O₄ 542.24 (M⁺), found 543.32 (M + H)⁺, 565.3 (M + Na)⁺.

Piperidinone-Containing Amide 13au

Compound 13au was prepared according to the general procedure D from carboxylic acid 8ab and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 6.77–6.72 (m, 2H), 6.71–6.65 (m, 1H), 6.36 (s, 1H), 5.94–5.89 (m, 2H), 5.36 (d, J = 15.8 Hz, 1H), 5.12 (t, J = 4.1 Hz, 1H), 4.42 (d, J = 15.8 Hz, 1H), 3.66 (s, 3H), 3.44–3.38 (m, 2H), 3.38–3.32 (m, 1H), 3.29 (s, 3H), 3.27–3.17 (m, 1H), 2.74 (dd, J = 14.5, 5.3 Hz, 1H), 2.63–2.54 (m, 1H), 2.49 (dd, J = 14.6, 4.7 Hz, 1H), 2.30 (dd, J = 13.0, 5.8 Hz, 1H), 2.20 (d, J = 13.6 Hz, 1H), 1.95 (t, J = 13.1 Hz, 1H), 1.90–1.86 (m, 2H), 1.77–1.68 (m, 2H), 1.45 (d, J = 13.6 Hz, 1H), 0.92 (s, 3H), 0.80 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.61, 170.76, 170.59, 148.00, 146.40, 136.34, 131.84, 119.49, 108.35, 108.17, 107.29, 101.01, 71.45, 58.84, 52.55, 49.13, 47.23, 45.65, 38.72, 38.43, 38.35, 37.86, 37.29, 31.85, 29.31, 28.63, 25.44; MS(ESI) calcd for C₂₇H₃₆N₂O₇ 500.25 (M⁺), found 501.33 (M + H)⁺, 523.31 (M + Na)⁺.

Piperidinone-Containing Amide 13av

Compound 13av was prepared according to the general procedure D from carboxylic acid 8ab and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 6.77–6.70 (m, 2H), 6.70–6.65 (m, 1H), 5.94–5.90 (m, 2H), 5.27 (d, J = 15.7 Hz, 1H), 5.17 (t, J = 4.1 Hz, 1H), 4.52 (d, J = 15.7 Hz, 1H), 3.65 (s, 3H), 3.03 (dd, J = 13.4, 6.8 Hz, 1H), 2.96–2.84 (m, 1H), 2.80 (dd, J = 13.4, 5.5 Hz, 1H), 2.63–2.50 (m, 2H), 2.34 (dd, J = 13.0, 5.6 Hz, 1H), 2.21 (d, J = 13.6 Hz, 1H), 1.97–1.91 (m, 3H), 1.89 (d, J = 4.0 Hz, 2H), 1.68 (d, J = 12.4 Hz, 4H), 1.65–1.55 (m, 4H), 1.49–1.39 (m, 7H), 0.93 (s, 3H), 0.80 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 171.4, 171.0, 148.0, 146.5, 136.1, 131.4, 119.7, 108.3, 107.4, 101.0, 52.5, 51.3, 49.0, 47.1, 45.6, 40.3, 40.2, 39.7, 38.7, 38.4, 37.4, 37.0, 36.5, 33.8, 31.8, 28.6, 28.3, 28.0, 25.4; MS(ESI) calcd for C₃₄H₄₄N₂O₆ 576.32 (M⁺), found 577.39 (M + H)⁺.

Piperidinone-Containing Amide 13aw

Compound 13aw was prepared according to the general procedure D from carboxylic acid 8d and amine 11r: ¹H NMR (500 MHz, CDCl₃) δ 7.49 (dd, J = 1.6, 0.8 Hz, 1H), 7.32 (dd, J = 1.7, 0.9 Hz, 1H), 7.04 (dd, J = 3.5, 0.9 Hz, 1H), 6.49 (dd, J = 3.5, 1.8 Hz, 1H), 6.34–6.28 (m, 2H), 5.38 (t, J = 4.1 Hz, 1H), 5.29 (d, J = 15.9 Hz, 1H), 4.56 (d, J = 15.9 Hz, 1H), 3.79 (s, 4H), 3.64 (s, 4H), 3.54 (t, J = 5.0 Hz, 2H), 2.83 (dd, J = 16.4, 6.7 Hz, 1H), 2.75 (dd, J = 16.4, 3.6 Hz, 1H), 2.67–2.59 (m, 1H), 2.30 (dd, J = 12.7, 5.9 Hz, 1H), 2.20 (d, J = 13.6 Hz, 1H), 2.00–1.95 (m, 2H), 1.91 (t, J = 12.8 Hz, 1H), 1.44 (d, J = 13.7 Hz, 1H), 0.94 (s, 3H), 0.83 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.7, 170.1, 169.4, 159.3, 151.4, 147.8, 144.1, 141.4, 136.2, 117.2, 111.6, 110.7, 108.0, 107.7, 52.6, 47.4, 45.7, 42.8, 38.8, 38.8, 36.6, 35.0, 31.8, 28.7, 25.4; MS(ESI) calcd for C₂₉H₃₅N₃O₇ 537.25 (M⁺), found 538.33 (M + H)⁺, 560.31 (M + Na)⁺.

Piperidinone-Containing Amide 13ax

Compound 13ax was prepared according to the general procedure D from carboxylic acid 8d and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (dd, J = 1.8, 0.9 Hz, 1H), 6.38–6.27 (m, 2H), 6.25 (dd, J = 3.2, 1.0 Hz, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.85 (dd, J = 2.7, 1.4 Hz, 1H), 5.40 (t, J = 4.1 Hz, 1H), 5.27 (d, J = 15.9 Hz, 1H), 4.53 (d, J = 15.9 Hz, 1H), 4.36 (dd, J = 15.4, 5.9 Hz, 1H), 4.17 (dd, J = 15.4, 5.1 Hz, 1H), 3.64 (s, 3H), 2.71 (dd, J = 14.4, 5.1 Hz, 1H), 2.62–2.53 (m, 1H), 2.50 (dd, J = 14.3, 4.9 Hz, 1H), 2.29 (dd, J = 13.0, 5.9 Hz, 1H), 2.24 (s, 3H), 2.20 (d, J = 13.6 Hz, 1H), 1.97 (d, J = 4.0 Hz, 2H), 1.80 (t, J = 13.1 Hz, 1H), 1.44 (d, J = 13.7 Hz, 1H), 0.95 (s, 3H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 170.6, 170.2, 151.8, 151.3, 149.6, 141.6, 136.0, 110.6, 108.2, 108.2, 107.9, 106.3, 52.6, 47.2, 45.6, 42.5, 38.8, 38.4, 38.4, 37.3, 36.7, 31.8, 28.7, 25.3, 13.7; MS(ESI) calcd for C₂₆H₃₂N₂O₆ 468.23 (M⁺), found 469.31 (M + H)⁺, 491.28 (M + Na)⁺.

Piperidinone-Containing Amide 13ay

Compound 13ay was prepared according to the general procedure D from carboxylic acid 8ac and amine 11h: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (dd, J = 6.8, 2.4 Hz, 1H), 7.87–7.81 (m, 1H), 7.77 (t, J = 4.8 Hz, 1H), 7.53–7.45 (m, 2H), 7.41–7.36 (m, 2H), 6.48 (t, J = 5.2 Hz, 1H), 5.34 (t, J = 3.5 Hz, 1H), 5.06 (dd, J = 14.5, 6.8 Hz, 1H), 4.94 (t, J = 4.0 Hz, 1H), 4.60 (dd, J = 14.5, 4.6 Hz, 1H), 3.59 (s, 3H), 3.42 (t, J = 8.3 Hz, 2H), 2.80 (dd, J = 13.9, 4.6 Hz, 1H), 2.51–2.38 (m, 2H), 2.25 (dd, J = 12.9, 5.7 Hz, 1H), 2.18 (d, J = 13.4 Hz, 1H), 2.05–1.91 (m, 6H), 1.90–1.84 (m, 2H), 1.77–1.64 (m, 2H), 1.62–1.50 (m, 4H), 1.38 (d, J = 13.6 Hz, 1H), 0.97 (s, 3H), 0.80 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 170.5, 169.5, 135.3, 134.9, 134.0, 134.0, 131.5, 128.8, 128.6, 126.9, 126.6, 125.9, 125.5, 123.9, 122.4, 106.8, 52.4, 47.2, 45.4, 43.3, 41.5, 38.8, 38.5, 38.1, 37.5, 34.4, 31.9, 28.6, 28.6, 25.4, 25.4, 23.0, 22.5; MS(ESI) calcd for C₃₄H₄₂N₂O₄ 542.31 (M⁺), found 543.38 (M + H)⁺.

Piperidinone-Containing Amide 13az

Compound 13az was prepared according to the general procedure D from carboxylic acid 8ac and amine 11k: ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.27 (m, 2H), 7.26–7.20 (m, 3H), 6.62 (t, J = 5.6 Hz, 1H), 5.44 (m, 1H), 5.21 (t, J = 4.1 Hz, 1H), 4.45 (dd, J = 14.6, 6.9 Hz, 1H), 4.32 (dd, J = 15.0, 5.5 Hz, 1H), 3.81–3.66 (m, 2H), 3.64 (s, 3H), 2.71 (dd, J = 13.7, 4.3 Hz, 1H), 2.57–2.45 (m, 2H), 2.28 (dd, J = 12.8, 5.6 Hz, 1H), 2.24–2.18 (m, 2H), 2.04–1.92 (m, 7H), 1.75 (t, J = 13.0 Hz, 1H), 1.65–1.51 (m, 4H), 1.45 (d, J = 13.7 Hz, 1H), 0.97 (s, 3H), 0.84 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 171.0, 169.8, 138.6, 135.4, 135.3, 128.7, 127.8, 127.4, 122.5, 106.9, 52.5, 47.3, 45.5, 43.6, 43.5, 38.9, 38.7, 38.4, 37.4, 34.8, 31.8, 28.7, 28.6, 25.5, 25.4, 23.1, 22.5; MS(ESI) calcd for C₃₀H₄₀N₂O₄ 492.30 (M⁺), found 493.35 (M + H)⁺, 515.34 (M + Na)⁺.

Piperidinone-Containing Amide 13ba

Compound 13ba was prepared according to the general procedure D from carboxylic acid 8ad and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 6.84–6.78 (m, 3H), 5.27 (t, J = 4.1 Hz, 1H), 3.93 (t, J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 3.42 (t, J = 5.9 Hz, 2H), 3.35–3.27 (m, 5H), 2.98–2.88 (m, 1H), 2.81–2.71 (m, 1H), 2.66–2.59 (m, 1H), 2.59–2.47 (m, 4H), 2.27 (dd, J = 12.6, 5.3 Hz, 1H), 2.24–2.18 (m, 1H), 2.05–1.99 (m, 2H), 1.82–1.69 (m, 3H), 1.46 (d, J = 13.6 Hz, 1H), 0.97 (s, 3H), 0.86 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 170.8, 170.0, 149.0, 147.7, 135.4, 132.1, 120.7, 112.2, 111.4, 106.8, 71.4, 58.9, 56.1, 56.0, 52.5, 47.3, 46.1, 45.5, 38.9, 38.5, 38.4, 37.8, 37.1, 32.7, 31.8, 29.4, 28.7, 25.4; MS(ESI) calcd for C₂₉H₄₂N₂O₇ 530.30 (M⁺), found 531.36 (M + H)⁺, 553.35 (M + Na)⁺.

Piperidinone-Containing Amide 13bb

Compound 13bb was prepared according to the general procedure D from carboxylic acid 8ad and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 6.84–6.76 (m, 3H), 6.24 (s, 1H), 5.29 (t, J = 4.0 Hz, 1H), 4.07–3.97 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 2.97–2.83 (m, 3H), 2.81–2.71 (m, 2H), 2.58–2.45 (m, 2H), 2.29 (dd, J = 12.9, 5.6 Hz, 1H), 2.23 (dd, J = 13.6, 1.7 Hz, 1H), 2.05–1.99 (m, 2H), 1.96–1.91 (m, 3H), 1.80 (t, J = 13.0 Hz, 1H), 1.73–1.55 (m, 8H), 1.50–1.40 (m, 7H), 0.97 (s, 3H), 0.86 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 171.1, 170.1, 149.0, 147.7, 135.3, 132.0, 120.6, 112.1, 111.4, 107.1, 56.0, 56.0, 52.5, 51.1, 47.3, 45.9, 45.6, 40.3, 39.7, 38.9, 38.6, 38.3, 37.5, 37.0, 36.5, 33.7, 32.6, 31.8, 28.7, 28.3, 28.0, 25.5; MS(ESI) calcd for C₃₆H₅₀N₂O₆ 606.37 (M⁺), found 607.42 (M + H)⁺.

Piperidinone-Containing Amide 13bc

Compound 13bc was prepared according to the general procedure D from carboxylic acid 8ae and amine 11b: ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J = 8.2 Hz, 1H), 7.93–7.87 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.54 (m, 2H), 7.42 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 5.94 (d, J = 16.7 Hz, 1H), 5.10 (t, J = 4.1 Hz, 1H), 4.97 (d, J = 16.7 Hz, 1H), 3.73 (s, 3H), 3.27 (s, 1H), 3.21 (dt, J = 13.2, 6.5 Hz, 1H), 2.99 (m, 1H), 2.74–2.66 (m, 1H), 2.63 (dd, J = 14.9, 7.0 Hz, 1H), 2.49 (dd, J = 13.2, 5.8 Hz, 1H), 2.28 (dd, J = 13.6, 1.8 Hz, 1H), 2.05 (t, J = 13.2 Hz, 1H), 1.91–1.77 (m, 2H), 1.71–1.57 (m, 6H), 1.51 (d, J = 13.8 Hz, 2H), 1.21–1.06 (m, 3H), 0.94 (s, 3H), 0.91–0.84 (m, 2H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.1, 172.1, 171.7, 135.9, 133.8, 131.0, 130.3, 129.1, 127.6, 126.4, 126.0, 125.7, 122.5, 122.2, 52.8, 48.5, 46.8, 45.6, 38.6, 38.5, 37.5, 37.0, 31.7, 30.9, 30.9, 30.4, 28.7, 26.4, 25.8, 25.8, 25.4, 25.3; MS(ESI) calcd for C₃₃H₄₂N₂O₄ 530.31 (M⁺), found 531.4 (M + H)⁺.

Piperidinone-Containing Amide 13bd

Compound 13bd was prepared according to the general procedure D from carboxylic acid 8ae and amine 11p: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.58–7.47 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 6.38 (s, 1H), 5.97 (d, J = 16.7 Hz, 1H), 4.97 (dd, J = 5.1, 3.0 Hz, 1H), 4.89 (d, J = 16.7 Hz, 1H), 3.71 (s, 3H), 3.46–3.36 (m, 3H), 3.30 (t, J = 6.6 Hz, 2H), 3.27–3.17 (m, 1H), 2.83 (dd, J = 14.6, 5.4 Hz, 1H), 2.72–2.62 (m, 1H), 2.49 (dd, J = 14.6, 4.6 Hz, 1H), 2.39 (dd, J = 13.0, 5.8 Hz, 1H), 2.25 (dd, J = 13.7, 1.8 Hz, 1H), 2.14 (t, J = 13.2 Hz, 1H), 1.89–1.74 (m, 2H), 1.74–1.65 (m, 2H), 1.56–1.44 (m, 3H), 1.35–1.23 (m, 2H), 0.92 (s, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.83 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.7, 170.7, 170.4, 136.6, 133.8, 131.9, 130.5, 128.9, 127.2, 126.1, 125.8, 125.7, 122.8, 122.6, 108.5, 71.0, 69.5, 52.6, 48.2, 47.3, 45.8, 38.6, 38.5, 38.2, 38.1, 37.5, 31.9, 31.9, 29.3, 28.7, 25.4, 19.5, 14.0; MS(ESI) calcd for C₃₃H₄₄N₂O₅ 548.33 (M⁺), found 549.41 (M + H)⁺, 571.39 (M + Na)⁺.

Piperidinone-Containing Amide 13be

Compound 13be was prepared according to the general procedure D from carboxylic acid 8af and amine 11e: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 2.0 Hz, 1H), 7.26–7.21 (m, 1H), 7.21–7.14 (m, 2H), 6.94–6.88 (m, 2H), 6.31 (s, 1H), 5.31 (d, J = 17.2 Hz, 1H), 4.88 (t, J = 4.0 Hz, 1H), 4.63–4.44 (m, 3H), 3.71 (s, 3H), 2.88 (dd, J = 15.1, 5.0 Hz, 1H), 2.64–2.54 (m, 1H), 2.44 (dd, J = 15.1, 4.4 Hz, 1H), 2.30 (dd, J = 12.9, 5.8 Hz, 1H), 2.23 (d, J = 13.7 Hz, 1H), 2.14 (t, J = 13.1 Hz, 1H), 1.91–1.86 (m, 2H), 1.50 (d, J = 13.6 Hz, 1H), 0.94 (s, 3H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.6, 170.6, 170.5, 141.0, 136.1, 133.3, 133.1, 132.8, 129.1, 128.6, 127.5, 127.0, 126.0, 125.2, 108.2, 52.7, 47.3, 47.2, 45.7, 38.6, 38.4, 38.2, 37.6, 37.1, 31.8, 28.7, 25.5; MS(ESI) calcd for C₂₇H₃₀Cl₂N₂O₄S 548.13 (M⁺), found 549.2 (M + H)⁺.

Piperidinone-Containing Amide 13bf

Compound 13bf was prepared according to the general procedure D from carboxylic acid 8af and amine 11j: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 1.8 Hz, 1H), 7.23–7.16 (m, 2H), 5.87 (s, 1H), 5.37 (d, J = 17.2 Hz, 1H), 4.87 (t, J = 4.1 Hz, 1H), 4.52 (d, J = 17.2 Hz, 1H), 3.71 (s, 3H), 3.28–3.17 (m, 1H), 3.16–3.05 (m, 1H), 2.85 (dd, J = 14.9, 5.0 Hz, 1H), 2.56 (dt, J = 15.0, 5.1 Hz, 1H), 2.40 (dd, J = 15.0, 4.3 Hz, 1H), 2.29 (dd, J = 12.9, 5.8 Hz, 1H), 2.22 (d, J = 13.7 Hz, 1H), 2.14 (t, J = 13.1 Hz, 1H), 1.90–1.85 (m, 2H), 1.49 (d, J = 13.7 Hz, 1H), 1.45–1.35 (m, 2H), 1.34–1.23 (m, 2H), 0.93 (s, 3H), 0.88 (t, J = 7.3 Hz, 3H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.6, 170.7, 170.7, 136.2, 133.3, 133.0, 132.8, 129.1, 128.5, 127.4, 108.2, 52.7, 47.5, 47.2, 45.7, 39.5, 38.6, 38.3, 37.7, 37.2, 31.8, 31.7, 28.7, 25.4, 20.2, 13.9; MS(ESI) calcd for C₂₆H₃₄Cl₂N₂O₄ 508.19 (M⁺), found 509.23 (M + H)⁺, 531.23 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27a ((3SR,4aRS,5RS,7RS)-Methyl 7-tert-Butyl-5-methyl-1-octyl-2-oxo-3-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2,3,4,4a,5,7-hexahydro-1H-pyrano[4,3-b]pyridine-4a-carboxylate)

Compound 27a was prepared according to the general procedure D from carboxylic acid 26e and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 5.48 (d, J = 1.8 Hz, 1H), 4.02 (ddd, J = 17.7, 5.2, 2.6 Hz, 1H), 3.96 (ddd, J = 17.5, 4.9, 2.6 Hz, 1H), 3.90 (q, J = 6.4 Hz, 1H), 3.83 (d, J = 1.6 Hz, 1H), 3.82–3.75 (m, 1H), 3.67 (s, 3H), 3.50–3.43 (m, 1H), 3.10–3.02 (m, 1H), 2.68–2.60 (m, 1H), 2.56 (dd, J = 14.8, 5.9 Hz, 1H), 2.46 (dd, J = 12.9, 7.6 Hz, 1H), 2.20 (t, J = 2.6 Hz, 1H), 1.69–1.58 (m, 2H), 1.50–1.41 (m, 1H), 1.34–1.20 (m, 12H), 1.17 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 15.2 Hz, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 172.6, 170.8, 170.7, 138.1, 110.0, 82.1, 74.7, 71.5, 52.7, 51.5, 44.5, 40.0, 37.5, 34.8, 31.9, 29.4, 29.4, 29.3, 29.1, 27.3, 27.0, 25.7, 22.8, 16.3, 14.2; MS(ESI) calcd for C₂₈H₄₄N₂O₅ 488.33 (M⁺), found 489.42 (M + H)⁺, 511.41 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27b

Compound 27b was prepared according to the general procedure D from carboxylic acid 26e and amine 11e: ¹H NMR (500 MHz, CDCl₃) δ 7.19 (dd, J = 5.0, 1.4 Hz, 1H), 6.97–6.90 (m, 3H), 5.47 (s, 1H), 4.62–4.51 (m, 2H), 3.90 (q, J = 6.4 Hz, 1H), 3.83 (d, J = 1.5 Hz, 1H), 3.75 (ddd, J = 13.5, 10.1, 6.0 Hz, 1H), 3.67 (s, 3H), 3.42 (ddd, J = 14.2, 10.0, 4.9 Hz, 1H), 3.10–3.02 (m, 1H), 2.62–2.56 (m, 2H), 2.48 (dd, J = 12.9, 7.6 Hz, 1H), 1.67 (dd, J = 12.9, 10.9 Hz, 1H), 1.63–1.54 (m, 1H), 1.48–1.38 (m, 1H), 1.34–1.21 (m, 13H), 1.18 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 17.9 Hz, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 172.6, 170.9, 170.8, 138.0, 127.0, 126.2, 125.2, 110.1, 82.1, 74.8, 52.7, 51.5, 44.4, 39.8, 38.5, 37.5, 34.8, 34.8, 31.9, 29.4, 29.4, 29.1, 27.3, 26.9, 25.7, 22.8, 16.3, 14.2; MS(ESI) calcd for C₃₀H₄₆N₂O₅S 546.31 (M⁺), found 547.43 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27c

Compound 27c was prepared according to the general procedure D from carboxylic acid 26a and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (t, J = 7.5 Hz, 2H), 7.24–7.17 (m, 3H), 6.35 (s, 1H), 5.39 (d, J = 1.6 Hz, 1H), 5.20 (d, J = 15.4 Hz, 1H), 4.54 (d, J = 15.5 Hz, 1H), 3.84 (q, J = 6.4 Hz, 1H), 3.71 (d, J = 1.5 Hz, 1H), 3.57 (s, 3H), 3.43 (t, J = 5.8 Hz, 2H), 3.40–3.24 (m, 5H), 3.14–3.06 (m, 1H), 2.66 (dd, J = 14.7, 4.9 Hz, 1H), 2.59 (dd, J = 14.9, 6.5 Hz, 1H), 2.50 (dd, J = 12.8, 7.4 Hz, 1H), 1.84–1.70 (m, 3H), 1.18 (d, J = 6.5 Hz, 3H), 0.74 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 171.1, 170.7, 138.4, 137.5, 128.7, 127.2, 127.0, 110.8, 82.0, 74.7, 71.5, 58.9, 52.7, 51.4, 48.9, 40.1, 37.9, 37.8, 34.7, 29.3, 29.1, 25.6, 16.4; MS(ESI) calcd for C₂₈H₄₀N₂O₆ 500.29 (M⁺), found 501.33 (M + H)⁺, 523.32 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27d

Compound 27d was prepared according to the general procedure D from carboxylic acid 26a and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 7.32–7.18 (m, 6H), 5.42 (d, J = 1.4 Hz, 1H), 5.17 (d, J = 15.6 Hz, 1H), 4.57 (d, J = 15.5 Hz, 1H), 3.85 (q, J = 6.4 Hz, 1H), 3.72 (d, J = 1.5 Hz, 1H), 3.70–3.52 (m, 8H), 3.46 (t, J = 4.7 Hz, 2H), 3.14–3.06 (m, 1H), 2.85 (dd, J = 16.0, 3.5 Hz, 1H), 2.76 (dd, J = 16.0, 7.5 Hz, 1H), 2.48 (dd, J = 12.6, 7.3 Hz, 1H), 1.84 (dd, J = 12.6, 10.9 Hz, 1H), 1.17 (d, J = 6.4 Hz, 3H), 0.76 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.2, 169.2, 138.6, 137.7, 128.5, 127.2, 127.0, 110.6, 82.1, 74.7, 67.0, 66.7, 52.6, 51.5, 48.9, 46.0, 42.0, 37.2, 36.5, 34.7, 29.1, 25.6, 16.4; MS(ESI) calcd for C₂₈H₃₈N₂O₆ 498.27 (M⁺), found 499.31 (M + H)⁺, 521.31 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27e

Compound 27e was prepared according to the general procedure D from carboxylic acid 26f and amine 11j: ¹H NMR (500 MHz, CDCl₃) δ 6.74 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 6.67 (dd, J = 7.9, 1.8 Hz, 1H), 6.00 (s, 1H), 5.92 (s, 2H), 5.45 (d, J = 1.5 Hz, 1H), 5.01 (d, J = 15.3 Hz, 1H), 4.53 (d, J = 15.3 Hz, 1H), 3.84 (q, J = 6.4 Hz, 1H), 3.72 (d, J = 1.5 Hz, 1H), 3.59 (s, 3H), 3.28–3.12 (m, 2H), 3.12–3.02 (m, 1H), 2.61 (dd, J = 5.6, 3.1 Hz, 2H), 2.48 (dd, J = 12.8, 7.4 Hz, 1H), 1.79 (dd, J = 12.9, 11.1 Hz, 1H), 1.49–1.39 (m, 2H), 1.37–1.26 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.78 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 171.2, 170.6, 148.0, 146.7, 138.4, 131.4, 120.4, 110.8, 108.3, 107.9, 101.1, 82.0, 74.7, 52.7, 51.4, 48.5, 40.0, 39.4, 37.9, 34.7, 31.8, 29.0, 25.6, 20.2, 16.3, 13.9; MS(ESI) calcd for C₂₉H₄₀N₂O₇ 528.28 (M⁺), found 529.37 (M + H)⁺, 551.37 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27f

Compound 27f was prepared according to the general procedure D from carboxylic acid 26f and amine 11u: ¹H NMR (500 MHz, CDCl₃) δ 6.79 (s, 1H), 6.73 (s, 2H), 5.91 (d, J = 1.6 Hz, 1H), 5.91 (d, J = 1.4 Hz, 1H), 5.44 (d, J = 1.5 Hz, 1H), 5.02 (d, J = 15.4 Hz, 1H), 4.54 (d, J = 15.4 Hz, 1H), 3.85 (q, J = 6.5 Hz, 1H), 3.75–3.72 (m, 2H), 3.59 (s, 3H), 3.58–3.52 (m, 1H), 3.52–3.44 (m, 1H), 3.44–3.33 (m, 2H), 3.12–3.03 (m, 1H), 2.87 (dd, J = 15.9, 3.2 Hz, 1H), 2.77–2.67 (m, 1H), 2.47 (dd, J = 12.6, 7.3 Hz, 1H), 1.80 (dd, J = 12.8, 10.7 Hz, 1H), 1.66–1.58 (m, 2H), 1.58–1.47 (m, 4H), 1.17 (d, J = 6.4 Hz, 3H), 0.80 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 171.5, 168.6, 147.9, 146.5, 138.7, 131.8, 120.5, 110.3, 108.2, 108.1, 101.0, 82.1, 74.8, 52.6, 51.5, 48.5, 46.6, 42.8, 37.3, 36.9, 34.7, 29.1, 26.5, 25.7, 25.6, 24.7, 16.4; MS(ESI) calcd for C₃₀H₄₀N₂O₇ 540.28 (M⁺), found 541.37 (M + H)⁺, 563.35 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27g

Compound 27g was prepared according to the general procedure D from carboxylic acid 26g and amine 11s: ¹H NMR (500 MHz, CDCl₃) δ 7.34–7.30 (m, 1H), 6.33–6.29 (m, 2H), 5.67 (s, 1H), 5.03 (d, J = 15.7 Hz, 1H), 4.57 (d, J = 15.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.87 (q, J = 6.4 Hz, 1H), 3.80 (d, J = 1.6 Hz, 1H), 3.60 (s, 3H), 3.59–3.49 (m, 1H), 3.49–3.37 (m, 6H), 3.13–3.05 (m, 1H), 2.84 (dd, J = 16.0, 3.5 Hz, 1H), 2.67 (dd, J = 15.9, 7.8 Hz, 1H), 2.48 (dd, J = 12.6, 7.4 Hz, 1H), 1.70 (t, J = 11.6 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.17 (d, J = 7.0 Hz, 3H), 0.86 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.9, 169.2, 155.5, 150.9, 141.6, 138.5, 110.7, 110.6, 108.4, 82.1, 74.7, 61.8, 52.8, 51.5, 45.3, 43.6, 42.0, 41.5, 37.2, 36.8, 34.8, 29.1, 25.6, 16.3, 14.8; MS(ESI) calcd for C₂₉H₄₁N₃O₈ 559.29 (M⁺), found 560.44 (M + H)⁺, 582.43 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27h

Compound 27h was prepared according to the general procedure D from carboxylic acid 26g and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (s, 1H), 6.31 (d, J = 1.4 Hz, 2H), 5.64 (d, J = 1.7 Hz, 1H), 5.04 (d, J = 15.7 Hz, 1H), 4.58 (d, J = 15.7 Hz, 1H), 3.86 (q, J = 6.4 Hz, 1H), 3.79 (s, 1H), 3.60 (s, 3H), 3.43 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 6.8 Hz, 2H), 3.10 (dtd, J = 10.9, 7.7, 3.5 Hz, 1H), 2.76 (dd, J = 16.2, 3.5 Hz, 1H), 2.60 (dd, J = 16.2, 7.9 Hz, 1H), 2.52 (dd, J = 12.6, 7.3 Hz, 1H), 1.97–1.87 (m, 2H), 1.83 (q, J = 6.8 Hz, 2H), 1.72 (dd, J = 12.7, 10.7 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.86 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.2, 169.0, 151.1, 141.5, 138.6, 110.7, 110.2, 108.3, 82.1, 74.8, 52.7, 51.5, 46.6, 45.8, 42.0, 38.2, 37.0, 34.8, 29.2, 26.2, 25.7, 24.5, 16.4; MS(ESI) calcd for C₂₆H₃₆N₂O₆ 472.26 (M⁺), found 473.4 (M + H)⁺, 495.38 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27i

Compound 27i was prepared according to the general procedure D from carboxylic acid 26h and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 6.37 (t, J = 5.7 Hz, 1H), 5.48 (d, J = 1.5 Hz, 1H), 5.47–5.43 (m, 1H), 3.89 (q, J = 6.5 Hz, 1H), 3.83 (d, J = 1.5 Hz, 1H), 3.79 (ddd, J = 13.4, 11.2, 5.0 Hz, 1H), 3.66 (s, 3H), 3.57 (ddd, J = 13.4, 11.0, 5.3 Hz, 1H), 3.43 (t, J = 5.9 Hz, 2H), 3.32 (s, 2H), 3.29 (q, J = 6.4, 5.5 Hz, 2H), 3.07–2.97 (m, 1H), 2.58 (dd, J = 14.7, 5.1 Hz, 1H), 2.53–2.39 (m, 2H), 2.36–2.24 (m, 1H), 2.08–1.91 (m, 5H), 1.80–1.68 (m, 3H), 1.66–1.57 (m, 3H), 1.57–1.49 (m, 2H), 1.17 (d, J = 6.5 Hz, 3H), 0.90 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 170.7, 170.6, 138.3, 135.1, 122.9, 109.5, 82.1, 74.7, 71.5, 58.9, 52.7, 51.5, 43.7, 40.4, 37.8, 37.7, 35.3, 34.8, 29.4, 29.4, 29.0, 28.6, 25.7, 25.7, 25.4, 23.0, 22.4, 16.4; MS(ESI) calcd for C₂₉H₄₆N₂O₆ 518.34 (M⁺), found 519.43 (M + H)⁺, 541.43 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27j

Compound 27j was prepared according to the general procedure D from carboxylic acid 26h and amine 11m: ¹H NMR (500 MHz, CDCl₃) δ 7.20 (td, J = 7.8, 1.7 Hz, 1H), 7.11 (dd, J = 7.4, 1.8 Hz, 1H), 6.93–6.81 (m, 2H), 6.07 (t, J = 5.6 Hz, 1H), 5.50–5.44 (m, 2H), 3.89 (q, J = 6.5 Hz, 1H), 3.87–3.79 (m, 4H), 3.81–3.72 (m, 1H), 3.66 (s, 3H), 3.56 (ddd, J = 13.4, 11.0, 5.4 Hz, 1H), 3.50–3.36 (m, 2H), 3.05–2.95 (m, 1H), 2.79 (t, J = 6.9 Hz, 2H), 2.54 (dd, J = 14.6, 5.0 Hz, 1H), 2.50–2.40 (m, 2H), 2.35–2.22 (m, 1H), 2.07–1.93 (m, 5H), 1.67–1.58 (m, 3H), 1.58–1.50 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H), 0.90 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 170.6, 170.6, 157.6, 138.3, 135.1, 130.7, 127.9, 127.5, 122.9, 120.8, 110.5, 109.5, 82.1, 74.7, 55.4, 52.7, 51.5, 43.8, 40.3, 39.8, 37.7, 35.3, 34.8, 30.4, 28.8, 28.6, 25.7, 25.4, 23.0, 22.5, 16.4; MS(ESI) calcd for C₃₄H₄₈N₂O₆ 580.35 (M⁺), found 581.45 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27k

Compound 27k was prepared according to the general procedure D from carboxylic acid 26i and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 6.80 (d, J = 7.9 Hz, 1H), 6.78–6.72 (m, 2H), 6.12 (t, J = 6.4 Hz, 1H), 5.38 (d, J = 1.5 Hz, 1H), 3.94–3.87 (m, 2H), 3.86 (s, 3H), 3.85 (s, 1H), 3.82 (d, J = 1.4 Hz, 1H), 3.78–3.70 (m, 1H), 3.65 (s, 3H), 3.10–3.02 (m, 1H), 2.96–2.88 (m, 2H), 2.88–2.83 (m, 1H), 2.83–2.76 (m, 1H), 2.64 (dd, J = 14.7, 5.3 Hz, 1H), 2.56–2.47 (m, 2H), 1.98–1.92 (m, 4H), 1.73–1.64 (m, 5H), 1.64–1.56 (m, 5H), 1.49–1.44 (m, 7H), 1.17 (d, J = 6.5 Hz, 3H), 0.87 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 171.0, 170.7, 149.2, 147.8, 138.6, 131.8, 120.7, 112.1, 111.5, 110.3, 82.1, 74.7, 56.0, 56.0, 52.7, 51.7, 51.1, 47.1, 40.6, 40.4, 40.3, 39.7, 37.9, 37.1, 37.0, 36.5, 34.7, 33.7, 33.0, 29.1, 28.4, 28.4, 28.0, 25.6, 16.3; MS(ESI) calcd for C₃₈H₅₄N₂O₇ 650.39 (M⁺), found 651.54 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27l

Compound 27l was prepared according to the general procedure D from carboxylic acid 26i and amine 11s: ¹H NMR (500 MHz, CDCl₃) δ 6.81–6.75 (m, 3H), 5.46 (d, J = 1.5 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.94–3.89 (m, 1H), 3.88–3.82 (m, 8H), 3.77–3.69 (m, 1H), 3.65 (s, 3H), 3.59–3.53 (m, 2H), 3.51–3.40 (m, 7H), 3.10–3.03 (m, 1H), 2.91–2.75 (m, 3H), 2.69 (dd, J = 16.1, 7.8 Hz, 1H), 2.48 (dd, J = 12.6, 7.5 Hz, 1H), 1.72–1.61 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.9, 169.1, 155.5, 149.1, 147.7, 138.7, 132.0, 120.7, 112.2, 111.5, 109.8, 82.2, 74.7, 61.8, 56.0, 56.0, 52.7, 51.7, 46.8, 45.3, 43.6, 41.5, 37.2, 37.1, 34.8, 32.9, 29.1, 25.7, 16.4, 14.8; MS(ESI) calcd for C₃₄H₄₉N₃O₉ 643.35 (M⁺), found 644.51 (M + H)⁺, 666.47 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27m

Compound 27m was prepared according to the general procedure D from carboxylic acid 26j and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 8.06–8.00 (m, 1H), 7.88 (dd, J = 8.0, 1.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.57–7.48 (m, 2H), 7.41 (dd, J = 8.2, 7.1 Hz, 1H), 7.31–7.25 (m, 3H), 7.24–7.14 (m, 4H), 6.08–6.02 (m, 1H), 5.46–5.39 (m, 2H), 5.28 (d, J = 16.0 Hz, 1H), 3.82 (q, J = 6.4 Hz, 1H), 3.71 (d, J = 1.4 Hz, 1H), 3.34–3.28 (m, 1H), 3.26 (s, 3H), 3.25–3.13 (m, 2H), 2.73 (dd, J = 14.7, 6.0 Hz, 1H), 2.67–2.58 (m, 4H), 2.52 (dd, J = 12.9, 7.4 Hz, 1H), 1.92 (dd, J = 12.9, 11.2 Hz, 1H), 1.68–1.60 (m, 3H), 1.56–1.48 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H), 0.78 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 171.0, 170.7, 142.3, 138.1, 133.9, 131.6, 131.2, 128.9, 128.5, 128.5, 128.4, 127.9, 126.5, 125.9, 125.9, 125.8, 125.3, 125.2, 123.3, 111.3, 82.0, 74.7, 52.4, 51.4, 46.5, 39.9, 39.5, 38.0, 35.6, 34.7, 29.3, 29.1, 28.8, 25.6; MS(ESI) calcd for C₃₈H₄₆N₂O₅ 610.34 (M⁺), found 611.48 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27n

Compound 27n was prepared according to the general procedure D from carboxylic acid 26j and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.1, 1.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.54–7.49 (m, 1H), 7.49–7.45 (m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 6.77 (t, J = 6.0 Hz, 1H), 5.45–5.40 (m, 2H), 5.26 (d, J = 16.0 Hz, 1H), 3.79 (q, J = 6.4 Hz, 1H), 3.69 (d, J = 1.5 Hz, 1H), 3.35–3.27 (m, 4H), 3.25 (s, 3H), 3.22–3.13 (m, 3H), 2.74 (dd, J = 15.0, 6.4 Hz, 1H), 2.67 (dd, J = 15.0, 4.8 Hz, 1H), 2.48 (dd, J = 12.7, 7.5 Hz, 1H), 2.38 (t, J = 8.1 Hz, 2H), 2.03–1.95 (m, 2H), 1.86 (dd, J = 12.8, 11.0 Hz, 1H), 1.69–1.61 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H), 0.75 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 175.8, 172.7, 170.9, 170.8, 138.3, 133.9, 131.8, 131.2, 128.8, 127.7, 126.3, 125.7, 125.4, 125.4, 123.4, 110.9, 82.1, 74.7, 52.4, 51.4, 47.4, 46.5, 39.8, 39.8, 37.6, 36.0, 34.7, 31.1, 28.9, 26.7, 25.6, 18.0, 16.3; MS(ESI) calcd for C₃₅H₄₅N₃O₆ 603.33 (M⁺), found 604.47 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27o

Compound 27o was prepared according to the general procedure D from carboxylic acid 26k and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4, 2.1 Hz, 1H), 5.71 (t, J = 5.7 Hz, 1H), 5.25 (d, J = 1.4 Hz, 1H), 5.19 (d, J = 16.7 Hz, 1H), 4.57 (d, J = 16.7 Hz, 1H), 3.84 (q, J = 6.5 Hz, 1H), 3.70 (d, J = 1.5 Hz, 1H), 3.67 (s, 3H), 3.29–3.13 (m, 3H), 3.05–2.96 (m, 1H), 2.78 (dd, J = 15.1, 5.7 Hz, 1H), 2.51 (dd, J = 15.1, 4.5 Hz, 1H), 2.44 (dd, J = 12.7, 7.1 Hz, 1H), 1.98 (t, J = 12.1 Hz, 1H), 1.63–1.53 (m, 1H), 1.38–1.30 (m, 2H), 1.21 (d, J = 6.5 Hz, 3H), 0.92–0.86 (m, 8H), 0.78 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.2, 170.3, 138.3, 133.3, 133.1, 133.0, 129.5, 129.2, 127.3, 110.5, 82.0, 74.8, 52.9, 51.5, 46.6, 38.9, 38.6, 38.0, 37.6, 34.7, 28.8, 26.0, 25.6, 22.6, 22.6, 22.6; MS(ESI) calcd for C₂₉H₄₀Cl₂N₂O₅ 566.23 (M⁺), found 567.39 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27p

Compound 27p was prepared according to the general procedure D from carboxylic acid 26k and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 6.80–6.74 (m, 3H), 6.00 (t, J = 5.7 Hz, 1H), 5.25 (d, J = 1.5 Hz, 1H), 5.20 (d, J = 16.8 Hz, 1H), 4.53 (d, J = 16.8 Hz, 1H), 4.36–4.31 (m, 2H), 3.84 (d, J = 7.2 Hz, 4H), 3.80 (s, 3H), 3.71 (d, J = 1.5 Hz, 1H), 3.67 (s, 3H), 3.08–2.99 (m, 1H), 2.84 (dd, J = 15.3, 5.6 Hz, 1H), 2.54 (dd, J = 15.3, 4.4 Hz, 1H), 2.45 (dd, J = 12.6, 7.1 Hz, 1H), 2.06 (t, J = 12.1 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H), 0.78 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.1, 170.3, 149.3, 148.5, 138.4, 133.3, 133.0, 132.9, 131.0, 129.5, 129.2, 127.3, 120.0, 111.2, 111.1, 110.5, 82.0, 74.8, 56.0, 56.0, 52.9, 51.5, 46.8, 43.4, 38.7, 37.5, 34.7, 28.9, 25.6, 16.3; MS(ESI) calcd for C₃₃H₄₀Cl₂N₂O₇ 646.22 (M⁺), found 647.38 (M + H)⁺, 669.34 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27q

Compound 27q was prepared according to the general procedure D from carboxylic acid 26l and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 6.54 (t, J = 5.6 Hz, 1H), 5.36 (d, J = 1.6 Hz, 1H), 4.08–3.93 (m, 4H), 3.79 (ddd, J = 13.6, 10.1, 5.9 Hz, 1H), 3.68 (s, 3H), 3.48 (ddd, J = 13.6, 10.1, 4.9 Hz, 1H), 3.02–2.92 (m, 1H), 2.63–2.52 (m, 2H), 2.40 (dd, J = 12.8, 7.1 Hz, 1H), 2.19 (t, J = 2.6 Hz, 1H), 2.03–1.92 (m, 1H), 1.81–1.35 (m, 11H), 1.35–1.22 (m, 10H), 1.20 (d, J = 6.5 Hz, 3H), 0.87 (t, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 170.7, 170.6, 136.4, 110.6, 79.8, 78.2, 74.6, 71.5, 52.8, 51.4, 44.9, 43.9, 39.7, 37.4, 31.9, 29.5, 29.4, 29.4, 29.3, 28.9, 28.6, 27.3, 26.8, 25.9, 25.8, 22.8, 16.7, 14.2; MS(ESI) calcd for C₂₉H₄₄N₂O₅ 500.33 (M⁺), found 501.45 (M + H)⁺, 524.44 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27r

Compound 27r was prepared according to the general procedure D from carboxylic acid 26l and amine 11j: ¹H NMR (500 MHz, CDCl₃) δ 6.12 (s, 1H), 5.34 (d, J = 1.6 Hz, 1H), 4.07–3.95 (m, 2H), 3.79 (ddd, J = 13.5, 10.1, 6.0 Hz, 1H), 3.68 (s, 3H), 3.46 (ddd, J = 14.2, 10.0, 4.9 Hz, 1H), 3.29–3.11 (m, 2H), 2.99–2.89 (m, 1H), 2.55 (d, J = 5.6 Hz, 2H), 2.40 (dd, J = 12.9, 7.1 Hz, 1H), 2.02–1.92 (m, 1H), 1.80–1.65 (m, 4H), 1.65–1.37 (m, 5H), 1.35–1.22 (m, 16H), 1.20 (d, J = 6.5 Hz, 3H), 0.94–0.83 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 170.8, 170.7, 136.5, 110.4, 78.2, 74.7, 52.8, 51.4, 44.9, 43.8, 39.9, 39.4, 37.7, 31.9, 31.8, 29.4, 29.4, 29.3, 28.9, 28.6, 27.3, 26.8, 25.8, 25.8, 22.8, 20.2, 16.7, 14.2, 13.9; MS(ESI) calcd for C₃₀H₅₀N₂O₅ 518.37 (M⁺), found 519.48 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27s

Compound 27s was prepared according to the general procedure D from carboxylic acid 26m and amine 11j: ¹H NMR (500 MHz, CDCl₃) δ 7.36–7.14 (m, 5H), 6.08 (s, 1H), 5.30 (d, J = 1.7 Hz, 1H), 5.12 (d, J = 15.6 Hz, 1H), 4.69 (d, J = 15.6 Hz, 1H), 3.99 (q, J = 6.5 Hz, 1H), 3.93 (dd, J = 7.8, 1.7 Hz, 1H), 3.60 (s, 3H), 3.28–3.15 (m, 2H), 3.06–2.96 (m, 1H), 2.64 (dd, J = 5.5, 2.4 Hz, 2H), 2.43 (dd, J = 12.9, 6.7 Hz, 1H), 1.90–1.82 (m, 2H), 1.72–1.62 (m, 1H), 1.53–1.45 (m, 4H), 1.45–1.38 (m, 4H), 1.38–1.25 (m, 3H), 1.20 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.1, 170.8, 137.2, 136.4, 128.6, 127.2, 127.0, 111.2, 77.9, 74.5, 52.8, 51.4, 48.0, 44.8, 39.5, 39.5, 37.8, 31.8, 29.5, 28.9, 28.4, 25.8, 25.7, 20.2, 16.9, 13.9; MS(ESI) calcd for C₂₉H₄₀N₂O₅ 496.29 (M⁺), found 497.33 (M + H)⁺, 519.32 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27t

Compound 27t was prepared according to the general procedure D from carboxylic acid 26m and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.13 (m, 10H), 6.10 (t, J = 6.0 Hz, 1H), 5.29 (d, J = 1.6 Hz, 1H), 5.09 (d, J = 15.6 Hz, 1H), 4.68 (d, J = 15.6 Hz, 1H), 3.99 (q, J = 6.5 Hz, 1H), 3.93 (dd, J = 7.8, 1.8 Hz, 1H), 3.59 (s, 3H), 3.31–3.15 (m, 3H), 3.05–2.95 (m, 1H), 2.65–2.57 (m, 5H), 2.42 (dd, J = 12.9, 6.6 Hz, 1H), 1.90–1.81 (m, 2H), 1.71–1.58 (m, 2H), 1.55–1.40 (m, 6H), 1.35–1.23 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H), 1.16–1.05 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.1, 170.8, 142.3, 137.2, 136.4, 128.6, 128.5, 128.4, 127.2, 127.0, 125.9, 111.2, 77.9, 74.5, 52.8, 51.4, 48.0, 44.8, 39.5, 39.5, 37.7, 35.6, 29.6, 29.3, 28.9, 28.8, 28.4, 25.8, 25.7, 16.9; MS(ESI) calcd for C₃₅H₄₄N₂O₅ 572.33 (M⁺), found 573.37 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27u

Compound 27u was prepared according to the general procedure D from carboxylic acid 26n and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.50 (d, J = 6.9 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.44–7.39 (m, 1H), 6.75–6.69 (m, 2H), 6.66 (dd, J = 7.9, 1.7 Hz, 1H), 6.62 (t, J = 6.0 Hz, 1H), 5.93–5.89 (m, 2H), 5.34 (d, J = 1.6 Hz, 1H), 4.92 (d, J = 15.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.50 (dd, J = 15.2, 5.8 Hz, 1H), 4.45 (dd, J = 15.2, 6.0 Hz, 1H), 4.00 (q, J = 6.6 Hz, 1H), 3.95 (dd, J = 7.9, 1.6 Hz, 1H), 3.62 (s, 3H), 3.08–3.00 (m, 1H), 2.70 (dd, J = 15.0, 5.5 Hz, 1H), 2.65 (dd, J = 15.0, 5.7 Hz, 1H), 2.42 (dd, J = 12.8, 6.7 Hz, 1H), 1.94–1.82 (m, 2H), 1.74–1.64 (m, 1H), 1.59–1.41 (m, 5H), 1.37–1.28 (m, 1H), 1.23–1.12 (m, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.1, 171.0, 148.0, 146.7, 139.7, 136.3, 131.2, 131.2, 131.0, 131.0 (q, ²J_C–F = 31.8 Hz), 129.2, 124.4 (q, ³J_C–F = 3.8 Hz), 124.3 (q, ³J_C–F = 3.8 Hz), 124.2 (q, ¹J_C–F = 272.7 Hz), 120.3, 111.3, 108.3, 107.7, 101.1, 78.0, 74.5, 52.9, 51.3, 47.7, 44.8, 43.1, 39.4, 37.6, 29.7, 28.9, 28.5, 25.8, 25.8, 16.8; MS(ESI) calcd for C₃₄H₃₇F₃N₂O₇ 642.26 (M⁺), found 643.32 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27v

Compound 27v was prepared according to the general procedure D from carboxylic acid 26n and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 6.78 (d, J = 1.5 Hz, 1H), 6.76–6.70 (m, 2H), 5.91 (s, 2H), 5.34 (d, J = 1.6 Hz, 1H), 4.95 (d, J = 15.4 Hz, 1H), 4.65 (d, J = 15.5 Hz, 1H), 4.01–3.93 (m, 2H), 3.70–3.63 (m, 4H), 3.62 (s, 5H), 3.46 (t, J = 4.9 Hz, 2H), 3.04–2.97 (m, 1H), 2.85–2.76 (m, 2H), 2.38 (dd, J = 12.5, 6.7 Hz, 1H), 1.95–1.86 (m, 2H), 1.74–1.64 (m, 1H), 1.60–1.41 (m, 5H), 1.33 (dq, J = 12.5, 7.9, 7.4 Hz, 1H), 1.22–1.13 (m, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 171.1, 169.1, 147.9, 146.6, 136.8, 131.5, 120.4, 110.8, 108.2, 108.0, 101.0, 78.2, 74.6, 67.0, 66.7, 52.7, 51.4, 47.9, 45.9, 44.7, 42.1, 37.0, 35.9, 29.4, 28.9, 28.4, 25.8, 25.8, 16.8; MS(ESI) calcd for C₃₀H₃₈N₂O₈ 554.26 (M⁺), found 555.37 (M + H)⁺, 577.33 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27w

Compound 27w was prepared according to the general procedure D from carboxylic acid 26o and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.32 (dd, J = 1.8, 0.9 Hz, 1H), 6.74 (t, J = 6.3 Hz, 1H), 6.31 (dd, J = 3.2, 1.8 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 5.53 (d, J = 1.5 Hz, 1H), 5.00 (d, J = 15.8 Hz, 1H), 4.63 (d, J = 15.7 Hz, 1H), 3.99 (dd, J = 8.0, 1.6 Hz, 1H), 3.95 (q, J = 6.5 Hz, 1H), 3.61 (s, 3H), 3.37 (t, J = 7.0 Hz, 2H), 3.31 (td, J = 6.5, 2.6 Hz, 2H), 3.21–3.08 (m, 2H), 3.06–2.99 (m, 1H), 2.64 (dd, J = 15.0, 5.0 Hz, 1H), 2.55 (dd, J = 14.9, 6.6 Hz, 1H), 2.42–2.35 (m, 3H), 2.08–1.99 (m, 2H), 1.99–1.90 (m, 1H), 1.77–1.61 (m, 6H), 1.61–1.45 (m, 3H), 1.41–1.32 (m, 1H), 1.29–1.21 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 172.8, 170.8, 170.7, 150.8, 141.6, 136.8, 111.1, 110.7, 108.4, 78.2, 74.6, 52.8, 51.3, 47.5, 44.8, 41.4, 39.8, 39.5, 37.3, 36.0, 31.1, 29.2, 28.9, 28.4, 26.7, 25.8, 25.8, 18.1, 16.7; MS(ESI) calcd for C₃₀H₄₁N₃O₇ 555.29 (M⁺), found 556.48 (M + H)⁺, 578.46 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27x

Compound 27x was prepared according to the general procedure D from carboxylic acid 26o and amine 11s: ¹H NMR (500 MHz, CDCl₃) δ 7.32 (dd, J = 1.7, 0.9 Hz, 1H), 6.31 (dd, J = 3.2, 1.8 Hz, 1H), 6.28 (d, J = 3.2 Hz, 1H), 5.55 (d, J = 1.5 Hz, 1H), 4.96 (d, J = 15.7 Hz, 1H), 4.69 (d, J = 15.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 3H), 4.00 (dd, J = 7.9, 1.5 Hz, 1H), 3.96 (q, J = 6.5 Hz, 1H), 3.64–3.57 (m, 4H), 3.56–3.37 (m, 6H), 3.07–2.99 (m, 1H), 2.84 (dd, J = 16.1, 3.5 Hz, 1H), 2.70 (dd, J = 16.2, 7.5 Hz, 1H), 2.42 (dd, J = 12.6, 6.9 Hz, 1H), 2.01–1.91 (m, 1H), 1.81–1.62 (m, 4H), 1.62–1.45 (m, 4H), 1.43–1.33 (m, 1H), 1.30–1.22 (m, 4H), 1.19 (d, J = 6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.7, 169.2, 155.5, 150.8, 141.6, 136.9, 111.2, 110.7, 108.4, 78.3, 74.6, 61.8, 52.8, 51.4, 45.3, 44.7, 43.7, 41.5, 41.4, 37.0, 36.3, 29.4, 28.9, 28.4, 25.9, 25.8, 16.7, 14.8; MS(ESI) calcd for C₃₀H₄₁N₃O₈ 571.29 (M⁺), found 572.48 (M + H)⁺, 594.46 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27y

Compound 27y was prepared according to the general procedure D from carboxylic acid 26b and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 6.25 (s, 1H), 5.45 (d, J = 3.3 Hz, 1H), 5.37 (d, J = 1.6 Hz, 1H), 4.07–3.97 (m, 2H), 3.89 (ddd, J = 13.4, 11.0, 5.3 Hz, 1H), 3.68 (s, 3H), 3.56 (ddd, J = 13.5, 10.8, 5.2 Hz, 1H), 3.04–2.79 (m, 3H), 2.60 (d, J = 5.7 Hz, 2H), 2.40 (dd, J = 12.9, 6.7 Hz, 1H), 2.25 (ddd, J = 15.2, 10.7, 5.1 Hz, 1H), 2.11–1.88 (m, 10H), 1.80–1.67 (m, 7H), 1.67–1.57 (m, 7H), 1.57–1.48 (m, 2H), 1.47–1.37 (m, 5H), 1.33–1.23 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 171.1, 170.6, 136.2, 135.1, 122.9, 110.2, 78.1, 74.5, 52.8, 51.4, 51.1, 45.1, 42.9, 40.3, 39.8, 37.8, 37.1, 36.5, 34.9, 33.7, 32.3, 29.5, 29.0, 28.7, 28.6, 28.4, 28.0, 25.8, 25.8, 25.4, 23.0, 22.4, 16.8; MS(ESI) calcd for C₃₇H₅₄N₂O₅ 606.40 (M⁺), found 607.55 (M + H)⁺, 609.57 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27z

Compound 27z was prepared according to the general procedure D from carboxylic acid 26b and amine 11p: ¹H NMR (500 MHz, CDCl₃) δ 6.42 (t, J = 5.5 Hz, 1H), 5.45 (t, J = 3.4 Hz, 1H), 5.37 (d, J = 1.6 Hz, 1H), 4.08–3.95 (m, 2H), 3.81 (ddd, J = 13.4, 11.0, 5.2 Hz, 1H), 3.68 (s, 3H), 3.59 (ddd, J = 13.3, 10.9, 5.3 Hz, 1H), 3.47 (t, J = 5.8 Hz, 2H), 3.40 (t, J = 6.6 Hz, 3H), 3.35–3.26 (m, 2H), 2.97–2.87 (m, 1H), 2.59 (dd, J = 14.8, 5.1 Hz, 1H), 2.47 (dd, J = 14.8, 6.4 Hz, 1H), 2.38 (dd, J = 12.8, 6.9 Hz, 1H), 2.30–2.22 (m, 1H), 2.09–2.01 (m, 1H), 2.01–1.93 (m, 5H), 1.80–1.69 (m, 5H), 1.69–1.58 (m, 5H), 1.58–1.48 (m, 6H), 1.46–1.24 (m, 5H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.7, 170.5, 136.5, 135.2, 122.9, 109.9, 78.2, 74.6, 71.0, 69.7, 52.8, 51.4, 45.0, 43.0, 39.7, 38.1, 37.5, 35.0, 31.9, 29.4, 29.4, 29.0, 28.7, 28.6, 25.8, 25.8, 25.4, 23.0, 22.5, 19.5, 16.8, 14.1; MS(ESI) calcd for C₃₃H₅₂N₂O₆ 572.38 (M⁺), found 573.53 (M + H)⁺, 595.53 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27aa

Compound 27aa was prepared according to the general procedure D from carboxylic acid 26p and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 6.83–6.73 (m, 3H), 6.32 (q, J = 5.9 Hz, 1H), 5.34 (d, J = 1.6 Hz, 1H), 4.05–3.98 (m, 2H), 3.94 (ddd, J = 13.5, 10.5, 6.2 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.78–3.68 (m, 1H), 3.66 (s, 3H), 3.44 (t, J = 5.9 Hz, 2H), 3.37–3.27 (m, 6H), 3.01–2.91 (m, 1H), 2.91–2.81 (m, 1H), 2.81–2.72 (m, 1H), 2.61 (dd, J = 14.9, 5.1 Hz, 1H), 2.54 (dd, J = 14.8, 6.5 Hz, 1H), 2.41 (dd, J = 12.8, 7.0 Hz, 1H), 1.99–1.87 (m, 1H), 1.80–1.64 (m, 6H), 1.64–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.44–1.36 (m, 1H), 1.32–1.22 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.7, 170.6, 149.1, 147.7, 136.8, 131.8, 120.7, 112.2, 111.5, 110.4, 78.2, 74.6, 71.6, 58.9, 56.0, 56.0, 52.8, 51.5, 46.0, 45.0, 39.7, 38.0, 37.5, 32.8, 29.4, 29.3, 29.0, 28.7, 25.8, 25.7, 16.8; MS(ESI) calcd for C₃₂H₄₆N₂O₈ 586.33 (M⁺), found 587.48 (M + H)⁺, 609.47 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ab

Compound 27ab was prepared according to the general procedure D from carboxylic acid 26p and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 6.83–6.74 (m, 3H), 5.37 (d, J = 1.6 Hz, 1H), 4.06–3.90 (m, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.79–3.69 (m, 1H), 3.66 (d, J = 5.8 Hz, 6H), 3.63–3.51 (m, 3H), 3.45 (t, J = 4.9 Hz, 2H), 3.03–2.93 (m, 1H), 2.91–2.73 (m, 3H), 2.70 (dd, J = 16.2, 7.5 Hz, 1H), 2.41 (dd, J = 12.6, 6.9 Hz, 1H), 2.01–1.89 (m, 1H), 1.80–1.73 (m, 2H), 1.72–1.65 (m, 1H), 1.65–1.49 (m, 4H), 1.49–1.36 (m, 1H), 1.34–1.23 (m, 1H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 170.7, 169.2, 149.1, 147.7, 136.9, 131.9, 120.7, 112.2, 111.4, 110.2, 78.3, 74.7, 67.0, 66.7, 56.0, 56.0, 52.8, 51.5, 45.9, 45.0, 42.1, 36.9, 36.3, 32.7, 29.4, 29.0, 28.7, 25.8, 25.8, 16.8; MS(ESI) calcd for C₃₂H₄₄N₂O₈ 584.31 (M⁺), found 585.47 (M + H)⁺, 607.45 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ac

Compound 27ac was prepared according to the general procedure D from carboxylic acid 26q and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 8.06–8.00 (m, 1H), 7.85 (dd, J = 8.0, 1.5 Hz, 1H), 7.75 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.47 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.40–7.37 (m, 1H), 5.41 (d, J = 16.0 Hz, 1H), 5.37–5.30 (m, 2H), 3.95 (dd, J = 7.4, 1.5 Hz, 1H), 3.91 (q, J = 6.5 Hz, 1H), 3.67 (dd, J = 5.4, 3.0 Hz, 4H), 3.64–3.57 (m, 2H), 3.48 (t, J = 4.8 Hz, 2H), 3.25 (s, 3H), 3.13–3.06 (m, 1H), 2.91 (dd, J = 16.2, 6.9 Hz, 1H), 2.81 (dd, J = 16.2, 3.4 Hz, 1H), 2.42 (dd, J = 12.5, 6.8 Hz, 1H), 2.00 (dd, J = 12.5, 11.4 Hz, 1H), 1.95–1.86 (m, 1H), 1.70–1.61 (m, 1H), 1.52–1.38 (m, 5H), 1.35–1.25 (m, 1H), 1.21–1.15 (m, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 171.0, 169.2, 136.9, 133.9, 131.8, 131.3, 128.8, 127.7, 126.3, 125.7, 125.5, 125.5, 123.3, 111.7, 78.1, 74.6, 67.0, 66.7, 52.4, 51.4, 46.0, 45.9, 44.6, 42.1, 37.0, 35.9, 29.3, 28.6, 28.3, 25.9, 25.8, 16.6; MS(ESI) calcd for C₃₃H₄₀N₂O₆ 560.29 (M⁺), found 561.44 (M + H)⁺, 583.44 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ad

Compound 27ad was prepared according to the general procedure D from carboxylic acid 26q and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.2, 1.4 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.52 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.49–7.45 (m, 1H), 7.44–7.37 (m, 2H), 5.43 (d, J = 16.1 Hz, 1H), 5.36–5.30 (m, 2H), 3.96–3.88 (m, 2H), 3.51–3.44 (m, 2H), 3.44–3.38 (m, 2H), 3.27 (s, 3H), 3.09 (dtd, J = 10.5, 6.6, 3.2 Hz, 1H), 2.88 (dd, J = 16.3, 6.9 Hz, 1H), 2.74 (dd, J = 16.3, 3.4 Hz, 1H), 2.42 (dd, J = 12.6, 6.8 Hz, 1H), 2.06 (t, J = 12.1 Hz, 1H), 1.97–1.79 (m, 5H), 1.70–1.62 (m, 1H), 1.51–1.36 (m, 5H), 1.35–1.26 (m, 1H), 1.18 (d, J = 6.5 Hz, 3H), 1.16–1.08 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 171.3, 169.0, 136.8, 133.8, 131.8, 131.3, 128.8, 127.6, 126.3, 125.6, 125.5, 125.5, 123.3, 111.3, 78.1, 74.6, 52.4, 51.4, 46.6, 45.8, 45.8, 44.7, 37.4, 37.0, 29.4, 28.8, 28.4, 26.2, 25.8, 25.8, 24.5, 16.8; MS(ESI) calcd for C₃₃H₄₀N₂O₅ 544.29 (M⁺), found 545.44 (M + H)⁺, 567.43 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ae

Compound 27ae was prepared according to the general procedure D from carboxylic acid 26r and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 7.39 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.5, 2.1 Hz, 1H), 5.19–5.12 (m, 2H), 4.65 (d, J = 16.8 Hz, 1H), 3.98 (q, J = 6.5 Hz, 1H), 3.93 (dd, J = 7.8, 1.7 Hz, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.62–3.53 (m, 1H), 3.48–3.41 (m, 2H), 3.02–2.90 (m, 2H), 2.66 (dd, J = 16.2, 2.9 Hz, 1H), 2.32 (dd, J = 12.5, 6.2 Hz, 1H), 2.10 (t, J = 12.0 Hz, 1H), 1.94–1.85 (m, 1H), 1.71–1.61 (m, 1H), 1.55–1.40 (m, 6H), 1.33 (dt, J = 13.1, 7.4 Hz, 1H), 1.26–1.14 (m, 5H); ¹³C NMR (126 MHz, CDCl₃) δ 173.3, 171.2, 169.0, 136.7, 133.2, 133.1, 133.0, 129.6, 129.0, 127.3, 110.7, 78.0, 74.5, 67.0, 66.6, 52.9, 51.4, 46.1, 45.8, 44.7, 42.0, 36.8, 35.1, 29.1, 28.8, 28.4, 25.9, 25.8, 16.9; MS(ESI) calcd for C₂₉H₃₆Cl₂N₂O₆ 578.20 (M⁺), found 579.36 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27af

Compound 27af was prepared according to the general procedure D from carboxylic acid 26r and amine 11v: ¹H NMR (500 MHz, CDCl₃) δ 7.39 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 5.18–5.11 (m, 2H), 4.64 (d, J = 16.8 Hz, 1H), 3.98 (q, J = 6.5 Hz, 2H), 3.93 (dd, J = 7.7, 1.6 Hz, 1H), 3.92–3.78 (m, 1H), 3.75–3.66 (m, 5H), 3.02–2.90 (m, 2H), 2.69–2.55 (m, 5H), 2.31 (dd, J = 12.4, 6.3 Hz, 1H), 2.09 (t, J = 12.0 Hz, 1H), 1.95–1.85 (m, 1H), 1.71–1.62 (m, 1H), 1.56–1.40 (m, 6H), 1.37–1.27 (m, 1H), 1.27–1.14 (m, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 173.3, 171.2, 168.7, 136.7, 133.2, 133.1, 132.9, 129.6, 129.0, 127.3, 110.7, 78.0, 74.5, 52.9, 51.4, 48.2, 46.1, 44.7, 44.4, 36.9, 35.3, 29.1, 28.8, 28.3, 27.9, 27.5, 25.9, 25.8, 16.8; MS(ESI) calcd for C₂₉H₃₆Cl₂N₂O₅S 594.17 (M⁺), found 595.33 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ag

Compound 27ag was prepared according to the general procedure D from carboxylic acid 26s and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 5.34 (d, J = 1.8 Hz, 1H), 3.95 (dd, J = 6.6, 1.8 Hz, 1H), 3.82 (ddd, J = 13.8, 10.0, 6.3 Hz, 1H), 3.69 (s, 3H), 3.68–3.63 (m, 4H), 3.61–3.55 (m, 2H), 3.53–3.44 (m, 3H), 3.32 (d, J = 8.4 Hz, 1H), 3.05–2.98 (m, 1H), 2.86 (dd, J = 16.1, 3.5 Hz, 1H), 2.59 (dd, J = 16.1, 7.9 Hz, 1H), 2.52 (dd, J = 12.8, 6.6 Hz, 1H), 1.96–1.83 (m, 2H), 1.62–1.53 (m, 1H), 1.53–1.45 (m, 1H), 1.33–1.21 (m, 11H), 0.98 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.8 Hz, 4H), 0.86 (t, J = 6.7 Hz, 3H), 0.58–0.48 (m, 2H), 0.47–0.41 (m, 1H), 0.22–0.16 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.2, 170.7, 169.4, 136.3, 108.0, 82.2, 79.0, 67.0, 66.7, 52.7, 51.8, 46.0, 43.3, 42.1, 36.9, 36.2, 33.5, 31.9, 30.5, 29.4, 29.4, 27.3, 26.7, 22.8, 18.6, 18.5, 14.2, 12.1, 4.0, 2.7; MS(ESI) calcd for C₃₀H₄₈N₂O₆ 532.35 (M⁺), found 533.53 (M + H)⁺, 555.5 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ah

Compound 27ah was prepared according to the general procedure D from carboxylic acid 26s and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 6.89 (s, 1H), 5.31 (d, J = 1.9 Hz, 1H), 3.93 (dd, J = 6.6, 1.9 Hz, 1H), 3.79 (ddd, J = 13.6, 10.0, 6.0 Hz, 1H), 3.68 (s, 3H), 3.56–3.45 (m, 1H), 3.38 (t, J = 7.0 Hz, 2H), 3.35–3.28 (m, 3H), 3.23–3.12 (m, 2H), 3.04–2.95 (m, 1H), 2.64 (dd, J = 15.1, 5.4 Hz, 1H), 2.54–2.43 (m, 2H), 2.39 (t, J = 8.1 Hz, 2H), 2.10–1.99 (m, 2H), 1.92–1.81 (m, 2H), 1.67 (td, J = 6.4, 2.5 Hz, 2H), 1.61–1.52 (m, 1H), 1.52–1.43 (m, 1H), 1.35–1.18 (m, 10H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.6 Hz, 4H), 0.89–0.84 (m, 3H), 0.57–0.47 (m, 2H), 0.47–0.40 (m, 1H), 0.23–0.15 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 173.1, 171.0, 170.7, 136.2, 107.9, 82.0, 78.9, 52.8, 51.7, 47.5, 43.4, 39.8, 39.6, 37.1, 36.0, 33.5, 31.9, 31.1, 30.4, 29.4, 29.4, 27.2, 26.7, 26.7, 22.8, 18.6, 18.5, 18.1, 14.2, 12.2, 4.0, 2.6; MS(ESI) calcd for C₃₃H₅₃N₃O₆ 587.39 (M⁺), found 588.57 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ai

Compound 27ai was prepared according to the general procedure D from carboxylic acid 26t and amine 11b: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (t, J = 7.5 Hz, 2H), 7.25–7.17 (m, 3H), 6.14 (d, J = 6.8 Hz, 1H), 5.28 (d, J = 1.9 Hz, 1H), 5.10 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 3.80 (dd, J = 7.2, 1.9 Hz, 1H), 3.62 (s, 3H), 3.32 (d, J = 8.5 Hz, 1H), 3.07 (t, J = 6.4 Hz, 2H), 3.02–2.95 (m, 1H), 2.69–2.60 (m, 2H), 2.49 (dd, J = 13.2, 6.1 Hz, 1H), 2.11 (t, J = 12.7 Hz, 1H), 1.77–1.60 (m, 6H), 1.47–1.37 (m, 1H), 1.27–1.09 (m, 3H), 0.95–0.81 (m, 6H), 0.74 (d, J = 6.7 Hz, 3H), 0.60–0.53 (m, 1H), 0.51–0.40 (m, 2H), 0.25–0.19 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 171.3, 170.8, 137.1, 135.6, 128.7, 127.2, 126.9, 109.1, 81.9, 78.5, 52.8, 51.7, 47.4, 45.9, 39.4, 38.0, 37.7, 33.5, 30.9, 30.6, 26.5, 26.0, 18.6, 18.5, 12.3, 4.6, 2.6; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₃₂H₄₅N₂O₅ 537.3328, found 537.3327.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27aj

Compound 27aj was prepared according to the general procedure D from carboxylic acid 26t and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.29 (dd, J = 8.6, 6.7 Hz, 2H), 7.23–7.18 (m, 3H), 6.85 (d, J = 6.3 Hz, 1H), 5.25 (d, J = 1.9 Hz, 1H), 5.12 (d, J = 15.8 Hz, 1H), 4.75 (d, J = 15.8 Hz, 1H), 3.79 (dd, J = 7.2, 1.9 Hz, 1H), 3.62 (s, 3H), 3.38–3.27 (m, 5H), 3.24–3.12 (m, 2H), 3.08–3.01 (m, 1H), 2.70 (dd, J = 15.1, 5.2 Hz, 1H), 2.60 (dd, J = 15.1, 6.4 Hz, 1H), 2.44 (dd, J = 13.0, 6.2 Hz, 1H), 2.41–2.36 (m, 2H), 2.08 (t, J = 12.6 Hz, 1H), 2.06–1.99 (m, 2H), 1.68 (dp, J = 18.8, 6.5 Hz, 3H), 0.90–0.81 (m, 4H), 0.73 (d, J = 6.7 Hz, 3H), 0.59–0.52 (m, 1H), 0.50–0.38 (m, 2H), 0.23–0.17 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 173.1, 171.1, 170.9, 137.3, 135.7, 128.6, 127.0, 126.9, 108.6, 82.0, 78.6, 52.8, 51.7, 47.5, 47.4, 39.8, 39.2, 37.2, 36.0, 33.5, 31.1, 30.5, 26.7, 18.6, 18.5, 18.1, 12.3, 4.6, 2.6; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₃₂H₄₄N₃O₆ 566.3230, found 566.3225.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ak

Compound 27ak was prepared according to the general procedure D from carboxylic acid 26u and amine 11e: ¹H NMR (500 MHz, CDCl₃) δ 7.19 (dd, J = 5.0, 1.3 Hz, 1H), 6.97–6.90 (m, 2H), 6.73 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.67 (dd, J = 7.9, 1.7 Hz, 1H), 5.92 (s, 2H), 5.33 (d, J = 1.9 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.63–4.54 (m, 2H), 3.82 (dd, J = 7.2, 1.9 Hz, 1H), 3.64 (s, 3H), 3.33 (d, J = 8.5 Hz, 1H), 3.04–2.97 (m, 1H), 2.71 (dd, J = 14.9, 5.5 Hz, 1H), 2.65 (dd, J = 14.9, 5.5 Hz, 1H), 2.48 (dd, J = 13.1, 6.2 Hz, 1H), 2.09 (t, J = 12.7 Hz, 1H), 1.81–1.73 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H), 0.89–0.83 (m, 2H), 0.60–0.53 (m, 1H), 0.53–0.47 (m, 1H), 0.47–0.39 (m, 1H), 0.25–0.18 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 171.3, 170.7, 148.0, 146.7, 141.2, 135.6, 130.8, 127.0, 126.1, 125.1, 120.2, 109.2, 108.3, 107.6, 101.1, 81.8, 78.6, 52.9, 51.6, 47.1, 38.9, 38.4, 37.5, 33.5, 30.5, 18.6, 18.6, 12.3, 4.5, 2.7; MS(ESI) calcd for C₃₁H₃₆N₂O₇S 580.22 (M⁺), found 581.4 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27al

Compound 27al was prepared according to the general procedure D from carboxylic acid 26u and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.29–7.23 (m, 3H), 7.19–7.13 (m, 3H), 6.73 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.66 (dd, J = 8.0, 1.7 Hz, 1H), 5.91 (s, 2H), 5.32 (d, J = 2.0 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.73 (d, J = 15.5 Hz, 1H), 3.82 (dd, J = 7.1, 1.9 Hz, 1H), 3.63 (s, 3H), 3.32 (d, J = 8.5 Hz, 1H), 3.27–3.21 (m, 2H), 3.02–2.94 (m, 1H), 2.68–2.57 (m, 4H), 2.48 (dd, J = 13.1, 6.3 Hz, 1H), 2.07 (t, J = 12.7 Hz, 1H), 1.80–1.72 (m, 1H), 1.68–1.59 (m, 2H), 1.56–1.48 (m, 2H), 0.90 (d, J = 6.7 Hz, 3H), 0.89–0.82 (m, 1H), 0.79 (d, J = 6.7 Hz, 3H), 0.59–0.52 (m, 1H), 0.51–0.40 (m, 2H), 0.24–0.17 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 171.4, 170.8, 148.0, 146.7, 142.3, 135.7, 130.9, 128.5, 128.4, 125.9, 120.2, 108.3, 107.6, 101.1, 81.9, 78.6, 52.9, 51.7, 47.2, 39.6, 39.1, 37.6, 35.6, 33.5, 30.5, 29.3, 28.8, 18.6, 18.6, 12.3, 4.5, 2.6; MS(ESI) calcd for C₃₆H₄₄N₂O₇ 616.31 (M⁺), found 617.49 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27am

Compound 27am was prepared according to the general procedure D from carboxylic acid 26v and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (d, J = 2.3 Hz, 1H), 6.31 (dd, J = 3.2, 1.9 Hz, 1H), 6.25 (d, J = 3.2 Hz, 1H), 5.99 (s, 1H), 5.56 (d, J = 1.8 Hz, 1H), 5.07 (d, J = 15.8 Hz, 1H), 4.66 (d, J = 15.7 Hz, 1H), 3.89 (dd, J = 6.7, 1.8 Hz, 1H), 3.64 (s, 3H), 3.32 (d, J = 8.2 Hz, 1H), 3.24–3.13 (m, 2H), 3.03–2.95 (m, 1H), 2.58 (d, J = 5.3 Hz, 1H), 2.52 (dd, J = 13.1, 6.6 Hz, 1H), 1.95 (dd, J = 13.1, 11.8 Hz, 1H), 1.87–1.78 (m, 1H), 1.62–1.53 (m, 1H), 1.36–1.29 (m, 2H), 0.94 (d, J = 6.7 Hz, 3H), 0.92–0.85 (m, 11H), 0.57–0.46 (m, 2H), 0.46–0.39 (m, 1H), 0.22–0.16 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 171.1, 170.7, 150.7, 141.8, 136.2, 110.7, 109.4, 108.3, 81.8, 78.8, 52.9, 51.7, 41.0, 39.5, 38.6, 38.0, 37.7, 33.4, 30.3, 26.0, 22.6, 22.6, 22.6, 18.5, 18.4, 12.1, 4.0, 2.6; MS(ESI) calcd for C₂₈H₄₀N₂O₆ 500.29 (M⁺), found 501.45 (M + H)⁺, 523.44 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27an

Compound 27an was prepared according to the general procedure D from carboxylic acid 26v and amine 11q: ¹H NMR (500 MHz, CDCl₃) δ 7.31 (dd, J = 1.6, 0.9 Hz, 1H), 6.31 (dd, J = 3.1, 1.8 Hz, 1H), 6.27 (d, J = 3.2 Hz, 1H), 5.52 (d, J = 1.8 Hz, 1H), 5.02 (d, J = 15.8 Hz, 1H), 4.73 (d, J = 15.8 Hz, 1H), 3.90 (dd, J = 6.7, 1.8 Hz, 1H), 3.74–3.65 (m, 6H), 3.64 (s, 3H), 3.60 (s, 2H), 3.47 (s, 1H), 3.31 (d, J = 8.3 Hz, 1H), 3.12–3.03 (m, 1H), 2.89 (dd, J = 16.2, 3.7 Hz, 1H), 2.69 (s, 1H), 2.52 (dd, J = 12.8, 6.5 Hz, 1H), 1.98 (t, J = 11.6 Hz, 1H), 1.83 (h, J = 6.7 Hz, 1H), 1.70 (s, 1H), 1.00 (dt, J = 6.3, 3.2 Hz, 2H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 0.79 (dt, J = 8.0, 3.5 Hz, 2H), 0.56–0.46 (m, 2H), 0.45–0.39 (m, 1H), 0.21–0.14 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 170.8, 150.8, 141.6, 136.3, 110.7, 108.2, 81.9, 52.8, 51.8, 45.3, 42.0, 41.7, 40.9, 37.0, 36.0, 33.4, 30.5, 18.5, 18.5, 12.1, 11.2, 7.8, 4.0, 2.6; MS(ESI) calcd for C₃₁H₄₁N₃O₇ 567.29 (M⁺), found 568.48 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ao

Compound 27ao was prepared according to the general procedure D from carboxylic acid 26w and amine 11e: ¹H NMR (500 MHz, CDCl₃) δ 7.18 (dd, J = 5.0, 1.3 Hz, 1H), 6.96–6.88 (m, 2H), 6.61 (t, J = 5.8 Hz, 1H), 5.43 (t, J = 3.3 Hz, 1H), 5.36 (d, J = 1.9 Hz, 1H), 4.63 (dd, J = 15.2, 5.9 Hz, 1H), 4.51 (dd, J = 15.3, 5.3 Hz, 1H), 3.92 (dd, J = 7.0, 1.9 Hz, 1H), 3.78 (ddd, J = 13.5, 10.7, 5.4 Hz, 1H), 3.69 (s, 3H), 3.67–3.58 (m, 1H), 3.34 (d, J = 8.4 Hz, 1H), 2.95–2.86 (m, 1H), 2.62 (dd, J = 14.7, 5.6 Hz, 1H), 2.56 (dd, J = 14.7, 5.6 Hz, 1H), 2.47 (dd, J = 13.0, 6.3 Hz, 1H), 2.23–2.13 (m, 1H), 2.09–2.00 (m, 1H), 2.00–1.90 (m, 5H), 1.87 (dt, J = 13.5, 6.8 Hz, 1H), 1.61 (dq, J = 6.4, 4.1, 3.7 Hz, 2H), 1.57–1.49 (m, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.96–0.86 (m, 4H), 0.60–0.49 (m, 2H), 0.46 (dq, J = 10.2, 4.8 Hz, 1H), 0.26–0.18 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 170.7, 170.6, 141.4, 135.7, 135.0, 126.9, 125.9, 125.0, 123.0, 108.0, 81.9, 78.7, 52.9, 51.7, 42.5, 39.4, 38.3, 37.5, 34.9, 33.7, 30.5, 28.6, 25.4, 23.0, 22.4, 18.8, 18.7, 12.3, 4.4, 2.7; MS(ESI) calcd for C₃₁H₄₂N₂O₅S 554.28 (M⁺), found 555.44 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ap

Compound 27ap was prepared according to the general procedure D from carboxylic acid 26w and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 6.36 (t, J = 5.3 Hz, 1H), 6.06 (d, J = 3.0 Hz, 1H), 5.86 (d, J = 2.6 Hz, 1H), 5.47–5.41 (m, 1H), 5.35 (d, J = 1.9 Hz, 1H), 4.36 (dd, J = 15.4, 5.5 Hz, 1H), 4.29 (dd, J = 15.4, 5.1 Hz, 1H), 3.93 (dd, J = 6.9, 1.8 Hz, 1H), 3.79 (ddd, J = 13.5, 10.7, 5.3 Hz, 1H), 3.69 (s, 3H), 3.67–3.59 (m, 1H), 3.33 (d, J = 8.4 Hz, 1H), 2.96–2.88 (m, 1H), 2.62 (dd, J = 14.8, 5.4 Hz, 1H), 2.54 (dd, J = 14.7, 5.9 Hz, 1H), 2.47 (dd, J = 13.0, 6.4 Hz, 1H), 2.24 (s, 3H), 2.22–2.15 (m, 1H), 2.10–2.02 (m, 1H), 2.01–1.89 (m, 5H), 1.86 (dt, J = 13.5, 6.8 Hz, 1H), 1.65–1.57 (m, 2H), 1.57–1.49 (m, 2H), 0.98 (d, J = 6.7 Hz, 3H), 0.95–0.86 (m, 4H), 0.58–0.48 (m, 2H), 0.48–0.42 (m, 1H), 0.24–0.18 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 170.6, 170.6, 151.9, 149.7, 135.9, 135.1, 123.0, 108.2, 108.0, 106.3, 81.9, 78.7, 52.8, 51.8, 42.6, 39.5, 37.5, 36.8, 34.9, 33.6, 30.4, 28.6, 25.4, 23.0, 22.4, 18.7, 18.6, 13.7, 12.3, 4.2, 2.6; MS(ESI) calcd for C₃₂H₄₄N₂O₆ 552.32 (M⁺), found 553.49 (M + H)⁺, 575.47 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27aq

Compound 27aq was prepared according to the general procedure D from carboxylic acid 26c and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 6.82–6.74 (m, 3H), 6.02 (s, 1H), 5.31 (d, J = 1.8 Hz, 1H), 3.98–3.90 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.79 (ddd, J = 13.6, 9.8, 5.6 Hz, 1H), 3.68 (s, 3H), 3.33 (d, J = 8.3 Hz, 1H), 3.29–3.18 (m, 2H), 2.98–2.90 (m, 1H), 2.87–2.74 (m, 2H), 2.56 (dd, J = 9.4, 5.7 Hz, 1H), 2.50 (dd, J = 12.9, 6.5 Hz, 1H), 1.93 (dd, J = 13.1, 11.6 Hz, 1H), 1.86–1.78 (m, 1H), 1.63–1.54 (m, 1H), 1.37 (q, J = 7.3 Hz, 2H), 0.96 (d, J = 6.7 Hz, 3H), 0.94–0.85 (m, 11H), 0.58–0.48 (m, 2H), 0.48–0.41 (m, 1H), 0.24–0.17 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 170.9, 170.6, 149.1, 147.8, 136.2, 131.7, 120.7, 112.2, 111.5, 108.4, 81.9, 78.8, 56.0, 56.0, 52.9, 51.9, 45.6, 39.6, 38.6, 38.0, 37.6, 33.5, 32.7, 30.4, 26.0, 22.6, 22.6, 22.6, 18.6, 18.5, 12.2, 4.1, 2.6; MS(ESI) calcd for C₃₃H₄₈N₂O₇ 584.35 (M⁺), found 585.51 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ar

compound 27ar was prepared according to the general procedure D from carboxylic acid 26c and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 8.27 (s, 1H), 6.82–6.72 (m, 3H), 6.15 (t, J = 6.4 Hz, 1H), 5.31 (d, J = 1.9 Hz, 1H), 4.00 (ddd, J = 13.7, 9.7, 7.0 Hz, 1H), 3.92 (dd, J = 7.1, 1.9 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (ddd, J = 13.9, 9.5, 5.5 Hz, 1H), 3.68 (s, 3H), 3.34 (d, J = 8.4 Hz, 1H), 2.98 (dd, J = 13.6, 6.4 Hz, 1H), 2.92 (dd, J = 11.8, 6.1 Hz, 1H), 2.89–2.75 (m, 3H), 2.62 (dd, J = 5.6, 2.0 Hz, 2H), 2.49 (dd, J = 13.1, 6.4 Hz, 1H), 2.06–1.89 (m, 5H), 1.86–1.78 (m, 1H), 1.74–1.55 (m, 10H), 1.45 (d, J = 2.9 Hz, 6H), 0.96 (d, J = 6.6 Hz, 3H), 0.92–0.84 (m, 5H), 0.58–0.48 (m, 2H), 0.48–0.42 (m, 1H), 0.25–0.19 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 170.9, 170.8, 149.1, 147.8, 136.0, 131.7, 120.7, 112.2, 111.5, 108.2, 81.8, 78.7, 56.0, 56.0, 52.9, 51.8, 51.3, 51.0, 45.5, 40.4, 40.3, 39.7, 39.6, 37.7, 37.1, 37.0, 36.5, 33.8, 33.6, 32.6, 32.3, 30.4, 28.4, 28.3, 28.0, 18.7, 18.6, 12.3, 4.3, 2.7; MS(ESI) calcd for C₃₉H₅₄N₂O₇ 662.39 (M⁺), found 663.55 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27as

Compound 27as was prepared according to the general procedure D from carboxylic acid 26x and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.48 (ddd, J = 7.9, 6.8, 1.2 Hz, 1H), 7.44–7.35 (m, 2H), 5.47 (d, J = 16.0 Hz, 1H), 5.32 (d, J = 16.3 Hz, 1H), 5.29 (d, J = 1.8 Hz, 1H), 3.86–3.79 (m, 1H), 3.71–3.63 (m, 5H), 3.63–3.55 (m, 2H), 3.54–3.43 (m, 2H), 3.32 (s, 3H), 3.27 (d, J = 8.2 Hz, 1H), 3.20–3.12 (m, 1H), 2.86 (d, J = 5.2 Hz, 2H), 2.54 (dd, J = 12.7, 6.5 Hz, 1H), 2.19 (t, J = 12.2 Hz, 1H), 1.78–1.68 (m, 1H), 0.99–0.87 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H), 0.55–0.44 (m, 2H), 0.44–0.36 (m, 1H), 0.19–0.10 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 171.2, 169.3, 136.3, 133.9, 131.7, 131.2, 128.9, 127.7, 126.3, 125.7, 125.5, 125.2, 123.2, 109.8, 78.8, 67.0, 66.7, 52.4, 51.8, 46.0, 45.3, 42.1, 37.1, 35.7, 33.4, 30.4, 18.4, 18.2, 12.0, 3.9, 2.6; MS(ESI) calcd for C₃₃H₄₀N₂O₆ 560.29 (M⁺), found 561.46 (M + H)⁺, 583.44 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27at

Compound 27at was prepared according to the general procedure D from carboxylic acid 26x and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.48 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.28 (dd, J = 7.2, 1.3 Hz, 1H), 6.82 (t, J = 6.3 Hz, 1H), 5.42 (d, J = 16.2 Hz, 1H), 5.35 (d, J = 16.2 Hz, 1H), 5.23 (d, J = 1.8 Hz, 1H), 3.80 (dd, J = 6.5, 1.8 Hz, 1H), 3.38 (s, 3H), 3.36–3.24 (m, 5H), 3.23–3.09 (m, 3H), 2.70 (d, J = 5.6 Hz, 2H), 2.52 (dd, J = 13.0, 6.5 Hz, 1H), 2.37 (t, J = 8.1 Hz, 2H), 2.14 (t, J = 12.4 Hz, 1H), 2.04–1.93 (m, 2H), 1.83 (s, 1H), 1.76–1.60 (m, 3H), 0.99–0.86 (m, 1H), 0.83 (d, J = 6.7 Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H), 0.61–0.43 (m, 2H), 0.44–0.36 (m, 1H), 0.21–0.12 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 173.0, 171.1, 170.9, 136.1, 133.8, 131.5, 131.1, 128.9, 127.7, 126.3, 125.7, 125.5, 124.7, 123.1, 109.5, 81.9, 78.7, 52.5, 51.7, 47.4, 45.3, 39.8, 39.3, 37.4, 36.0, 33.4, 31.1, 30.4, 26.7, 18.4, 18.3, 18.0, 12.1, 4.1, 2.6; MS(ESI) calcd for C₃₆H₄₅N₃O₆ 615.33 (M⁺), found 616.51 (M + H)⁺, 638.49 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27au

Compound 27au was prepared according to the general procedure D from carboxylic acid 26y and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (t, J = 1.2 Hz, 1H), 7.21 (d, J = 1.2 Hz, 2H), 6.21 (t, J = 5.6 Hz, 1H), 5.10 (d, J = 2.0 Hz, 1H), 5.05 (d, J = 16.8 Hz, 1H), 4.88 (d, J = 16.8 Hz, 1H), 3.78 (dd, J = 7.4, 2.0 Hz, 1H), 3.71 (s, 3H), 3.44 (t, J = 5.8 Hz, 2H), 3.38–3.27 (m, 5H), 2.99–2.89 (m, 1H), 2.70 (dd, J = 15.2, 5.8 Hz, 1H), 2.59 (dd, J = 15.2, 4.8 Hz, 1H), 2.43 (dd, J = 13.0, 6.0 Hz, 1H), 2.24 (t, J = 12.8 Hz, 1H), 1.83–1.67 (m, 4H), 0.90 (d, J = 6.6 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.59 (td, J = 8.8, 4.1 Hz, 1H), 0.55–0.41 (m, 2H), 0.30–0.21 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.2, 171.2, 170.5, 135.4, 133.3, 133.1, 132.8, 129.2, 129.0, 127.5, 108.3, 81.8, 78.5, 71.7, 58.9, 53.0, 51.7, 44.9, 38.4, 38.1, 37.3, 33.6, 30.4, 29.3, 18.7, 18.7, 12.4, 4.8, 2.6; MS(ESI) calcd for C₂₉H₃₈Cl₂N₂O₆ 580.21 (M⁺), found 581.39 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27av

Compound 27av was prepared according to the general procedure D from carboxylic acid 26y and amine 11p: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 1.7 Hz, 1H), 7.24–7.18 (m, 2H), 6.28 (t, J = 5.4 Hz, 1H), 5.09 (d, J = 2.0 Hz, 1H), 5.06 (d, J = 16.8 Hz, 1H), 4.87 (d, J = 16.8 Hz, 1H), 3.78 (dd, J = 7.4, 2.0 Hz, 1H), 3.71 (s, 3H), 3.48 (t, J = 5.8 Hz, 2H), 3.39 (t, J = 6.6 Hz, 2H), 3.36–3.30 (m, 2H), 2.99–2.89 (m, 1H), 2.70 (dd, J = 15.2, 5.8 Hz, 1H), 2.58 (dd, J = 15.2, 4.6 Hz, 1H), 2.42 (dd, J = 13.0, 5.9 Hz, 1H), 2.24 (t, J = 12.7 Hz, 1H), 1.80–1.69 (m, 3H), 1.59–1.49 (m, 2H), 1.40–1.31 (m, 2H), 0.96–0.86 (m, 8H), 0.77 (d, J = 6.7 Hz, 3H), 0.59 (dtd, J = 10.1, 5.6, 4.8, 2.8 Hz, 1H), 0.54–0.41 (m, 2H), 0.29–0.22 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.2, 171.2, 170.4, 133.3, 133.1, 132.8, 129.2, 129.1, 127.5, 108.3, 81.8, 78.5, 71.1, 69.9, 53.0, 51.7, 44.9, 38.4, 38.3, 37.2, 33.6, 31.9, 30.3, 29.3, 19.5, 18.7, 18.7, 14.1, 12.4, 4.8, 2.6; MS(ESI) calcd for C₃₂H₄₄Cl₂N₂O₆ 622.26 (M⁺), found 623.44 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27aw

Compound 27aw was prepared according to the general procedure D from carboxylic acid 26z and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.32 (m, 4H), 7.32–7.28 (m, 1H), 6.46 (t, J = 5.4 Hz, 1H), 5.35 (d, J = 1.7 Hz, 1H), 4.61 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.50 (td, J = 6.0, 1.8 Hz, 1H), 4.11 (q, J = 6.5 Hz, 1H), 4.03 (ddd, J = 17.6, 5.4, 2.5 Hz, 1H), 3.95 (ddd, J = 17.4, 5.0, 2.5 Hz, 1H), 3.85–3.75 (m, 2H), 3.70 (s, 3H), 3.56 (dd, J = 9.8, 6.4 Hz, 1H), 3.52–3.45 (m, 1H), 3.43 (dd, J = 9.7, 5.7 Hz, 1H), 2.93 (m, 1H), 2.59 (dd, J = 15.0, 5.6 Hz, 1H), 2.54 (dd, J = 15.0, 5.7 Hz, 1H), 2.37 (dd, J = 12.8, 6.7 Hz, 1H), 2.19 (t, J = 2.6 Hz, 1H), 1.71 (t, J = 12.3 Hz, 1H), 1.65–1.53 (m, 1H), 1.53–1.42 (m, 1H), 1.36–1.23 (m, 10H), 1.22 (d, J = 6.6 Hz, 3H), 0.91–0.84 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.6, 170.7, 170.5, 138.1, 136.4, 128.6, 127.9, 127.9, 107.3, 79.8, 74.5, 73.6, 73.3, 72.8, 71.5, 52.9, 51.3, 43.6, 39.3, 37.3, 31.9, 29.5, 29.5, 29.4, 29.3, 27.3, 26.7, 22.8, 17.0, 14.2; MS(ESI) calcd for C₃₂H₄₄N₂O₆ 552.32 (M⁺), found 553.5 (M + H)⁺, 575.48 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ax

Compound 27ax was prepared according to the general procedure D from carboxylic acid 26z and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.30 (m, 4H), 7.30–7.27 (m, 1H), 6.84–6.75 (m, 3H), 6.33 (t, J = 5.7 Hz, 1H), 5.32 (d, J = 1.8 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.50 (td, J = 5.9, 1.7 Hz, 1H), 4.32 (dd, J = 14.1, 5.4 Hz, 2H), 4.11 (q, J = 6.6 Hz, 1H), 3.96 (d, J = 12.6 Hz, 2H), 3.89–3.85 (m, 3H), 3.85–3.82 (m, 3H), 3.68 (s, 3H), 3.56 (dd, J = 9.8, 6.4 Hz, 1H), 3.43 (dd, J = 9.9, 5.6 Hz, 1H), 2.95 (m, 1H), 2.60 (dd, J = 14.8, 5.5 Hz, 1H), 2.53 (dd, J = 14.8, 5.9 Hz, 1H), 2.37 (dd, J = 12.8, 6.6 Hz, 1H), 1.72 (t, J = 12.2 Hz, 1H), 1.61–1.50 (m, 1H), 1.49–1.40 (m, 1H), 1.33–1.22 (m, 10H), 1.21 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 191.1, 172.6, 170.7, 170.5, 149.2, 148.5, 138.1, 136.5, 131.2, 128.6, 127.9, 127.9, 127.0, 120.1, 119.8, 111.3, 111.3, 111.2, 110.9, 110.5, 109.1, 107.0, 74.5, 73.6, 73.3, 72.9, 56.3, 56.1, 56.1, 56.1, 56.1, 56.0, 56.0, 56.0, 56.0, 52.9, 44.6, 43.5, 43.5, 39.5, 37.4, 31.9, 29.6, 29.5, 29.4, 29.4, 27.3, 26.7, 22.8, 17.0, 14.2; MS(ESI) calcd for C₃₈H₅₂N₂O₈ 664.37 (M⁺), found 665.55 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ay

Compound 27ay was prepared according to the general procedure D from carboxylic acid 26aa and amine 11h: ¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, J = 8.1 Hz, 1H), 7.87 (dd, J = 7.7, 1.7 Hz, 1H), 7.80 (dd, J = 6.3, 3.3 Hz, 1H), 7.56–7.45 (m, 2H), 7.43–7.36 (m, 2H), 7.34–7.26 (m, 4H), 7.26–7.15 (m, 6H), 6.20 (t, J = 5.6 Hz, 1H), 5.27 (d, J = 1.9 Hz, 1H), 4.91–4.78 (m, 3H), 4.74 (d, J = 15.8 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 4.43 (d, J = 12.1 Hz, 1H), 4.40 (td, J = 5.6, 2.8 Hz, 1H), 4.13 (q, J = 6.5 Hz, 1H), 3.59 (s, 3H), 3.47 (dd, J = 9.8, 6.4 Hz, 1H), 3.31 (dd, J = 9.8, 5.7 Hz, 1H), 3.04–2.96 (m, 1H), 2.70–2.58 (m, 2H), 2.38 (dd, J = 12.8, 6.3 Hz, 1H), 1.87 (t, J = 12.4 Hz, 1H), 1.18 (d, J = 6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 170.8, 170.4, 138.1, 136.8, 136.2, 134.0, 133.7, 131.5, 128.9, 128.7, 128.6, 128.5, 127.8, 127.8, 127.2, 127.0, 126.8, 126.8, 126.1, 125.5, 123.7, 107.7, 74.2, 73.5, 72.9, 72.9, 52.9, 51.4, 47.4, 41.8, 39.0, 37.5, 29.6, 17.2; MS(ESI) calcd for C₃₉H₄₀N₂O₆ 632.29 (M⁺), found 633.45 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27az

Compound 27az was prepared according to the general procedure D from carboxylic acid 26aa and amine 11u: ¹H NMR (500 MHz, CDCl₃) δ 7.35–7.27 (m, 5H), 7.26–7.19 (m, 5H), 5.29 (d, J = 1.8 Hz, 1H), 4.98 (d, J = 15.7 Hz, 1H), 4.87 (d, J = 15.7 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.41 (td, J = 6.6, 1.5 Hz, 1H), 4.12 (q, J = 6.6 Hz, 1H), 3.64–3.56 (m, 4H), 3.48 (dd, J = 9.9, 6.6 Hz, 1H), 3.45–3.32 (m, 1H), 3.30 (dd, J = 9.8, 5.7 Hz, 1H), 3.01–2.93 (m, 1H), 2.87 (dd, J = 16.2, 3.4 Hz, 1H), 2.76 (dd, J = 16.2, 7.5 Hz, 1H), 2.37 (dd, J = 12.7, 6.2 Hz, 1H), 1.94 (t, J = 12.2 Hz, 1H), 1.68–1.59 (m, 3H), 1.59–1.47 (m, 5H), 1.20 (d, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 171.2, 168.6, 138.2, 137.2, 136.7, 128.6, 128.5, 127.8, 127.8, 127.2, 127.0, 107.1, 74.4, 73.5, 73.0, 52.8, 51.4, 47.5, 46.6, 42.9, 37.0, 35.9, 29.8, 26.5, 25.7, 24.7, 17.2; MS(ESI) calcd for C₃₃H₄₀N₂O₆ 560.29 (M⁺), found 561.46 (M + H)⁺, 583.44 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27ba

Compound 27ba was prepared according to the general procedure D from carboxylic acid 26ab and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 7.36–7.31 (m, 2H), 7.31–7.26 (m, 2H), 7.25 (d, J = 1.4 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 1.5 Hz, 1H), 6.67 (dd, J = 7.9, 1.8 Hz, 1H), 6.28 (t, J = 5.0 Hz, 1H), 5.92 (s, 2H), 5.34 (d, J = 1.8 Hz, 1H), 4.88 (d, J = 15.5 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H), 4.41 (td, J = 6.1, 1.8 Hz, 1H), 4.12 (q, J = 6.5 Hz, 1H), 4.00 (dd, J = 5.3, 2.6 Hz, 2H), 3.64 (s, 3H), 3.49 (dd, J = 9.8, 6.3 Hz, 1H), 3.33 (dd, J = 9.8, 5.7 Hz, 1H), 2.97 (m, 1H), 2.66 (dd, J = 14.9, 5.6 Hz, 1H), 2.60 (dd, J = 15.0, 5.4 Hz, 1H), 2.37 (dd, J = 12.9, 6.4 Hz, 1H), 2.20 (t, J = 2.5 Hz, 1H), 1.84 (t, J = 12.4 Hz, 1H), 1.64 (s, 1H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 171.0, 170.5, 148.0, 146.7, 138.1, 136.3, 130.7, 128.5, 127.9, 127.8, 120.3, 108.4, 108.0, 107.7, 101.1, 79.7, 74.3, 73.5, 72.9, 72.8, 71.6, 53.0, 51.4, 47.4, 38.8, 37.4, 29.6, 29.3, 17.1; MS(ESI) calcd for C₃₂H₃₄N₂O₈ 574.23 (M⁺), found 575.35 (M + H)⁺, 597.34 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bb

Compound 27bb was prepared according to the general procedure D from carboxylic acid 26ab and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 7.35–7.24 (m, 5H), 6.79 (d, J = 1.1 Hz, 1H), 6.72 (t, J = 1.1 Hz, 2H), 5.90 (d, J = 1.2 Hz, 2H), 5.30 (d, J = 1.7 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.79 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.3 Hz, 1H), 4.42 (td, J = 6.6, 6.2, 1.7 Hz, 1H), 4.12 (q, J = 6.4, 6.0 Hz, 1H), 3.64 (s, 3H), 3.54–3.48 (m, 2H), 3.43 (m, 4H), 3.33 (dd, J = 9.8, 5.7 Hz, 1H), 2.99–2.91 (m, 1H), 2.82 (dd, J = 16.4, 6.6 Hz, 1H), 2.68 (dd, J = 16.5, 3.5 Hz, 1H), 2.33 (dd, J = 12.6, 6.2 Hz, 1H), 2.02 (t, J = 12.3 Hz, 1H), 1.93 (m, 2H), 1.87–1.80 (m, 2H), 1.21 (d, J = 6.4 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 171.3, 168.9, 147.9, 146.5, 138.2, 136.8, 131.2, 128.5, 127.8, 127.8, 120.3, 108.2, 107.9, 107.0, 101.0, 74.4, 73.5, 73.1, 73.0, 52.8, 51.4, 47.3, 46.6, 45.8, 36.9, 36.7, 29.6, 26.2, 24.5, 17.2; MS(ESI) calcd for C₃₃H₃₈N₂O₈ 590.26 (M⁺), found 591.38 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bc

Compound 27bc was prepared according to the general procedure D from carboxylic acid 26d and amine 11d: ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.26 (m, 5H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H), 5.91 (t, J = 5.4 Hz, 1H), 5.56 (d, J = 1.8 Hz, 1H), 4.95 (d, J = 15.8 Hz, 1H), 4.72 (d, J = 15.8 Hz, 1H), 4.58 (d, J = 12.1 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.46 (td, J = 6.0, 1.8 Hz, 1H), 4.09 (q, J = 6.5 Hz, 1H), 3.62 (s, 3H), 3.54 (dd, J = 9.7, 6.4 Hz, 1H), 3.40 (dd, J = 9.8, 5.7 Hz, 1H), 3.20–3.14 (m, 2H), 2.94 (m, 1H), 2.55 (dd, J = 5.6, 2.0 Hz, 2H), 2.38 (dd, J = 12.9, 6.6 Hz, 1H), 1.75 (dd, J = 12.9, 11.6 Hz, 1H), 1.61–1.51 (m, 1H), 1.43–1.34 (m, 1H), 1.34–1.27 (m, 2H), 1.19 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 1.2 Hz, 3H), 0.87 (d, J = 1.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.6, 170.8, 170.6, 150.4, 141.8, 138.2, 136.6, 128.5, 127.8, 127.8, 110.6, 108.5, 108.3, 74.4, 73.6, 73.2, 72.8, 53.0, 51.4, 41.0, 39.2, 38.5, 38.0, 37.6, 29.4, 26.0, 22.6, 22.6, 17.0; MS(ESI) calcd for C₃₁H₄₀N₂O₇ 552.28 (M⁺), found 553.46 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bd

Compound 27bd was prepared according to the general procedure D from carboxylic acid 26d and amine 11x: ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.27 (m, 6H), 7.25–7.17 (m, 4H), 6.32–6.27 (m, 2H), 5.53 (d, J = 1.8 Hz, 1H), 4.95–4.79 (m, 2H), 4.76–4.70 (m, 1H), 4.60 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.51–4.47 (m, 1H), 4.10 (dd, J = 6.6, 4.7 Hz, 1H), 4.00–3.92 (m, 1H), 3.62 (d, J = 2.6 Hz, 3H), 3.60–3.53 (m, 1H), 3.42 (dd, J = 9.8, 5.5 Hz, 1H), 3.14–3.05 (m, 1H), 3.04–2.96 (m, 1H), 2.90 (ddd, J = 17.2, 14.2, 3.4 Hz, 1H), 2.80–2.67 (m, 2H), 2.66–2.57 (m, 1H), 2.46–2.37 (m, 1H), 1.86 (q, J = 12.1, 11.6 Hz, 3H), 1.69–1.56 (m, 3H), 1.28–1.18 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 170.9, 168.8, 168.7, 150.6, 145.3, 141.6, 138.2, 137.0, 128.9, 128.7, 128.6, 128.5, 128.5, 127.9, 127.8, 127.8, 127.8, 127.2, 126.9, 126.8, 126.8, 126.6, 110.6, 108.4, 108.3, 107.7, 107.6, 74.5, 73.5, 73.4, 73.3, 73.0, 52.9, 51.4, 51.4, 46.2, 44.7, 42.9, 42.6, 42.6, 40.9, 40.8, 40.7, 37.0, 36.9, 36.1, 36.1, 33.9, 33.8, 33.0, 33.0, 30.0, 29.6, 17.0, 17.0; MS(ESI) calcd for C₃₇H₄₂N₂O₇ 626.30 (M⁺), found 627.47 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27be

Compound 27be was prepared according to the general procedure D from carboxylic acid 26ac and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.56–7.48 (m, 2H), 7.48–7.38 (m, 2H), 7.38–7.31 (m, 4H), 7.31–7.27 (m, 1H), 6.73 (q, J = 6.5, 6.0 Hz, 1H), 5.44–5.40 (m, 1H), 5.37 (d, J = 1.7 Hz, 1H), 4.60 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.53–4.46 (m, 2H), 4.40 (dd, J = 15.2, 5.7 Hz, 1H), 4.14 (q, J = 6.3 Hz, 1H), 3.80 (ddd, J = 13.1, 10.8, 5.3 Hz, 1H), 3.69 (s, 3H), 3.61–3.51 (m, 2H), 3.44 (dd, J = 9.7, 5.8 Hz, 1H), 2.96–2.86 (m, 1H), 2.62 (dd, J = 14.7, 5.8 Hz, 1H), 2.55 (dd, J = 15.0, 5.5 Hz, 1H), 2.36 (dd, J = 12.7, 6.4 Hz, 1H), 2.23–2.13 (m, 1H), 2.08–1.99 (m, 1H), 1.99–1.91 (m, 4H), 1.70 (t, J = 12.4 Hz, 1H), 1.64–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.6, 171.1, 170.5, 139.7, 138.1, 136.0, 134.9, 131.2, 129.2, 128.6, 127.9, 127.9, 124.4 (q, ³J_C–F = 3.6 Hz), 124.3 (q, ³J_C–F = 3.5 Hz), 124.2 (q, ¹J_C–F = 273.3 Hz), 123.0, 107.0, 74.3, 73.6, 73.0, 72.9, 53.0, 51.3, 43.1, 42.6, 39.5, 37.4, 34.7, 29.8, 28.6, 25.4, 23.0, 22.4, 17.1; MS(ESI) calcd for C₃₇H₄₃F₃N₂O₆ 668.31 (M⁺), found 669.42 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bf

Compound 27bf was prepared according to the general procedure D from carboxylic acid 26ac and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 7.36–7.32 (m, 4H), 7.31–7.27 (m, 1H), 5.50–5.40 (m, 1H), 5.37 (d, J = 1.8 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.52 (td, J = 6.1, 1.6 Hz, 1H), 4.12 (q, J = 6.5 Hz, 1H), 3.86 (ddd, J = 13.5, 11.0, 5.4 Hz, 1H), 3.70 (s, 3H), 3.68–3.62 (m, 4H), 3.62–3.49 (m, 4H), 3.47–3.39 (m, 3H), 2.96–2.88 (m, 1H), 2.83 (dd, J = 16.2, 3.4 Hz, 1H), 2.62 (dd, J = 16.2, 7.7 Hz, 1H), 2.37 (dd, J = 12.6, 6.5 Hz, 1H), 2.28–2.18 (m, 1H), 2.12–2.02 (m, 1H), 1.99–1.91 (m, 4H), 1.75 (t, J = 12.0 Hz, 1H), 1.63–1.56 (m, 2H), 1.56–1.49 (m, 2H), 1.23 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 170.3, 169.3, 138.1, 136.7, 135.1, 128.5, 127.9, 127.8, 122.8, 106.4, 74.5, 73.5, 73.3, 73.0, 67.0, 66.6, 52.9, 51.4, 45.9, 42.6, 42.1, 36.8, 35.9, 34.7, 29.6, 28.6, 25.4, 23.0, 22.5, 17.1; MS(ESI) calcd for C₃₃H₄₄N₂O₇ 580.31 (M⁺), found 581.45 (M + H)⁺, 603.42 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bg

Compound 27bg was prepared according to the general procedure D from carboxylic acid 26ad and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.58–7.37 (m, 4H), 7.36–7.30 (m, 4H), 7.30–7.27 (m, 1H), 6.78–6.69 (m, 3H), 6.56 (t, J = 6.0 Hz, 1H), 5.37 (d, J = 1.8 Hz, 1H), 4.60 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H), 4.53–4.49 (m, 1H), 4.46 (dd, J = 18.7, 5.8 Hz, 1H), 4.14 (q, J = 6.5 Hz, 1H), 3.94 (ddd, J = 13.5, 10.4, 6.2 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.76–3.69 (m, 1H), 3.69 (s, 3H), 3.55 (dd, J = 9.7, 6.3 Hz, 1H), 3.41 (dd, J = 9.7, 6.0 Hz, 1H), 2.96 (m, 1H), 2.85–2.77 (m, 1H), 2.77–2.69 (m, 1H), 2.65–2.56 (m, 2H), 2.38 (dd, J = 12.8, 6.5 Hz, 1H), 1.75 (t, J = 12.3 Hz, 1H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.6, 171.0, 170.6, 149.1, 147.8, 139.7, 138.1, 136.3, 131.5, 131.2, 131.1, 131.1 (²J_C–F = 32.4 Hz), 129.2, 128.6, 127.9, 127.9, 124.4 (³J_C–F = 3.8 Hz), 124.3 (³J_C–F = 3.8 Hz), 124.2 (¹J_C–F = 272.9 Hz), 120.7, 74.4, 73.6, 73.1, 72.9, 56.1, 56.0, 53.0, 51.4, 45.4, 43.1, 39.4, 37.4, 32.6, 29.7, 17.1; MS(ESI) calcd for C₃₉H₄₃F₃N₂O₈ 724.30 (M⁺), found 725.46 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bh

Compound 27bh was prepared according to the general procedure D from carboxylic acid 26ad and amine 11q: ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.30 (m, 4H), 7.29 (s, 1H), 6.77 (d, J = 10.7 Hz, 3H), 5.37 (d, J = 1.8 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.58–4.49 (m, 2H), 4.11 (q, J = 6.6 Hz, 1H), 3.98 (ddd, J = 13.3, 10.6, 6.2 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.78–3.71 (m, 1H), 3.71–3.60 (m, 8H), 3.56 (dd, J = 9.7, 6.6 Hz, 1H), 3.41 (dd, J = 9.7, 5.9 Hz, 1H), 3.01–2.91 (m, 1H), 2.89–2.81 (m, 2H), 2.81–2.71 (m, 3H), 2.38 (dd, J = 12.6, 6.6 Hz, 1H), 1.84–1.76 (m, 1H), 1.72 (s, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.01 (dq, J = 6.6, 3.9 Hz, 3H), 0.83–0.76 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 170.5, 149.1, 147.7, 138.1, 136.9, 131.8, 128.6, 127.9, 120.7, 112.2, 111.4, 74.6, 73.5, 73.3, 72.9, 56.0, 56.0, 52.9, 51.4, 45.5, 45.3, 41.9, 41.7, 36.8, 36.0, 32.6, 29.5, 17.0, 11.2, 7.8; MS(ESI) calcd for C₃₉H₄₉N₃O₉ 703.35 (M⁺), found 704.5 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bi

Compound 27bi was prepared according to the general procedure D from carboxylic acid 26ae and amine 11i: ¹H NMR (500 MHz, CDCl₃) δ 8.27 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.87 (dd, J = 7.9, 1.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.58–7.46 (m, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.24 (dd, J = 6.4, 2.7 Hz, 3H), 7.14 (dd, J = 6.6, 3.0 Hz, 2H), 6.10 (s, 1H), 5.53 (d, J = 16.2 Hz, 1H), 5.30–5.20 (m, 2H), 4.45 (d, J = 12.1 Hz, 1H), 4.39 (d, J = 12.2 Hz, 1H), 4.36 (td, J = 6.4, 6.0, 2.3 Hz, 1H), 4.11 (q, J = 6.5 Hz, 1H), 3.44 (dd, J = 9.8, 6.5 Hz, 1H), 3.35 (s, 3H), 3.27 (dd, J = 9.8, 5.5 Hz, 1H), 3.07–3.00 (m, 1H), 2.92 (d, J = 6.2 Hz, 2H), 2.75 (dd, J = 14.6, 5.8 Hz, 1H), 2.70–2.62 (m, 3H), 2.43 (dd, J = 12.9, 6.3 Hz, 1H), 2.06–2.01 (m, 2H), 2.01–1.90 (m, 2H), 1.75–1.56 (m, 8H), 1.51–1.39 (m, 3H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 171.0, 170.9, 138.0, 136.2, 133.9, 131.2, 131.0, 128.9, 128.5, 127.8, 127.8, 127.8, 126.4, 125.8, 125.5, 124.6, 123.0, 108.2, 74.2, 73.5, 72.9, 72.8, 52.7, 51.4, 51.3, 51.1, 45.4, 40.4, 40.3, 39.8, 39.2, 37.9, 37.1, 37.1, 36.5, 33.7, 32.3, 29.7, 28.4, 28.3, 28.0, 17.1; MS(ESI) calcd for C₄₃H₅₀N₂O₆ 690.37 (M⁺), found 691.53 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bj

Compound 27bj was prepared according to the general procedure D from carboxylic acid 26ae and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.53 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.49 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.25–7.18 (m, 3H), 7.16–7.10 (m, 2H), 6.80 (t, J = 6.3 Hz, 1H), 5.43 (d, J = 16.4 Hz, 1H), 5.32 (d, J = 16.5 Hz, 1H), 5.23 (d, J = 1.8 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.40–4.34 (m, 2H), 4.09 (q, J = 6.5 Hz, 1H), 3.44 (dd, J = 9.8, 6.7 Hz, 1H), 3.39 (s, 3H), 3.35–3.24 (m, 5H), 3.18 (q, J = 6.2 Hz, 2H), 3.10–3.03 (m, 1H), 2.70 (t, J = 5.7 Hz, 1H), 2.37 (dd, J = 9.5, 7.0 Hz, 3H), 2.03–1.93 (m, 3H), 1.65 (tt, J = 6.4 Hz, J = 6.4 Hz, 2H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 172.8, 170.9, 170.8, 138.1, 136.6, 133.9, 131.2, 131.1, 128.9, 128.4, 127.8, 127.7, 127.7, 126.4, 125.8, 125.6, 124.6, 123.1, 107.7, 74.3, 73.4, 73.0, 72.9, 52.7, 51.4, 47.5, 45.6, 39.8, 38.9, 37.3, 37.2, 36.0, 31.1, 29.6, 26.7, 18.0, 17.1; MS(ESI) calcd for C₃₉H₄₅N₃O₇ 667.33 (M⁺), found 668.51 (M + H)⁺, 690.45 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bk

Compound 27bk was prepared according to the general procedure D from carboxylic acid 26af and amine 11o: ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.27 (m, 4H), 7.25–7.21 (m, 2H), 7.19–7.13 (m, 2H), 6.06 (d, J = 3.0 Hz, 1H), 6.02 (t, J = 5.3 Hz, 1H), 5.88–5.84 (m, 1H), 5.10 (d, J = 1.9 Hz, 1H), 5.01 (d, J = 16.9 Hz, 1H), 4.79 (d, J = 16.9 Hz, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.38 (td, J = 6.2, 1.9 Hz, 1H), 4.33 (d, J = 5.2 Hz, 2H), 4.16 (q, J = 6.6 Hz, 1H), 3.72 (s, 3H), 3.48 (dd, J = 9.8, 6.4 Hz, 1H), 3.31 (dd, J = 9.8, 5.6 Hz, 1H), 2.96–2.86 (m, 1H), 2.77 (dd, J = 15.2, 5.8 Hz, 1H), 2.58 (dd, J = 15.3, 4.6 Hz, 1H), 2.34 (dd, J = 12.9, 6.1 Hz, 1H), 2.24 (s, 3H), 2.02 (t, J = 12.6 Hz, 1H), 1.23 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.9, 170.2, 152.0, 149.4, 138.1, 136.1, 133.4, 133.1, 132.5, 129.2, 128.8, 128.5, 128.5, 127.8, 127.8, 127.5, 108.4, 107.2, 106.4, 74.2, 73.5, 72.8, 72.8, 53.1, 51.4, 45.5, 38.0, 37.2, 36.8, 29.5, 17.3, 13.7; MS(ESI) calcd for C₃₄H₃₆Cl₂N₂O₇ 654.19 (M⁺), found 655.37 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Amide 27bl

Compound 27bl was prepared according to the general procedure D from carboxylic acid 26af and amine 11p: ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.27 (m, 4H), 7.25–7.14 (m, 4H), 6.27 (t, J = 5.5 Hz, 1H), 5.08 (d, J = 1.9 Hz, 1H), 5.04 (d, J = 17.0 Hz, 1H), 4.79 (d, J = 17.0 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.38 (td, J = 5.8, 1.9 Hz, 1H), 4.16 (q, J = 6.5 Hz, 1H), 3.72 (s, 3H), 3.51–3.43 (m, 3H), 3.39 (t, J = 6.6 Hz, 2H), 3.35–3.26 (m, 2H), 2.93–2.83 (m, 1H), 2.73 (dd, J = 15.3, 5.8 Hz, 1H), 2.54 (dd, J = 15.3, 4.4 Hz, 1H), 2.32 (dd, J = 12.8, 6.0 Hz, 1H), 2.04 (t, J = 12.5 Hz, 1H), 1.73 (tt, J = 6.0 Hz, 2H), 1.58–1.49 (m, 2H), 1.40–1.30 (m, 2H), 1.23 (d, J = 6.5 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 170.9, 170.3, 138.1, 136.2, 133.3, 133.1, 132.6, 129.2, 128.9, 128.5, 127.8, 127.8, 127.5, 107.0, 74.2, 73.5, 72.9, 72.8, 71.1, 70.0, 53.1, 51.4, 45.6, 38.5, 38.0, 37.2, 31.9, 29.6, 29.2, 19.5, 17.3, 14.1; MS(ESI) calcd for C₃₅H₄₄Cl₂N₂O₇ 674.25 (M⁺), found 675.41 (M + H)⁺.

Tricyclic Amide 42 ((6RS,7aSR)-Ethyl 6-(2-((3,4-Dimethoxybenzyl)amino)-2-oxoethyl)-5-oxo-2,3,5,6,7,7a,8,9-octahydro-1H-cyclopenta[ij]quinolizine-7a-carboxylate)

Compound 42 was prepared according to the general procedure D from carboxylic acid 38 and amine 11f: ¹H NMR (500 MHz, CDCl₃) δ 6.81 (s, 1H), 6.77 (s, 2H), 6.58 (t, J = 5.9 Hz, 1H), 4.40 (dd, J = 14.6, 6.2 Hz, 1H), 4.25 (dd, J = 14.6, 5.4 Hz, 1H), 4.18–4.07 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79 (ddd, J = 13.1, 6.9, 4.0 Hz, 1H), 3.36 (ddd, J = 12.7, 8.6, 3.7 Hz, 1H), 2.84–2.74 (m, 1H), 2.65 (dd, J = 14.5, 4.9 Hz, 1H), 2.58–2.41 (m, 2H), 2.27 (dd, J = 12.9, 6.9 Hz, 1H), 2.20 (dd, J = 15.3, 8.7 Hz, 1H), 2.15–2.06 (m, 1H), 2.03 (dt, J = 17.2, 5.6 Hz, 1H), 1.86–1.65 (m, 3H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 171.2, 168.7, 149.2, 148.4, 133.9, 131.4, 120.0, 118.5, 111.2, 111.2, 61.3, 56.0, 56.0, 53.6, 43.3, 40.3, 38.4, 37.7, 36.0, 35.9, 32.6, 23.0, 21.7, 14.3; MS(ESI) calcd for C₂₅H₃₂N₂O₆ 456.23 (M⁺), found 457.11 (M + H)⁺.

Tricyclic Amide 43

Compound 43 was prepared according to the general procedure D from carboxylic acid 38 and amine 11p: ¹H NMR (500 MHz, CDCl₃) δ 6.49 (s, 1H), 4.20–4.08 (m, 2H), 3.94 (ddd, J = 13.0, 6.2, 4.3 Hz, 1H), 3.44 (t, J = 6.0 Hz, 2H), 3.41–3.21 (m, 5H), 2.75 (dt, J = 12.9, 5.5 Hz, 1H), 2.61–2.41 (m, 3H), 2.27 (dd, J = 12.9, 6.9 Hz, 1H), 2.19 (dd, J = 15.3, 8.7 Hz, 1H), 2.15–1.99 (m, 2H), 1.90–1.75 (m, 3H), 1.75–1.64 (m, 3H), 1.53 (tt, J = 8.1, 6.4 Hz, 2H), 1.39–1.29 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 171.2, 168.7, 134.1, 118.2, 71.0, 69.4, 61.3, 53.6, 40.3, 38.3, 37.8, 37.5, 36.0, 35.8, 32.6, 31.9, 29.5, 23.0, 21.8, 19.5, 14.3, 14.0; MS(ESI) calcd for C₂₃H₃₆N₂O₅ 420.26 (M⁺), found 421.52 (M + H)⁺.

Tricyclic Amide 44

Compound 44 was prepared according to the general procedure D from carboxylic acid 37 and amine 11h: ¹H NMR (500 MHz, CDCl₃) δ 8.05–7.98 (m, 1H), 7.86–7.80 (m, 1H), 7.77 (dd, J = 5.8, 3.7 Hz, 1H), 7.48 (m, 2H), 7.41–7.35 (m, 2H), 6.66–6.58 (m, 1H), 5.08 (dd, J = 14.6, 6.9 Hz, 1H), 4.61 (dd, J = 14.6, 4.5 Hz, 1H), 4.33–4.24 (m, 1H), 4.16–4.03 (m, 2H), 2.84–2.71 (m, 2H), 2.64–2.54 (m, 1H), 2.50 (dd, J = 14.1, 5.4 Hz, 1H), 2.35 (dd, J = 13.0, 5.6 Hz, 1H), 2.23–2.15 (m, 1H), 2.01–1.91 (m, 3H), 1.75–1.58 (m, 3H), 1.46–1.29 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 170.8, 168.6, 134.2, 133.9, 131.4, 129.3, 128.7, 128.5, 126.6, 126.5, 125.9, 125.5, 123.9, 116.3, 61.4, 46.1, 41.5, 40.6, 38.6, 37.3, 36.5, 34.7, 29.8, 28.1, 21.5, 19.1, 14.3; MS(ESI) calcd for C₂₈H₃₂N₂O₄ 460.24 (M⁺), found 461.30 (M + H)⁺.

Tricyclic Amide 45

Compound 45 was prepared according to the general procedure D from carboxylic acid 37 and amine 11j: ¹H NMR (500 MHz, CDCl₃) δ 6.45 (s, 1H), 4.63–4.49 (m, 1H), 4.22–4.00 (m, 2H), 3.30–3.08 (m, 2H), 3.00–2.83 (m, 1H), 2.63–2.53 (m, 2H), 2.53–2.45 (m, 1H), 2.34 (dd, J = 13.1, 5.5 Hz, 1H), 2.20 (ddd, J = 12.3, 3.9, 2.3 Hz, 1H), 2.16–2.05 (m, 1H), 2.05–1.97 (m, 2H), 1.97–1.83 (m, 2H), 1.73–1.61 (m, 2H), 1.52–1.35 (m, 4H), 1.35–1.25 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 171.2, 169.0, 129.7, 116.3, 61.4, 46.2, 40.8, 39.2, 38.9, 37.3, 36.8, 34.7, 31.8, 29.8, 28.1, 21.9, 20.2, 19.1, 14.3, 13.8; MS(ESI) calcd for C₂₁H₃₂N₂O₄ 376.24 (M⁺), found 377.47 (M + H)⁺.

Tricyclic Amide 46

Compound 46 was prepared according to the general procedure D from carboxylic acid 40 and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 6.96 (t, J = 5.7 Hz, 1H), 4.18–4.03 (m, 2H), 3.83 (dt, J = 12.6, 4.7 Hz, 1H), 3.44 (t, J = 6.0 Hz, 2H), 3.36–3.27 (m, 5H), 3.27–3.18 (m, 1H), 2.90 (t, J = 6.8 Hz, 1H), 2.62 (dd, J = 15.2, 7.1 Hz, 1H), 2.54 (dt, J = 12.6, 3.2 Hz, 1H), 2.18–1.64 (m, 8H), 1.60–1.47 (m, 1H), 1.41 (ddd, J = 13.7, 12.4, 3.0 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0, 172.1, 171.1, 132.0, 110.4, 71.4, 61.4, 59.0, 51.8, 49.5, 39.1, 37.9, 34.0, 30.7, 29.6, 27.3, 25.9, 21.4, 20.3, 14.5; MS(ESI) calcd for C₂₀H₃₀N₂O₅ 378.22 (M⁺), found 379.10 (M + H)⁺.

Tricyclic Amide 47

Compound 47 was prepared according to the general procedure D from carboxylic acid 40 and amine 11m: ¹H NMR (500 MHz, CDCl₃) δ 7.21–7.16 (m, 1H), 7.14 (dd, J = 7.4, 1.7 Hz, 1H), 6.90–6.81 (m, 2H), 6.75 (t, J = 5.6 Hz, 1H), 4.16–4.01 (m, 2H), 3.88–3.75 (m, 4H), 3.55–3.39 (m, 2H), 3.28–3.18 (m, 1H), 2.91–2.77 (m, 3H), 2.61 (dd, J = 15.2, 7.1 Hz, 1H), 2.54 (dt, J = 12.7, 3.2 Hz, 1H), 2.17–1.78 (m, 6H), 1.77–1.65 (m, 1H), 1.60–1.45 (m, 1H), 1.40 (ddd, J = 13.8, 12.5, 3.0 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.8, 171.8, 170.8, 157.7, 131.7, 130.7, 127.8, 127.5, 120.6, 110.4, 110.1, 61.1, 55.3, 51.6, 49.2, 39.8, 38.8, 33.6, 30.4, 30.4, 27.0, 25.6, 21.2, 20.0, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₅H₃₃N₂O₅ 441.2389, found 441.2384.

Tricyclic Amide 48

Compound 48 was prepared according to the general procedure D from carboxylic acid 41 and amine 11t: ¹H NMR (500 MHz, CDCl₃) δ 3.77–3.69 (m, 1H), 3.69–3.60 (m, 7H), 3.60–3.52 (m, 1H), 3.50–3.43 (m, 1H), 3.43–3.37 (m, 1H), 3.28–3.18 (m, 2H), 2.79 (dd, J = 16.6, 5.0 Hz, 1H), 2.59–2.50 (m, 1H), 2.22 (dd, J = 16.6, 7.3 Hz, 1H), 2.16–2.03 (m, 3H), 1.98–1.90 (m, 1H), 1.89–1.80 (m, 2H), 1.75–1.63 (m, 2H), 1.64–1.54 (m, 2H), 1.34 (dddd, J = 13.2, 10.5, 8.0, 2.8 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 172.5, 172.1, 169.2, 135.0, 114.8, 67.0, 66.6, 55.7, 52.1, 48.7, 46.0, 42.4, 38.7, 36.0, 33.5, 30.1, 29.6, 27.6, 26.9, 20.9; HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₀H₂₉N₂O₅ 377.2076, found 377.2086.

Tricyclic Amide 49

Compound 49 was prepared according to the general procedure D from carboxylic acid 41 and amine 11k: ¹H NMR (500 MHz, CDCl₃) δ 7.39 (t, J = 5.8 Hz, 1H), 7.36–7.29 (m, 3H), 7.29–7.23 (m, 1H), 4.50 (dd, J = 14.9, 5.9 Hz, 1H), 4.42 (dd, J = 14.9, 5.5 Hz, 1H), 3.76 (dt, J = 12.8, 4.8 Hz, 1H), 3.65 (s, 3H), 3.25–3.14 (m, 1H), 2.98 (dd, J = 8.5, 4.8 Hz, 1H), 2.56 (dd, J = 15.1, 8.5 Hz, 1H), 2.47 (dt, J = 13.8, 4.0 Hz, 1H), 2.21 (dd, J = 15.1, 4.8 Hz, 1H), 2.17–2.03 (m, 3H), 2.02–1.94 (m, 1H), 1.90–1.81 (m, 2H), 1.80–1.65 (m, 1H), 1.56 (ddd, J = 13.8, 12.2, 4.0 Hz, 1H), 1.44–1.32 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 172.5, 171.8, 170.7, 138.6, 134.5, 128.7, 127.8, 127.3, 115.5, 55.6, 52.2, 49.2, 43.8, 38.6, 35.2, 33.9, 33.3, 29.5, 27.2, 26.9, 20.8; MS(ESI) calcd for C₂₃H₂₈N₂O₄ 396.20 (M⁺), found 397.13 (M + H)⁺.

Tricyclic Amide 50

Compound 50 was prepared according to the general procedure D from carboxylic acid 39 and amine 11a: ¹H NMR (500 MHz, CDCl₃) δ 6.68 (t, J = 5.3 Hz, 1H), 5.11 (t, J = 4.0 Hz, 1H), 4.21–4.08 (m, 4H), 4.05 (ddd, J = 17.5, 5.6, 2.6 Hz, 1H), 3.95 (ddd, J = 17.5, 5.1, 2.5 Hz, 1H), 3.72 (dd, J = 6.9, 4.3 Hz, 2H), 3.05–2.92 (m, 1H), 2.63–2.51 (m, 2H), 2.36–2.28 (m, 2H), 2.28–2.17 (m, 2H), 2.17–2.11 (m, 2H), 2.11–2.01 (m, 1H), 1.82–1.71 (m, 2H), 1.60 (t, J = 13.1 Hz, 1H), 1.24 (t, J = 7.1 Hz, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 173.3, 172.9, 171.0, 170.2, 136.2, 108.7, 79.9, 71.3, 61.7, 60.8, 48.8, 41.1, 38.0, 36.7, 33.1, 32.8, 29.6, 29.2, 22.8, 21.8, 14.3, 14.2; MS(ESI) calcd for C₂₂H₃₀N₂O₆ 418.21 (M⁺), found 419.36 (M + H)⁺.

Tricyclic Amide 51

Compound 51 was prepared according to the general procedure D from carboxylic acid 39 and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 5.04 (t, J = 4.0 Hz, 1H), 4.21–4.04 (m, 4H), 3.90 (ddd, J = 12.7, 6.3, 4.2 Hz, 1H), 3.53 (ddd, J = 12.3, 7.4, 4.4 Hz, 1H), 3.42 (m, 4H), 3.03 (m, 1H), 2.73 (dd, J = 16.4, 4.2 Hz, 1H), 2.57 (dd, J = 16.3, 6.8 Hz, 1H), 2.34 (ddd, J = 8.9, 6.1, 2.1 Hz, 2H), 2.28–2.17 (m, 2H), 2.17–2.00 (m, 3H), 1.97–1.86 (m, 2H), 1.86–1.70 (m, 4H), 1.28–1.17 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 173.6, 173.1, 170.2, 169.4, 136.7, 107.4, 61.5, 60.7, 48.8, 46.6, 45.7, 40.9, 36.2, 35.8, 33.3, 32.3, 29.7, 26.2, 24.5, 22.9, 21.7, 14.3, 14.2; MS (ESI) calcd for C₂₃H₃₄N₂O₆ 434.24 (M⁺), found 435.5 (M + H)⁺.