Enantioselective remote methylene c-h (hetero)arylation of cycloalkanecarboxylic acids

Abstract

The present application discloses the use of bifunctional chiral palladium catalysts that enable remote γ- and δ-methylene C–H (hetero)arylation of cyclic carbocyclic acids. In particular, the present application discloses methods of enantioselective remote γ-C–H arylation or heteroarylation, δ-C–H arylation or heteroarylation, or sequential γ-methylene C–H arylation or heteroarylation of various free cycloalkanecarboxylic acids, comprising the use of palladium catalysts having chiral oxazoline-pyridinone ligands.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 614,733, filed on December 26, 2023, which is hereby incorporated by reference in its entirety.

[0002] Government support This invention was completed with government support under NIGMS license number GM084019 granted by the National Institutes of Health (NIH). The government holds certain rights to this invention. Technical Field

[0003] This application relates to the use of bifunctional chiral palladium catalysts capable of achieving long-range γ- and δ-methylene CH (hetero)arylation of cyclic carbocyclic acids. Specifically, this application relates to methods for the enantioselective long-range γ-CH arylation or heteroarylation, δ-CH arylation or heteroarylation, or sequential γ-methylene CH arylation or heteroarylation of various free cycloalkane carboxylic acids, the methods comprising using palladium catalysts having chiral oxazoline-pyridone ligands. Background Technology

[0004] Constructing α-, β-, γ-, and δ-chiral centers on carbonyl compounds is a key objective in asymmetric synthesis. Although enantioselective β-CH functionalization reactions have been developed to establish α- and β-chiral centers, enantioselective γ- and δ-CH functionalization reactions for obtaining long-range chiral centers remain extremely difficult.

[0005] Transition metal-catalyzed enantioselective CH activation reactions have recently become a powerful and versatile method for the asymmetric synthesis of molecules containing point chirality (1-5), axial chirality (6), and planar chirality (7). Chiral bifunctional mono- N The discovery of protected amino acid (MPAA) ligand classes and the subsequent development of related chiral ligands have enabled the desymmetrization of geminal centers via selective activation on one of the methyl groups and direct asymmetric activation of the methylene center (8). However, enantioselective methylene C-H activation methods remain limited to substrates containing stronger exogenous directing groups (11-16), except for cyclopropyl (9) and cyclobutyl (10) substrates (which are more reactive due to the increased s-property of their C-H bonds). Furthermore, these methods are limited to setting the near-terminal stereocenter at a distance of no more than three bonds from the directing atom (1). Figure 1A). Compared to the progress made in enantioselective intramolecular γ-metal-oxolation (17) and azene insertion reactions (18), the enantioselective long-range metallization of γ- and δ-methylene CH bonds in a large number of free fatty acids has not yet been confirmed. Given that the vast majority of bioactive natural products and drug molecules contain carbon rings, which are beneficial for limiting conformational flexibility and thus improving ADME properties such as oral bioavailability, the γ- and δ-CH functionalization of general cycloalkane carboxylic acid starting materials is crucial for the synthesis of sp-rich... 3 Bioactive molecules will be particularly valuable (19-21).

[0006] Therefore, in the field of synthetic organic chemistry, there is still a need to develop methods to achieve enantioselective γ- and δ-CH functionalization of remote chiral centers. Attached Figure Description

[0007] Figure 1 Enantioselective functionalization via activation of the methylene CH bond (A) Transition metal-catalyzed enantioselective methylene β-C (sp 3 (B) Ligand-enabled enantioselective long-range methylene C(sp) 3 )-H functionalization.

[0008] Figure 2 Range of (hetero)aryl iodides used for enantioselective γ-arylation. Reaction conditions: substrate (0.1 mmol), Pd(PhCN)₂Cl₂ (10 mol%), ligand TZ-10 (12 mol%), Ag₂CO₃ (2.0 equivalents), KH₂PO₄ (2.0 equivalents), HFIP (1.0 mL), MeCN (0.1 mL), 80 °C, 12 h. Separation yield. *65 °C instead of 80 °C, 24 h.

[0009] Figure 3 For enantioselective γ-arylation of cyclic aliphatic compounds. Reaction conditions: substrate (0.1 mmol), Pd(PhCN)₂Cl₂ 10 mol%, ligand TZ-10 12 mol%, Ag₂CO₃ (2.0 equivalence), KH₂PO₄ (2.0 equivalence), HFIP (1.0 mL), MeCN (0.1 mL), 80 °C, 12 h. Ar = 4-MeOOCC₆H₄, Ar' = 3,5-diMeOOCC₆H₃. Separation yield. *65 °C instead of 80 °C, 24 h. ‡ Replace 80℃ with 90℃, 24 hours. § 120℃ instead of 80℃, 24 hours.

[0010] Figure 4Enantioselective δ-(hetero)arylation range. Reaction conditions: substrate (0.1 mmol), Pd(PhCN)₂Cl₂ 10 mol%, ligand TZ-7 12 mol%, Ag₂CO₃ (2.0 equivalent), KH₂PO₄ (2.0 equivalent), HFIP (2.0 mL), 120 °C, 24 h. Separation yield.

[0011] Figure 5 Enantioselective d-(hetero)arylation of cyclic aliphatic compounds. Reaction conditions: substrate (0.1 mmol), Pd(PhCN)₂Cl₂ 10 mol%, ligand ( R Separation yield: 12 mol% Ag₂CO₃ (2.0 equivalent), KH₂PO₄ (2.0 equivalent), HFIP (1.0 mL), 80 °C, 24 h. Summary of the Invention

[0012] This article reports a chiral oxazoline-pyridone ligand capable of enantioselective long-range γ-CH (hetero)arylation of a variety of cyclic free carboxylic acids. This enantioselective C–H (hetero)arylation reaction constructs g-tertiary chiral centers with up to >99% ee, while simultaneously desymmetrizing α-quaternary centers, thus providing a highly enantioselective pathway for various cyclic chiral synthons and bioactive molecules. Sequential enantioselective editing of the two methylene C–H bonds is also demonstrated by constructing a third stereocenter in these spatially crowded carbocyclic rings using chiral ligands with opposite configurations. Notably, the chiral Pd / oxazoline-pyridone catalyst also enables enantioselective δ-C–H (hetero)arylation, further demonstrating its ability for enantioselective long-range C–H functionalization. Figure 1 B).

[0013] This application provides methods for the enantioselective long-range γ-CH arylation or heteroarylation, δ-CH arylation or heteroarylation, or sequential γ-methyleneCH arylation or heteroarylation of free cycloalkane carboxylic acids, the methods comprising using a palladium catalyst having a chiral oxazoline-pyridone ligand.

[0014] This application provides the above-described method, which includes the following steps in reaction i) for γ-CH arylation or heteroarylation; reaction ii) for δ-CH arylation or heteroarylation; and reaction iii) for sequential γ-methyleneCH arylation or heteroarylation: i) ; ii) ;and iii) in Each R 1 Independently H, (C1-C6)alkyl, (C6-C 10 )Aryl, Bn, (C1-C6)alkyl (C6-C 10 aryl, -O-(C1-C6)alkyl, (C1-C6)alkyl-O-(C1-C6)alkyl, halo(C1-C6)alkyl, hetero(C1-C6)alkyl or (C1-C6)alkyl-C(=O)O(C1-C6)alkyl, wherein each alkyl and aryl group is optionally surrounded by one or more R 1’ replace; Each R 1’ It can be independently a halogen, (C1-C6)alkyl, -O-(C1-C6)alkyl, or -C(=O)O(C1-C6)alkyl; Each Ar is independently, optionally by one or more Rs 2 Replacement (C6-C) 10 ) aryl or (C5-C 14 ) heteroaryl; Each R 2 Independently, it is a halogen, (C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, NO2, CN, -O(C1-C6)alkyl, -C(=O)H, -C(=O)(C1-C6)alkyl, CF3, or Ts; and n is 1, 2, 3 or 4; This includes its enantiomers, non-racemic or racemic mixtures, and pharmaceutically acceptable salts.

[0015] This application further provides the above-described method for the enantioselective long-range γ-CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: .

[0016] This application further provides the above-described method for the enantioselective long-range δ-CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: .

[0017] This application further provides the above-described method for the enantioselective long-range sequential γ-methylene CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: . Detailed Implementation

[0018] This paper reports palladium catalysts employing chiral oxazoline-pyridone ligands, which enable enantioselective long-range γ-CH (hetero)arylation of various free cycloalkane carboxylic acids (the fundamental carbocyclic structural units in organic synthesis). This enantioselective C–H (hetero)arylation reaction simultaneously establishes γ-tertiary chiral centers and α-quaternary centers with up to >99% ee, thus providing a highly enantioselective pathway for various cyclic chiral synthons and bioactive molecules. Sequential enantioselective editing of two methylene CH bonds was achieved by constructing a carbocyclic ring containing three chiral centers using chiral ligands with opposite configurations. Notably, enantioselective long-range δ-CH arylation was also achieved to establish δ-chiral centers that are particularly difficult to obtain using classical methods.

[0019] Reaction Development. The formation of α-, β-, γ-, and δ-stereocenters in carbonyl compounds is one of the most desirable and versatile synthetic cleavages in asymmetric organic synthesis (22, 23). Over the past three decades, numerous enantioselective enolization or enolization equivalents (24) and conjugation addition (25) reactions have been reported that can establish α- and β-stereocenters with high selectivity. In contrast, the catalytic, enantioselective formation of γ- and δ-stereocenters in carbonyl compounds remains a significant challenge (26). Inspired by previous successes in establishing α- and β-carbonyl stereocenters via C–H activation (1, 8), there is a search for chiral Pd catalysts capable of enantioselectively long-range γ- and δ-C–H functionalization to address this important unmet need. Given the importance of cyclic systems in organic chemistry (19–21), 1-propylcyclopentane-1-carboxylic acid (1a) and methyl 4-iodobenzoate (2b) were chosen as model substrates for reaction development and ligand design. Previously reported promotion of β-C (sp 3A series of bifunctional chiral ligands activated by γ-H, such as monoprotected amino acids (MPAA), aminoethylamine (MPAAM), aminooxazoline (MPAO), and aminoethylphenyl sulfide (MPAThio) (27), failed to provide the desired γ-arylation products. In contrast, chiral pyridone-sulfonamide ligands (L6) and binaphthol-derived pyridine-pyridone ligands (L7) provided the desired arylation products in moderate yields (45-57%), demonstrating the important role of the pyridone motif in achieving the activation of the methylene CH bond (28), despite poor enantioselectivity (5%-10% ee). Notably, quinine-pyridones (L8), previously used to achieve racemic transcyclic γ-C-H arylation of the carbocyclic ring, produced moderate ee (36%) (29) (Table S4). However, extensive modification of these ligands failed to yield significant improvements in enantioselectivity, indicating a need for a new class of chiral bidentate pyridone ligands. Previously, it was found that incorporating chiral oxazolines into MPAA-derived ligands significantly increased the selectivity of enantioselective activation of the methyl CH bond (30), thus it was hypothesized that chiral oxazoline-pyridone ligands could achieve higher enantioselectivity for methylene CH activation. Therefore, a series of chiral oxazoline-pyridone ligands that could coordinate with Pd(II) in either pentagonal (TZ 1–4) or hexaagonal (TZ 5–12) chelates were synthesized and tested in model reactions. While the pentagonal chelates showed poor reactivity, providing γ-arylated products in <10% yield, the hexaagonal chelates (TZ 5–12) provided moderate to good yields. The presence of aryl substituents on the oxazoline ring proved crucial for obtaining steric control in this reaction, with the arylated analogues (TZ 7–10) providing γ-arylated products with excellent levels of enantioselectivity (85%–96% ee). After extensive optimization of reaction conditions, the six-membered chelate oxazoline-pyridone ligand TZ-10 was identified as the optimal ligand, forming the γ-arylated product in 68% yield and 96% ee.

[0020] Scope of aryl and heteroaryl iodides. Under optimized ligand and conditions, the scope of aryl and heteroaryl iodides in the reaction of cyclopentylcarboxylic acid 1a was initially examined. Figure 2A variety of para-substituents on aryl iodides, ranging from electron-donating (OMe) (2d) to electron-withdrawing (NO2, CN, and COOMe, etc.) (2a-c, 2e-g), are compatible, providing the corresponding γ-arylated acids (3a-g) in 58%-78% yields and with excellent enantioselectivity (90%-97% ee). Halogen-tolerant substituents such as fluorine (2h), chlorine (2i), and even bromine (2j) provide the desired product (3h-j) in 64%-69% yields and with 93%-98% ee. Aryl iodides with meta (2k-o) or ortho (2p) substitutions also perform well, forming the desired product in moderate to good yields (61%-85%) and with high ee (91%-98% ee). Given the importance of heterocyclic compounds in drug discovery, the ability of this reaction to undergo heteroarylation is next examined. Satisfactorily, a variety of 2-substituted heteroaryl iodides (2q-y) were found to form the corresponding products in moderate yields and with excellent ee (82%-99%). Notably, even 4-iodopyridine (2v) – a highly coordinated and challenging coupling partner in the CH activation reaction (31) – yielded the corresponding product (3v) in 41% yield and with 91% ee.

[0021] Enantioselective dC–H (hetero)arylation. Encouraged by these results regarding the γ-methylene C–H arylation, it was considered whether these chiral oxazoline-pyridone ligands could also achieve enantioselective arylation of the more distal δ-methylene C–H bond. 2-(1-methylcyclopentyl)acetic acid (5a) was chosen as the model substrate and coupled with methyl 4-iodobenzoate (2a). Similar to the γ-methylene arylation reaction, the chiral ligand with an aryl group on the oxazoline ring provided the desired product with excellent enantioselectivity (90%–93% ee), although the yields were moderate (38%–53%). Through extensive optimization of the reaction conditions (Table S6), the yield was increased to 64% while maintaining 91% ee. The range of aryl and heteroaryl iodides with substrate 5a was then explored. Various functional groups at the para (2a–2h), meta (2i–2m), and ortho (2n) positions are compatible, providing δ-arylated products (6a–n) in moderate to good yields (42%–81%) and 81%–95% ee. Furthermore, various heteroaryl iodides containing furan, thiophene, benzothiazole, indole, and pyridine were successfully coupled, yielding the desired product (6o–v) in 47%–85% yield and 71%–92% ee. Carboxylic acids with β-ethyl (5w) and β-propyl (5x) substituents also performed well, providing the target product (6w–x) in 32%–48% yield and 90%–93% ee. Notably, this single operation simultaneously constructs both β-quaternary and δ-chiral centers on the carbon ring, which was highly challenging using previous methods. Although the desired δ-arylation was obtained for 2-cyclopentylacetic acid (5y), the yield (20%) and ee (66%) were significantly reduced. However, the substrate with the β-phenyl substituent (5z) was also compatible, yielding a 32% yield and the highest ee (99%) in the δ-arylation reaction.

[0022] Therefore, this paper discloses the enantioselective long-range γ-methylene C–H (hetero)arylation of cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl carboxylic acids using chiral oxazoline-pyridone ligands (TZ-7 and TZ-10). Sequential γ-methylene C–H arylation of aryl and heteroaryl groups was also achieved by constructing two γ-chiral centers using chiral ligands with opposite configurations, while simultaneously desymmetrizing the α-center of the crowded carbocyclic ring. Enantioselective δ-C–H arylation was also demonstrated using these chiral ligands, thus demonstrating the potential for further long-range enantioselective functionalization.

[0023] Implementation Plan Implementation Scheme 1. A method for enantioselective long-range γ-CH arylation or heteroarylation, δ-CH arylation or heteroarylation, or sequential γ-methyleneCH arylation or heteroarylation of free cycloalkane carboxylic acids, said method comprising using a palladium catalyst having a chiral oxazoline-pyridone ligand.

[0024] Implementation Scheme 2. The method as described in Implementation Scheme 1, comprising the steps of reaction i) for γ-CH arylation or heteroarylation; reaction ii) for δ-CH arylation or heteroarylation; and reaction iii) for sequential γ-methyleneCH arylation or heteroarylation: i) ; ii) ;and iii) in Each R 1 Independently H, (C1-C6)alkyl, (C6-C 10 )Aryl, Bn, (C1-C6)alkyl (C6-C 10 aryl, -O-(C1-C6)alkyl, (C1-C6)alkyl-O-(C1-C6)alkyl, halo(C1-C6)alkyl, hetero(C1-C6)alkyl or (C1-C6)alkyl-C(=O)O(C1-C6)alkyl, wherein each alkyl and aryl group is optionally surrounded by one or more R 1’ replace; Each R 1’ It can be independently a halogen, (C1-C6)alkyl, -O-(C1-C6)alkyl, or -C(=O)O(C1-C6)alkyl; Each Ar is independently, optionally by one or more Rs 2 Replacement (C6-C) 10 ) aryl or (C5-C 14 ) heteroaryl; Each R 2 Independently, it is a halogen, (C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, NO2, CN, -O(C1-C6)alkyl, -C(=O)H, -C(=O)(C1-C6)alkyl, CF3, or Ts; and n is 1, 2, 3 or 4; This includes its enantiomers, non-racemic or racemic mixtures, and pharmaceutically acceptable salts.

[0025] Implementation Scheme 3. The method as described in Implementation Scheme 1 or Implementation Scheme 2, wherein the ligand (L) is selected from the group consisting of: Implementation Scheme 4. The method as described in Implementation Scheme 2, wherein the ligand (L) is .

[0026] Implementation Scheme 5. The method as described in Implementation Scheme 2, wherein the ligand (L) is .

[0027] Implementation Scheme 6. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is a (C1-C6) alkyl group.

[0028] Implementation Scheme 7. The method as described in Implementation Scheme 6, wherein R 1 yes n Pr or Me.

[0029] Implementation Scheme 8. The method as described in any one of Implementation Schemes 1-5, wherein R 1 Ph is an optional substitution.

[0030] Implementation Scheme 9. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is Bn that can be substituted arbitrarily.

[0031] Implementation Scheme 10. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is an optionally substituted (C1-C6) alkyl (C6-C 10 Aryl.

[0032] Implementation Scheme 11. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is an optional substituted -O-(C1-C6) alkyl group.

[0033] Implementation Scheme 12. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is an optional substituted (C1-C6)alkyl-O-(C1-C6)alkyl.

[0034] Implementation Scheme 13. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is an optionally substituted haloalkyl (C1-C6).

[0035] Implementation Scheme 14. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is an optionally substituted hetero(C1-C6) alkyl group.

[0036] Implementation Scheme 15. The method as described in any one of Implementation Schemes 1-5, wherein R 1 It is an optional substituted (C1-C6)alkyl-C(=O)O(C1-C6)alkyl.

[0037] Implementation Scheme 16. The method of any one of Implementation Schemes 1-15, wherein Ar is an optionally substituted phenyl group.

[0038] Implementation Scheme 17. The method as described in any one of Implementation Schemes 1-15, wherein Ar is optionally substituted (C5-C) 10 ) Mixed aromatic compounds.

[0039] Implementation Scheme 18. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It is a halogen group.

[0040] Implementation Scheme 19. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It is a (C1-C6) alkyl group.

[0041] Implementation Scheme 20. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It is a -C(=O)O(C1-C6) alkyl group.

[0042] Implementation Scheme 21. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It's NO2.

[0043] Implementation Scheme 22. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It's CN.

[0044] Implementation Scheme 23. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It is an -O(C1-C6) alkyl group.

[0045] Implementation Scheme 24. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It is -C(=O)H.

[0046] Implementation Scheme 25. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It is a -C(=O)(C1-C6) alkyl group.

[0047] Implementation Scheme 26. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It's CF3.

[0048] Implementation Scheme 27. The method as described in Implementation Scheme 16 or Implementation Scheme 17, wherein R 2 It's Ts.

[0049] Implementation Scheme 28. The method as described in any one of Implementation Schemes 1-27, wherein n is 1.

[0050] Implementation Scheme 29. The method as described in any one of Implementation Schemes 1-27, wherein n is 2.

[0051] Implementation scheme 30. The method as described in any one of implementation schemes 1-27, wherein n is 3.

[0052] Implementation Scheme 31. The method as described in any one of Implementation Schemes 1-27, wherein n is 4.

[0053] Implementation Scheme 32. The method of any one of Implementation Schemes 1-31, wherein the base is KH2PO4.

[0054] Implementation Scheme 33. The method as described in any one of Implementation Schemes 1-31, wherein the base is NaH2PO4.

[0055] Implementation Scheme 34. The method of any one of Implementation Schemes 1-31, wherein the base is K2HPO4.

[0056] Implementation Scheme 35. The method of any one of Implementation Schemes 1-31, wherein the base is Na2CO3.

[0057] Implementation Scheme 36. The method of any one of Implementation Schemes 1-31, wherein the base is Na2HPO4•2H2O.

[0058] Implementation Scheme 37. The method of any one of Implementation Schemes 1-31, wherein the base is NaHCO3.

[0059] Implementation Scheme 38. The method of any one of Implementation Schemes 1-31, wherein the base is Na2HPO4.

[0060] Implementation Scheme 39. The method of any one of Implementation Schemes 1-31, wherein the base is Na3PO4.

[0061] Implementation Scheme 40. The method of any one of Implementation Schemes 1-31, wherein the base is Na2HPO4•7H2O.

[0062] Implementation Scheme 41. The method as described in any one of Implementation Schemes 1-31, wherein the base is Li2CO3.

[0063] Implementation Scheme 42. The method as described in any one of Implementation Schemes 1-31, wherein the base is NaOAc.

[0064] Implementation Scheme 43. The method of any one of Implementation Schemes 1-31, wherein the base is K2CO3.

[0065] Implementation Scheme 44. The method of any one of Implementation Schemes 1-31, wherein the base is Cs2CO3.

[0066] Implementation Scheme 45. The method of any one of Implementation Schemes 1-44, wherein the oxidant is Ag2CO3.

[0067] Implementation Scheme 46. The method of any one of Implementation Schemes 1-44, wherein the oxidant is Ag2O.

[0068] Implementation Scheme 47. The method of any one of Implementation Schemes 1-44, wherein the oxidant is AgTFA.

[0069] Implementation Scheme 48. The method of any one of Implementation Schemes 1-44, wherein the oxidant is Ag3PO4.

[0070] Implementation Scheme 49. The method of any one of Implementation Schemes 1-44, wherein the oxidant is AgOAc.

[0071] Implementation Scheme 50. The method of any one of Implementation Schemes 1-49, wherein the palladium source is Pd(PhCN)2Cl2.

[0072] Implementation Scheme 51. The method of any one of Implementation Schemes 1-49, wherein the palladium source is Pd(MeCN)2Cl2.

[0073] Implementation Scheme 52. The method of any one of Implementation Schemes 1-49, wherein the palladium source is Pd(allyl)2Cl2.

[0074] Implementation Scheme 53. The method of any one of Implementation Schemes 1-49, wherein the palladium source is Pd(OAc)2.

[0075] Implementation Scheme 54. The method of any one of Implementation Schemes 1-49, wherein the palladium source is Pd(TFA)2.

[0076] Implementation Scheme 55. The method of any one of Implementation Schemes 1-49, wherein the palladium source is Pd(PPh3)2Cl2.

[0077] Implementation Scheme 56. The method of any one of Implementation Schemes 1-55, wherein the solvent is HFIP or HFIP and MeOH.

[0078] Implementation Scheme 57. The method of any one of Implementation Schemes 1-56, wherein the reaction temperature is between about 70°C and about 140°C.

[0079] Implementation Scheme 58. The method of any one of Implementation Schemes 1-57, wherein the reaction temperature is 80°C.

[0080] Implementation Scheme 59. The method of any one of Implementation Schemes 1-57, wherein the reaction temperature is 100°C.

[0081] Implementation Scheme 60. The method of any one of Implementation Schemes 1-57, wherein the reaction temperature is 120°C.

[0082] Implementation Scheme 61. The method of any one of Implementation Schemes 1-5, wherein product 3 is selected from the group consisting of: (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-isocyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-formylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Propyl-3-(4-(trifluoromethyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-fluorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-bromophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-propylcyclopentane-1-carboxylic acid; (1R,3S)-3-(3-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(2-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(5-formylfuran-2-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(5-acetylthiophen-2-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(2-chloropyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(2-bromopyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Propyl-3-(pyridin-4-yl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(2-methylbenzo[d]thiazolyl-6-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Propyl-3-(1-Toluenesulfonyl-1H-indol-5-yl)cyclopentane-1-carboxylic acid; (1R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S 1-Benzyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-phenylpropyl)cyclopentane-1-carboxylic acid; (1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcycloheptane-1-carboxylic acid; (1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cycloheptane-1-carboxylic acid; and (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclooctane-1-carboxylic acid.

[0083] Implementation Scheme 62. The method of any one of Implementation Schemes 1-5, wherein product 6 is selected from the group consisting of: 2-((1 S ,3 R 3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 3-(4-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3R 1-Methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1S,3R)-1-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-benzoylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-fluorophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(5-formylfuran-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(2-chloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(5-acetylthiophen-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-1-methyl-3-(1-toluenesulfonyl-1H-indol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(2-methylbenzo[d]thiazo-6-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(1-methyl-1H-indazol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; and 2-((1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentyl)acetic acid.

[0084] Implementation Scheme 63. The method of any one of Implementation Schemes 1-5, wherein product 7 is selected from the group consisting of: (1 R ,3 S 4 R )-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 S ,3 R 4 S )-3-(4-methoxyphenyl)-4-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid; and (1 S ,3 S 4 R)-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid.

[0085] Implementation Scheme 64. A compound selected from the group consisting of: Implementation Scheme 65. A compound selected from the group consisting of: (1 R ,3 S 3-(4-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-isocyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1R,3S)-3-(3-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(5-formylfuran-2-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-1-propyl-3-(pyridin-4-yl)cyclopentane-1-carboxylic acid; and (1 R ,3 S )-3-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid.

[0086] Implementation Scheme 66. A compound selected from the group consisting of: (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3S 1-Benzyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-phenylpropyl)cyclopentane-1-carboxylic acid; (1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcycloheptane-1-carboxylic acid; (1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cycloheptane-1-carboxylic acid; and (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclooctane-1-carboxylic acid.

[0087] Implementation Scheme 67. A compound selected from the group consisting of: 2-((1 S ,3 R 3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 3-(4-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 1-Methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1S,3R)-1-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1R ,3 S 3-(4-benzoylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-fluorophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(5-formylfuran-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(5-acetylthiophen-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(2-chloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-1-methyl-3-(1-toluenesulfonyl-1H-indol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(2-methylbenzo[d]thiazo-6-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(1-methyl-1H-indazol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; and 2-((1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentyl)acetic acid.

[0088] Implementation Scheme 68. A compound selected from the group consisting of: (1 R ,3 S 4 R )-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 S ,3 R 4 S )-3-(4-methoxyphenyl)-4-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid; and (1 S ,3 S 4 R )-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid.

[0089] Implementation Scheme 69. A method for the enantioselective long-range γ-CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: .

[0090] Implementation Scheme 70. A method for enantioselective long-range δ-CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: .

[0091] Implementation Scheme 71. A method for the enantioselective long-range sequential γ-methylene CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: .

[0092] Implementation scheme 72. Any compound or method as described herein.

[0093] definition As used herein, the phrase “a” or “an” refers to one or more of the same entity; for example, a compound refers to one or more compounds or at least one compound. Therefore, the terms “a” (or “an”), “one or more”, and “at least one” are used interchangeably herein.

[0094] The phrase "as defined above" refers to the broadest definition of each group provided in the summary, detailed description, experiment, or the broadest claims. In all other embodiments provided below, substituents that may be present in each embodiment and are not explicitly defined retain the broadest definition provided in the summary.

[0095] As used herein, the term "comprising" is to be interpreted in an open-ended sense, whether in transitional phrases or in the body of the claims. That is, the term is to be interpreted as synonymous with the phrases "having at least" or "comprising at least". When used in the context of a method, the term "comprising" means that the method includes at least the listed steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the listed features or components, but may also include additional features or components.

[0096] As used herein, unless otherwise explicitly stated, the word "or" is used in an inclusive sense of "and / or" rather than in an exclusive sense of "either / or".

[0097] This document uses the term "independently" to mean that a variable is applied in any given case, regardless of the presence or absence of variables with the same or different definitions within the same compound. Therefore, in compounds where "R" appears twice and is defined as "independently selected," it means that each occurrence of the R group is individually identified as a member of the set conforming to the definition of that R group. For example, "each R..." 1 and R 2 "Independently selected from carbon and nitrogen" means R 1 and R 2Both can be carbon, R 1 and R 2 Both can be nitrogen, or R 1 or R 2 It could be carbon and the other could be nitrogen, or vice versa.

[0098] When any variable appears more than once in any part or chemical formula of a compound used in or claimed in the description and illustration of this invention, its definition for each occurrence is independent of its definition for each subsequent occurrence. Furthermore, combinations of substituents and / or variables are permitted only if the resulting compound is a stable compound.

[0099] The symbol “*” at the end of a bond, or the line or “~~~~” that passes through a bond, respectively indicates the connection point between a functional group or other chemical part and the rest of the molecule to which it belongs.

[0100] A bond drawn into a ring system (as opposed to a bond attached to a specific vertex) indicates that the bond can be attached to any suitable ring atom.

[0101] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may occur but does not have to occur, and the description includes instances where the event or situation occurs and instances where it does not occur. For example, “optionally substituted” means that the “optionally substituted” portion may contain hydrogen or substituents.

[0102] The phrase "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds. If a substituent is specified as "bonded" or "not present," the atom attached to the substituent is directly connected.

[0103] The term "about" in this document means approximately, roughly, roughly, or about. When the term "about" is used in conjunction with a numerical range, it modifies the range by expanding the upper and lower boundaries of the listed numerical value. Generally, the term "about" is used in this document to modify a value that fluctuates by 20%.

[0104] Some of the compounds disclosed herein exhibit tautomerism. Tautomers can exist in the form of two or more interconvertible substances. Proton transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers typically exist in equilibrium, and attempts to separate individual tautomers usually yield mixtures with chemical and physical properties consistent with those of the mixture of compounds. The position of equilibrium depends on the intramolecular chemical signature. For example, in many aliphatic aldehydes and ketones (such as acetaldehyde), the ketone form is dominant; while in phenols, the enol form is dominant. Common proton transfer tautomers include ketone / enol (-C(=O)-CH- -C(-OH)=CH-), amide / imino acid (-C(=O)-NH-) -C(-OH)=N-) and amidine (-C(=NR)-NH-) -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic compounds, and this invention covers all tautomer forms of the compounds.

[0105] In this disclosure, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic acid or base salt of the compounds described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetates, 4,4-diaminostilbene-2,2-disulfonate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, ethanedisulfonate, etolate, esylate, fumarate, glucono-p-aminobenzoarsylate, gluconate, glutamate, glycolyl-p-aminobenzoarsylate, hexafluorophosphate, hexylresorcinol salt, hyaluronic acid, hydrobromide, hydrochloride, hydroxynaphthyl carboxylate, iodine Compounds, isothiosulfates, lactates, lacturonic acids, laurates, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucilages, naphthalenesulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, bis(hydroxynaphthoate) (1,1-methylene-bis-2-hydroxy-3-naphthoate, emborate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonic acids, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suraminates, tannates, tartrates, theochloroate, toluenesulfonates, triiodoacetate, and valerates. Pharmaceutically acceptable salts may have more than one charged atom in their structure. In this case, pharmaceutically acceptable salts may have multiple counterions. Therefore, pharmaceutically acceptable salts can have one or more charged atoms and / or one or more counterions.

[0106] Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Various methods and substances known to those skilled in the art are mentioned herein. Standard references explaining the general principles of pharmacology include Goodman and Gilman's works. The Pharmacological Basis of Therapeutics10th Edition, McGraw Hill Companies Inc., New York (2001). Any suitable substances and / or methods known to those skilled in the art can be used to carry out this invention. However, preferred substances and methods are described herein. Unless otherwise stated, the substances, reagents, etc. mentioned in the following description and examples are available from commercial sources.

[0107] The definitions described herein can be appended to form chemically related combinations, such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclic,” “alkylcarbonyl,” “alkoxyalkyl,” etc. When the term “alkyl” is used as a suffix following another term, such as in “phenylalkyl” or “hydroxyalkyl,” this is intended to refer to an alkyl group as defined above that is substituted with one or two substituents selected from other specifically named groups. Thus, for example, “phenylalkyl” refers to an alkyl group having one or two phenyl substituents, and therefore includes benzyl, phenethyl, and biphenyl. “alkylaminoalkyl” is an alkyl group having one or two alkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, etc. Therefore, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups as defined below. The term -(aryl)alkyl refers to an unsubstituted alkyl or arylalkyl group. The term "(hetero)aryl" refers to aryl or heteroaryl.

[0108] As used herein, the term "acyl" denotes a group of the formula -C(=O)R, where R is hydrogen or a lower alkyl group as defined herein. The term "alkylcarbonyl" as used herein denotes a group of the formula C(=O)R, where R is an alkyl group as defined herein. The term C... 1-6 An acyl group is a group -C(=O)R containing 6 carbon atoms. As used herein, the term "aryl carbonyl" refers to a group of the formula C(=O)R, where R is an aryl group; and the term "benzoyl" refers to an aryl carbonyl group, where R is a phenyl group.

[0109] As used herein, the term "alkyl" refers to a non-branched or branched saturated monovalent hydrocarbon residue containing 1 to 12 carbon atoms. As used herein, the terms "lower alkyl" or "C1-C6 alkyl" refer to straight-chain or branched hydrocarbon residues containing 1 to 6 carbon atoms. 12 "Alkyl" means an alkyl group consisting of 1 to 12 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

[0110] When the term "alkyl" is used as a suffix following another term, such as in "phenylalkyl" or "hydroxyalkyl," it is intended to refer to an alkyl group as defined above, substituted with one or two substituents selected from other specifically named groups. Thus, for example, "phenylalkyl" indicates the group R'R"-, where R' is phenyl and R" is an alkylene group as defined herein, and it should be understood that the phenylalkyl moiety will be connected at the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, and 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly, except that R' is aryl. The terms "(hetero)arylalkyl" or "(hetero)arylalkyl" are interpreted similarly, except that R' is optionally aryl or heteroaryl.

[0111] When listing a range of values, it is intended to cover every value within that range and its subranges. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0112] "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 15 carbon atoms (“C15”). 1-15 Alkyl group). In some embodiments, the alkyl group has 1 to 14 carbon atoms (“C14”). 1-14 Alkyl group). In some embodiments, the alkyl group has 1 to 13 carbon atoms (“C13”). 1-13 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 11 carbon atoms (“C1”). 1-11 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc.

[0113] "Alkenyl" or "olefin" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds ("C"). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octtrienyl (C8).

[0114] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group ("alkynyl group"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("alkynyl group"). C2-4 The alkynyl group ("alkynyl group"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("alkynyl group"). C2-3 The alkynyl group (“C2-alkynyl”) is used in some embodiments. The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0115] The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refer to straight-chain or branched hydrocarbon residues containing 1 to 6 carbon atoms, wherein one or more carbon atoms are replaced by one or more halogen atoms.

[0116] Unless otherwise stated, the terms "alkylene" or "alkanediol" as used herein refer to a divalent saturated straight-chain hydrocarbon group of 1 to 10 carbon atoms (e.g., (CH2)). n ) or branched saturated divalent hydrocarbon groups of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH). i-Pr)CH2-). Except for the case of methylene, the free valences of alkylene groups are not attached to the same atom. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, and 2-ethylbutylene.

[0117] As used herein, the term "alkoxy" means -O-alkyl, where the alkyl group is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, including their isomers. As used herein, "lower alkoxy" refers to an alkoxy group having a "lower alkyl group" as previously defined. As used herein, "C1- 10 "Alkoxy" refers to -O-alkyl, where the alkyl group is C. 1-10 .

[0118] As used herein, the term "hydroxyalkyl" means an alkyl group as defined herein, in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxyl groups.

[0119] As used herein, the terms “alkylsulfonyl” and “arylsulfonyl” refer to a group of the formula -S(=O)2R, where R is either alkyl or aryl, and alkyl and aryl are as defined herein. As used herein, the term “heteroalkylsulfonyl” denotes a group of the formula -S(=O)2R, where R is a “heteroalkyl” as defined herein.

[0120] As used herein, the terms "alkylsulfonylamino" and "arylsulfonylamino" refer to groups of the formula -NR'S(=O)2R, where R is either alkyl or aryl, and R' is hydrogen or C. 1-3 Alkyl groups, and alkyl and aryl groups as defined herein.

[0121] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, namely cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. As used herein, "C 3-7 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 7 carbons in its carbon ring.

[0122] As used herein, the term carboxyl-alkyl refers to an alkyl moiety in which one hydrogen atom has been replaced by a carboxyl group. It is important to understand that heteroalkyl groups are connected via carbon atoms. The term "carboxy" refers to the –CO2H moiety.

[0123] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a monocyclic or bicyclic group having 5 to 12 ring atoms having at least one aromatic ring, each ring containing four to eight atoms, incorporating one or more N, O, or S heteroatoms, with the remaining ring atoms being carbon. It should be understood that the heteroaryl group's linkage will be on the aromatic ring. As is well known to those skilled in the art, the aromatic properties of heteroaryl rings are weaker than their all-carbon counterparts. Therefore, for the purposes of this invention, heteroaryl groups only need to possess a certain degree of aromaticity. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including but not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyrroleyl, pyrazolyl, imidazolyl, oxazole, isoxazole, thiazole, isothiazole, triazoline, thiadiazole, and oxadiazoline, which may optionally be substituted by one or more, preferably one or two, substituents selected from hydroxyl, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, benzoxazole, benzoisoxazole, benzothiazole, and benzoisothiazole. The bicyclic moieties may optionally be substituted on either ring; however, the bonding point is on the ring containing the heteroatom.

[0124] Unless otherwise stated, as used herein, the terms “heterocyclic group,” “heterocyclic alkyl group,” or “heterocyclic” refer to a monovalent saturated cyclic group consisting of one or more rings, preferably one or two rings, including spirocyclic systems with three to eight atoms per ring, incorporating one or more cyclic heteroatoms (selected from N, O, or S(O)). 0-2 It may optionally be independently substituted by one or more, preferably one or two, substituents selected from hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, and arylcarbonylamino. Examples of heterocyclic groups include, but are not limited to, aziridine, pyrrolidinyl, hexahydroaziridine, oxadiazinyl, tetrahydrofuranyl, tetrahydrophenylthio, oxazolidinyl, thiazolyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quininecycloyl, and imidazolinyl.

[0125] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 14-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence state allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused ring, bridged ring, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and can be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic systems may include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring, or a ring system in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members still refers to the number of ring members in the heterocyclic ring system.

[0126] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0127] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxetane, and thiopyrane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridanebutane, oxetanebutane, and thiopyranebutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopentyl, oxothiopentanyl, and dithiopentanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiadialkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphridyl, decahydro-1,8-naphridyl, octahydropyrrolo[3,2-b]pyrrole, indololinyl, phthalimide, naphthalimide, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyranolo[3,4-b]pyrrole, 5, 6-Dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-Dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-Dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-Dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-Dihydrofurano[2,3-b]pyridyl, 4,5,6,7-Tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-Tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-Tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-Tetrahydro-1,6-naphthidyl, etc.

[0128] "Aryl" refers to a monocyclic or polycyclic aromatic ring (e.g., bicyclic or tricyclic) group having 6-14 ring carbon atoms and no heteroatoms in the aromatic ring system (e.g., a 4n+2 aromatic ring system in which 6, 10, or 14 π electrons are enjoyed in a ring array). 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl (α-naphthyl) and 2-naphthyl (β-naphthyl)). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system.

[0129] "Heteroaryl" refers to a 5-14 member monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., a ring array with 6, 10, or 14 π electrons) having a ring carbon atom and providing 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence state allows. Heteroaryl polycyclic systems may include one or more heteroatoms in one or two rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the ring membership number still refers to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, wherein the linking point is on the aryl or heteroaryl ring, and in such cases, the ring membership number still refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl rings (e.g., indolyl, quinolinyl, carbazolyl, etc.) where one ring does not contain a heteroatom, the linking point can be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0130] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0131] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and phenylthioyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aziryl, oxazinyl, and thioazinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzobenzylthio, isobenzobenzylthio, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridine, dibenzofuranyl, carbazole, acridineyl, phenothiazinyl, phenotoxazinyl, and phenothiazinyl.

[0132] "Saturation" refers to a ring portion that does not contain double or triple bonds, meaning that the ring contains only single bonds.

[0133] Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted. Optional substitution refers to groups that can be substituted or are not substituted. Generally, the term "substituted" means that at least one hydrogen atom present on the group is replaced by a non-hydrogen substituent, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo transformations such as through rearrangement, cyclization, elimination, or other reactions. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents that satisfy the heteroatom's valence state and lead to the formation of a stable compound.

[0134] As used herein, an exemplary non-hydrogen substituent where a portion is "optionally substituted" means that the portion may be substituted by any other portion selected from, but not limited to, the following: halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR aa –N(R) bb 2. –N(OR) cc )R bb –SH, –SR aa –C(=O)R aa –CO2H, –CHO, –CO2R aa –OC(=O)R aa –OCO2R aa –C(=O)N(R) bb )2、–OC(=O)N(R bb )2、–NR bb C(=O)R aa –NR bb CO2R aa –NR bb C(=O)N(R bb )2、–C(=NR bb )R aa –C(=NR) bb OR aa –OC(=NR) bb )R aa –OC(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–OC(=NR bb )N(R bb )2、–NR bb C(=NR bb )N(R bb )2、–C(=O)NR bb SO2R aa –NR bb SO2R aa –SO2N(R) bb)2、–SO2R aa –S(=O)R aa –OS(=O)R aa -B(OR) cc 2. C 1–10 Alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 Aryl and 5 to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, or the replacement of two hydrogen atoms on a carbon atom by the =O group; each R that appears aa Selected independently from C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; each R that appears bb Independently selected from hydrogen, –OH, –OR aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –SO2N(R) cc )2、–SOR aa C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; each R that appears cc Independently selected from hydrogen and C 1–10 Alkyl, C1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; and each R that appears dd Independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(OC) 1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C 1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl group, –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6 Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)(C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC (=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups, –OC(NH)NH2, –NHC(NH)N(C 1–6Alkyl)2, –NHC(=NH)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –SO2NH2, –SO2C 1–6 Alkyl group, -B(OH)2, -B(OC) 1–6 Alkyl)2, C 1–6 Alkyl, C 1–6 All-halogenated alkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 aryl, 3- to 10-membered heterocyclic and 5- to 10-membered heteroaryl; or two geminal R groups on a carbon atom. dd Substituents can connect to form =O.

[0135] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0136] As used herein, the term "composition" is intended to cover products that contain the specified ingredients and any products produced directly or indirectly from combinations of the specified ingredients.

[0137] “Salt” includes any and all salts. “Pharmaceutically acceptable salts” are those salts that, within reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in… J. Pharmaceutical SciencesPharmaceutically acceptable salts are described in detail in (1977) 66:1–19. Pharmaceutically acceptable salts include salts derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed by amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods employed in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and nitrogen salts. + (C 1–4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed, where appropriate, with the use of counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0138] Unless otherwise stated, the compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC). The compounds described herein may be in the form of individual isomers substantially free of other isomers, or in mixtures of various isomers.

[0139] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the invention but with hydrogen replaced by deuterium or tritium... 19 F was18 F replacement, carbon bedding 13 C- or 14 C-enrichment carbon substitution and / or oxygen atoms being... 18 O-substituted compounds are within the scope of this disclosure. Other examples of isotopes include... 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I. Compounds with such isotopically enriched atoms can be used as analytical tools or probes, for example, in bioassays.

[0140] Some isotope-labeled compounds (e.g., with) 3 H and 14 C-labeled compounds can be used for the determination of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0141] Certain isotope-labeled compounds of formula (I) can be used for medical imaging purposes, such as positron-emitting isotopes. 11 C or 18 F-labeled compounds can be used in positron emission tomography (PET) applications and to emit isotopes using gamma rays, such as... 123 I-labeled compounds can be used in single-photon emission computed tomography (SPECT) applications. Furthermore, heavier isotopes such as deuterium (i.e.,...) can be used... 2 H) substitution can offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. Furthermore, the use of heavier isotopes such as deuterium (i.e., 2 H) substitution can offer certain therapeutic advantages due to increased metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. Additionally, isotopic substitution at the site of epimerization can slow down or weaken the epimerization process, thereby maintaining the more active or more potent form of the compound for a longer period. Isotopically labeled compounds of formula (I), particularly those containing a longer half-life (t), can generally be prepared by replacing the non-isotopically labeled reagent with a suitable isotopically labeled reagent according to a procedure similar to that disclosed in the schemes and / or examples herein. 1 / 2 Compounds of isotopes with a concentration greater than 1 day.

[0142] If there is a discrepancy between the described structure and the name given to that structure, the described structure shall prevail. Furthermore, if the stereochemistry of a structure or part thereof is not indicated, for example, in bold or dashed lines, then that structure or part thereof should be interpreted to encompass all its stereoisomers. However, in some cases where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry. Those skilled in the art of organic synthesis will know from the methods used to prepare the compound whether it is prepared as a single enantiomer.

[0143] Example abbreviation Commonly used abbreviations include: Acetyl (Ac), Azobisisobutyronitrile (AIBN), Atmospheric pressure (Atm), 9-boronbicyclo[3.3.1]nonane (9-BBN or BBN), tert-butyloxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Service Registry Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2-dichloro Ethane (DCE), dichloromethane (DCM), diethyl azodicarbonate (DEAD), diisopropyl azodicarbonate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), 1,3-diisopropylcarbodiimide (DIC), diisopropylethylamine (DIPEA), N,N-dimethylacetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1'-bis-(diphenylphosphino)ethane (dppe), 1,1'-bis-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2 H1-Quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylureonium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high performance liquid chromatography (HPLC), isopropanol (IPA), lithium hexamethyldisilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2-(methanesulfonyl) Or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperoxybenzoic acid (MCPBA), mass spectrometry (ms), methyl tert-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxylic anhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), isopropyl ( i -Pr), psi, pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t -BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO), trifluoromethanesulfonate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethylureon tetrafluoroborate (TBTU), thin-layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or toluenesulfonyl (Ts), N-urethane-N-carboxylic anhydride (UNCA). Including the prefix positive ( n ),different( i- ), Zhong( sec- Uncle tert- ) and new ( neo Conventional nomenclature, including alkyl moiety, has its usual meaning when used with alkyl groups. (J. Rigaudy and DP Klesney, Nomenclature in Organic Chemistry IUPAC 1979 Pergamon Press, Oxford.).

[0144] 1. General Information Pd(PhCN)₂Cl₂ and Ag₂CO₃ were purchased from Sigma-Aldrich and Strem. Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, and Acros and used directly without further purification. Unless otherwise specified, other reagents were purchased at the highest commercial quality and used without further purification. Analytical thin-layer chromatography was performed on 0.25 mm silica gel 60-F254. 1 1H NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 instruments. The following abbreviations (or combinations thereof) are used to explain multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. Coupling constant. J Report in Hertz (Hz). 13 C10 NMR spectra were recorded on a Bruker DRX-600 and fully decoupled by broadband proton decoupling. Chemical shifts were referenced to appropriate residual solvent peaks. Column chromatography was performed using E. Merck silica (60, particle size 0.043–0.063 mm) and pTLC on Merck silica plates (60F-254). High-resolution mass spectra (HRMS) were recorded on an Agilent mass spectrometer using ESI-TOF (electrospray ionization time-of-flight). Single-crystal X-ray diffraction studies were performed on a Mo K200 instrument equipped with a Mo K200 micrometer. α Melting point was measured using a Stuart SMP50 on a Bruker D8 Venture Ultra diffractometer with radiation (λ = 0.71073). Enantiomer ratio (er) was determined using a commercially available chiral column on an Agilent Technologies supercritical fluid chromatography (SFC) system.

[0145] 2. Preparation of bidentate TZ-pyridone ligands Preparation of TZ1-4 NaH (12.0 mmol, 480 mg) was added to an anhydrous THF (30.0 mL) solution of 2-trimethylsilyl ethanol (15.0 mmol, 1.54 mL), and the mixture was stirred at room temperature for 30 min. Then, 6-bromopyridine carboxynitrile was added at room temperature, and the mixture was stirred at 80 °C for 12 h. The mixture was removed from the heating bath and cooled to room temperature, water (10 mL) was added, and extraction was performed with EtOAc (10 mL x 3). The organic phase was washed with concentrated brine (10 mL x 3) and dried over anhydrous Na₂SO₄. The dried organic phase was passed through a silica gel pad and washed with EtOAc (30 mL). The solvent was removed by rotary evaporation, and the mixture was purified by rapid silica gel column chromatography (5% EtOAc / hexane) to give 6-(2-(trimethylsilyl)ethoxy)pyridine carboxynitrile Ls₃ as a yellow oil.

[0146] NaOMe (10 mol%) was added to a solution of 6-(2-(trimethylsilyl)ethoxy)pyridinecarboxynitrile in anhydrous MeOH, and the mixture was stirred at room temperature for 24 hours. AcOH (1.0 equivalent) was added, and the solvent was removed under reduced pressure to give Ls4, a yellow oil, which was used directly in the next step without purification.

[0147] Add TsOH (10 mol%) and an appropriate amount of amino alcohol to an anhydrous toluene solution of Ls4. Reflux the mixture under N2 atmosphere for 12 hours. Remove the mixture from the heating bath and cool to room temperature. Remove the solvent by rotary evaporation and purify by rapid silica gel column chromatography (10% EtOAc / hexane) to give Ls5 as a colorless oil.

[0148] TBAF (3.0 equivalents) was added to anhydrous THF solution of Ls5 and the solution was stirred at room temperature for 12 hours. The solvent was removed by rotary evaporation and purified by rapid silica gel column chromatography (20% to 100% EtOAc / hexane) to obtain TZ1-4 as a white foamy solid.

[0149] 6-(( S )-4-( R (-sec-butyl)-4,5-dihydrooxazol-2-yl)XXXpyridine-2-ol (TZ-1) 1 H NMR (600 MHz, chloroform-) d ) δ 7.50 – 7.35 (m, 1H), 6.78 – 6.49 (m, 2H), 4.48 (dd, J= 9.2, 7.9 Hz, 1H), 4.22 (td, J = 8.7, 6.3 Hz, 1H), 4.18 (d, J = 7.9Hz, 1H), 1.62 (ddtt, J = 19.3, 11.8, 7.4, 3.3 Hz, 3H), 1.22 (ddt, J = 15.1, 7.7,3.9 Hz, 1H), 0.95 (t, J = 7.3 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H). 13C NMR (151 MHz, chloroform- d ) δ 162.24, 157.59, 140.09, 132.64, 125.09, 106.97, 71.65, 71.23, 39.29, 25.84, 14.78, 11.36.

[0150] C 12 H 17 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 221.1285, and the measured value is 221.1294.

[0151] ( S )-6-(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)XXXpyridine-2-ol (TZ-2) 1 H NMR (600 MHz, chloroform-) d ) δ 9.81 (s, 1H), 7.42 (dd, J = 9.3, 6.7 Hz, 1H), 6.82 – 6.43 (m, 2H), 4.43 (dd, J = 10.1, 8.8 Hz, 1H), 4.28 (t, J = 8.6 Hz, 1H), 4.10 (dd, J = 10.1, 8.5 Hz, 1H), 0.94 (s, 9H). 13 C NMR (151 MHz, chloroform-) d) δ 162.19,157.62, 140.10, 132.54, 125.17, 106.88, 75.98, 70.30, 34.01, 25.86.

[0152] C 12 H 17 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 221.1285, and the measured value is 221.1290.

[0153] ( S )-6-(4-phenyl-4,5-dihydrooxazol-2-yl)XXXpyridine-2-ol (TZ-3) 1 H NMR (600 MHz, chloroform-) d ) δ 9.94 (s, 1H), 7.48 – 7.42 (m, 1H), 7.42 –7.36 (m, 2H), 7.36 – 7.30 (m, 1H), 7.30 – 7.24 (m, 2H), 6.81 (d, J = 6.6 Hz, 1H), 6.75 (d, J = 9.3 Hz, 1H), 5.55 – 5.42 (m, 1H), 4.89 (dd, J = 10.1, 8.6 Hz, 1H), 4.35 (t, J = 8.5 Hz, 1H). 13 C NMR (151 MHz, chloroform-) d ) δ 162.16, 159.00, 141.00,139.99, 132.34, 129.03, 128.13, 126.61, 125.64, 107.55, 76.05, 69.74.

[0154] C 14 H 13 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 241.0972, and the measured value is 241.0980.

[0155] 6-((3 aR 8 aS )-3 a 8 a-dihydro-8 H -Indophen[1,2- d Oxazol-2-yl)XXXpyridine-2-ol (TZ-4) 1 H NMR (600 MHz, chloroform-) d ) δ 7.53 – 7.46 (m, 1H), 7.40 (dd, J = 9.2, 6.8Hz, 1H), 7.34 – 7.30 (m, 3H), 6.78 – 6.66 (m, 2H), 5.77 (d, J = 7.7 Hz, 1H),5.61 – 5.51 (m, 1H), 3.53 (dd, J = 18.1, 6.8 Hz, 1H), 3.38 (d, J = 18.0 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 162.00, 158.34, 140.86, 139.98, 139.37, 132.63,129.07, 127.89, 125.67, 125.52, 125.26, 107.23, 85.21, 76.67, 39.58.

[0156] C 15 H 13 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 253.0972, and the measured value is 253.0978.

[0157] Preparation of TZ5-13 NaH (12.0 mmol, 480 mg) was added to a solution of 2-trimethylsilyl ethanol (15.0 mmol, 1.54 mL) in anhydrous THF (30.0 mL), and the mixture was stirred at room temperature for 30 min. Then, 2,6-dibromopyridine was added at room temperature, and the mixture was stirred at 80 °C for 12 h. The mixture was removed from the heating bath and cooled to room temperature, water (10 mL) was added, and extraction was performed with EtOAc (10 mL x 3). The organic phase was washed with concentrated brine (10 mL x 3) and dried over anhydrous Na₂SO₄. The dried organic phase was passed through a silica gel pad and washed with EtOAc (30 mL). The solvent was removed by rotary evaporation, and the mixture was purified by rapid silica gel column chromatography (5% EtOAc / hexane) to give 2-bromo-6-(2-(trimethylsilyl)ethoxy)pyridine as a colorless oil.

[0158] Methyl isobutyrate (13 mmol, 1.3 equivalents) was added to a solution of LiCy2 (13 mmol, 1.3 equivalents) in anhydrous toluene (30.0 mL), and the mixture was stirred at room temperature under a N2 atmosphere for 30 minutes. Then, Pd2(dba)3 (228 mg, 2.5 mol%) and P were added. t After adding Bu3·HBF4 and 2-bromo-6-(2-(trimethylsilyl)ethoxy)pyridine, the mixture was stirred at room temperature for 12 hours. Water (10 mL) was added and extracted with EtOAc (10 mL x 3). The organic phase was washed with concentrated brine (10 mL x 3) and dried over anhydrous Na2SO4. The dried organic phase was passed through a silica gel pad and washed with EtOAc (30 mL). The solvent was removed by rotary evaporation and purified by rapid silica gel column chromatography (10% EtOAc / hexane) to give methyl 2-methyl-2-(6-(2-(trimethylsilyl)ethoxy)pyridin-2-yl)propionate as a yellow oil.

[0159] LiOH·6H2O (15 mmol, 3 equivalents) was added to a solution of methyl 2-methyl-2-(6-(2-(trimethylsilyl)ethoxy)pyridin-2-yl)propionate (5 mmol) in MeOH / H2O (1:1), and the mixture was stirred at 50 °C for 24 h. The reaction mixture was cooled to room temperature and adjusted to pH 2 with 2N HCl. The aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give Ls9, which was used directly in the next step without purification.

[0160] Add Ls9 (5 mmol) to a solution of anhydrous DCM at 0°C N1-Methylmorpholine (3.0 equivalents) and isobutyl chloroformate (1.0 equivalents). The mixture was stirred at room temperature for 1 hour, and then an appropriate amount of amino alcohol (1.2 equivalents) was added. The mixture was then stirred at room temperature for 12 hours, and the solvent was removed by rotary evaporation and purified by rapid silica gel column chromatography (25% EtOAc / hexane) to give Ls10 as a colorless oil.

[0161] TEA (4 mmol, 2.0 equivalent), MsCl (3 mmol, 1.5 equivalent), and DMAP (0.2 mmol, 10 mol%) were added to a solution of Ls10 (2 mmol) in anhydrous DCM. The mixture was stirred at room temperature for 12 hours, the solvent was removed by rotary evaporation, and the solution was purified by rapid silica gel column chromatography (20% EtOAc / hexane) to give Ls11 as a colorless oil.

[0162] Add TBAF (6 mmol, 6 equivalents) to a solution of Ls11 (1 mmol). Stir the mixture at room temperature for 12 hours. Remove the solvent by rotary evaporation and purify by rapid silica gel column chromatography (20% to 100% EtOAc / hexane) to give TZ 5-13 as a white foamy solid.

[0163] 6-(2-(( S )-4-(( R )-sec-butyl)-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-5) 1 H NMR (600 MHz, chloroform-) d ) δ 10.15 (s, 1H), 7.37 (dd, J = 9.2, 7.0 Hz, 1H), 6.46 (d, J = 9.2 Hz, 1H), 6.16 (d, J = 7.0 Hz, 1H), 4.25 (dd, J = 9.7, 8.4 Hz, 1H), 4.12 (ddd, J = 9.8, 7.9, 5.8 Hz, 1H), 4.02 (t, J = 8.1 Hz, 1H), 1.67 (tt, J =13.3, 6.9 Hz, 1H), 1.59 (d, J= 5.3 Hz, 6H), 1.55 – 1.46 (m, 1H), 1.19 (tt, J =15.0, 7.5 Hz, 1H), 0.95 (t, J = 7.4 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H). 13 C NMR (151MHz, CDCl3) δ 168.75, 163.54, 150.50, 141.06, 119.22, 101.99, 70.60, 69.98,39.86, 38.79, 26.44, 26.10, 25.80, 14.20, 11.70.

[0164] C 15 H 23 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 263.1754, and the measured value is 263.1761.

[0165] ( S )-6-(2-(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-6) 1 H NMR (600 MHz, chloroform-) d ) δ 10.18 (s, 1H), 7.36 (dd, J = 9.1, 7.0 Hz,1H), 6.52 – 6.41 (m, 1H), 6.15 (d, J = 7.0 Hz, 1H), 4.26 – 4.16 (m, 1H), 4.11(t, J = 8.3 Hz, 1H), 3.92 (dd, J = 10.1, 7.7 Hz, 1H), 1.59 (d, J = 6.8 Hz, 6H), 0.91 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 168.80, 163.47, 150.50, 141.00,119.23, 101.88, 75.63, 69.23, 39.80, 33.88, 26.57, 25.88, 25.82.

[0166] C 15 H 23 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 263.1754, and the measured value is 263.1757.

[0167] ( S )-6-(2-(4-phenyl-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-7) 1 H NMR (600 MHz, chloroform-) d ) δ 10.46 (s, 1H)7.48 – 7.33 (m, 1H), 7.33 –7.26 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 6.48 (d, J = 9.1 Hz, 1H), 6.21 (d, J = 7.0Hz, 1H), 5.26 (dd, J = 10.1, 8.4 Hz, 1H), 4.68 (dd, J = 10.2, 8.6 Hz, 1H), 4.16(t, J = 8.4 Hz, 1H), 1.70 (d, J = 6.0 Hz, 6H). 13 C NMR (151 MHz, chloroform-) d ) δ 170.46,163.86, 150.41, 141.72, 141.08, 128.94, 127.88, 126.59, 119.29, 102.32,75.40, 69.62, 40.25, 26.45, 25.59.

[0168] C 17 H 19 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 283.1441, and the measured value is 283.1444.

[0169] (S) -6-(2-(4-(4-fluorophenyl)-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-8) 1 H NMR (400 MHz, chloroform-) d ) δ 7.40 (dd, J = 9.2, 7.0 Hz, 1H), 7.23 – 7.14(m, 2H), 7.10 – 6.97 (m, 2H), 6.48 (dd, J = 9.2, 0.9 Hz, 1H), 6.22 (dd, J = 7.0, 0.8 Hz, 1H), 5.25 (dd, J = 10.1, 8.3 Hz, 1H), 4.68 (dd, J = 10.2, 8.6 Hz, 1H), 4.12 (t, J = 8.4 Hz, 1H), 1.69 (d, J = 3.5 Hz, 6H). 13 C NMR (151 MHz, chloroform-) d ) δ170.65, 163.54 (d, J = 92.1 Hz), 158.19, 150.26, 141.13, 137.49 (d, J = 3.0 Hz), 128.26 (d, J = 7.6 Hz), 127.79 (d, J = 357.9 Hz), 119.83 (d, J = 21.14 Hz), 102.37, 75.38, 69.00, 40.22, 26.41, 25.57. 19 F NMR (376 MHz, CDCl3) δ -117.27.

[0170] C 17 H 18 FN2O2[M+H] + The calculated HRMS (ESI-TOF) value is 301.1347, and the measured value is 301.1349.

[0171] ( S )-6-(2-(4-(naphth-1-yl)-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-9) 1 H NMR (600 MHz, chloroform-) d) δ 11.05 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.54 – 7.46 (m, 3H), 7.43 (t, J =7.6 Hz, 1H), 7.40 – 7.34 (m, 1H), 6.47 (d, J = 9.1 Hz, 1H), 6.23 (d, J = 6.9 Hz, 1H), 5.94 (t, J = 9.5 Hz, 1H), 4.96 – 4.82 (m, 1H), 4.05 (t, J = 8.5 Hz, 1H), 1.76 (d, J = 18.2 Hz, 6H). 13 C NMR (151 MHz, chloroform-) d ) δ 170.87, 164.41, 150.87,141.11, 138.02, 133.84, 130.48, 129.10, 127.94, 126.38, 125.78, 125.70,123.20, 122.64, 119.08, 102.60, 74.98, 66.39, 40.74, 26.42, 25.58.

[0172] C 21 H 21 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 333.1598, and the measured value is 333.1605.

[0173] ( S )-6-(2-(4-(3,5-di-tert-butylphenyl)-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-10) 1 H NMR (600 MHz, chloroform-) d ) δ 7.43 – 7.33 (m, 2H), 7.03 (s, 2H), 6.48 (d, J = 9.2 Hz, 1H), 6.22 (d, J= 7.0 Hz, 1H), 5.22 (t, J = 8.7 Hz, 1H), 4.66 (t, J =9.3 Hz, 1H), 4.25 (t, J = 7.9 Hz, 1H), 1.72 (d, J = 2.8 Hz, 6H), 1.34 – 1.29 (m,18H). 13 C NMR (151 MHz, CDCl3) δ 170.01, 164.01, 151.23, 141.00, 140.95,121.99, 121.98, 120.68, 119.06, 102.33, 75.55, 70.04, 40.37, 34.88, 31.44, 26.43, 25.56.

[0174] C 25 H 35 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 395.2693, and the measured value is 395.2697.

[0175] ( S )-4-methoxy-6-(2-(4-phenyl-4,5-dihydrooxazol-2-yl)propyl-2-yl)pyridin-2-ol (TZ-11) 1 H NMR (600 MHz, chloroform-) d ) δ 9.67 (s, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.31(d, J = 7.4 Hz, 1H), 7.22 (d, J = 7.2 Hz, 2H), 5.94 (d, J = 2.1 Hz, 1H), 5.79 (d, J =2.0 Hz, 1H), 5.25 (t, J = 9.2 Hz, 1H), 4.68 (dd, J = 10.1, 8.7 Hz, 1H), 4.17 (t, J = 8.4 Hz, 1H), 3.79 (s, 3H), 1.66 (d, J = 6.6 Hz, 6H).13 C NMR (600 MHz, chloroform-) d ) δ170.24, 169.57, 165.47, 149.97, 141.68, 128.98, 127.93, 126.61, 97.83, 95.55,75.44, 69.63, 55.65, 40.02, 26.25, 25.34.

[0176] C 18 H 21 N₂O₃[M+H] + The calculated HRMS (ESI-TOF) value is 313.1547, and the measured value is 313.1550.

[0177] ( S )-6-(1-(4-phenyl-4,5-dihydrooxazol-2-yl)cyclohexyl)pyridin-2-ol (TZ-12) 1 H NMR (600 MHz, chloroform-) d ) δ 9.39 (s, 1H), 7.45 – 7.34 (m, 3H), 7.33 –7.30 (m, 1H), 7.25 – 7.20 (m, 2H), 6.49 (dd, J = 9.2, 0.8 Hz, 1H), 6.29 – 6.22(m, 1H), 5.28 (dd, J = 10.1, 8.8 Hz, 1H), 4.67 (dd, J = 10.3, 8.6 Hz, 1H), 4.15(dd, J = 17.3, 8.6 Hz, 1H), 2.53 – 2.41 (m, 2H), 1.84 – 1.64 (m, 6H), 1.62 –1.52 (m, 1H), 1.33 (qd, J = 11.7, 11.2, 6.0 Hz, 1H). 13 C NMR (151 MHz, chloroform-) d) δ168.50, 163.49, 149.55, 141.75, 141.15, 129.03, 127.94,126.73,119.53, 102.56,75.23, 69.97, 44.33, 34.38, 32.94, 25.31, 23.17, 23.09.

[0178] C 20 H 23 N₂O₂[M+H] + The calculated HRMS (ESI-TOF) value is 323.1754, and the measured value is 323.1762.

[0179] 3. Enantioselectivity screening of γ-arylation 4. Enantioselectivity screening of δ-arylation 5. Substrate preparation Preparation of γ-arylated cycloalkane carboxylic acids LDA (55 mmol) was added dropwise at -78°C to the solution. α The mixture of -H-fatty acid (22 mmol) and THF (50 mL) was heated to room temperature and stirred for 1 hour. The reaction mixture was then recooled to -78°C, and RI or RBr (22 mmol) was added dropwise. The resulting solution was heated to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was quenched with 10% HCl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give a crude product. This crude product was then purified by silica gel chromatography to obtain the desired cycloalkane carboxylic acid.

[0180] Preparation of δ-arylated cycloalkane carboxylic acids RLi (40 mmol) was added dropwise to a mixture of CuI (40 mmol) and Et₂O (150 mL) at -0 °C, and the mixture was stirred for 0.5 h. The solvent was removed under reduced pressure at 25 °C. Anhydrous DCM (30 mL) was added, and the mixture was cooled to -78 °C. TMSCl (40 mmol) and an α,β-unsaturated carbonyl compound (20 mmol) were added dropwise. The mixture was stirred for 1 h and slowly heated to room temperature. After 16 h, the reaction mixture was quenched by adding saturated NH₄Cl aqueous solution (30 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure to give the crude product. This crude product was used directly in the next step without any purification.

[0181] The crude product was refluxed in a mixture of MeOH (30 mL) and water (30 mL). After 12 hours, the mixture was cooled to room temperature and quenched with 2N HCl, then extracted with EtOAc. The combined organic extracts were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated to give the crude product. This crude product was then purified by silica gel chromatography to obtain the desired cycloalkane carboxylic acid.

[0182] 6. General procedure for γ-(hetero)arylation In a sealed 10 mL vial equipped with a magnetic stir bar, appropriate amounts of fatty acid substrate (0.10 mmol), aryl iodide (0.20 mmol), Ag₂CO₃ (55.0 mg, 0.20 mmol), and KH₂PO₄ (27.2 mg, 0.2 mmol) were added. A solution of Pd(PhCN)₂Cl₂ (3.8 mg, 10 mol%) and TZ-10 (4.8 mg, 12 mol%) in HFIP (1.0 mL) and MeCN (0.1 mL) was premixed and added. The vial was then capped and tightly sealed. The reaction mixture was then stirred at 200 rpm for 24 hours at the appropriate temperature. After cooling to room temperature, the mixture was acidified with 100 μL of acetic acid and stirred for 30 seconds. The mixture was passed through a diatomaceous earth pad, using EtOAc as the eluent to remove any insoluble precipitates. The resulting solution was concentrated, and the residual mixture was purified by pTLC to give the enantioselective γ-(hetero)arylated product. This was achieved by using ligands... rac -TZ-7 was used to replace ligand TZ-10 to prepare racemic samples of γ-(hetero)arylated products for chiral HPLC analysis.

[0183] 7. General procedure for δ-(hetero)arylation In a sealed 10 mL vial equipped with a magnetic stir bar, appropriate amounts of fatty acid substrate (0.10 mmol), aryl iodide (0.20 mmol), Ag₂CO₃ (55.0 mg, 0.20 mmol), and KH₂PO₄ (27.2 mg, 0.2 mmol) were added. A solution of Pd(PhCN)₂Cl₂ (3.8 mg, 10 mol%) and TZ-7 (3.4 mg, 12 mol%) in HFIP (2.0 mL) was premixed and added. The vial was then capped and tightly sealed. The reaction mixture was then stirred at 200 rpm for 24 hours at 120 °C. After cooling to room temperature, the mixture was acidified with 100 μL of acetic acid and stirred for 30 seconds. The mixture was passed through a diatomaceous earth pad, using EtOAc as the eluent to remove any insoluble precipitates. The resulting solution was concentrated, and the residual mixture was purified by pTLC to give the enantioselective (hetero)arylated product. The product was then further purified by using ligands. rac -TZ-7 was used to replace ligand TZ-7 in the preparation of racemic samples of γ-(hetero)arylated products for chiral HPLC analysis.

[0184] 8. General procedure for γ-di(hetero)arylation In a sealed 10 mL vial equipped with a magnetic stir bar, add appropriate amounts of γ-(hetero)aryl substrate (0.10 mmol), aryl iodide (0.20 mmol), Ag₂CO₃ (55.0 mg, 0.20 mmol), and KH₂PO₄ (27.2 mg, 0.2 mmol). Add Pd(PhCN)₂Cl₂ (3.8 mg, 10 mol%) and (… R A solution of 4.2 mg (15 mol%) of α-TZ-7 in HFIP (1.0 mL) was premixed and added. The vial was then capped and tightly sealed. The reaction mixture was then stirred at 200 rpm for 24 hours at 80 °C. After cooling to room temperature, the mixture was acidified with 100 μL of acetic acid and stirred for 30 seconds. The mixture was passed through a diatomaceous earth pad, using EtOAc as the eluent to remove any insoluble precipitates. The resulting solution was concentrated, and the residual mixture was purified by pTLC to give the enantioselective di-(hetero)arylated product.

[0185] 9. Characterization data of products obtained from γ-(hetero)arylation (1 R ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentane-1-carboxylic acid (3a) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3a (yellow oil, 21.4 mg, 74% yield, 97% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.096 min (minor) and 6.832 min (major).

[0186] 1 H NMR (600 MHz, chloroform-) d ) δ 7.98 – 7.92 (m, 2H), 7.35 – 7.29 (m, 2H), 3.9 (s, 3H), 3.18 (tt, J = 11.0, 7.5 Hz, 1H), 2.43 (ddd, J = 13.2, 7.8, 2.5 Hz,1H), 2.24 (dd, J = 13.6, 10.8 Hz, 1H), 2.16 – 2.06 (m, 2H), 1.84 – 1.63 (m,4H), 1.40 – 1.30 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ184.3, 167.3, 150.2, 129.9, 128.2, 127.3, 53.6, 52.1, 45.1, 43.4, 42.1, 36.5, 34.4, 19.1, 14.7. The NMR data matched the reported data (29).

[0187] Absolute stereochemistry is specified by analogy with compound 6z.

[0188] (1 R ,3 S 3-(4-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid (3b) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3b (yellow oil, 21.6 mg, 78% yield, 94% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min), with retention times of 16.890 min (minor) and 18.438 min (major).

[0189] 1 H NMR (600 MHz, chloroform-) d ) δ 8.14 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 3.24 (tt, J = 10.8, 7.4 Hz, 1H).2.44 (ddd, J = 13.1, 7.5, 2.4 Hz, 1H), 2.27(dd, J = 13.6, 10.6 Hz, 1H), 2.18 – 2.11 (m, 2H), 1.81 – 1.68 (m, 4H), 1.37 –1.33 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.1, 152.7,146.6, 128.1, 123.8, 53.8, 45.0, 43.1, 42.0, 36.7, 34.5, 19.1, 14.6. The NMR data matched the reported data (29).

[0190] Absolute stereochemistry is specified by analogy with compound 6z.

[0191] (1 R ,3 S 3-(4-isocyanophenyl)-1-propylcyclopentane-1-carboxylic acid (3c) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3c (yellow oil, 18.0 mg, 70% yield, 90% ee). Enantiomer purity was determined by SFC analysis, with retention times of 0.90 min (major) and 1.42 min (minor).

[0192] 1 H NMR (600 MHz, chloroform-) d ) δ 7.57 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 3.18 (tt, J = 10.7, 7.4 Hz, 1H), 2.42 (ddd, J = 12.9, 7.3, 2.4 Hz, 1H), 2.23(dd, J = 13.6, 10.5 Hz, 1H), 2.16 – 2.06 (m, 2H), 1.81 – 1.62 (m, 4H), 1.43 –1.28 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.1, 150.3,132.2, 128.0, 119.1, 109.9, 53.6, 45.1, 43.0, 42.0, 36.6, 34.3, 19.0, 14.5. The NMR data matched the reported data (29).

[0193] Absolute stereochemistry is specified by analogy with compound 6z.

[0194] (1 R ,3 S 3-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid (3d) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3d (yellow oil, 17.3 mg, 66% yield, 95% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 8.804 min (minor) and 11.201 min (major).

[0195] 1 H NMR (600 MHz, chloroform-) d ) δ 7.18 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz,2H), 3.79 (s, 3H), 3.08 (tt, J = 11.0, 7.2 Hz, 1H), 2.40 (ddd, J = 13.1, 7.7, 2.4Hz, 1H), 2.18 (dd, J = 13.3, 11.0 Hz, 1H), 2.12 – 2.02 (m, 2H), 1.78 – 1.59 (m,4H), 1.36 – 1.32 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ184.1, 158.1, 136.8, 128.1, 113.9, 55.4, 53.4, 44.4, 44.0, 42.2, 36.4, 34.8,19.1, 14.7.

[0196] Absolute stereochemistry is specified by analogy with compound 6z.

[0197] (1 R ,3 S 3-(4-formylphenyl)-1-propylcyclopentane-1-carboxylic acid (3e) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3e (yellow oil, 15.1 mg, 58% yield, 97% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min) with retention times of 20.330 min (minor) and 22.765 min (major). NMR data matched reported data (29).

[0198] 1 H NMR (600 MHz, chloroform-) d ) δ 9.97 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.43(d, J = 8.1 Hz, 1H), 3.25 – 3.18 (m, 1H), 2.45 (ddd, J = 13.4, 7.8, 2.5 Hz, 1H),2.28 (dd, J = 13.6, 10.8 Hz, 1H), 2.17 – 2.12 (m, 2H), 1.84 – 1.67 (m, 4H), 1.39 – 1.32 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ192.2, 183.8, 152.3, 134.9, 130.1, 128.0, 53.7, 45.3, 43.3, 42.1, 36.4, 34.5, 19.1, 14.7.

[0199] Absolute stereochemistry is specified by analogy with compound 6z.

[0200] (1 R ,3 S 3-(4-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid (3f) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3f (yellow oil, 15.9 mg, 58% yield, 95% ee). Enantiomer purity was determined by SFC analysis, with retention times of 1.49 min (minor) and 2.06 min (major).

[0201] 1 H NMR (600 MHz, chloroform-) d ) δ 7.89 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.19 (tt, J = 10.8, 7.3 Hz, 1H), 2.58 (s, 3H), 2.43 (ddd, J = 13.1, 7.7,2.5 Hz, 1H), 2.25 (dd, J = 13.5, 10.8 Hz, 1H), 2.18 – 2.05 (m, 2H), 1.82 – 1.65(m, 4H), 1.38 – 1.31 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 198.1, 184.1, 150.6, 135.4, 128.7, 127.5, 53.6, 45.1, 43.4, 42.1, 36.6, 34.5, 26.7, 19.1, 14.7. The NMR data matched the reported data (29).

[0202] Absolute stereochemistry is specified by analogy with compound 6z.

[0203] (1 R ,3 S 1-Propyl-3-(4-(trifluoromethyl)phenyl)cyclopentane-1-carboxylic acid (3g) The compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, yielding 3 g (yellow oil, 18.3 mg, 61% yield, 94% ee). Enantiomer purity was determined by SFC analysis, with retention times of 0.72 min (minor) and 0.89 min (major).

[0204] 1 H NMR (600 MHz, chloroform-) d ) δ 7.54 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 3.19 (tt, J = 10.7, 7.4 Hz, 1H),2.43 (ddd, J = 13.2, 7.6, 2.4 Hz, 1H), 2.25(dd, J = 13.6, 10.8 Hz, 1H), 2.15 – 2.10 (m, 2H), 1.82 – 1.65 (m, 4H), 1.38 –1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.8, 148.7(q, J = 1.8 Hz), 128.5 (q, J = 32.3 Hz), 127.5, 125.3 (q, J = 3.8 Hz), 124.3 (d, J =271.6 Hz), 53.5, 44.8, 43.3, 41.9, 36.5, 34.4, 19.0, 14.5. 19 F NMR (151 MHz, chloroform- d δ -65.0. The NMR data matches the reported data (29).

[0205] Absolute stereochemistry is specified by analogy with compound 6z.

[0206] (1 R ,3S 3-(4-fluorophenyl)-1-propylcyclopentane-1-carboxylic acid (3h) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give a yellow oil (16.5 mg, 66% yield, 93% ee) at 3 h. Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.579 min (major) and 9.434 min (minor).

[0207] 1 H NMR (600 MHz, chloroform-) d ) δ 7.23 – 7.18 (m, 2H), 6.98 – 6.95 (m, 2H), 3.11 (tt, J = 10.9, 7.4 Hz, 1H), 2.41 (ddd, J = 13.0, 7.6, 2.4 Hz, 1H), 2.19 (dd, J = 13.5, 10.9 Hz, 1H), 2.12 – 2.05 (m, 2H), 1.76 – 1.61 (m, 4H), 1.36 – 1.32(m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.5, 161.5 (d, J =243.8 Hz), 140.3 (d, J = 3.1 Hz), 128.6 (d, J = 7.7 Hz), 115.2 (d, J = 21.1 Hz),53.5, 44.4, 43.8, 42.1, 36.5, 34.8, 19.1, 14.7. 19 F NMR (376 MHz, chloroform- d ) δ -120.1. The NMR data matches the reported data (29).

[0208] Absolute stereochemistry is specified by analogy with compound 6z.

[0209] (1 R ,3 S 3-(4-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid (3i) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3i (yellow oil, 18.4 mg, 69% yield, 98% ee). Enantiomer purity was determined by SFC analysis, with retention times of 1.18 min (minor) and 1.6 min (major).

[0210] 1 H NMR (600 MHz, chloroform-) d ) δ 7.26 – 7.25 (m, 2H), 7.19 – 7.18 (m, 2H), 3.11 (tt, J = 10.9, 7.3 Hz, 1H), 2.41 (ddd, J = 13.0, 7.6, 2.4 Hz, 1H), 2.19 (dd, J = 13.5, 10.9 Hz, 1H), 2.15 – 2.05 (m, 2H), 1.77 – 1.62 (m, 4H), 1.42 – 1.29(m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.0, 143.2,131.9, 128.6, 128.5, 53.5, 44.5, 43.6, 42.1, 36.5, 34.6, 19.1, 14.7. The NMR data matched the reported data (29).

[0211] Absolute stereochemistry is specified by analogy with compound 6z.

[0212] (1 R ,3 S3-(4-bromophenyl)-1-propylcyclopentane-1-carboxylic acid (3j) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3j (yellow oil, 19.9 mg, 64% yield, 96% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 7.710 min (major) and 9.024 min (minor).

[0213] 1 H NMR (600 MHz, chloroform-) d ) δ 7.40 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 3.09 (tt, J = 10.8, 7.3 Hz, 1H), 2.41 (ddd, J = 13.0, 7.5, 2.4 Hz, 1H), 2.19(dd, J = 13.5, 10.9 Hz, 1H), 2.11 – 2.05 (m, 2H), 1.77 – 1.61 (m, 4H), 1.37 –1.30 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.1, 143.7,131.5, 129.0, 119.9, 53.5, 44.6, 43.5, 42.1, 36.5, 34.6, 19.1, 14.7. The NMR data matched the reported data (29).

[0214] Absolute stereochemistry is specified by analogy with compound 6z.

[0215] (1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-propylcyclopentane-1-carboxylic acid (3k) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3k (yellow oil, 16.8 mg, 58% yield, 97% ee). Enantiomer purity was determined by SFC analysis, with retention times of 1.01 min (major) and 1.25 min (minor).

[0216] 1 H NMR (600 MHz, chloroform-) d ) δ 7.93 (t, J = 1.8 Hz, 1H), 7.86 (dt, J = 7.7,1.4 Hz, 1H), 7.47 – 7.45 (m, 1H), 7.36 (t, J = 7.7 Hz, 1H), 3.19 (ddd, J = 18.4,11.1, 7.5 Hz, 1H), 2.44 (ddd, J = 13.2, 7.9, 2.4 Hz, 1H), 2.24 (dd, J = 13.4,11.0 Hz, 1H), 2.16 – 2.08 (m, 2H), 1.86 – 1.61 (m, 4H), 1.39 – 1.32 (m, 2H),0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.8, 167.4 145.0, 131.9,130.3, 128.6, 128.5, 127.6, 53.5, 52.2, 44.9, 43.6 42.1, 36.5, 34.6, 19.1,14.7. The NMR data matched the reported data (29).

[0217] Absolute stereochemistry is specified by analogy with compound 6z.

[0218] (1R,3S)-3-(3-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid (3l) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3 μL (yellow oil, 18.8 mg, 73% yield, 90% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min), with retention times of 13.546 min (minor) and 14.747 min (major).

[0219] 1 H NMR (600 MHz, chloroform-) d ) δ 7.57 (s, 1H), 7.53 – 7.50 (m, 2H), 7.41 (t, J = 7.7 Hz, 1H), 3.18 (ddd, J = 18.3, 10.7, 7.8 Hz, 1H), 2.46 (ddd, J = 13.1, 7.4,2.3 Hz, 1H), 2.24 (dd, J = 13.5, 10.7 Hz, 1H), 2.17 – 2.12 (m, 2H), 1.81 – 1.68(m, 4H), 0.97 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.0, 146.2,131.9, 131.0, 130.1, 129.3, 119.2, 112.5, 53.6, 44.7, 43.2 42.0, 36.6, 34.4,19.1, 14.6. The NMR data matched the reported data (29).

[0220] Absolute stereochemistry is specified by analogy with compound 6z.

[0221] (1 R ,3 S 3-(3-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid (3m) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3m (yellow oil, 21.4 mg, 78% yield, 93% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.850 min (minor) and 7.461 min (major).

[0222] 1 H NMR (600 MHz, chloroform-) d ) δ 7.87 – 7.84 (m, 2H), 7.78 (dt, J = 7.7, 1.4Hz, 1H), 7.49 – 7.46 (m, 1H), 7.38 (t, J = 7.7 Hz, 1H), 3.20 (tt, J = 10.9, 7.3Hz, 1H), 2.60 (s, 3H), 2.44 (ddd, J = 13.3, 7.8, 2.4 Hz, 1H), 2.25 (dd, J = 13.5,10.8 Hz, 1H), 2.19 – 2.08 (m, 2H), 1.84 – 1.60 (m, 4H), 1.39 – 1.31 (m, 2H),0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 198.6, 184.2, 145.3, 137.4, 132.1, 130.1, 128.8, 127.1, 126.5, 53.6, 44.9, 43.6, 42.1, 36.5, 34.5, 26.8, 19.1, 14.7. The NMR data matched the reported data (29).

[0223] Absolute stereochemistry is specified by analogy with compound 6z.

[0224] (1 R ,3 S 3-(3-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid (3n) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3n (yellow oil, 23.5 mg, 85% yield, 91% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min), with retention times of 13.378 min (minor) and 14.566 min (major).

[0225] 1 H NMR (600 MHz, chloroform-) d ) δ 8.13 – 8.12 (m, 1H), 8.06 – 8.04 (m, 1H), 7.61 – 7.59 (m, 1H), 7.45 (t, J = 8.0 Hz, 1H), 3.25 (tt, J = 10.9, 7.4 Hz, 1H), 2.60 (s, 3H), 2.45 (ddd, J = 13.0, 7.6, 2.3 Hz, 1H), 2.27 (dd, J = 13.6, 10.6 Hz,1H), 2.19 – 2.14 (m, 2H), 1.84 – 1.67 (m, 4H), 1.39 – 1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.1, 148.5, 146.9, 133.6, 129.4, 122.3, 121.4, 53.7, 44.7, 43.3, 42.1, 36.5, 34.4, 19.1, 14.6. The NMR data matched the reported data (29).

[0226] Absolute stereochemistry is specified by analogy with compound 6z.

[0227] (1 R ,3 S 3-(3-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid (3o) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3O (yellow oil, 16.2 mg, 61% yield, 93% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 8.005 min (major) and 14.649 min (minor).

[0228] 1 H NMR (600 MHz, chloroform-) d ) δ 7.28 – 7.84 (m, 2H), 7.19 – 7.13 (m, 2H), 3.16 – 3.08 (m, 1H), 2.45 – 2.40 (m, 1H), 2.24 – 2.14 (m, 1H), 2.14 – 2.08(m, 2H), 1.81 – 1.63 (m, 4H), 1.39 – 1.33 (m, 2H), 0.97 – 0.93 (m, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.5, 146.8, 134.3, 129.7, 127.5, 126.4, 125.5, 53.5, 44.8, 43.5, 42.1, 36.4, 34.4, 19.1, 14.7. The NMR data matched the reported data (29).

[0229] Absolute stereochemistry is specified by analogy with compound 6z.

[0230] (1 R ,3 S 3-(2-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid (3p) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3p (yellow oil, 16.2 mg, 63% yield, 98% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (3% IPA / CO2, 2.0 mL / min), with retention times of 15.607 min (major) and 17.537 min (minor).

[0231] 1 H NMR (600 MHz, chloroform-) d ) δ 7.61 – 7.59 (m, 1H), 7.56 – 7.53 (m, 1H), 7.50 – 7.49 (m, 1H), 7.28 (td, J = 7.6, 1.3 Hz, 1H), 3.61 – 3.55 (m, 1H), 2.44(ddd, J = 12.8, 6.9, 2.6 Hz, 1H), 2.28 – 2.15 (m, 3H), 1.83 – 1.71 (m, 4H), 1.39 – 1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.6,148.6, 133.3, 132.9, 127.5, 126.8, 126.7, 118.4, 112.6, 53.8, 43.2, 42.8,41.9, 36.8, 34.2, 19.2, 14.6. The NMR data matched the reported data (29).

[0232] Absolute stereochemistry is specified by analogy with compound 6z.

[0233] (1 R ,3 S 3-(5-formylfuran-2-yl)-1-propylcyclopentane-1-carboxylic acid (3q) The compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) according to the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides to give 3q (yellow oil, 15.0 mg, 60% yield).

[0234] 1 H NMR (600 MHz, chloroform-) d ) δ 9.51 (s, 1H), 7.17 (d, J = 3.6 Hz, 1H), 6.28(d, J= 3.6 Hz, 1H), 3.33 – 3.27 (m, 1H), 2.37 – 2.34 (m, 1H), 2.13 – 2.11 (m,1H), 1.89 – 1.82 (m, 2H), 1.69 – 1.62 (m, 4H), 1.35 – 1.28 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.2, 177.3, 166.1, 164.9, 151.9, 107.8, 125.5, 53.6, 41.8, 40.5, 38.3, 35.9, 31.6, 19.1, 14.6. The NMR data matched the reported data (29).

[0235] Absolute stereochemistry is specified by analogy with compound 6z.

[0236] (1 R ,3 S 3-(5-acetylthiophene-2-yl)-1-propylcyclopentane-1-carboxylic acid (3r) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3r (yellow oil, 17.1 mg, 61% yield, 91% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (15% IPA / CO2, 2.0 mL / min), with retention times of 9.989 min (major) and 13.535 min (minor).

[0237] 1 H NMR (600 MHz, chloroform-) d ) δ 7.53 (d, J = 3.8 Hz, 1H), 6.87 (d, J = 3.8 Hz, 1H), 3.38 (tt, J = 10.5, 7.3 Hz, 1H), 2.51 (s, 3H), 2.41 (ddd, J = 13.4, 7.8, 2.6Hz, 1H), 2.29 (dd, J= 13.6, 10.3 Hz, 1H), 2.23 – 2.13 (m, 2H), 1.89 – 1.75 (m,1H), 1.75 – 1.58 (m, 3H), 1.40 – 1.27 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 190.7, 183.4, 158.9, 141.9, 133.0, 124.5, 53.5, 43.9, 42.0, 40.8, 36.2, 35.3, 26.6, 19.0, 14.6. The NMR data matched the reported data (29).

[0238] Absolute stereochemistry is specified by analogy with compound 6z.

[0239] (1 R ,3 S 3-(2-chloropyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid (3S) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3s (yellow oil, 18.4 mg, 69% yield, >99% ee). Enantiomer purity was determined by SFC on a Chiralpak IC column (20% IPA / CO2, 2.0 mL / min) at a retention time of 4.554 min (major).

[0240] 1 H NMR (600 MHz, chloroform-) d ) δ 8.31 (d, J = 5.2 Hz, 1H), 7.25 – 7.24 (m,1H), 7.16 (d, J = 5.1 Hz, 1H), 3.13 (tt, J = 10.5, 7.5 Hz, 1H), 2.43 (ddd, J =13.0, 7.1, 2.4 Hz, 1H), 2.25 (dd, J= 13.6, 10.3 Hz, 1H), 2.17 – 2.01 (m, 2H), 1.84 – 1.61 (m, 4H), 1.43 – 1.29 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151MHz, chloroform-) d ) δ 183.2, 158.2, 151.4, 149.2, 123.4, 121.8, 53.8, 44.2, 42.3, 41.9, 36.7, 33.8, 19.2, 14.6. The NMR data matched the reported data (29).

[0241] Absolute stereochemistry is specified by analogy with compound 6z.

[0242] (1 R ,3 S 3-(2-bromopyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid (3t) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3t (yellow oil, 24.3 mg, 78% yield, 99% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (20% IPA / CO2, 2.0 mL / min) at a retention time of 5.258 min (major).

[0243] 1 H NMR (600 MHz, chloroform-) d ) δ 8.28 (d, J = 5.2 Hz, 1H), 7.40 – 7.39 (m,1H), 7.18 (dd, J = 5.1, 1.5 Hz, 1H), 3.10 (tt, J = 10.5, 7.5 Hz, 1H), 2.43 (ddd, J = 13.1, 7.1, 2.4 Hz, 1H), 2.24 (dd, J= 13.6, 10.3 Hz, 1H), 2.18 – 1.98 (m,2H), 1.86 – 1.57 (m, 4H), 1.45 – 1.29 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.2, 157.8, 149.8, 142.1, 127.2, 122.1, 53.8, 44.1, 42.3, 41.9, 36.7, 33.8, 19.1, 14.6. The NMR data matched the reported data (29).

[0244] Absolute stereochemistry is specified by analogy with compound 6z.

[0245] (1 R ,3 S 3-(2,6-dichloropyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid (3u) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3u (yellow oil, 10.0 mg, 63% yield, 85% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 11.133 min (major) and 15.444 min (minor).

[0246] 1 H NMR (600 MHz, chloroform-) d ) δ 7.15 (s, 2H), 3.10 (tt, J = 10.5, 7.3 Hz,1H), 2.43 (ddd, J = 12.9, 7.0, 3.1 Hz, 1H), 2.23 (dd, J = 13.6, 10.3 Hz, 1H),2.15 – 2.09 (m, 2H), 1.77 – 1.65 (m, 4H), 1.44 – 1.28 (m, 2H), 0.94 (t, J = 7.3Hz, 3H). 13C NMR (151 MHz, chloroform-) d ) δ 183.0, 160.0, 150.7, 121.9, 53.7, 44.0, 42.1, 41.9, 36.6, 33.7, 19.1, 14.6. The NMR data matched the reported data (29).

[0247] Absolute stereochemistry is specified by analogy with compound 6z.

[0248] (1 R ,3 S 1-Propyl-3-(pyridin-4-yl)cyclopentane-1-carboxylic acid (3v) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3v (yellow oil, 9.6 mg, 41% yield, 92% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (20% IPA / CO2, 1.0 mL / min) with retention times of 10.366 min (major) and 20.266 min (minor).

[0249] 1 H NMR (600 MHz, chloroform-) d ) δ 8.57 (d, J = 5.3 Hz, 2H), 7.49 (d, J = 5.7 Hz,2H), 3.28 – 3.20 (m, 1H), 2.46 (ddd, J = 12.9, 6.8, 2.4 Hz, 1H), 2.38 (dd, J =13.6, 9.3 Hz, 1H), 2.18 – 2.10 (m, 2H), 1.89 – 1.60 (m, 4H), 1.44 – 1.29 (m,2H), 0.93 (t, J = 7.2 Hz, 2H). 13 C NMR (151 MHz, chloroform-) d ) δ 181.2, 147.8, 145.8, 124.2, 60.6, 54.4, 44.8, 42.2, 37.4, 34.3, 19.4, 14.7. The NMR data matched the reported data (29).

[0250] Absolute stereochemistry is specified by analogy with compound 6z.

[0251] (1 R ,3 S 3-(2-Methylbenzo[d]thiazo-6-yl)-1-propylcyclopentane-1-carboxylic acid (3w) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3 w (yellow oil, 23 mg, 76% yield, 82% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AS column (15% IPA / CO2, 2.0 mL / min) with retention times of 3.382 min (minor) and 4.032 min (major).

[0252] 1 H NMR (600 MHz, chloroform-) d ) δ 8.01 (d, J = 8.5 Hz, 1H), 7.76 – 7.74 (m,1H), 7.44 (dd, J = 8.5, 1.7 Hz, 1H), 3.28 (tt, J = 10.8, 7.4 Hz, 1H), 2.98 (s,3H), 2.45 (ddd, J = 13.2, 7.6, 2.4 Hz, 1H), 2.29 (dd, J = 13.6, 10.6 Hz, 1H),2.22 – 2.07 (m, 2H), 1.94 – 1.61 (m, 4H), 1.48 – 1.30 (m, 2H), 0.95 (t, J = 7.3Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 182.5, 166.7, 151.9, 143.5, 135.8, 127.2,121.1, 119.7, 53.6, 45.1, 43.7, 42.1, 36.7, 34.9, 19.2, 14.7. The NMR data matched the reported data (29).

[0253] Absolute stereochemistry is specified by analogy with compound 6z.

[0254] (1 R ,3 S 3-(1-Methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid (3x) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 3x (yellow oil, 17.2 mg, 60% yield, 98% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min), with retention times of 11.569 min (minor) and 13.347 min (major).

[0255] 1 H NMR (600 MHz, chloroform-) d ) δ 7.95 (s, 1H), 7.60 – 7.59 (m, 1H), 7.48 –7.31 (m, 2H), 4.09 (s, 3H), 3.26 (tt, J = 11.1, 7.3 Hz, 1H), 2.45 (ddd, J = 13.1,7.8, 2.4 Hz, 1H), 2.29 (dd, J = 13.5, 10.9 Hz, 1H), 2.21 – 2.01 (m, 2H), 1.88 –1.63 (m, 4H), 1.40 – 1.33 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.9, 139.1, 137.4, 132.0, 127.3, 123.9, 118.6, 109.1, 53.5, 45.0,44.0, 42.2, 36.5, 35.6, 35.0, 19.1, 14.7.

[0256] Absolute stereochemistry is specified by analogy with compound 6z.

[0257] (1 R ,3 S )-1-propyl-3-(1-toluenesulfonyl-1H-indol-5-yl)cyclopentane-1-carboxylic acid (3y) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 3y (yellow oil, 23.8 mg, 56% yield, 95% ee). Enantiomer purity was determined by SFC analysis, with retention times of 1.49 min (minor) and 2.06 min (major).

[0258] 1 H NMR (600 MHz, chloroform-) d ) δ 7.90 – 7.88 (m, 1H), 7.76 – 7.74 (m, 2H), 7.53 – 7.51 (m, 1H), 7.40 (s, 1H), 7.22 – 7.19 (m, 3H), 6.60 – 6.58 (m, 1H), 3.22 – 3.15 (m, 1H), 2.44 – 2.39 (m, 1H), 2.32 (s, 1H), 2.22 (dd, J = 13.5,10.8 Hz, 1H), 2.14 – 2.09 (m, 2H), 1.81 – 1.64 (m, 4H), 1.38 – 1.30 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 184.6, 145.0, 139.8, 135.5, 133.6, 131.0, 130.0, 126.9, 126.6, 124.3, 119.4, 113.5, 109.1. The NMR data matched the reported data (29).

[0259] Absolute stereochemistry is specified by analogy with compound 6z.

[0260] (1 R ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentane-1-carboxylic acid (4a) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give 4a (yellow oil, 15.2 mg, 58% yield, 76% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.036 min (minor) and 6.835 min (major).

[0261] 1 H NMR (600 MHz, chloroform-) d ) δ 7.98 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 3.92 (s, 3H), 3.29 (ddd, J = 10.9, 7.4, 3.6 Hz, 1H), 2.46 (ddd, J = 12.6,8.6, 3.2 Hz, 1H), 2.33 (dd, J = 12.8, 11.5 Hz, 1H), 2.19 (ddq, J = 13.4, 6.9,3.4, 2.8 Hz, 1H), 2.07 (dd, J = 12.7, 7.8 Hz, 1H), 1.89 (ddd, J = 21.1, 12.6,10.0 Hz, 1H), 1.69 (ddd, J = 13.2, 9.7, 7.4 Hz, 1H), 1.42 (s, 3H). 13 C NMR (151MHz, chloroform-) d ) δ 184.7, 167.1, 150.0, 129.8, 128.1, 127.2, 52.0, 48.8, 45.5, 45.0, 38.3, 34.5, 25.5. The NMR data matched the reported data (29).

[0262] Absolute stereochemistry is specified by analogy with compound 6z.

[0263] (1 R ,3 S)-1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid (4b) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give 4b (yellow oil, 18.8 mg, 68% yield, 92% ee). Enantiomer purity was determined by SFC analysis, with retention times of 0.93 min (minor) and 1.45 min (major).

[0264] 1 H NMR (600 MHz, chloroform-) d ) δ 7.96 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 3.90 (s, 3H), 3.23 – 3.11 (m, 1H), 2.42 (ddd, J = 13.2, 7.8, 2.3 Hz, 1H),2.24 (dd, J = 13.6, 11.0 Hz, 1H), 2.16 – 2.10 (m, 2H), 1.85 – 1.73 (m, 3H), 1.67 (ddd, J = 13.3, 10.9, 6.9 Hz, 1H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 183.7, 167.2, 150.2, 129.8, 128.2, 127.3, 54.0, 52.1, 45.1, 43.0, 36.1, 34.4, 32.4, 10.1. The NMR data matched the reported data (29).

[0265] Absolute stereochemistry is specified by analogy with compound 6z.

[0266] (1 R ,3 S 1-Benzyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid (4c) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to 4c (yellow oil, 13.9 mg, 41% yield, 80% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min), with retention times of 10.709 min (minor) and 11.781 min (major).

[0267] 1 H NMR (600 MHz, chloroform-) d ) δ 7.98 (d, J = 8.0 Hz, 2H), 7.36 – 7.19 (m,7H), 3.92 (s, 3H), 3.25 – 3.16 (m, 1H), 3.16 – 3.08 (m, 2H), 2.45 – 2.37 (m,1H), 2.33 – 2.23 (m, 2H), 2.222 – 2.15 (m, 1H), 1.92 – 1.78 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 183.1, 167.2, 150.1, 137.9, 129.9, 129.9, 128.4, 128.2, 127.2, 126.9, 54.7, 52.1, 44.8, 44.2, 42.7, 36.1, 34.1. The NMR data matched the reported data (29).

[0268] (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-phenylpropyl)cyclopentane-1-carboxylic acid (4d) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to 4d (yellow oil, 20.5 mg, 56% yield, 89% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min) with retention times of 10.310 min (major) and 15.072 min (minor). NMR data matched reported data (29).

[0269] 1 H NMR (600 MHz, chloroform-) d ) δ 7.96 (d, J = 8.2 Hz, 2H), δ 7.33 – 7.24 (m,4H), 7.22 – 7.11 (m, 3H), 3.90 (s, 3H), 3.25 – 2.97 (m, 1H), 2.65 (t, J = 7.6Hz, 2H), 2.42 (ddd, J = 13.1, 7.7, 1.9 Hz, 1H), 2.24 (dd, J = 13.4, 11.1 Hz, 1H), 2.14 – 2.06 (m, 2H), 1.88 – 1.74 (m, 3H), 1.72 – 1.61 (m, 3H). 13 C NMR (151MHz, chloroform-) d ) δ 184.0, 167.2, 150.1, 142.1, 129.8, 128.5, 128.2, 127.2, 126.0, 53.4, 52.1, 45.1, 43.4, 39.2, 36.5, 36.3, 34.4, 27.5. The NMR data matched the reported data (29).

[0270] Absolute stereochemistry is specified by analogy with compound 6z.

[0271] (1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cyclopentane-1-carboxylic acid (4f) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give 4f (yellow oil, 14.4 mg, 45% yield, 92% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min), with retention times of 11.746 min (minor) and 15.307 min (major).

[0272] 1 H NMR (600 MHz, chloroform-) d ) δ 7.82 (d, J= 8.2 Hz, 2H), 7.25 – 7.11 (m,2H), 3.77 (s, 3H), 3.28 (t, J = 6.3 Hz, 2H), 3.21 (s, 3H), 3.07 (td, J = 10.8,5.4 Hz, 1H), 2.38 – 2.24 (m, 1H), 2.13 (dd, J = 13.4, 11.1 Hz, 1H), 2.04 –1.94(m, 2H), 1.74 – 1.62 (m, 3H), 1.58 – 1.52 (m, 1H), 1.51 –1.43 (m, 2H). 13 C NMR (151 MHz, chloroform-) d δ 183.1, 167.2, 150.1, 129.8, 128.2, 127.3, 72.9, 58.7, 53.1, 52.1, 45.1, 43.5, 36.5, 36.2, 34.4, 26.0. The NMR data matched the reported data (29).

[0273] Absolute stereochemistry is specified by analogy with compound 6z.

[0274] (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentane-1-carboxylic acid (4h) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give a yellow oil (16.8 mg, 52% yield, 80% ee) after 4 h. Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min) with retention times of 11.230 min (major) and 19.576 min (minor).

[0275] 1 H NMR (600 MHz, chloroform-) d) δ 8.12 – 7.90 (m, 2H), 7.49 – 7.43 (m, 2H), 7.40 – 7.21 (m, 5H), 3.90 (s, 3H), 3.30 – 3.09 (m, 1H), 2.81 (td, J = 8.2, 3.8Hz, 1H), 2.74 – 2.64 (m, 2H), 2.45 – 2.27 (m, 1H), 2.24 – 2.11 (m, 1H), 1.88 – 1.76 (m, 1H). 13 C NMR (151 MHz, chloroform-) d ) δ 182.0, 167.2, 150.6, 142.5, 129.9, 128.7, 128.2, 127.3, 127.3, 126.9, 58.5, 52.1, 44.3, 43.7, 36.6, 33.6. The NMR data matched the reported data (29).

[0276] Absolute stereochemistry is specified by analogy with compound 6z.

[0277] (1 R ,3 S )-1-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid (4i) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give 4i (yellow oil, 19.3 mg, 54% yield, 81% ee). Enantiomer purity was determined by SFC analysis, with retention times of 1.06 min (minor) and 1.21 min (major).

[0278] 1 H NMR (600 MHz, chloroform-) d ) δ 7.99 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.7 Hz,2H), 7.37 – 7.33 (m, 4H), 3.93 (s, 3H), 3.22 (p, J = 9.4 Hz, 1H), 2.81 (ddd, J=11.9, 7.8, 3.7 Hz, 1H), 2.73 (dd, J = 13.6, 9.9 Hz, 1H), 2.66 (dd, J = 13.7, 8.8Hz, 1H), 2.33 – 2.19 (m, 2H), 1.86 (dq, J = 12.7, 9.0 Hz, 1H). 13 NMR (100 MHz, chloroform-) d ) δ 181.5, 167.2, 150.3, 141.0, 133.3, 129.9, 128.8, 128.4, 128.3, 127.3, 58.0, 52.2, 44.2, 43.7, 36.6, 33.5. The NMR data matched the reported data (29).

[0279] Absolute stereochemistry is specified by analogy with compound 6z.

[0280] Absolute stereochemistry is specified by analogy with compound 6z.

[0281] (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcycloheptane-1-carboxylic acid (4m) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to 4m (yellow oil, 16.9 mg, 53% yield, 99% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 5.816 min (major) and 6.984 min (minor).

[0282] 1 H NMR (600 MHz, chloroform-) d ) δ 7.95 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz,2H), 3.90 (s, 2H), 2.74 (s, 1H), 2.33 (td, J= 14.5, 9.4 Hz, 2H), 1.95 – 1.84(m, 2H), 1.81 – 1.73 (m, 1H), 1.71 – 1.56 (m, 3H), 1.54 – 1.36 (m, 3H), 1.30– 1.17 (m, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 183.72,167.23, 155.06, 130.10, 127.88, 126.60, 77.34, 77.13, 76.92, 52.11, 49.21,42.86, 42.06, 41.09, 39.23, 36.51, 30.71, 23.91, 18.18, 14.70. 13 C NMR (151MHz, CDCl3) δ 183.7, 167.2, 155.1, 130.1, 127.9, 126.6, 52.1, 49.2, 42.9, 42.1, 41.1, 39.2, 36.5, 30.7, 23.9, 18.2, 14.7. The NMR data matched the reported data (29).

[0283] Absolute stereochemistry is specified by analogy with compound 6z.

[0284] (1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cycloheptane-1-carboxylic acid (4n) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give 4n (yellow oil, 12.9 mg, 37% yield, >99% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) at a retention time of 14832 min (major).

[0285] 1 H NMR (600 MHz, chloroform-) d ) δ 7.95 (d, J = 8.3 Hz, 2H), 7.24 (d,J = 8.3 Hz,2H), 3.90 (s, 3H), 3.39 – 3.31 (m, 2H), 3.30 (s, 3H), 2.74 (t, J = 10.7 Hz, 1H), 2.34 (ddd, J = 14.4, 9.4, 4.2 Hz, 2H), 1.93 (d, J = 14.7 Hz, 2H), 1.72 –1.56 (m, 2H), 1.72 – 1.60 (m, 2H), 1.57 – 1.35 (m, 5H). 13 C NMR (151 MHz, CDCl3) δ 182.7, 167.2, 154.9, 130.1, 127.9, 126.6, 72.9, 58.6, 52.1, 48.8, 42.8, 41.0, 39.2, 36.5, 36.1, 30.7, 25.1, 23.8. The NMR data matched the reported data (29).

[0286] Absolute stereochemistry is specified by analogy with compound 6z.

[0287] (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclooctane-1-carboxylic acid (4o) Following the general procedure for the γ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to give 4n (yellow oil, 12.9 mg, 37% yield, >99% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min), with retention times of 12.380 min (major) and 13.456 min (minor).

[0288] 1 H NMR (600 MHz, chloroform-) d ) δ 7.95 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz,2H), 3.90 (s, 3H), 3.39 – 3.31 (m, 2H), 3.30 (s, 3H), 2.74 (t, J= 10.7 Hz, 1H), 2.34 (ddd, J = 14.4, 9.4, 4.2 Hz, 2H), 1.93 (d, J = 14.7 Hz, 2H), 1.72 –1.56 (m, 2H), 1.72 – 1.60 (m, 2H), 1.57 – 1.35 (m, 5H). 13 C NMR (151 MHz, CDCl3) δ 182.7, 167.2, 154.9, 130.1, 127.9, 126.6, 72.9, 58.6, 52.1, 48.8, 42.8, 41.0, 39.2, 36.5, 36.1, 30.7, 25.1, 23.8. The NMR data matched the reported data (29).

[0289] Absolute stereochemistry is specified by analogy with compound 6z.

[0290] 10. Characterization data of products obtained from δ-(hetero)arylation 2-((1 S ,3 R 3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid (6a) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6a (yellow oil, 17.9 mg, 65% yield, 91% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min), with retention times of 12.380 min (major) and 13.456 min (minor).

[0291] 1 H NMR (500 MHz, chloroform-) d ) δ 7.97 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 3.92 (s, 3H), 3.49 – 3.03 (m, 1H), 2.49 (s, 2H), 2.26 – 2.14 (m, 1H), 2.04 (dd, J = 12.7, 7.2 Hz, 1H), 1.92 (ddd,J = 13.1, 9.3, 4.9 Hz, 1H), 1.86 –1.76 (m, 1H), 1.78 – 1.64 (m, 1H), 1.24 (s, 3H). 13 C NMR (126 MHz, chloroform-) d ) δ177.98, 167.27, 151.42, 129.82, 127.96, 127.17, 52.10, 48.20, 46.87, 44.38,41.23, 39.46, 33.29, 27.03.

[0292] Absolute stereochemistry is specified by analogy with compound 6z.

[0293] 2-((1 S ,3 R 3-(4-cyanophenyl)-1-methylcyclopentyl)acetic acid (6b) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6b (yellow oil, 17.7 mg, 73% yield, 91% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 8.908 min (major) and 10.665 min (minor).

[0294] 1 H NMR (600 MHz, chloroform-) d ) δ 7.59 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.1 Hz,2H), 3.41 – 3.17 (m, 1H), 2.48 (s, 2H), 2.26 – 2.14 (m, 1H), 2.05 (dt, J =12.7, 6.4 Hz, 1H), 1.92 (ddd, J = 13.7, 9.2, 4.9 Hz, 1H), 1.81 – 1.59 (m, 3H), 1.24 (s, 3H). 13 C NMR (151 MHz, chloroform-) d) δ 178.60, 151.46, 132.21, 127.88,119.11, 109.67, 47.89, 46.81, 44.37, 41.15, 39.32, 33.14, 26.96.

[0295] C 15 H 18 NO2[M+H] + The calculated HRMS (ESI-TOF) value is 244.1332; the measured value is 244.1336.

[0296] Absolute stereochemistry is specified by analogy with compound 6z.

[0297] 2-((1 S ,3 R 1-Methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid (6c) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6c (yellow oil, 17.4 mg, 61% yield, 95% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 8.417 min (major) and 10.200 min (minor).

[0298] 1 H NMR (600 MHz, chloroform-) d ) δ 7.56 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.9 Hz,2H), 3.35 – 3.26 (m, 1H), 2.49 (s, 2H), 2.25 – 2.08 (m, 1H), 2.05 (dd, J =12.7, 7.3 Hz, 1H), 1.93 (ddd, J = 13.6, 9.3, 4.8 Hz, 1H), 1.84 – 1.66 (m, 3H), 1.25 (s, 3H). 13 C NMR (151 MHz, chloroform-) d) δ 177.50, 149.86, 128.23 (q, J = 126.4Hz), 127.35, 126.22 (q, J = 306.7 Hz), 125.25 (q, J = 3.7 Hz), 48.09, 46.67, 44.09, 41.10, 39.34, 33.25, 27.00. 19 F NMR (376 MHz, CDCl3) δ -64.96.

[0299] C 15 H 18 NO2[MH] - The calculated HRMS (ESI-TOF) value is 285.1102; the measured value is 285.1096.

[0300] Absolute stereochemistry is specified by analogy with compound 6z.

[0301] 2-((1S,3R)-1-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid (6d) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6d (yellow oil, 21.3 mg, 81% yield, 81% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 8.908 min (major) and 10.665 min (minor).

[0302] 1 H NMR (600 MHz, chloroform-) d ) δ 8.16 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz,1H), 3.46 – 3.21 (m, 1H), 2.50 (s, 1H), 2.29 – 2.18 (m, 1H), 2.07 (dd, J =12.7, 7.2 Hz, 1H), 1.94 (ddd, J= 13.8, 9.3, 4.9 Hz, 1H), 1.84 – 1.64 (m, 2H), 1.25 (s, 1H). 13 C NMR (151 MHz, chloroform-) d ) δ 178.22, 153.68, 146.31, 127.85,123.66, 47.95, 46.72, 44.22, 41.20, 39.31, 33.25, 26.98.

[0303] C 15 H 18 NO2[MH] - The calculated HRMS (ESI-TOF) value is 285.1102; the measured value is 285.1096.

[0304] Absolute stereochemistry is specified by analogy with compound 6z.

[0305] 2-((1 R ,3 S 3-(4-formylphenyl)-1-methylcyclopentyl)acetic acid (6e) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6e (yellow oil, 15.0 mg, 60% yield, 94% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min), with retention times of 8.534 min (major) and 10.771 min (minor).

[0306] 1 H NMR (600 MHz, chloroform-) d ) δ 9.99 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.42(d, J = 7.9 Hz, 2H), 3.44 – 3.21 (m, 1H), 2.50 (s, 2H), 2.22 (dt, J = 12.8, 6.4Hz, 1H), 2.06 (dd, J= 12.6, 7.2 Hz, 1H), 1.94 (ddd, J = 13.7, 9.4, 4.9 Hz, 1H), 1.86 – 1.66 (m, 3H), 1.25 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 192.06, 178.09, 153.32, 134.57, 129.99, 127.74, 48.04, 46.77, 44.50, 41.18, 39.38, 33.19, 26.94.

[0307] C 15 H 18 O3[M+H] + The calculated HRMS (ESI-TOF) value is 247.1334; the measured value is 247.1335.

[0308] Absolute stereochemistry is specified by analogy with compound 6z.

[0309] 2-((1 R ,3 S 3-(4-benzoylphenyl)-1-methylcyclopentyl)acetic acid (6f) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6f (yellow oil, 19.6 mg, 62% yield, 90% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min), with retention times of 7.155 min (major) and 10.785 min (minor).

[0310] 1 H NMR (600 MHz, chloroform-) d ) δ 7.82 (d, J = 7.1 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.37 (d, J= 8.1 Hz, 2H), 3.39 – 3.27 (m, 1H), 2.51 (s, 2H), 2.24 (dt, J = 8.8, 4.9 Hz, 1H), 2.08 (dd, J =12.6, 7.2 Hz, 1H), 1.95 (ddd, J = 13.5, 9.4, 4.8 Hz, 1H), 1.88 – 1.66 (m, 3H), 1.26 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 196.50, 177.85, 151.00, 137.91,135.33, 132.22, 130.42, 129.99, 128.23, 126.99, 48.15, 46.77, 44.32, 41.17,39.41, 33.25, 26.97.

[0311] C 21 H 22 O3[M+H] + The calculated HRMS (ESI-TOF) value is 323.1647; the measured value is 323.1648.

[0312] Absolute stereochemistry is specified by analogy with compound 6z.

[0313] 2-((1 R ,3 S 3-(4-acetylphenyl)-1-methylcyclopentyl)acetic acid (6g) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6 g (yellow oil, 15.9 mg, 61% yield, 91% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min), with retention times of 7.155 min (major) and 10.785 min (minor).

[0314] 1 H NMR (600 MHz, chloroform-) d ) δ 7.91 (d,J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz,2H), 3.36 – 3.26 (m, 1H), 2.60 (s, 3H), 2.49 (s, 2H), 2.26 – 2.18 (m, 1H),2.05 (dd, J = 12.7, 7.2 Hz, 1H), 1.93 (ddd, J = 13.4, 9.3, 4.9 Hz, 1H), 1.84 –1.61 (m, 3H), 1.25 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 197.98, 178.05, 151.67,135.11, 128.58, 127.26, 48.06, 46.80, 44.29, 41.15, 39.38, 33.21, 26.96,26.57.

[0315] C 21 H 22 O3[M+H] + The calculated HRMS (ESI-TOF) value is 261.1491; the measured value is 261.1487.

[0316] Absolute stereochemistry is specified by analogy with compound 6z.

[0317] 2-((1 R ,3 S 3-(4-fluorophenyl)-1-methylcyclopentyl)acetic acid (6h).

[0318] The compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, yielding 6 g (yellow oil, 15.6 mg, 66% yield, 84% ee). Enantiomer purity was determined by SFC analysis, with retention times of 6.65 min (minor) and 8.49 min (major).

[0319] 1 H NMR (600 MHz, chloroform-) d ) δ 7.26 – 7.16 (m, 2H), 6.99 (t, J= 8.7 Hz,2H), 3.31 – 3.11 (m, 1H), 2.48 (s, 2H), 2.22 – 2.10 (m, 1H), 2.01 (dd, J =12.7, 7.1 Hz, 1H), 1.91 (ddd, J = 13.5, 9.2, 4.7 Hz, 1H), 1.79 – 1.61 (m, 3H), 1.23 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 178.13, 161.21 (d, J = 244.62 Hz), 141.26 (d, J = 3.2 Hz), 128.31 (d, J = 7.7 Hz), 114.99 (d, J = 21.0 Hz), 48.43, 46.90, 43.53, 40.97, 39.33, 33.56, 27.10.

[0320] C 21 H 22 O3[M+H] + The calculated HRMS (ESI-TOF) value is 273.1603; the measured value is 273.1602.

[0321] Absolute stereochemistry is specified by analogy with compound 6z.

[0322] 2-((1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid (6i) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6i (yellow oil, 11.6 mg, 42% yield, 90% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.560 min (major) and 10.227 min (minor).

[0323] 1H NMR (600 MHz, chloroform-) d ) δ 7.93 (s, 1H), 7.90 – 7.84 (m, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 3.94 (s, 3H), 3.38 – 3.23 (m, 1H), 2.49 (s, 2H), 2.21 (ddt, J = 12.7, 7.8, 3.6 Hz, 1H), 2.05 (dd, J = 12.7, 7.1 Hz,1H), 1.93 (ddd, J = 13.7, 9.4, 4.8 Hz, 1H), 1.86 – 1.78 (m, 1H), 1.78 – 1.72(m, 1H), 1.69 (dt, J = 13.1, 7.8 Hz, 1H), 1.24 (s, 3H). 13 C NMR (151 MHz, chloroform-) d )δ 177.47, 167.35, 146.06, 131.76, 130.14, 128.38, 128.19, 127.23, 52.10,48.32, 46.79, 44.03, 41.05, 39.32, 33.26, 26.96.

[0324] C 21 H 22 O3[M+H] + The calculated HRMS (ESI-TOF) value is 277.1440, and the measured value is also 277.1440. Absolute stereochemistry is specified by analogy with compound 6z.

[0325] 2-((1 R ,3 S )-3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid (6j) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6j (yellow oil, 16.6 mg, 64% yield, 87% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.560 min (major) and 10.227 min (minor).

[0326] 1 H NMR (600 MHz, chloroform-) d ) δ 7.86 (t, J = 1.8 Hz, 1H), 7.79 (dt, J = 7.6, 1.4 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 3.37 – 3.24 (m,1H), 2.63 (s, 3H), 2.50 (s, 2H), 2.33 – 2.16 (m, 1H), 2.05 (dd, J = 12.8, 7.2Hz, 1H), 1.94 (ddd, J = 13.7, 9.4, 4.8 Hz, 1H), 1.85 – 1.58 (m, 3H), 1.25 (s, 3H).

[0327] Absolute stereochemistry is specified by analogy with compound 6z.

[0328] 2-((1R,3S)-3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid (6k) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6k (yellow oil, 15.6 mg, 64% yield, 88% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min), with retention times of 7.573 min (major) and 8.423 min (minor).

[0329] 1H NMR (600 MHz, chloroform-) d ) δ 7.54 (s, 1H), 7.51 – 7.47 (m, 2H), 7.40 (t, J = 7.7 Hz, 1H), 3.27 (p, J = 8.7 Hz, 1H), 2.49 (s, 2H), 2.22 (dt, J = 12.1, 6.2Hz, 1H), 2.05 (dd, J = 12.5, 7.1 Hz, 1H), 1.93 (ddd, J = 13.3, 9.1, 4.8 Hz, 1H), 1.82 – 1.66 (m, 3H), 1.24 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 178.1, 147.1,131.7, 130.7, 129.7, 129.1, 119.1, 112.3, 48.0, 46.8, 43.8, 41.1, 39.3, 33.2,27.0.

[0330] Absolute stereochemistry is specified by analogy with compound 6z.

[0331] 2-((1 R ,3 S 3-(3-formylphenyl)-1-methylcyclopentyl)acetic acid (6l) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6 μL (yellow oil, 14.8 mg, 60% yield, 85% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 5.580 min (major) and 7.173 min (minor).

[0332] 1 H NMR (600 MHz, chloroform-) d ) δ 10.02 (s, 1H), 7.78 (s, 1H), 7.72 (d, J = 7.5Hz, 1H), 7.53 (d, J= 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 3.38 – 3.30 (m, 1H), 2.50 (s, 2H), 2.28 – 2.19 (m, 1H), 2.07 (dd, J = 12.7, 7.2 Hz, 1H), 1.94 (ddd, J = 13.6, 9.4, 4.8 Hz, 1H), 1.86 – 1.65 (m, 3H), 1.25 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 192.67, 177.19, 146.85, 136.54, 133.47, 129.01, 127.92, 127.87,48.19, 46.67, 43.95, 41.08, 39.33, 33.26, 27.00.

[0333] Absolute stereochemistry is specified by analogy with compound 6z.

[0334] 2-((1 R ,3 S 1-Methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid (6m) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6 L (yellow oil, 14.8 mg, 60% yield, 85% ee). Enantiomer purity was determined by SFC analysis, with retention times of 6.65 min (minor) and 7.173 min (major).

[0335] 1 H NMR (600 MHz, chloroform-) d ) δ 7.50 (s, 1H), 7.47 – 7.38 (m, 3H), 3.36 –3.27 (m, 1H), 2.50 (s, 2H), 2.27 – 2.17 (m, 1H), 2.06 (dd, J = 12.7, 7.2 Hz,1H), 1.93 (ddd, J= 13.7, 9.4, 4.8 Hz, 1H), 1.83 – 1.66 (m, 3H), 1.25 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 178.15, 146.61, 130.90, 130.59 (q, J = 31.71 Hz), 130.43 (q, J = 1.51 Hz), δ 123.80 (q, J = 4.0 Hz), 124.30 (q, J = 271.8 Hz), 122.78(q, J = 4.1 Hz), 48.19, 46.85, 44.05, 41.06, 39.30, 33.24, 26.97.

[0336] Absolute stereochemistry is specified by analogy with compound 6z.

[0337] 2-((1 R ,3 S 3-(2-cyanophenyl)-1-methylcyclopentyl)acetic acid (6n) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6n (yellow oil, 14.6 mg, 60% yield, 85% ee). Enantiomer purity was determined by SFC analysis, with retention times of 4.909 min (major) and 5.491 min (minor).

[0338] 1 H NMR (600 MHz, chloroform-) d ) δ 7.65 – 7.60 (m, 1H), 7.58 – 7.52 (m, 1H),7.48 – 7.39 (m, 1H), 7.33 – 7.26 (m, 1H), 3.73 – 3.61 (m, 1H), 2.51 (s, 2H),2.34 – 2.23 (m, 1H), 2.10 (dd, J = 12.5, 7.1 Hz, 1H), 1.96 (dq, J= 13.8, 5.3 Hz,1H), 1.85 – 1.70 (m, 3H), 1.27 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 177.98,149.56, 133.06, 132.93, 126.66, 126.46, 118.30, 112.25, 47.60, 46.67, 42.56,41.36, 39.40, 32.95, 26.80.

[0339] Absolute stereochemistry is specified by analogy with compound 6z.

[0340] 2-((1 R ,3 S )-3-(5-formylfuran-2-yl)-1-methylcyclopentyl)acetic acid (6o) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6n (yellow oil, 16.3 mg, 60% yield, 88% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 6.940 min (major) and 7.556 min (minor).

[0341] 1 H NMR (600 MHz, chloroform-) d ) δ 9.53 (s, 1H), 7.19 (d, J = 3.5 Hz, 1H), 6.27(d, J = 3.5 Hz, 1H), 3.47 – 3.31 (m, 1H), 2.47 (s, 2H), 2.26 – 2.15 (m, 1H), 2.06 (dd, J = 12.9, 7.7 Hz, 1H), 1.94 – 1.80 (m, 3H), 1.65 (dd, J = 13.3, 6.6 Hz, 1H), 1.20 (s, 3H). 13 C NMR (151 MHz, chloroform-) d) δ 177.96, 177.12, 166.90, 151.79, 107.44, 46.32, 44.91, 41.22, 38.87, 37.68, 30.42, 26.26.

[0342] Absolute stereochemistry is specified by analogy with compound 6z.

[0343] 2-((1R,3S)-3-(5-acetylthiophen-2-yl)-1-methylcyclopentyl)acetic acid (6p) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6p (yellow oil, 12.5 mg, 47% yield, 87% ee). Enantiomer purity was determined by SFC analysis, with retention times of 3.36 min (minor) and 3.78 min (major).

[0344] 1 H NMR (600 MHz, chloroform-) d ) δ 7.55 (d, J = 3.7 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 3.50 (p, J = 9.4, 8.7 Hz, 1H), 2.53 (s, 3H), 2.47 (s, 2H), 2.27 (dq, J =12.6, 7.7, 6.1 Hz, 1H), 2.12 (dd, J = 12.5, 7.3 Hz, 1H), 1.97 – 1.89 (m, 1H), 1.87 – 1.75 (m, 2H), 1.71 – 1.63 (m, 1H), 1.22 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 190.63, 177.67, 160.27, 141.59, 132.87, 124.24, 48.68, 46.59, 41.13,40.23, 39.06, 34.27, 26.87, 26.48.

[0345] Absolute stereochemistry is specified by analogy with compound 6z.

[0346] 2-((1R,3S)-3-(2-chloropyridin-4-yl)-1-methylcyclopentyl)acetic acid (6q) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6q (yellow oil, 15.2 mg, 60% yield, 88% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 10.849 min (major) and 14.545 min (minor).

[0347] 1 H NMR (600 MHz, chloroform-) d ) δ 8.29 (d, J = 5.2 Hz, 1H), 7.22 (s, 1H), 7.12– 7.09 (m, 1H), 3.31 – 3.14 (m, 1H), 2.49 (s, 2H), 2.25 – 2.18 (m, 1H), 2.05(dd, J = 12.8, 7.3 Hz, 1H), 1.92 (ddd, J = 13.8, 9.2, 5.0 Hz, 1H), 1.82 – 1.66 (m, 3H), 1.23 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 176.93, 158.47, 151.57,149.40, 122.94, 121.46, 47.13, 46.48, 43.36, 41.16, 39.18, 32.49, 26.89.

[0348] Absolute stereochemistry is specified by analogy with compound 6z.

[0349] 2-((1R,3S)-1-methyl-3-(1-toluenesulfonyl-1H-indol-5-yl)cyclopentyl)acetic acid (6r) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6q (yellow oil, 18.5 mg, 45% yield, 92% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (30% IPA / CO2, 2.0 mL / min), with retention times of 11.524 min (major) and 17.492 min (minor).

[0350] 1 H NMR (600 MHz, chloroform-) d ) δ 7.91 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 3.6 Hz, 1H), 7.39 (s, 1H), 7.24 – 7.20 (m, 3H), 6.61 (d, J =3.6 Hz, 1H), 3.36 – 3.26 (m, 1H), 2.48 (s, 2H), 2.35 (s, 3H), 2.18 (ddt, J =12.6, 7.8, 3.6 Hz, 1H), 2.02 (dd, J = 12.7, 7.1 Hz, 1H), 1.91 (ddd, J = 13.5,9.3, 4.7 Hz, 1H), 1.82 – 1.77 (m, 1H), 1.77 – 1.71 (m, 1H), 1.67 (dt, J = 13.0,7.8 Hz, 1H), 1.23 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 178.21, 144.82, 140.84,135.39, 133.32, 130.90, 129.86, 126.82, 126.44, 124.15, 119.16, 113.31,108.97, 48.67, 46.94, 44.10, 41.01, 39.41, 33.71, 27.08, 21.57.

[0351] Absolute stereochemistry is specified by analogy with compound 6z.

[0352] 2-((1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-methylcyclopentyl)acetic acid (6S) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6s (yellow oil, 18.7 mg, 65% yield, 80% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min), with retention times of 7.231 min (major) and 8.341 min (minor).

[0353] 1 H NMR (600 MHz, chloroform-) d ) δ 7.14 (s, 1H), 3.29 – 3.09 (m, 1H), 2.49 (s, 2H), 2.25 – 2.19 (m, 1H), 2.06 (dd, J = 12.7, 7.2 Hz, 1H), 1.91 (ddd, J = 13.9,9.0, 5.1 Hz, 1H), 1.81 – 1.66 (m, 3H), 1.22 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ177.77, 160.91, 150.52, 121.67, 47.00, 46.47, 43.24, 41.15, 39.09, 32.35,26.81.

[0354] Absolute stereochemistry is specified by analogy with compound 6z.

[0355] 2-((1 R ,3 S )-3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-methylcyclopentyl)acetic acid (6t) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6t (yellow oil, 27.3 mg, 85% yield, 71% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (5% IPA / CO2, 2.0 mL / min), with retention times of 7.966 min (major) and 8.778 min (minor).

[0356] 1 H NMR (600 MHz, chloroform-) d ) δ 7.48 (s, 1H), 7.39 (s, 1H), 3.40 – 3.14 (m,1H), 2.51 (s, 2H), 2.33 – 2.22 (m, 1H), 2.10 (dd, J = 12.7, 7.2 Hz, 1H), 1.94(ddd, J = 13.9, 9.2, 5.0 Hz, 1H), 1.85 – 1.67 (m, 3H), 1.24 (s, 3H). 13 C NMR (151MHz, CDCl3) δ 177.89, 160.16, 152.10, 148.22 (q, J = 35.4 Hz), 125.83, 120.81(q, J = 274.4 Hz). 118.27 (q, J = 2.7 Hz), 47.05, 46.45, 43.49, 41.21, 39.09, 32.47, 26.86.

[0357] Absolute stereochemistry is specified by analogy with compound 6z.

[0358] 2-((1 R ,3 S 1-Methyl-3-(2-methylbenzo[d]thiazo-6-yl)cyclopentyl)acetic acid (6u) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6u (yellow oil, 17.9 mg, 62% yield, 90% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (15% IPA / CO2, 2.0 mL / min), with retention times of 7.966 min (major) and 8.778 min (minor).

[0359] 1 H NMR (600 MHz, chloroform-) d ) δ 7.88 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.35(dd, J = 8.4, 1.5 Hz, 1H), 3.42 – 3.30 (m, 1H), 2.84 (s, 3H), 2.51 (s, 2H), 2.29 – 2.19 (m, 1H), 2.07 (dd, J = 12.5, 7.3 Hz, 1H), 1.96 (ddd, J = 13.4, 9.4,4.7 Hz, 1H), 1.88 – 1.78 (m, 2H), 1.70 (dt, J = 13.1, 7.8 Hz, 1H), 1.26 (s, 3H). 13 C NMR (151 MHz, chloroform-) d ) δ 177.06, 166.39, 151.63, 142.74, 135.73, 125.57,121.95, 119.23,48.48, 46.81, 44.27, 41.07, 39.36, 35.52, 33.74, 27.19, 20.02.

[0360] Absolute stereochemistry is specified by analogy with compound 6z.

[0361] 2-((1 R ,3 S )-1-Methyl-3-(1-methyl-1H-indazol-5-yl)cyclopentyl)acetic acid (6v) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6v (yellow oil, 13.3 mg, 49% yield, 82% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (20% IPA / CO2, 2.0 mL / min), with retention times of 7.966 min (major) and 8.778 min (minor).

[0362] 1 H NMR (600 MHz, chloroform-) d ) δ 7.93 (s, 1H), 7.58 (s, 1H), 7.36 – 7.31 (m,2H), 4.07 (s, 3H), 3.42 – 3.28 (m, 1H), 2.51 (s, 2H), 2.23 (dt, J = 8.5, 4.8Hz, 1H), 2.07 (dd, J = 13.1, 6.7 Hz, 1H), 1.95 (ddd, J = 13.5, 9.3, 4.7 Hz, 1H),1.88 – 1.76 (m, 2H), 1.70 (dt, J = 13.0, 7.8 Hz, 1H), 1.27 (s, 3H). 13 C NMR (151MHz, chloroform-) d ) δ 177.63, 138.91, 137.89, 132.32, 126.57, 124.15, 118.08, 108.84,48.62, 46.95, 44.14, 41.02, 39.41, 35.51, 33.77, 27.17.

[0363] Absolute stereochemistry is specified by analogy with compound 6z.

[0364] 2-((1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid (6w) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6v (yellow oil, 9.3 mg, 32% yield, 93% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak AD column (20% IPA / CO2, 2.0 mL / min), with retention times of 7.966 min (major) and 8.778 min (minor).

[0365] 1 H NMR (600 MHz, chloroform-) d ) δ 7.97 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz,2H), 3.92 (s, 3H), 3.23 – 3.12 (m, 1H), 2.51 – 2.43 (m, 2H), 2.17 – 2.04 (m,2H), 1.88 (ddd, J = 12.2, 8.1, 3.4 Hz, 1H), 1.82 – 1.76 (m, 1H), 1.75 – 1.68(m, 2H), 1.66 – 1.57 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0366] 13 C NMR (151 MHz, chloroform-) d ) δ 177.46, 167.16, 151.05, 129.69, 127.86,127.07, 51.99, 45.60, 44.80, 44.51, 43.09, 37.30, 33.40, 31.95, 9.04.

[0367] Absolute stereochemistry is specified by analogy with compound 6z.

[0368] 2-((1 R ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentyl)acetic acid (6x) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6v (yellow oil, 14.6 mg, 48% yield, 90% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min), with retention times of 13.998 min (major) and 15.087 min (minor).

[0369] 1 H NMR (600 MHz, chloroform-) d ) δ 7.97 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz,2H), 3.92 (s, 3H), 3.30 – 3.15 (m, 1H), 2.53 – 2.43 (m, 2H), 2.20 – 2.04 (m,2H), 1.88 (dd, J = 14.2, 6.7 Hz, 1H), 1.89 – 1.66 (m, 3H), 1.62 – 1.46 (m, 2H), 1.44 – 1.35 (m, 2H), 0.97 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 177.75,167.17, 151.07, 129.69, 127.86, 127.07, 52.00, 46.06, 44.82, 44.27, 43.73,42.18, 37.77, 33.41, 17.93, 14.83.

[0370] Absolute stereochemistry is specified by analogy with compound 6z.

[0371] 2-((1 R ,3 S 3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid (6y) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to give 6y (yellow oil, 6.6 mg, 25% yield, 65% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min) with retention times of 11.047 min (minor) and 12.582 min (major).

[0372] 1 H NMR (600 MHz, chloroform-) d ) δ 7.98 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 3.93 (s, 3H), 3.23 – 3.12 (m, 1H), 2.50 (s, 3H), 2.37 (dd, J = 12.2, 5.8Hz, 1H), 2.17 (dd, J = 12.8, 5.2 Hz, 1H), 2.11 – 2.06 (m, 1H) 1.81 – 1.71 (m,1H), 1.57 – 1.49 (m, 1H), 1.41 – 1.33 (m, 1H).

[0373] Absolute stereochemistry is specified by analogy with compound 6z.

[0374] 2-((1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentyl)acetic acid (6z) Following the general procedure for the δ-(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to 6 z (white solid, 10.8 mg, 25% yield, 65% ee). Enantiomer purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min) with retention times of 12.217 min (major) and 13.735 min (minor).

[0375] 1 H NMR (600 MHz, chloroform-) d) δ 7.98 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 7.3 Hz, 11H), 3.93 (s, 3H), 3.15 (p, J = 8.3 Hz, 1H), 2.88 – 2.75 (m, 3H), 2.51 (dd, J = 11.5, 6.9 Hz, 1H), 2.19 (tt, J = 9.8, 4.8 Hz, 1H), 2.02 (dd, J = 13.0, 11.4 Hz, 1H),1.93 – 1.79 (m, 1H). 13 C NMR (126 MHz, chloroform-) d ) δ 184.50, 167.13, 150.05, 129.90,129.77, 128.11, 127.17, 125.30, 52.02, 48.80, 45.48, 45.00, 38.25, 34.46,25.52.

[0376] 11. Characterization data of products obtained from γ-di(hetero)arylation (1 R ,3 S 4 R )-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid (7a) The compound was purified by pTLC (25% EtOAc / hexane + 1% formic acid) according to the general procedure for the γ-di(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides to give 7a (yellow oil, 19.4 mg, 49% yield).

[0377] 1 H NMR (600 MHz, chloroform-) d ) δ 7.76 (d, J = 8.3 Hz, 2H), 6.94 (d, J= 8.3 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H), 3.71 (s,3H), 3.70 – 3.64 (m, 2H), 2.74 (dd, J = 13.8, 7.8 Hz, 1H), 2.69 (dd, J = 13.9,7.6 Hz, 1H), 2.447 – 2.18 (m, 2H), 1.94 – 1.85 (m, 2H), 1.53 – 1.39 (m, 2H),1.02 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 182.9, 167.2, 157.8, 147.2,132.9, 129.3, 128.9, 128.5, 127.6, 113.1, 55.1, 52.2, 51.9, 49.3, 48.5, 42.2, 40.2, 39.4, 19.0, 14.5.

[0378] (1 S ,3 R 4 S 3-(4-methoxyphenyl)-4-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid (7b) Following the general procedure for the γ-di(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides, the compound was purified by pTLC (25% EtOAc / hexane + 1% formic acid) to give 7b (yellow oil, 29.0 mg, 74% yield).

[0379] 1 H NMR (600 MHz, chloroform-) d ) δ 7.85 (s, 1H), 7.29 (d, J = 9.7 Hz, 1H), 7.07(d, J = 8.7 Hz, 1H), 6.84 (dd, J = 8.7, 1.4 Hz, 1H), 6.76 (d, J = 8.7 Hz, 2H), 6.580 (d, J= 8.7 Hz, 2H), 4.02 (s, 3H), 3.76 (q, J = 8.1 Hz, 1H), 3.69 (s, 3H), 3.68 – 3.63 (m, 1H), 2.79 (dd, J = 13.8, 8.7 Hz, 1H), 2.74 (dd, J = 13.9, 8.3 Hz,1H), 2.27 – 2.23 (m, 1H), 2.23 – 2.20 (m, 1H), 1.96 – 1.92 (m, 2H), 1.48 (dq, J = 14.9, 7.4 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H).

[0380] (1 S ,3 S 4 R )-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid (7d) The compound was purified by pTLC (25% EtOAc / hexane + 1% formic acid) following the general procedure for the γ-di(hetero)arylation of cyclic fatty acids and (hetero)aryl iodides to give 7d (yellow oil, 11.2 mg, 30% yield).

[0381] 1 H NMR (600 MHz, chloroform-) d ) δ 8.08 (d, J = 5.2 Hz, 1H), 6.87 (s, 1H), 6.79(d, J = 8.7 Hz, 2H), 6.71 (dd, J = 5.2, 1.2 Hz, 2H), 6.69 – 6.67 (m, 2H), 3.74(s, 3H), 3.70 (q, J = 8.4 Hz, 1H), 3.58 (q, J = 7.9 Hz, 1H), 2.70 (dd, J = 14.1, 8.1 Hz, 1H), 2.64 (dd, J= 14.0, 9.1 Hz, 1H), 2.26 – 2.18 (m, 3H), 1.95 – 1.82(m, 3H), 1.45 (dq, J = 15.1, 7.3 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H).

[0382] For purposes of clarity and understanding, the foregoing disclosure has been described in detail to a certain extent by way of example and embodiments. It will be apparent to those skilled in the art that variations and modifications can be made within the scope of the appended claims. Therefore, it is to be understood that the foregoing description is intended to be illustrative and not restrictive. Consequently, the scope of this disclosure should not be determined by reference to the foregoing description, but rather by reference to the following appended claims and the full scope of their equivalents.

[0383] This application references various granted patents, published patent applications, journal articles and other publications, each of which is incorporated herein by reference.

Claims

1. A method for enantioselective long-range γ-CH arylation or heteroarylation, δ-CH arylation or heteroarylation, or sequential γ-methyleneCH arylation or heteroarylation of free cycloalkane carboxylic acids, said method comprising using a palladium catalyst having a chiral oxazoline-pyridone ligand.

2. The method of claim 1, comprising the steps of: reaction i) for γ-CH arylation or heteroarylation; reaction ii) for δ-CH arylation or heteroarylation; and reaction iii) for sequential γ-methyleneCH arylation or heteroarylation. i) ； ii) ;and iii) in Each R 1 Independently H, (C1-C6)alkyl, (C6-C 10 )Aryl, Bn, (C1-C6)alkyl (C6-C 10 aryl, -O-(C1-C6)alkyl, (C1-C6)alkyl-O-(C1-C6)alkyl, halo(C1-C6)alkyl, hetero(C1-C6)alkyl or (C1-C6)alkyl-C(=O)O(C1-C6)alkyl, wherein each alkyl and aryl group is optionally surrounded by one or more R 1’ replace; Each R 1’ It can be independently a halogen, (C1-C6)alkyl, -O-(C1-C6)alkyl, or -C(=O)O(C1-C6)alkyl; Each Ar is independently, optionally by one or more Rs 2 Replacement (C6-C) 10 ) aryl or (C5-C 14 ) heteroaryl; Each R 2 Independently, it is a halogen, (C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, NO2, CN, -O(C1-C6)alkyl, -C(=O)H, -C(=O)(C1-C6)alkyl, CF3, or Ts; and n is 1, 2, 3 or 4; This includes its enantiomers, non-racemic or racemic mixtures, and pharmaceutically acceptable salts.

3. The method of claim 1 or claim 2, wherein the ligand (L) is selected from the group consisting of: 。 4. The method of claim 2, wherein the ligand (L) is .

5. The method of claim 2, wherein the ligand (L) is .

6. The method according to any one of claims 1-5, wherein R 1 It is a (C1-C6) alkyl group.

7. The method of claim 6, wherein R 1 yes n Pr or Me.

8. The method according to any one of claims 1-5, wherein R 1 Ph is an optional substitution.

9. The method according to any one of claims 1-5, wherein R 1 It is Bn that can be substituted arbitrarily.

10. The method according to any one of claims 1-5, wherein R 1 It is an optionally substituted (C1-C6) alkyl (C6-C 10 Aryl.

11. The method according to any one of claims 1-5, wherein R 1 It is an optional substituted -O-(C1-C6) alkyl group.

12. The method according to any one of claims 1-5, wherein R 1 It is an optional substituted (C1-C6)alkyl-O-(C1-C6)alkyl.

13. The method according to any one of claims 1-5, wherein R 1 It is an optionally substituted haloalkyl (C1-C6).

14. The method according to any one of claims 1-5, wherein R 1 It is an optionally substituted hetero(C1-C6) alkyl group.

15. The method according to any one of claims 1-5, wherein R 1 It is an optional substituted (C1-C6)alkyl-C(=O)O(C1-C6)alkyl.

16. The method of any one of claims 1-15, wherein Ar is an optionally substituted phenyl group.

17. The method according to any one of claims 1-15, wherein Ar is optionally substituted (C5-C) 10 ) Mixed aromatic compounds.

18. The method of claim 16 or claim 17, wherein R 2 It is a halogen group.

19. The method of claim 16 or claim 17, wherein R 2 It is a (C1-C6) alkyl group.

20. The method of claim 16 or claim 17, wherein R 2 It is a -C(=O)O(C1-C6) alkyl group.

21. The method of claim 16 or claim 17, wherein R 2 It's NO2.

22. The method of claim 16 or claim 17, wherein R 2 It's CN.

23. The method of claim 16 or claim 17, wherein R 2 It is an -O(C1-C6) alkyl group.

24. The method of claim 16 or claim 17, wherein R 2 It is -C(=O)H.

25. The method of claim 16 or claim 17, wherein R 2 It is a -C(=O)(C1-C6) alkyl group.

26. The method of claim 16 or claim 17, wherein R 2 It's CF3.

27. The method of claim 16 or claim 17, wherein R 2 It's Ts.

28. The method of any one of claims 1-27, wherein n is 1.

29. The method of any one of claims 1-27, wherein n is 2.

30. The method of any one of claims 1-27, wherein n is 3.

31. The method of any one of claims 1-27, wherein n is 4.

32. The method according to any one of claims 1-31, wherein the base is KH2PO4.

33. The method according to any one of claims 1-31, wherein the base is NaH2PO4.

34. The method according to any one of claims 1-31, wherein the base is K2HPO4.

35. The method according to any one of claims 1-31, wherein the base is Na2CO3.

36. The method according to any one of claims 1-31, wherein the base is Na2HPO4•2H2O.

37. The method according to any one of claims 1-31, wherein the base is NaHCO3.

38. The method according to any one of claims 1-31, wherein the base is Na2HPO4.

39. The method according to any one of claims 1-31, wherein the base is Na3PO4.

40. The method according to any one of claims 1-31, wherein the base is Na2HPO4•7H2O.

41. The method according to any one of claims 1-31, wherein the base is Li2CO3.

42. The method according to any one of claims 1-31, wherein the base is NaOAc.

43. The method according to any one of claims 1-31, wherein the base is K2CO3.

44. The method according to any one of claims 1-31, wherein the base is Cs2CO3.

45. The method of any one of claims 1-44, wherein the oxidant is Ag2CO3.

46. ​​The method of any one of claims 1-44, wherein the oxidant is Ag₂O.

47. The method of any one of claims 1-44, wherein the oxidant is AgTFA.

48. The method of any one of claims 1-44, wherein the oxidant is Ag3PO4.

49. The method of any one of claims 1-44, wherein the oxidant is AgOAc.

50. The method according to any one of claims 1-49, wherein the palladium source is Pd(PhCN)2Cl2.

51. The method according to any one of claims 1-49, wherein the palladium source is Pd(MeCN)2Cl2.

52. The method according to any one of claims 1-49, wherein the palladium source is Pd(allyl)2Cl2.

53. The method of any one of claims 1-49, wherein the palladium source is Pd(OAc)2.

54. The method of any one of claims 1-49, wherein the palladium source is Pd(TFA)2.

55. The method according to any one of claims 1-49, wherein the palladium source is Pd(PPh3)2Cl2.

56. The method of any one of claims 1-55, wherein the solvent is HFIP or HFIP and MeOH.

57. The method of any one of claims 1-56, wherein the reaction temperature is between about 70°C and about 140°C.

58. The method according to any one of claims 1-57, wherein the reaction temperature is 80°C.

59. The method according to any one of claims 1-57, wherein the reaction temperature is 100°C.

60. The method according to any one of claims 1-57, wherein the reaction temperature is 120°C.

61. The method of any one of claims 1-5, wherein the product 3 is selected from the group consisting of: (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-isocyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-formylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Propyl-3-(4-(trifluoromethyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-fluorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-bromophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-propylcyclopentane-1-carboxylic acid; (1R,3S)-3-(3-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(2-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(5-formylfuran-2-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(5-acetylthiophen-2-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(2-chloropyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(2-bromopyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Propyl-3-(pyridin-4-yl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(2-methylbenzo[d]thiazolyl-6-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Propyl-3-(1-Toluenesulfonyl-1H-indol-5-yl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S 1-Benzyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-phenylpropyl)cyclopentane-1-carboxylic acid; (1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcycloheptane-1-carboxylic acid; (1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cycloheptane-1-carboxylic acid; and (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclooctane-1-carboxylic acid.

62. The method of any one of claims 1-5, wherein the product 6 is selected from the group consisting of: 2-((1 S ,3 R 3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 3-(4-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 1-Methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1S,3R)-1-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-benzoylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-fluorophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(5-formylfuran-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(2-chloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(5-acetylthiophen-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-1-methyl-3-(1-toluenesulfonyl-1H-indol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(2-methylbenzo[d]thiazo-6-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(1-methyl-1H-indazol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; and 2-((1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentyl)acetic acid.

63. The method of any one of claims 1-5, wherein the product 7 is selected from the group consisting of: (1 R ,3 S 4 R )-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 S ,3 R 4 S )-3-(4-methoxyphenyl)-4-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid; and (1 S ,3 S 4 R )-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid.

64. A compound selected from the group consisting of: 。 65. A compound selected from the group consisting of: (1 R ,3 S 3-(4-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(4-isocyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1R,3S)-3-(3-cyanophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-acetylphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-nitrophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S 3-(3-chlorophenyl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(5-formylfuran-2-yl)-1-propylcyclopentane-1-carboxylic acid; (1 R ,3 S )-1-propyl-3-(pyridin-4-yl)cyclopentane-1-carboxylic acid; and (1 R ,3 S )-3-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid.

66. A compound selected from the group consisting of: (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S 1-Benzyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-phenylpropyl)cyclopentane-1-carboxylic acid; (1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentane-1-carboxylic acid; (1 R ,3 S 1-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-1-carboxylic acid; (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcycloheptane-1-carboxylic acid; (1 S ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-(3-methoxypropyl)cycloheptane-1-carboxylic acid; and (1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclooctane-1-carboxylic acid.

67. A compound selected from the group consisting of: 2-((1 S ,3 R 3-(4-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 3-(4-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 S ,3 R 1-Methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1S,3R)-1-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-benzoylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(4-fluorophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-(methoxycarbonyl)phenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(3-acetylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(3-formylphenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-cyanophenyl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(5-formylfuran-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(5-acetylthiophen-2-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-3-(2-chloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1R,3S)-1-methyl-3-(1-toluenesulfonyl-1H-indol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(2,6-dichloropyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-methylcyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(2-methylbenzo[d]thiazo-6-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Methyl-3-(1-methyl-1H-indazol-5-yl)cyclopentyl)acetic acid; 2-((1 R ,3 S 1-Ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)-1-propylcyclopentyl)acetic acid; 2-((1 R ,3 S )-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; and 2-((1 S ,3 S 3-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopentyl)acetic acid.

68. A compound selected from the group consisting of: (1 R ,3 S 4 R )-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid; (1 S ,3 R 4 S )-3-(4-methoxyphenyl)-4-(1-methyl-1H-indazol-5-yl)-1-propylcyclopentane-1-carboxylic acid; and (1 S ,3 S 4 R )-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-1-propylcyclopentane-1-carboxylic acid.

69. A method for the enantioselective long-range γ-CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: 。 70. A method for the enantioselective long-range δ-CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: 。 71. A method for the enantioselective long-range γ-methylene CH arylation or heteroarylation of free cycloalkane carboxylic acids according to the following reaction scheme: 。 72. Any compound or method as described herein.

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