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

Abstract

The application discloses the use of a bifunctional chiral palladium catalyst that enables remote γ- and d-methylene C-H (hetero)arylation of cyclic carbocyclic acids. Specifically, the 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 diverse free cycloalkane carboxylic acids comprising the use of palladium catalysts with chiral oxazoline-pyridone ligands.

Description

ENANTIOSELECTIVE REMOTE METHYLENE C-H (HETERO)ARYLATION OFCYCLOALKANE CARBOXYLIC ACIDSCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional patent application No. 63 / 614,733, which was filed on December 26, 2023, and which is hereby incorporated by reference in its entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under GM084019 awarded by NIGMS of the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION

[0003] The application relates to the use of a bifunctional chiral palladium catalyst that enables remote y- and 6-methylene C-H (hetero)arylation of cyclic carbocyclic acids.Specifically, the application relates to methods of enantioselective remote y-C-H arylation or heteroaryl ati on, δ-C-H arylation or heteroarylation, or sequential y-methylene C-H arylation or heteroarylation of diverse free cycloalkane carboxylic acids comprising the use of palladium catalysts with chiral oxazoline-pyridone ligands.BACKGROUND OF THE INVENTION

[0004] Construction of a-, P-, y-, and δ-chiral centers on carbonyl compounds are pivotal objectives in asymmetric synthesis. While enantioselective P-C-H functionalization reactions have been developed to establish a- and P-chiral centers, enantioselective y- and 5-C-H functionalization reactions for accessing remote chiral centers remain exceedingly difficult.

[0005] Transition-metal-catalyzed enantioselective C-H activation reactions have recently emerged as a powerful and versatile approach for the asymmetric synthesis of molecules containing point (1-5), axial (6) and planar chirality (7). The discovery of the chiral bifunctional mono-N-protected amino acid (MPAA) ligand class and the subsequentdevelopment of several generations of related chiral ligands has enabled the desymmetrization of gem-dimethyl centers via selective activation on one of the methyl groups as well as the direct asymmetric activation of methylene centers (8). However, with the exception of cyclopropyl (9) and cyclobutyl (10) substrates, which are more reactive by virtue of the increased s-character of their C-H bonds, enantioselective methylene C-H activation methodology has remained limited to substrates containing stronger, exogenous directing groups (11-16). Moreover, these methods are limited to setting proximal stereocenters at most three bonds away from the directing atoms (1) (Figure 1A). Compared to the progress in enantioselective intramolecular y-metal-oxo (17) and nitrene insertion reactions (18), enantioselective remote metalation of the y- and 5-methylene C-H bonds of abundant free aliphactic acids have not been demonstrated. Considering that the vast majority of bioactive natural products and drug molecules contain carbocycles, which are beneficial for restricting conformational flexibility and thereby improving ADME properties such as oral bioavailability, y- and 5-C-H functionalization of versatile cycloalkane carboxylic acid starting materials would be especially valuable for the synthesis of sp3-rich bioactive molecules (19-21).

[0006] Thus, there remains a need in the field of synthetic organic chemistry for the development of methods of enantioselective y- and 5-C-H functionalization that enables the accessing to remote chiral centers.BRIEF DESCRIPTION OF THE FIGURES

[0007] Figure 1. Enantioselective functionalization via activation of methylene C-H bonds (A) Transition metal-catalyzed enantioselective methylene β-C(sp3)-H functionalization. (B) Ligand-enabled enantioselective remote methylene C(sp3)-H functionalization.

[0008] Figure 2. (Hetro)Aryl iodide scope for enantioselective y-arylation. Reaction conditions: Substrate (0.1 mmol), Pd(PhCN)2Cl2(10 mol%), Ligand TZ-10 (12 mol%), Ag2CO3(2.0 equiv.), KH2PO4(2.0 equiv.), HFIP (1.0 mL), MeCN (0.1 mL), 80 °C, 12 h. Isolated yields. *65 °C instead of 80 °C, 24 h.

[0009] Figure 3. Cyclic aliphatic scope for enantioselective y-arylation. Reaction conditions: Substrate (0.1 mmol), Pd(PhCN)2Cl210 mol%, Ligand TZ-10 12 mol%, Ag2CO3(2.0 equiv.), KH2PO4(2.0 equiv.), HFIP (1.0 mL), MeCN (0.1 mL) 80 °C, 12 h. Ar = 4-MeOOCC6H4, Ar’ = 3,5-diMeOOCC6H3. Isolated yields. *65 °C instead of 80 °C, 24 h.:90 °C instead of 80 °C, 24 h.§120 °C instead of 80 °C, 24 h.

[0010] Figure 4. Scope for enantioselective 5-(hetero)arylation. Reaction conditions: Substrate (0.1 mmol), Pd(PhCN)2Cl210 mol%, Ligand TZ-7 12 mol%, Ag2CO3(2.0 equiv.), KH2PO4(2.0 equiv.), HFIP (2.0 mL), 120 °C, 24 h. Isolated yields.

[0011] Figure 5. Cyclic aliphatic scope for enantioselective d-(hetero)arylation. Reaction conditions: Substrate (0.1 mmol), Pd(PhCN)2Cl210 mol%, Ligand (R)-TZ-7 12 mol%, Ag2CO3(2.0 equiv.), KH2PO4(2.0 equiv.), HFIP (1.0 mL), 80 °C, 24 h. Isolated yields.SUMMARY OF THE INVENTION

[0012] Herein reported are chiral oxazoline-pyridone ligands that enable enantioselective remote y-C-H (hetero)arylations of a wide range of cyclic free carboxylic acids. This enantioselective C-H (hetero)arylation reaction builds g-tertiary chiral centers with simultaneous desymmetrization of the a-quaternary center in up to >99% ee, providing highly enantioselective access to a wide range of cyclic chiral synthons and bioactive molecules. The sequential enantioselective editing of two methylene C-H bonds is also demonstrated by using the chiral ligands with the opposite configurations to construct a third stereocenter in these sterically congested carbocycles. Remarkably, the chiral Pd / oxazoline-pyridone catalysts are also capable of enantioselective 5-C-H (hetero)arylation, further demonstrating this catalyst’s capabilities for enantioselective remote C-H functionalization (Figure IB).

[0013] The application provides a method of enantioselective remote y-C-H arylation or heteroaryl ati on, 6-C-H arylation or heteroarylation, or sequential y-methylene C-H arylation or heteroarylation of free cycloalkane carboxylic acids comprising the use of palladium catalysts with chiral oxazoline-pyridone ligands.

[0014] The application provides the above method, comprising the following steps in reaction i) for y-C-H arylation or heteroarylation; reaction ii) for 6-C-H arylation or heteroarylation; and iii) for sequential y-methylene C-H arylation or heteroarylation:Ligand (L)Ligand (L) 1wherein each R1is independently H, (C1-C6)alkyl, (C6-C10)aryl, Bn, (C1-C6)alkyl (C6-C10)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 is optionally substituted with one or more R1; each R1is independently halo, (C1-C6)alkyl, -O-(C1-C6)alkyl, or -C(=O)O(C1-C6)alkyl; each Ar is independently (C6-C10)aryl or (C5-C14)heteroaryl optionally substituted with one or more R2; each R2is independently halo, (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; including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.

[0015] The application further provides the above method of enantioselective remote y- C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

[0016] The application further provides the above method of enantioselective remote 5- C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

[0017] The application further provides the above method of enantioselective remote sequential γ-methylene C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:DETAILED DESCRIPTION OF THE INVENTION

[0018] Herein reported are palladium catalysts that employ chiral oxazoline-pyridone ligands that enable the enantioselective remote y-C-H (hetero)arylations of diverse free cycloalkane carboxylic acids, which are essential carbocyclic building blocks in organic synthesis. This enantioselective C-H arylation reaction establishes y-tertiary chiral centers and a-quaternary centers simultaneously in up to >99% ee, providing highly enantioselective access to a wide range of cyclic chiral synthons and bioactive molecules. The sequential enantioselective editing of two methylene C-H bonds sequentially was achieved by using chiral ligands with the opposite configurations to construct carbocycles containing three chiral centers. Remarkably, enantioselective remote 5-C-H arylation is also realized to establish 6-chiral centers that are particularly challenging to access using classic methodologies.

[0019] Reaction development. The formation of stereocenterscarbonyls are among the most desirable and versatile synthetic disconnections in asymmetric organic synthesis (22,23). Over the past three decades, numerous enantioselective enolate or enolate equivalent functionalizations (24) and conjugate addition (25) reactions capable of establishing stereocenters with high selectivity have been reported. In contrast, thecatalytic, enantioselective formation of stereocenters y- and to carbonyls has remainedtremendously challenging (26). Encouraged by prior success at establishing a- and P- carbonyl sterocenters via C-H activation (1,8), the development of chiral Pd catalysts capable of enantioselective remote and -C-H functionalizations was sought to address thisimportant unmet need. Given the importance of cyclic systems in organic chemistry (19-21), 1 -propylcyclopentane- 1 -carboxylic acid (la) and methyl 4-iodobenzoate (2b) were selected as model substrates for reaction development and ligand design. A series of bifunctional chiral ligands previously reported to promote-H activation such as mono-protected amino acid (MPAA), aminoethyl amine (MPAAM), amino oxazoline (MP AO) and aminoethyl phenyl thioether (MPAThio) (27) failed to provide the desired y-arylated product. In contrast, chiral pyridone-sulfonamide ligand (L6) and binaphthol-derived pyridine- pyridone ligand (L7) afforded the desired arylation product in moderate yield (45-57%) — indicating the essential role of the pyridone motif for enabling the activation of methylene C- H bonds (28), albeit in poor enantioselectivity (5-10% ee). Notably, quinuclidine-pyridone (L8) previously used to achieve racemic transannular arylation of carbocycles gavemoderate ee (36%) (29) (Table S4). However, extensive modification of these ligands failed to give a noticeable improvement in enantioselectivity, pointing to the need for a new class of chiral bidentate pyridone ligands. Previously, it was found that the incorporation of a chiral oxazoline into MPAA-derived ligands significantly increases selectivity in enantioselective activations of methyl C-H bonds (30), it was thus hypothesized that chiral oxazoline- pyridone ligands could achieve higher enantioselectivities for methylene C-H activation. Accordingly, a series of chiral oxazoline-pyridone ligands that can coordinate with Pd(II) as either a five- (TZ 1-4) or six-membered (TZ 5-12) chelate were synthesized and tested in thid model reaction. While the five-membered chelates proved poorly reactive, providing the y-arylated product in <10% yield, the six-membered chelates (TZ 5-12) afforded moderate to good yields. The presence of an aryl substituent on the oxazoline ring proved crucial for obtaining stereocontrol in this reaction, with arylated analogs (TZ 7-10) affording the arylation product with excellent levels of enantioselectivity (85-96% ee). After extensive optimization of the reaction, the six-membered chelating oxazoline-pyridone ligand TZ-10 was identified as the optimal ligand, forming the y-arylated product in 68% yield and 96% ee.

[0020] Aryl and heteroaryl iodides substrate scope. With optimized ligand and conditions in hand, the examination of the scope of aryl and heteroaryl iodides in the reaction of cyclopentyl carboxylic acid la (Figure 2) was initiated. A wide range of substituentson the aryl iodides ranging from electron-donating (OMe) (2d) to electron-withdrawing (2a-c, 2e-g) were compatible, affording the corresponding y-arylated acids (3a-g) in 58-78% yield and excellent enantioselectivity (90-97% ee). Halogen substituents such as fluoro (2h), chloro (2i) and even bromo (2j) were tolerated, providing desired products (3h-j) in 64-69% yield and 93-98% ee. Aryl iodides bearing meta (2k-o) or an ortho (2p) substitution also performed well forming the desired products in moderate to good yield (61-85%) and high ee (91-98% ee). Given the importance of heterocycles in drug discovery, the ability of this reaction to perform heteroaryl ati on reactions was next examined. Gratifyingly, a broad range of 2-substituted heteroaryl iodides (2q-y) was found to form the corresponding products in moderate yields and excellent ees (82-99%). Notably, even 4- iodopyridine (2v) — a highly coordinative and challenging coupling partner in C- H activation reactions (31) — afforded the corresponding product (3v) in 41% yield and 91% ee.

[0021] Enantioselective d-C-H (hetero)arylation. Encouraged by these results on y- methylene C-H arylation, whether these chiral oxazoline-pyridone ligands could also enable enantioselective arylations of more dista -methylene C-H bonds was contemplated. 2-(l-methylcyclopentyl)acetic acid (5a) was selected as the model substrate to couple with methyl 4-iodobenzoate (2a). Similar to the -methylene arylation reaction, chiral ligands bearing anaryl group on the oxazoline ring afforded the desired product in excellent enantioselectivity (90-93% ee), albeit in moderate yields (38-53%). Through extensive optimization of the reaction conditions (Table S6), the yield to 64% while maintaining 91% ee was improved. The examination of the scope of aryl and heteroaryl iodides with substrate 5a was next explored. A variety of different functional groups at the para- (2a-2h), meta- (2i-2m), andpositions (2n) were compatible, affording the arylated products (6a-n) in moderate togood yield (42-81%) and 81-95% ee. In addition, a variety of heteroaryl iodides containing furan-, thiophene-, benzothiazole-, indole-, and pyridine were successfully coupled to give the desired products (6o-v) in 47-85% yield and 71-92% ee. Carboxylic acids bearing -ethyl(5w) and propyl (5x) substituents also performed well, providing the target product (6w-x) with 32-48% yield and 90-93% ee. Notably, this single operation constructs P-quaternary andchiral centers on carbocycles simultaneously, which are highly challenging by previousmethodologies. Although the desired arylation was obtained for 2-cyclopentylacetic acid(5y), the yield (20%) and ee (66%) are significantly reduced. But the substrate with aphenyl substituent (5z) was also compatible, giving 32% yield and the highest ee (99%) in the arylation reaction.

[0022] Thus, disclosed herein is the achievement of enantioselective remote y-methylene C-H (hetero)arylation of cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl carboxylic acids with chiral oxazoline-pyridone ligands (TZ-7 and TZ-10). Sequential-methylene C-H arylation with aryls and heteroaryls was also realized by using chiral ligands with opposite configurations to construct two chiral centers whilst desymmetrizing the a-center ofcongested carbocyles. Enantioselective arylation was also demonstrated using thischiral ligand, demonstrating the potential for further remote enantioselective functionalizations.Embodiments

[0023] Embodiment 1. A method of enantioselective remote arylation orheteroaryl ati on, arylation or heteroarylation, or sequential methylene C-H arylationor heteroarylation of free cycloalkane carboxylic acids comprising the use of palladium catalysts with chiral oxazoline-pyridone ligands.

[0024] Embodiment 2. The method of embodiment 1, comprising the following steps in reaction i) for y-C-H arylation or heteroarylation; reaction ii) for arylation orheteroarylation; and iii) for sequential y-methylene C-H arylation or heteroarylation:Ligand (L)Ligand (L)wherein each R1is independently H, (C1-C6)alkyl, (C6-C1o)aryl, Bn, (C1-C6)alkyl (C6-C1o)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 is optionally substituted with one or more R1; each R1is independently halo, (C1-C6)alkyl, -O-(C1-C6)alkyl, or -C(=O)O(C1- C6)alkyl; each Ar is independently (C6-C10)aryl or (C5-C14)heteroaryl optionally substituted with one or more R2; each R2is independently halo, (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; andn is 1, 2, 3, or 4; including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.

[0025] Embodiment 3. The method of Embodiment 1 or Embodiment 2, wherein Ligand (L) is selected from the group consisting of:

[0026] Embodiment 4. The method of Embodiment 2, wherein Ligand (L) is

[0028] Embodiment 6. The method of any one of Embodiments 1-5, wherein R1is (C1- C6)alkyl.

[0029] Embodiment 7. The method of Embodiments 6, wherein R1is nPr or Me.

[0030] Embodiment 8. The method of any one of Embodiments 1-5, wherein R1is optionally substituted Ph.

[0031] Embodiment 9. The method of any one of Embodiments 1-5, wherein R1is optionally substituted Bn.

[0032] Embodiment 10. The method of any one of Embodiments 1-5, wherein R1is optionally substituted (C1-C6)alkyl (C6-C10)aryl.

[0033] Embodiment 11. The method of any one of Embodiments 1-5, wherein R1is optionally substituted -O-(C1-C6)alkyl.

[0034] Embodiment 12. The method of any one of Embodiments 1-5, wherein R1is optionally substituted (C1-C6)alkyl-O-(C1-C6)alkyl.

[0035] Embodiment 13. The method of any one of Embodiments 1-5, wherein R1is optionally substituted halo (C1-C6)alkyl.

[0036] Embodiment 14. The method of any one of Embodiments 1-5, wherein R1is optionally substituted hetero (C1-C6)alkyl.

[0037] Embodiment 15. The method of any one of Embodiments 1-5, wherein R1is optionally substituted (C1-C6)alkyl-C(=O)O(C1-C6)alkyl.

[0038] Embodiment 16. The method of any one of Embodiments 1-15, wherein Ar is optionally substituted phenyl.

[0039] Embodiment 17. The method of any one of Embodiments 1-15, wherein Ar is optionally substituted (C5-C10)heteroaryl.

[0040] Embodiment 18. The method of Embodiment 16 or Embodiment 17, wherein R2is halo.

[0041] Embodiment 19. The method of Embodiment 16 or Embodiment 17, wherein R2is (C1-C6)alkyl.

[0042] Embodiment 20. The method of Embodiment 16 or Embodiment 17, wherein R2is -C(=O)O(C1-C6)alkyl.

[0043] Embodiment 21. The method of Embodiment 16 or Embodiment 17, wherein R2is NO2.

[0044] Embodiment 22. The method of Embodiment 16 or Embodiment 17, wherein R2is CN.

[0045] Embodiment 23. The method of Embodiment 16 or Embodiment 17, wherein R2is -O(C1-C6)alkyl.

[0046] Embodiment 24. The method of Embodiment 16 or Embodiment 17, wherein R2is -C(=O)H.

[0047] Embodiment 25. The method of Embodiment 16 or Embodiment 17, wherein R2is -C(=O)(C1-C6)alkyl.

[0048] Embodiment 26. The method of Embodiment 16 or Embodiment 17, wherein R2is CF3.

[0049] Embodiment 27. The method of Embodiment 16 or Embodiment 17, wherein R2is Ts.

[0050] Embodiment 28. The method of any one of Embodiments 1-27, wherein n is 1.

[0051] Embodiment 29. The method of any one of Embodiments 1-27, wherein n is 2.

[0052] Embodiment 30. The method of any one of Embodiments 1-27, wherein n is 3.

[0053] Embodiment 31. The method of any one of Embodiments 1-27, wherein n is 4.

[0054] Embodiment 32. The method of any one of Embodiments 1-31, wherein the base is KH2PO4.

[0055] Embodiment 33. The method of any one of Embodiments 1-31, wherein the base is

[0056] Embodiment 34. The method of any one of Embodiments 1-31, wherein the base is

[0057] Embodiment 35. The method of any one of Embodiments 1-31, wherein the base is

[0058] Embodiment 36. The method of any one of Embodiments 1-31, wherein the base is

[0059] Embodiment 37. The method of any one of Embodiments 1-31, wherein the base is

[0060] Embodiment 38. The method of any one of Embodiments 1-31, wherein the base is

[0061] Embodiment 39. The method of any one of Embodiments 1-31, wherein the base is

[0062] Embodiment 40. The method of any one of Embodiments 1-31, wherein the base is

[0063] Embodiment 41. The method of any one of Embodiments 1-31, wherein the base is

[0064] Embodiment 42. The method of any one of Embodiments 1-31, wherein the base is

[0065] Embodiment 43. The method of any one of Embodiments 1-31, wherein the base is

[0066] Embodiment 44. The method of any one of Embodiments 1-31, wherein the base is

[0067] Embodiment 45. The method of any one of Embodiments 1-44, wherein the oxidant is

[0068] Embodiment 46. The method of any one of Embodiments 1-44, wherein the oxidant is A

[0069] Embodiment 47. The method of any one of Embodiments 1-44, wherein the oxidant is AgTFA.

[0070] Embodiment 48. The method of any one of Embodiments 1-44, wherein the oxidant i

[0071] Embodiment 49. The method of any one of Embodiments 1-44, wherein the oxidant is

[0072] Embodiment 50. The method of any one of Embodiments 1-49, wherein the palladium source is

[0073] Embodiment 51. The method of any one of Embodiments 1-49, wherein the palladium source is

[0074] Embodiment 52. The method of any one of Embodiments 1-49, wherein the palladium source is

[0075] Embodiment 53. The method of any one of Embodiments 1-49, wherein the palladium source is

[0076] Embodiment 54. The method of any one of Embodiments 1-49, wherein the palladium source isPd(TFA)2.

[0077] Embodiment 55. The method of any one of Embodiments 1-49, wherein the palladium source is

[0078] Embodiment 56. The method of any one of Embodiments 1-55, wherein the solvent is HFIP or HFIP and

[0079] Embodiment 57. The method of any one of Embodiments 1-56, wherein the reaction temperature is between approximately 70 °C and approximately 140 °C.

[0080] Embodiment 58. The method of any one of Embodiments 1-57, wherein the reaction temperature is 80 °C.

[0081] Embodiment 59. The method of any one of Embodiments 1-57, wherein the reaction temperature is 100 °C.

[0082] Embodiment 60. The method of any one of Embodiments 1-57, wherein the reaction temperature is 120 °C.

[0083] Embodiment 61. The method of any one of embodiments 1-5, wherein the product 3 is selected from the group consisting of: -3-(4-(methoxycarbonyl)phenyl)-l-propylcyclopentane-l-carboxylic acid;3-(4-nitrophenyl)-l-propylcyclopentane-l-carboxylic acid; 3-(4-isocyanophenyl)-l-propylcyclopentane-l-carboxylic acid;3-(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid;3-(4-formylphenyl)-l-propylcyclopentane-l-carboxylic acid;3-(4-acetylphenyl)-l-propylcyclopentane-l-carboxylic acid;- 1 -propyl-3 -(4-(trifluoromethyl)phenyl)cyclopentane- 1 -carboxylic acid;3-(4-fluorophenyl)-l-propylcyclopentane-l-carboxylic acid;-3 -(4-chlorophenyl)- 1 -propylcyclopentane- 1 -carboxylic acid;3 -(4-bromophenyl)- 1 -propylcyclopentane- 1 -carboxylic acid;-3-(3-(methoxycarbonyl)phenyl)-l-propylcyclopentane-l-carboxylic acid; )-3-(3-cyanophenyl)-l-propylcyclopentane-l-carboxylic acid;5)-3-(3-acetylphenyl)-l-propylcyclopentane-l-carboxylic acid;-3-(3-nitrophenyl)-l-propylcyclopentane-l-carboxylic acid;-3-(3-chlorophenyl)-l-propylcyclopentane-l-carboxylic acid;-3-(2-cyanophenyl)-l-propylcyclopentane-l-carboxylic acid;3-(5-formylfuran-2-yl)-l-propylcyclopentane-l-carboxylic acid;-3-(5-acetylthiophen-2-yl)-l-propylcyclopentane-l-carboxylic acid;3-(2-chloropyridin-4-yl)- l-propylcyclopentane- l -carboxylic acid;-3-(2-bromopyridin-4-yl)-l-propylcyclopentane-l-carboxylic acid;)-3-(2,6-dichloropyridin-4-yl)-l-propylcyclopentane-l-carboxylic acid; l-propyl-3-(pyridin-4-yl)cyclopentane-l-carboxylic acid;-3 -(2-methylbenzo[d]thiazol-6-yl)- 1 -propylcyclopentane- 1 -carboxylic acid;5)-3-(l-methyl-lH-indazol-5-yl)-l-propylcyclopentane-l-carboxylic acid;5)-l-propyl-3-(l-tosyl-lH-indol-5-yl)cyclopentane-l-carboxylic acid;S)-3 -(4-(m ethoxy carbonyl)phenyl)- 1 -methylcyclopentane- 1 -carboxylic acid;5)-l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid;- 1 -benzyl-3 -(4-(m ethoxy carbonyl)phenyl)cy cl opentane- 1 -carboxylic acid;)-3-(4-(methoxycarbonyl)phenyl)-l-(3-phenylpropyl)cyclopentane-l-carboxylic acid;5)-3-(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cyclopentane-l-carboxylic acid;-3 -(4-(m ethoxy carbonyl)phenyl)- 1 -phenylcyclopentane- 1 -carboxylic acid;)-l-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid;)-3-(4-(methoxycarbonyl)phenyl)-l-propylcycloheptane-l-carboxylic acid;3-(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cycloheptane-l-carboxylic acid;and -3-(4-(methoxycarbonyl)phenyl)-l-propylcyclooctane-l-carboxylic acid.

[0084] Embodiment 62. The method of any one of embodiments 1-5, wherein the product6 is selected from the group consisting of: -3-(4-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid; 3-(4-cyanophenyl)-l-methylcyclopentyl)acetic acid; l-methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; -l-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid;-3-(4-formyl phenyl)- ! -methyl cyclopentyl)acetic acid;3-(4-benzoylphenyl)-l-methylcyclopentyl)acetic acid;3-(4-acetylphenyl)-l-methylcyclopentyl)acetic acid;)-3-(4-fluorophenyl)-l-methylcyclopentyl)acetic acid;)-3-(3-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid;-3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid;3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid; -3-(3-formylphenyl)-l-methylcyclopentyl)acetic acid;-l-methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid;-3-(2-cyanophenyl)-l-methylcyclopentyl)acetic acid;-3-(5-formylfuran-2-yl)-l-methylcyclopentyl)acetic acid;S)-3-(2-chloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; 3-(5-acetylthiophen-2-yl)-l-methylcyclopentyl)acetic acid;-l-methyl-3-(l-tosyl-lH-indol-5-yl)cyclopentyl)acetic acid;)-3-(2,6-dichloropyridin-4-yl)-l-methylcyclopentyl)acetic acid;)-3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-l-methylcyclopentyl)acetic acid;)-l-methyl-3-(2-methylbenzo[d]thiazol-6-yl)cyclopentyl)acetic acid; -l-methyl-3-(l-methyl-lH-indazol-5-yl)cyclopentyl)acetic acid;l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid;-3-(4-(methoxycarbonyl)phenyl)-l-propylcyclopentyl)acetic acid;)-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; and3-(4-(methoxycarbonyl)phenyl)-l-phenylcyclopentyl)acetic acid.

[0085] Embodiment 63. The method of any one of embodiments 1-5, wherein the product 7 is selected from the group consisting of:-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid; 5)-3-(4-methoxyphenyl)-4-(l-methyl-lH-indazol-5-yl)-l-propylcyclopentane-l-carboxylic acid; and -3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid.

[0086] Embodiment 64. A compound selected from the group consisting of:

[0087] Embodiment 65. A compound selected from the group consisting of: 3-(4-nitrophenyl)-l-propylcyclopentane-l-carboxylic acid;3-(4-isocyanophenyl)-l-propylcyclopentane-l-carboxylic acid;-3-(3-cyanophenyl)-l-propylcyclopentane-l-carboxylic acid;-(3-acetylphenyl)-l-propylcyclopentane-l-carboxylic acid;3-(3-nitrophenyl)-l-propylcyclopentane-l-carboxylic acid;3 -(3 -chlorophenyl)- 1 -propylcyclopentane- 1 -carboxylic acid;-3-(5-formylfuran-2-yl)-l-propylcyclopentane-l-carboxylic acid;-l-propyl-3-(pyridin-4-yl)cyclopentane-l-carboxylic acid; and3-(l-methyl-lH-indazol-5-yl)-l-propylcyclopentane-l-carboxylic acid.

[0088] Embodiment 66. A compound selected from the group consisting of:-3 -(4-(m ethoxy carbonyl)phenyl)- 1 -methylcyclopentane- 1 -carboxylic acid; l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid;1 -benzyl-3 -(4-(m ethoxy carbonyl)phenyl)cy cl opentane- 1 -carboxylic acid;)-3-(4-(methoxycarbonyl)phenyl)-l-(3-phenylpropyl)cyclopentane-l-carboxylic acid; -3-(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cyclopentane-l-carboxylic acid;-3 -(4-(m ethoxy carbonyl)phenyl)- 1 -phenylcyclopentane- 1 -carboxylic acid;-l-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid;5)-3-(4-(methoxycarbonyl)phenyl)-l-propylcycloheptane-l-carboxylic acid;3-(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cycloheptane-l-carboxylic acid; and -3-(4-(methoxycarbonyl)phenyl)-l-propylcyclooctane-l-carboxylic acid.

[0089] Embodiment 67. A compound selected from the group consisting of: 3-(4-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid;3-(4-cyanophenyl)-l-methylcyclopentyl)acetic acid;-methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid;-l-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; )-3-(4-formylphenyl)-l-methylcyclopentyl)acetic acid;-3-(4-benzoylphenyl)-l-methylcyclopentyl)acetic acid;-3-(4-acetylphenyl)-l-methylcyclopentyl)acetic acid; -3-(4-fluorophenyl)-l-methylcyclopentyl)acetic acid; -3-(3-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid; -3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid; )-3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid; -3-(3-formylphenyl)-l-methylcyclopentyl)acetic acid; -l-methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; -3-(2-cyanophenyl)-l-methylcyclopentyl)acetic acid; -3-(5-formylfuran-2-yl)-l-methylcyclopentyl)acetic acid; )-3-(5-acetylthiophen-2-yl)-l-methylcyclopentyl)acetic acid; )-3-(2-chloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; )-l-methyl-3-(l-tosyl-lH-indol-5-yl)cyclopentyl)acetic acid; -3-(2,6-dichloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; -3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-l-methylcyclopentyl)acetic acid; -l-methyl-3-(2-methylbenzo[d]thiazol-6-yl)cyclopentyl)acetic acid; -l-methyl-3-(l-methyl-lH-indazol-5-yl)cyclopentyl)acetic acid; -l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; -3-(4-(methoxycarbonyl)phenyl)-l-propylcyclopentyl)acetic acid; -3-(4-(m ethoxy carbonyl)phenyl)cy cl opentyl)acetic acid; and -3-(4-(methoxycarbonyl)phenyl)-l-phenylcyclopentyl)acetic acid.

[0090] Embodiment 68. A compound selected from the group consisting of: -3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid; -3-(4-methoxyphenyl)-4-(l-methyl-lH-indazol-5-yl)-l-propylcyclopentane-l-carboxylic acid; and-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid.

[0091] Embodiment 69. A method of enantioselective remote -H arylation orheteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

[0092] Embodiment 70. A method of enantioselective remote-C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

[0093] Embodiment 71. A method of enantioselective remote sequential y-methylene C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

[0094] Embodiment 72. Any compound or method as described herein.Definitions

[0095] The phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0096] The phrase "as defined herein above" refers to the broadest definition for each group as provided in the Summary of the Invention, the Detailed Description of the Invention, the Experimental s, or the broadest claim. In all other embodiments provided below, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.

[0097] As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited 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 recited features or components, but may also include additional features or components.

[0098] As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and / or" and not the "exclusive" sense of "either / or".

[0099] The term "independently" is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which “R” appearstwice and is defined as "independently selected from” means that each instance of that R group is separately identified as one member of the set which follows in the definition of that R group. For example, “each R1and R2is independently selected from carbon and nitrogen" means that both R1and R2can be carbon, both R1and R2can be nitrogen, or R1or R2can be carbon and the other nitrogen or vice versa.

[0100] When any variable occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such compounds result in stable compounds.

[0101] The symbols at the end of a bond or a line drawn through a bond or “ - ” drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part.

[0102] A bond drawn into ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.

[0103] The term “optional” or “optionally” as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted” means that the “optionally substituted” moiety may incorporate a hydrogen or a substituent.

[0104] The phrase “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated to be a "bond" or "absent", the atoms linked to the substituents are then directly connected.

[0105] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.

[0106] Certain compounds disclosed herein may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture ofcompounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto / enol (-C(=O)-CH--C(-OH)=CH-), amide / imidic acid (-C(=O)-NH- and amidine (-C(=NR)-NH- -C(-NHR)=N-) tautomers. The latter two areparticularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.

[0107] In this disclosure, a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3- naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In this instance the pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0108] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and / or methods known to those of skill can be utilized in carrying out the present invention. However,preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

[0109] The definitions described herein may be appended to form chemically-relevant combinations, such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,” “alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents.“Hydroxy alkyl" includes 2-hydroxy ethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 2,3 -dihydroxybutyl, 2-(hydroxymethyl), 3 -hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below. The term -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.

[0110] The term “acyl” as used herein denotes a group of formula -C(=O)R wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C(=O)R wherein R is alkyl as defined herein. The term C1-6acyl refers to a group -C(=O)R contain 6 carbon atoms. The term "aryl carbonyl" as used herein means a group of formula C(=O)R wherein R is an aryl group; the term "benzoyl" as used herein an "arylcarbonyl" group wherein R is phenyl.

[0111] The term “alkyl” as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 12 carbon atoms. The term “lower alkyl” or “C1-C6alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C1-12 alkyl" as used herein refers to an alkyl composed of 1 to 12 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, z-propyl,y z-butyl, / -butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0112] When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3 -phenylpropyl. The terms “arylalkyl” or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.

[0113] When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example, “C1-6alkyl” is intended to encompass,andalkyl.

[0114] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C1-15alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C1-14alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C1-13alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C1-11alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n- pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C5) and the like.

[0115] “Alkenyl” or “olefin” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon doublebonds (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2 4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C24 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C5), octatrienyl (C5), and the like.

[0116] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C5), and the like.

[0117] The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.

[0118] The term "alkylene" or "alkylenyl" as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH2)n)or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH(z-Pr)CH2-), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.

[0119] The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, zz-propyloxy, z-propyloxy, zz-butyloxy, z-butyloxy, t- butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "C1-10alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C1-10.

[0120] The term "hydroxy alkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups.

[0121] The terms "alkyl sulfonyl" and "aryl sulfonyl" as used herein refers to a group of formula -S(=O)2R wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein. The term “heteroalkyl sulfonyl” as used herein refers herein denotes a group of formula -S(=O)2R wherein R is “heteroalkyl” as defined herein.

[0122] The terms "alkylsulfonylamino" and "arylsulfonylamino"as used herein refers to a group of formula -NR'S(=O)2R wherein R is alkyl or aryl respectively, R' is hydrogen or C1-3alkyl, and alkyl and aryl are as defined herein.

[0123] The term “cycloalkyl” as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7 cycloalkyl" as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.

[0124] The term carboxy-alkyl as used herein refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom. The term “carboxy” or “carboxyl” refers to a -CO2H moiety.

[0125] The term "heteroaryl” or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ringatoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. As well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Examples of heteroaryl moi eties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, 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 moi eties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.

[0126] The term "heterocyclyl", “heterocycloalkyl” or "heterocycle" as used herein denotes a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,0 or S(0)o-2), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.

[0127] “Heterocyclyl” or “heterocyclic” refers to a group or radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms,the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0128] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0129] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH- pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0130] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1 -naphthyl (a-naphthyl) and 2-naphthyl(P p y )) In some embodiments, an aryl group has 14 ring carbon atoms; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0131] “Heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0132] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided 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 has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0133] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0134] “ Saturated” refers to a ring moiety that does not contain a double or triple bond, / .<?., the ring contains all single bonds.

[0135] Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.

[0136] Exemplary non-hydrogen substituents wherein a moiety is “optionally substituted” as used herein means the moiety may be substituted with any additional moiety selected from, but not limited to, the group consisting of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, - OH, -ORaa, -N(Rbb)2, -N(ORcc)Rbb, -SH, -SRaa, -C(=O)Raa, -CO2H, -CHO, -CO2Raa, - OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, - C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, - NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -S(=O)Raa, -OS(=O)Raa, -B(ORCC)2, C1-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, C6-14 aryl, and 5- to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =0; each instance of Raais, independently, selected from the group consisting of C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, C6-14 aryl, and 5- to 14- membered heteroaryl, or two Raagroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, - SO2N(RCC)2, -SORaa, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, C6-14 aryl, and 5- to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, C6-14 aryl, and 5- to 14- membered heteroaryl, or two Rccgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, - OC1-6alkyl, -0N(C1-6alkyl)2, -N(C1-6alkyl)2, -N(0C1-6alkyl)(C1-6alkyl), -N(0H)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), - OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=0)NH2, -C(=O)N(C1-6alkyl)2, - 0C(=0)NH(C1-6alkyl), -NHC(=0)( C1-6alkyl), -N(C1-6alkyl)C(=O)( C1-6alkyl), - NHC02(C1-6alkyl), -NHC(=0)N(C1-6alkyl)2, -NHC(=0)NH(C1 6alkyl), -NHC(=0)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -0C(=NH)0C1 6alkyl, -C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -0C(=NH)N(C1-6alkyl)2, -OC(NH)NH( C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, - NHSO2( C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(CI6alkyl), -SO2NH2-SO2C1-6alkyl, - B(OH)2, -B(0C1-6alkyl)2,C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-1oaryl, 3-to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =0.

[0137] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0138] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients.

[0139] “ Salt” includes any and all salts. “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed 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 using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0140] Unless otherwise indicated, compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC). Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0141] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, replacement of a carbon by a13C- or14C- enriched carbon, and / or replacement of an oxygen atom with18O, are within the scope of the disclosure. Other examples of isotopes include15N,180,170,31P,32P,35S,18F,36C1and123I. Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.

[0142] Certain isotopically-labelled compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability.

[0143] Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes likeor18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like123I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greatermetabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer halflives (ti / 2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

[0144] If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.EXAMPLESAbbreviations

[0145] Commonly used abbreviations include: acetyl (Ac), azo-Z»A-isobutyrylnitrile (AIBN), atmospheres (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), leri- butoxycarbonyl (Boc), di- / c / 7-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Cl2emical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), l,4-diazabicyclo[2.2.2]octane (DABCO), di ethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2- di chloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-Ao- propyl azodi carb oxy late (DIAD), di-Ao-butylaluminumhydride (DIBAL or DIBAL-H), 1,3- Diisopropylcarbodiimide (DIC), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), l,l'-Z»A-(diphenylphosphino)ethane (dppe),(diphenylphosphino)ferrocene (dppf), 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimidehydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-27 / - quinoline-1 -carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole- l-yl)-N, N,N’N’-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HO Ac), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), propanol (IP A), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), , methyl (Me), acetonitrile (MeCN), zw-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl / -butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), Ao-propyl (z-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT),triethylamine (TEA or EtsN), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA),-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p- toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or tosyl (Ts), N- urethane-N-carboxyanhydride (UNCA),. Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).1. General Information

[0145] Pd(PhCN)2Cl2, Ag2CO3were purchased from Sigma-Aldrich and Strem. Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, and Acros, and used directly without further purification. Other reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254.1H NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 instruments. The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants, J, were reported in Hertz unit (Hz).13C NMR spectra were recorded on Bruker DRX-600 and were fully decoupled by broad band proton decoupling. Chemical shifts were referenced to the appropriate residual solvent peaks. Column chromatography was performed using E. Merck silica (60, particle size 0.043-0.063 mm), and pTLC was performed on Merck silicaplates (60F-254). High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of flight). The single crystal X- ray diffraction studies were carried out on a Bruker D8 Venture Ultra diffractometer equipped with Mo Kαradiation (1 = 0.71073). Melting points were measured using a Stuart SMP50. Enantiomeric ratios (er) were determined on the Agilent Technologies supercritical fluid chromatography (SFC) system using commercially available chiral columns.2. Preparation of Bidentate TZ-Pyridone Ligands

[0146] To the dry THF (30.0 mL) solution of 2-Trimethyl silyl ethanol (15.0 mmol, 1.54 mL) was added NaH (12.0 mmol, 480 mg) and the mixture was stirred at rt for 30 min. Then 6-bromopicolinonitrile 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 down to room temperature, water (10 mL) was added and extracted by EtOAc (10 mL x 3). The organic phase was washed by cone, brine (10 mL x 3) and dried by anhydrousThe dried organic phase was passed through a pad of silica gel and washed by EtOAc (30 mL). The solvent was removed by a rotavapor and purified by flash silica gel column chromatography (5% EtOAc / hexane) to give the 6-(2-(trimethylsilyl)ethoxy)picolinonitrile Ls3 as a yellow oil.

[0147] To a solution of 6-(2-(trimethylsilyl)ethoxy)picolinonitrile in dry MeOH was added NaOMe (10 mol%) and the mixture was stirred at room temperature for 24 h. AcOH (1.0 equiv) was added and the solvent was removed under reduced pressure to give Ls4 as a yellow oil. which was used directly in the next step without purification.

[0148] To the dry toluene solution of Ls4 were added TsOH (10 mol%) and the appropriate amino alcohol. The mixture was refluxed 12 h under N2 atmosphere. The mixture was removed from the heating bath and cooled down to room temperature. The solvent was removed by a rotavapor and purified by flash silica gel column chromatography (10% EtOAc / hexane) to give the Ls5 as a colorless oil.

[0149] To the dry THF solution of Ls5 was added TBAF (3.0 equiv.) and the solution was stirred at room temperature for 12 h. The solvent was removed by a rotavapor and purified by flash silica gel column chromatography (20% to 100% EtOAc / hexane) to give the TZ1-4 as white foam solids.-4,5-dihydrooxazol-2-yl)39yridine-2-ol (TZ-1)'HNMR (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= 7.9 Hz, 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- J) 162.24, 157.59, 140.09, 132.64, 125.09, 106.97, 71.65, 71.23, 39.29, 25.84, 14.78, 11.36.HRMS (ESI-TOF) Calculated for : 221.1285, Found: 221.1294.(5)-6-(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)40yridine-2-ol (TZ-2)'HNMR (600 MHz, 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).13C NMR (151 MHz, Chloroform-d) 162.19, 157.62, 140.10, 132.54,125.17, 106.88, 75.98, 70.30, 34.01, 25.86. Calculated for C12H17N2O2[M+H]+: 221.1285, Found: 221.1290.(3)-6-(4-phenyl-4,5-dihydrooxazol-2-yl)40yridine-2-ol (TZ-3)'HNMR (600 MHz, Chloroform-d)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).13C 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.HRMS (ESI-TOF) Calculated for 241.0972, Found: 241.0980.'H NMR (600 MHz, Chloroform-d) δ 7.53 - 7.46 (m, 1H), 7.40 (dd, J= 9.2, 6.8 Hz, 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).13C NMR (151 MHz, CDCh)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.HRMS (ESI-TOF) Calculated for C : 253.0972, Found: 253.0978.Preparation of TZ5-13tolueneLs6 Ls2 Ls71 ) Isobutyl chloroformateDMAP MsCI

[0150] To the dry THF (30.0 mL) solution of 2-Trimethyl silyl ethanol (15.0 mmol, 1.54 mL) was added NaH (12.0 mmol, 480 mg) and the mixture was stirred at rt 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 down to room temperature, water (10 mL) was added and extracted by EtOAc (10 mL x 3). The organic phase was washed by cone. Brine (10 mL x 3) and dried by anhydrousThe dried organic phase was passed through a pad of silica gel and washed by EtOAc (30 mL). The solvent was removed by a rotavapor and purified by flash silica gel column chromatography (5% EtOAc / hexane) to give the 2-bromo-6-(2-(trimethylsilyl)ethoxy)pyridine as a colorless oil.

[0151] To the dry toluene (30.0 mL) solution of LiCy2 (13 mmol, 1.3 equiv) was added Methyl isobutyrate (13 mmol, 1.3 equiv) and the mixture was stirred at rt for 30 min under N2 atmosphere. Then the mixture were stirred at room temperature 12 h after (228 mg,2.5 mol%)HBF4 and2-bromo-6-(2-(trimethylsilyl)ethoxy)pyridine were added. Water (10 mL) was added and extracted by EtOAc (10 mL x 3), the organic phase was washed by cone, brine (10 mL x 3) and dried by anhydrou . The dried organic phase was passedthrough a pad of silica gel and washed by EtOAc (30 mL). The solvent was removed by a rotavapor and purified by flash silica gel column chromatography (10% EtOAc / hexane) to give the methyl 2-methyl-2-(6-(2-(trimethylsilyl)ethoxy)pyridin-2-yl)propanoate as a yellow oil.

[0152] To a solution of methyl 2-methyl-2-(6-(2-(trimethylsilyl)ethoxy)pyridin-2- yl)propanoate (5 mmol) in (1 : 1) was added 15 mmol, 3 equiv) andstirred 24 h at 50 °C. the reaction mixture was cooled to room temperature and adjusted thepH=2 with 2N HC1. The aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrousand concentrated under vacuum to give Ls9, which was used directly in the next step without purification.

[0153] To a solution of Ls9 (5 mmol) in dry DCM were added A-Methylmorpholine (3.0 equiv) and Isobutyl chloroformate (1.0 equiv) at 0 °C. the mixture was stirred Ih at room temperature before the appropriate amino alcohol (1.2 equiv) was added. Then the mixture was stirred at room temperature 12h and the solvent was removed by a rotavapor and purified by flash silica gel column chromatography (25% EtOAc / hexane) to give the LslO as a colorless oil.

[0154] To a solution of LslO (2 mmol) in dry DCM were added TEA (4 mmol, 2.0 equiv), MsCl (3 mmol, 1.5 equiv) and DMAP (0.2 mmol, 10 mol%). The mixture was stirred 12h at room temperature and the solvent was removed by a rotavapor and purified by flash silica gel column chromatography (20% EtOAc / hexane) to give the Lsll as a colorless oil.

[0155] To a solution of Lsll (1 mmol) was added TBAF (6 mmol, 6 equiv). The mixture was stirred at 12h at room temperature. The solvent was removed by a rotavapor and purified by flash silica gel column chromatography (20% to 100% EtOAc / hexane) to give the TZ 5- 13 as a white foam solid.6-(2-((3)-4-((l?)-sec-butyl)-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-5)'H NMR (600 MHz, 10.15 (s, IH), 7.37 (dd, J= 9.2, 7.0 Hz, IH), 6.46 (d, J= 9.2 Hz, IH), 6.16 (d, J= 7.0 Hz, IH), 4.25 (dd, J= 9.7, 8.4 Hz, IH), 4.12 (ddd, J= 9.8, 7.9, 5.8 Hz, IH), 4.02 (t, J= 8.1 Hz, IH), 1.67 (tt, J= 13.3, 6.9 Hz, IH), 1.59 (d, J= 5.3 Hz, 6H), 1.55 - 1.46 (m, IH), 1.19 (tt, J = 15.0, 7.5 Hz, IH), 0.95 (t, J= 7.4 Hz, 3H), 0.82 (d, J= 6.8 Hz, 3H).13C NMR (151 MHZ, C 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.HRMS (ESI-TOF) Calculated fo 263.1754, Found: 263.1761.6-(2-(4-( / er / -butyl)-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-6)JH NMR (600 MHz, 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).13C NMR (151 MHz, 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.HRMS (ESI-TOF) Calculated for 263.1754, Found: 263.1757.-6-(2-(4-phenyl-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-7)'HNMR (600 MHz 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= 7.0 Hz, 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). 13C NMR (151 MHz, 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.HRMS (ESI-TOF) Calculated for 283.1441, Found: 283.1444.)-6-(2-(4-(4-fluorophenyl)-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-8)‘H NMR (400 MHz 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). 13C NMR (151 MHz, 170.65, 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, 25.57.19F NMR (376 MHz, CDCI3)-117.27.HRMS (ESI-TOF) Calculated for .1347, Found: 301.1349.(3)-6-(2-(4-(naphthalen-l-yl)-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-9) 'HNMR (600 MHz, 11.05 (s, 1H), 7.88 (d, J= 7.6 Hz, 1H), 7.76 (d, J= 8.1Hz, 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).13C NMR (151 MHz,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.HRMS (ESI-TOF) Calculated for 333.1598, Found: 333.1605.(3)-6-(2-(4-(3,5-di-tert-butylphenyl)-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-10)'H NMR (600 MHz, 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).13C NMR (151 MHz, CDCI3)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.HRMS (ESI-TOF) Calculated for : 395.2693, Found: 395.2697.(3)-4-methoxy-6-(2-(4-phenyl-4,5-dihydrooxazol-2-yl)propan-2-yl)pyridin-2-ol (TZ-11) 'HNMR (600 MHz, 6 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).13C NMR (600 MHz, 70.24, 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.HRMS (ESI-TOF) Calculated for 313.1547, Found: 313.1550.(3)-6-(l-(4-phenyl-4,5-dihydrooxazol-2-yl)cyclohexyl)pyridin-2-ol (TZ-12)'HNMR (600 MHz 6 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).13C NMR (151 MHz, 168.50, 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.HRMS (ESI-TOF) Calculated fo 323.1754, Found: 323.1762.Condition screenings for the enantioselective of y-arylationTable S3. Palladium source screening3[Pd] (10 mol%)"1 — < C°OH+TZ-7 (15 mol%) COOH Ly^pr Ar- 1 Ag2CO3, KH2PO4*■ Ly^Pr2 HFIP / MeCN, 80 °C Ar = 4-COOMeC6H4Entry [pq] Yield (%) ee (%)1 Pd(PhCN)2Cb 8 =882Pd(MeCN)2Cl246 853 Pd(OAc)238 854Pd(TFA)230 825 Pd(PPh3)2Cl222 88ondition screenings for the Enantioselective of-arylation5. Preparation for the Substrates

[0156] Preparation of cycloalkane carboxylic acids for y-arylation

[0157] LDA (55 mmol) was added dropwise to a mixture of a-H-aliphatic acid (22 mmol) and THF (50 mL) at -78 °C, and the mixture was allowed to warm up to room temperature and stirred for 1 h. Then the reaction mixture was recooled to -78 °C and RI or RBr (22 mmol) was added dropwise. The resulting solution was allowed to warm up to room temperature and stirred overnight. After the reaction finished, the reaction mixture was quenched with 10% HC1solution and extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrousand concentrated under reduced pressure to give the crude product. Then purified by chromatography on silica gel to afford the desired cycloalkane carboxylic acids.

[0158] Preparation of cycloalkane carboxylic acids for 6-arylationRLi (40 mmol) was added dropwise to a mixture of Cui (40 mmol) in Et20 (150 mL) at -0 °C, and the mixture was stirred for 0.5 h. The solvent was removed at 25 °C under reduced pressure. Dry DCM (30 mL) was added and the mixture was cooled to -78 °C. TMSC1(40 mmol) and the unsaturated carbonyl compound (20 mmol) were added dropwise. The mixture was stirred Ih and allowed to slowly warm up to room temperature. After 16 h, The reaction was quenched by the addition of sat. aq. NH4Q solution (30 mL) and extracted by EtOAc. The combined organic extract was washed with brine, dried over anhydrous andconcentrated under reduced pressure to give the crude product. Which was used in the next step directly without any purification.

[0159] The mixture of the crude product in MeOH (30 mL) and water (30 mL) was refluxed. After 12 h, the mixture was cooled down to room temperature and quenched by 2N HC1, extracted by EtOAc. The combined organic extract was washed with brine (15 mL), dried over anhydrous and concentrated to give the crude product. Then purified bychromatography on silica gel to afford the desired cycloalkane carboxylic acids.6. General Procedure for the -(Hetero)Arylation

[0160] In a sealed 10 mL vial equipped with a magnetic stir bar was charged with the appropriate aliphatic acid substrate (0.10 mmol), Aryl Iodides (0.20 mmol), Ag2COs (55.0 mg, 0.20 mmol), and KH2PO4(27.2 mg, 0.2 mmol). A solution of (3.8 mg, 10mol%) and TZ-10 (4.8 mg, 12 mol%) in HFIP (1.0 mL) and MeCN (0.1 mL) was premixed and added. Subsequently the vial was capped and closed tightly. The reaction mixture was then stirred at the rate of 200 rpm at the corresponding temperature for 24 h. After being allowed to cool to room temperature, the mixture was acidified with 100 μL of acetic acid and stirred for 30 seconds. The mixture was passed through a pad of celite with EtOAc as the eluent to remove any insoluble precipitate. The resulting solution was concentrated, and the residual mixture was purified using pTLC to afford enantioselective γ-(hetero)arylation products. Racemic samples of the -(Hetero)Arylation products for chiral HPLC analysiswere prepared by using ligand rac-TZ-7 instead of ligand TZ-10.7. General Procedure for theHetero)Arylation

[0161] In a sealed 10 mL vial equipped with a magnetic stir bar was charged with the appropriate aliphatic acid substrate (0.10 mmol), Aryl Iodides (0.20 mmol), (55.0mg, 0.20 mmol), and KH2PO4(27.2 mg, 0.2 mmol). A solution of Pd(PhCN)2Cl2(3.8 mg, 10mol%) and TZ-7 (3.4 mg, 12 mol%) in HFIP (2.0 mL) was premixed and added. Subsequently the vial was capped and closed tightly. The reaction mixture was then stirred at the rate of 200 rpm at 120 °C for 24 h. After being allowed to cool to room temperature, the mixture was acidified with 100 μL of acetic acid and stirred for 30 seconds. The mixture was passed through a pad of celite with EtOAc as the eluent to remove any insoluble precipitate. The resulting solution was concentrated, and the residual mixture was purified using pTLC to afford enantioselective (hetero)arylation products. Racemic samples of the(Hetero)Arylation products for chiral HPLC analysis were prepared by using ligand rac-TZ-7 instead of ligand TZ-7.8. General Procedure for the y-Di(Hetero)Arylation

[0162] In a sealed 10 mL vial equipped with a magnetic stir bar was charged with the appropriate (hetero)arylation substrate (0.10 mmol), Aryl Iodides (0.20 mmol),(55.0 mg, 0.20 mmol), and KH2PO4(27.2 mg, 0.2 mmol). A solution of Pd(PhCN)2Cl2(3.8 mg, 10 mol%) and TZ-7 (4.2 mg, 15 mol%) in HFIP (1.0 mL) was premixed and added.Subsequently the vial was capped and closed tightly. The reaction mixture was then stirred at the rate of 200 rpm at 80 °C for 24 h. After being allowed to cool to room temperature, the mixture was acidified with 100 μL of acetic acid and stirred for 30 seconds. The mixture was passed through a pad of celite with EtOAc as the eluent to remove any insoluble precipitate. The resulting solution was concentrated, and the residual mixture was purified using pTLC to afford enantioselective di-(hetero)arylation products.9. Characterization Data of Products Obtained from the y-(Hetero)Arylation-(4-(methoxycarbonyl)phenyl)-l-propylcyclopentane-l-carboxylic acid (3a)Following the general procedure for the -(hetero)arylation of cyclic aliphatic acids and(hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3a (yellow oil, 21.4 mg, 74% yield, 97% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 6.096 min (minor) and 6.832 min (major).'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).13C NMR (151 MHZ, Chloroform-d) δ 184.3, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.(ll?,3‘V)-3-(4-nitrophenyl)-l-propylcyclopentane-l-carboxylic acid (3b)Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3b (yellow oil, 21.6 mg, 78% yield, 94% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min) with retention time 16.890 min (minor) and 18.438 min (major).'HNMR (600 MHz, Chloroform-d)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= 13 Hz, 3H).13C NMR (151 MHz, Chloroform-d) 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.3-(4-isocyanophenyl)-l-propylcyclopentane-l-carboxylic acid (3c)Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3c (yellow oil, 18.0 mg, 70% yield, 90% ee). The enantiomeric purity was determined by SFC analysis on with retention time 0.90 min (major) and 1.42 min (minor).'HNMR (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). 13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.(ll?,3‘V)-3-(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid (3d)Following the general procedure for the -(hetero)arylation of cyclic aliphatic acids and(hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3d (yellow oil, 17.3 mg, 66% yield, 95% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 8.804 min (minor) and 11.201 min (major).'HNMR (600 MHz, Chloroform-d) 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, 2.4 Hz, 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 = 7.2Hz, 3H).13C NMR (151 MHZ, Chloroform-d) δ 184.1, 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.The absolute stereochemistry was assigned by analogy to compound 6z.-(4-formylphenyl)-l-propylcyclopentane-l-carboxylic acid (3e)Following the general procedure for the hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formicacid) to afford 3e (yellow oil, 15.1 mg, 58% yield, 97% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min) with retention time 20.330 min (minor) and 22.765 min (major). The NMR data matches the reported data (29).‘H NMR (600 MHz, Chloroform-d) 9.97 (s, 1H), 7.81 (d, J= 8.3 Hz, 2H), 7.43 (d, J= 8.1Hz, 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). 13C NMR (151 MHz, Chloroform-d) 192.2, 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.The absolute stereochemistry was assigned by analogy to compound 6z.-(4-acetylphenyl)-l-propylcyclopentane-l-carboxylic acid (30Following the general procedure for the (hetero)arylation of cyclic aliphatic acids and(hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3f (yellow oil, 15.9 mg, 58% yield, 95% ee). The enantiomeric purity was determined by SFC analysis with retention time 1.49 min (minor) and 2.06 min (major).'HNMR (600 MHz, Chloroform-d) 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).13CNMR (151 MHZ, Chloroform-d)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 matches the reported data (29). The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3g (yellow oil, 18.3 mg, 61% yield, 94% ee). The enantiomeric purity was determined by SFC analysis with retention time 0.72 min (minor) and 0.89 min (major).'HNMR (600 MHz, Chloroform-d)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 = 13 Hz, 3H).13C NMR (151 MHz, Chloroform-d)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, 14.5.19F NMR (151 MHz, Chloroform-d) -65.0. The NMR data matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the -(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3h (yellow oil, 16.5 mg, 66% yield, 93% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) with retention time 6.579 min (major) and 9.434 min (minor).‘H NMR (600 MHz, Chloroform-d) 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 = 13 Hz, 3H).13C NMR (151 MHz, Chloroform-d) 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, 7= 21.1 Hz), 53.5, 44.4, 43.8, 42.1, 36.5, 34.8, 19.1, 14.7.19FNMR (376 MHz, Chloroform-d) -120.1. The NMR data matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.(17?,35)-3-(4-chlorophenyl)-l-propylcyclopentane-l-carboxylic acid (3i)Following the general procedure for the -(hetero)arylation of cyclic aliphatic acids and(hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3i (yellow oil, 18.4 mg, 69% yield, 98% ee). The enantiomeric purity was determined by SFC analysis with retention time 1.18 min (minor) and 1.6 min (major).‘H NMR (600 MHz, Chloroform- J) 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 = 13 Hz, 3H).13C NMR (151 MHz, Chloroform-d)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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3j (yellow oil, 19.9 mg, 64% yield, 96% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 7.710 min (major) and 9.024 min (minor).'HNMR (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).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3k (yellow oil, 16.8 mg, 58% yield, 97% ee). The enantiomeric purity was determined by SFC analysis on with retention time 1.01 min (major) and 1.25 min (minor).'H NMR (600 MHz, Chloroform-d) δ 7.93 (t, 7= 1.8 Hz, 1H), 7.86 (dt, J = 7.7, 1.4 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.36 (t, 7= 7.7 Hz, 1H), 3.19 (ddd, 7= 18.4, 11.1, 7.5 Hz, 1H), 2.44 (ddd, 7= 13.2, 7.9, 2.4 Hz, 1H), 2.24 (dd, 7= 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, 7= 7.3 Hz, 3H).13CNMR (151 MHz, Chloroform-d) δ183.8, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.(lR,3S)-3-(3-cyanophenyl)-l-propylcyclopentane-l-carboxylic acid (31)Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 31 (yellow oil, 18.8 mg, 73% yield, 90% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min) with retention time 13.546 min (minor) and 14.747 min (major).'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, 7= 7.3 Hz, 3H).13CNMR(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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3m (yellow oil, 21.4 mg, 78% yield, 93% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 6.850 min (minor) and 7.461 min (major).'HNMR (600 MHz, Chloroform-d) δ 7.87 - 7.84 (m, 2H), 7.78 (dt, J= 7.7, 1.4 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.38 (t, J= 1.1 Hz, 1H), 3.20 (tt, J= 10.9, 7.3 Hz, 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).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.( l / ?.3.S)-3-(3-nitrophenyl)-l -propylcyclopentane- 1 -carboxylic acid (3n)Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3n (yellow oil, 23.5 mg, 85% yield, 91% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (5% IPA / CO2, 2.0 mL / min) with retention time 13.378 min (minor) and 14.566 min (major).'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).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3o (yellow oil, 16.2 mg, 61% yield, 93% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) with retention time 8.005 min (major) and 14.649 min (minor).'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).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3p (yellow oil, 16.2 mg, 63% yield, 98% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (3% IPA / CO2, 2.0 mL / min) with retention time 15.607 min (major) and 17.537 min (minor).'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). 13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3q (yellow oil, 15.0 mg, 60% yield, ).‘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 = 13 Hz, 3H).13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3r (yellow oil, 17.1 mg, 61% yield, 91% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak AD column (15% IPA / CO2, 2.0 mL / min) with retention time 9.989 min (major) and 13.535 min (minor).'HNMR (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, 2.6 Hz, 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, 7= 7.3 Hz, 3H).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3s (yellow oil, 18.4 mg, 69% yield, >99% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (20% IPA / CO2, 2.0 mL / min) with retention time 4.554 min (major). 'HNMR (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= 13 Hz, 3H).13CNMR (151 MHZ, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3t (yellow oil, 24.3 mg, 78% yield, >99% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (20% IPA / CO2, 2.0 mL / min) with retention time 5.258 min (major).'HNMR (600 MHz, Chloroform-d) δ 8.28 (d, J= 5.2 Hz, 1H), 7.40 - 7.39 (m, 1H), 7.18 (dd, 7= 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 = 13 Hz, 3H).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3u (yellow oil, 10.0 mg, 63% yield, 85% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) with retention time 11.133min (major) and 15.444 min (minor).‘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= 7.3 Hz, 3H).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3v (yellow oil, 9.6 mg, 41% yield, 92% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (20% IPA / CO2, 1.0 mL / min) with retention time 10.366 min (major) and 20.266 min (minor).'HNMR (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).13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3w (yellow oil, 23 mg, 76% yield, 82% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AS column (15% IPA / CO2, 2.0 mL / min) with retention time 3.382 min (minor) and 4.032 min (major).1H 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= 13 Hz, 3H).13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3x (yellow oil, 17.2 mg, 60% yield, 98% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 11.569 min (minor) and 13.347 min (major).'HNMR (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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 3y (yellow oil, 23.8 mg, 56% yield, 95% ee). The enantiomeric purity was determined by SFC analysis on with retention time 1.49 min (minor) and 2.06ss min (major). '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).13CNMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4a (yellow oil, 15.2 mg, 58% yield, 76% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 6.036 min (minor) and 6.835 min (major).'HNMR (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).13C NMR (151 MHz, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4b (yellow oil, 18.8 mg, 68% yield, 92% ee). The enantiomeric purity was determined by SFC analysis with retention time 0.93 min (minor) and 1.45 min (major).'HNMR (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).13C 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 matches the reported data (29). The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4c (yellow oil, 13.9 mg, 41% yield, 80% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 10.709 min (minor) and 11.781 min (major).'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).13C NMR (151 MHz, CDCh) 6 183.1, 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 matches the reported data (29).Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4d (yellow oil, 20.5 mg, 56% yield, 89% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min) with retention time 10.310 min (major) and 15.072 min (minor). The NMR data matches the reported data (29).'H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 8.2 Hz, 2H), 6 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= 7.6 Hz, 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).13C NMR (151 MHz, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4f (yellow oil, 14.4 mg, 45% yield, 92% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 11.746 min (minor) and 15.307 min (major).‘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).13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4h (yellow oil, 16.8 mg, 52% yield, 80% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min) with retention time 11.230 min (major) and 19.576 min (minor).'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, 3.8 Hz, 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).13C 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ (hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4i (yellow oil, 19.3 mg, 54% yield, 81% ee). The enantiomeric purity was determined by SFC analysis with retention time 1.06 min (minor) and 1.21 min (major).'HNMR (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, 8.8 Hz, 1H), 2.33 - 2.19 (m, 2H), 1.86 (dq, J = 12.7, 9.0 Hz, 1H).13NMR (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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4m (yellow oil, 16.9 mg, 53% yield, 99% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 5.816 min (major) and 6.984 min (minor).'HNMR (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 = 13 Hz, 3H).13C NMR(151 MHz, CDCh) 6 183.72, 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, 14.70.13C NMR (151 MHz, CDCh) 6 183.7, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4n (yellow oil, 12.9 mg, 37% yield, >99% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (10% IPA / CO2, 2.0 mL / min) with retention time 14832 min (major).‘HNMR (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).13C NMR (151 MHz, CDCh) 6 182.7, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the γ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (15% EtOAc / hexane + 1% formic acid) to afford 4n (yellow oil, 12.9 mg, 37% yield, >99% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min) with retention time 12.380 min (major) and 13.456 min (minor).‘HNMR (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).13C NMR (151 MHz, 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 matches the reported data (29).The absolute stereochemistry was assigned by analogy to compound 6z.10. Characterization Data of Products Obtained from the 6-(Hetero)ArylationFollowing the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6a (yellow oil, 17.9 mg, 65% yield, 91% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min) with retention time 12.380 min (major) and 13.456 min (minor).‘HNMR (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). 13C NMR (126 MHz, Chloroform-d) δ 177.98, 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formicacid) to afford 6b (yellow oil, 17.7 mg, 73% yield, 91% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 8.908 min (major) and 10.665 min (minor).'HNMR (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).13C NMR (151 MHz, Chloroform- d) 5 178.60, 151.46, 132.21, 127.88, 119.11, 109.67, 47.89, 46.81, 44.37, 41.15, 39.32, 33.14, 26.96.HRMS (ESI-TOF) Calcd for+: 244.1332; found: 244.1336.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6c (yellow oil, 17.4 mg, 61% yield, 95% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 8.417 min (major) and 10.200 min (minor).‘HNMR (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).13C NMR (151 MHz, Chloroform- d) 8 177.50, 149.86, 128.23 (q, J= 126.4 Hz), 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, 27.00.19F NMR (376 MHz, CDCh) 8 -64.96. HRMS (ESI-TOF) Calcd for 285.1102; found: 285.1096.The absolute stereochemistry was assigned by analogy to compound 6z.2-((lS,3R)-l-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid (6d)Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6d (yellow oil, 21.3 mg, 81% yield, 81% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 8.908 min (major) and 10.665 min (minor).'HNMR (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).13C NMR (151 MHz, Chloroform- d) 5 178.22, 153.68, 146.31, 127.85, 123.66, 47.95, 46.72, 44.22, 41.20, 39.31, 33.25, 26.98.HRMS (ESI-TOF) Calcd for 285.1102; found: 285.1096.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6e (yellow oil, 15.0 mg, 60% yield, 94% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (5% IPA / CO2, 2.0 mL / min) with retention time 8.534 min (major) and 10.771 min (minor).'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, 6.4 Hz, 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).13C 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.HRMS (ESI-TOF) Calcd for : 247.1334; found: 247.1335.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6f (yellow oil, 19.6 mg, 62% yield, 90% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min) with retention time 7.155 min (major) and 10.785 min (minor).'HNMR (600 MHz, Chloroform-d) δ 7.82 (d, J= 7.1 Hz, 2H), 7.77 (d, J= 8.2 Hz, 2H), 7.60 (t, 7= 7.4 Hz, 1H), 7.50 (t, J= 7.6 Hz, 2H), 7.37 (d, 7= 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, 7 = 13.5, 9.4, 4.8 Hz, 1H), 1.88 - 1.66 (m, 3H), 1.26 (s, 3H).13C 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.HRMS (ESI-TOF) Calcd for : 323.1647; found: 323.1648.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6g (yellow oil, 15.9 mg, 61% yield, 91% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OJ column (10% IPA / CO2, 2.0 mL / min) with retention time 7.155 min (major) and 10.785 min (minor).'HNMR (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).13C 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.HRMS (ESI-TOF) Calcd for C21H22O3[M+H]+: 261.1491; found: 261.1487.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6g (yellow oil, 15.6 mg, 66% yield, 84% ee). The enantiomeric purity was determined by SFC analysis with retention time 6.65 min (minor) and 8.49 min (major).‘HNMR (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).13C NMR (151 MHz, Chloroform-d) δ 178.13, 161.21 (d, J = 244.62 Hz), 141.26 (d, 7= 3.2 Hz), 128.31 (d, 7= 7.7 Hz), 114.99 (d, J = 21.0 Hz), 48.43, 46.90, 43.53, 40.97, 39.33, 33.56, 27.10.HRMS (ESI-TOF) Calcd for C21H22O3[M+H]+: 273.1603; found: 273.1602The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6i (yellow oil, 11.6 mg, 42% yield, 90% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min) with retention time 6.560 min (major) and 10.227 min (minor).'H 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).13C 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.HRMS (ESI-TOF) Calcd for C21H22O3[M+H]+: 277.1440, Found: 277.1440Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formicacid) to afford 6j (yellow oil, 16.6 mg, 64% yield, 87% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min) with retention time 6.560 min (major) and 10.227 min (minor).'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, 7.2 Hz, 1H), 1.94 (ddd, J= 13.7, 9.4, 4.8 Hz, 1H), 1.85 - 1.58 (m, 3H), 1.25 (s, 3H).The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6k (yellow oil, 15.6 mg, 64% yield, 88% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min) with retention time 7.573 min (major) and 8.423 min (minor).'H 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, 6.2 Hz, 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).13C NMR(151 MHz, CDCh) 6 178.1, 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 61 (yellow oil, 14.8 mg, 60% yield, 85% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) with retention time 5.580 min (major) and 7.173 min (minor).'HNMR (600 MHz, Chloroform-d) δ 10.02 (s, 1H), 7.78 (s, 1H), 7.72 (d, J= 7.5 Hz, 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, 7= 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).13C NMR (151 MHz, CDCh) 6 192.67, 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 61 (yellow oil, 14.8 mg, 60% yield, 85% ee). The enantiomeric purity was determined by SFC analysis on a with retention time 6.65 min (minor) and 7.173 min (major). 'HNMR (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).13C NMR (151 MHz, Chloroform-d) 6 178.15, 146.61, 130.90, 130.59 (q, J = 31.71 Hz), 130.43 (q, J= 1.51 Hz), 6 123.80 (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. The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6n (yellow oil, 14.6 mg, 60% yield, 85% ee). The enantiomeric purity was determined by SFC analysis on a with retention time 4.909 min (major) and 5.491 min (minor). '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, lH), 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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6n (yellow oil, 16.3 mg, 60% yield, 88% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) a with retention time 6.940 min (major) and 7.556 min (minor).'H NMR (600 MHz, Chloroform-d) 6 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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.2-((lR,3S)-3-(5-acetylthiophen-2-yl)-l-methylcyclopentyl)acetic acid (6p)Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6p (yellow oil, 12.5 mg, 47% yield, 87% ee). The enantiomeric purity was determined by SFC analysis a with retention time 3.36 min (minor) and 3.78 min (major).'HNMR (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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6q (yellow oil, 15.2 mg, 60% yield, 88% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) a with retention time 10.849 min (major) and 14.545 min (minor).'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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6q (yellow oil, 18.5 mg, 45% yield, 92% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak AD column (30% IPA / CO2, 2.0 mL / min) a with retention time 11.524 min (major) and 17.492 min (minor).'HNMR (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).13C NMR (151 MHz, CDCI3) 6 178.21, 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6s (yellow oil, 18.7 mg, 65% yield, 80% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (10% IPA / CO2, 2.0 mL / min) a with retention time 7.231 min (major) and 8.341 min (minor).‘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).13C NMR (151 MHz, Chloroform-d) δ 177.77, 160.91, 150.52, 121.67, 47.00, 46.47, 43.24, 41.15, 39.09, 32.35, 26.81.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6t (yellow oil, 27.3 mg, 85% yield, 71% ee). The enantiomeric purity wasdetermined by SFC analysis on a Chiralpak AD column (5% IPA / CO2, 2.0 mL / min) a with retention time 7.966 min (major) and 8.778 min (minor).'HNMR (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).13C NMR (151 MHz, CDCI3) 6 177.89, 160.16, 152.10, 148.22 (q, 7= 35.4 Hz), 125.83, 120.81 (q, J = 274.4 Hz). 118.27 (q, 7= 2.7 Hz), 47.05, 46.45, 43.49, 41.21, 39.09, 32.47, 26.86.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6u (yellow oil, 17.9 mg, 62% yield, 90% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (15% IPA / CO2, 2.0 mL / min) a with retention time 7.966 min (major) and 8.778 min (minor).'HNMR (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, 7 = 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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6v (yellow oil, 13.3 mg, 49% yield, 82% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (20% IPA / CO2, 2.0 mL / min) a with retention time 7.966 min (major) and 8.778 min (minor).'HNMR (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, 4.8 Hz, 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).13C NMR (151 MHz, 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6v (yellow oil, 9.3 mg, 32% yield, 93% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak AD column (20% IPA / CO2, 2.0 mL / min) a with retention time 7.966 min (major) and 8.778 min (minor).'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).13C 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6v (yellow oil, 14.6 mg, 48% yield, 90% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min) a with retention time 13.998 min (major) and 15.087 min (minor).'HNMR (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).13C NMR (151 MHz, CDCh) 6 177.75, 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.The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6y (yellow oil, 6.6 mg, 25% yield, 65% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak IC column (7.5% IPA / CO2, 2.0 mL / min) a with retention time 11.047 min (minor) and 12.582 min (major).'HNMR (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, 5.8 Hz, 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). The absolute stereochemistry was assigned by analogy to compound 6z.Following the general procedure for the δ-(hetero)arylation of cyclic aliphatic acids and(hetero)aryl iodide, the compound was purified by pTLC (20% EtOAc / hexane + 1% formic acid) to afford 6z (white solid, 10.8 mg, 25% yield, 65% ee). The enantiomeric purity was determined by SFC analysis on a Chiralpak OD column (10% IPA / CO2, 2.0 mL / min) a with retention time 12.217 min (major) and 13.735 min (minor).'H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J= 8.4 Hz, 2H), 7.42 (d, J= 13 Hz, 2H), 7.36 (t, J= 7.8 Hz, 2H), 7.31 (d, 7= 8.1 Hz, 2H), 7.26 (d, J= 13 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, 7= 9.8, 4.8 Hz, 1H), 2.02 (dd, 7= 13.0, 11.4 Hz, 1H), 1.93 - 1.79 (m, 1H).13C NMR (126 MHz, Chloroform- e 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.Following the general procedure for the y-di(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (25% EtOAc / hexane + 1% formic acid) to afford 7a (yellow oil, 19.4 mg, 49% yield).‘HNMR (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= 13 Hz, 3H).13C NMR (151 MHz, CDCh) 6 182.9, 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.Following the general procedure for the γ-di(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (25% EtOAc / hexane + 1% formic acid) to afford 7b (yellow oil, 29.0 mg, 74% yield).'H NMR (600 MHz, Chloroform-d) 6 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).Following the general procedure for the y-di(hetero)arylation of cyclic aliphatic acids and (hetero)aryl iodide, the compound was purified by pTLC (25% EtOAc / hexane + 1% formic acid) to afford 7d (yellow oil, 11.2 mg, 30% yield).'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).

[0163] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

[0164] This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which are incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:

1. A method of enantioselective remote y-C-H arylation or heteroaryl ati on, 6-C-H arylation or heteroaryl ati on, or sequential y-methylene C-H arylation or heteroarylation of free cycloalkane carboxylic acids comprising the use of palladium catalysts with chiral oxazoline-pyridone ligands.

2. The method of claim 1, comprising the following steps in reaction i) for y-C-H arylation or heteroarylation; reaction ii) for 6-C-H arylation or heteroarylation; and iii) for sequential y- for sequential y-methylene C-H arylation or heteroarylation:wherein each R1is independently H, (C1-C6)alkyl, (C6-C10)aryl, Bn, (C1-C6)alkyl (C6-C10)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 is optionally substituted with one or more R1; each R1is independently halo, (C1-C6)alkyl, -O-(C1-C6)alkyl, or -C(=O)O(C1- C6)alkyl; each Ar is independently (C6-C10)aryl or (C5-C14)heteroaryl optionally substituted with one or more R2;each R2is independently halo, (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; including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.

3. The method of Claim 1 or Claim 2, wherein Ligand (L) is selected from the group consisting of:

4. The method of Claim 2, wherein Ligand (L) is5. The method of Claim 2, wherein Ligand (L) is6. The method of any one of Claims 1-5, wherein R1is (C1-C6)alkyl.

7. The method of Claims 6, wherein R1is nPr or Me.

8. The method of any one of Claims 1-5, wherein R1is optionally substituted Ph.

9. The method of any one of Claims 1-5, wherein R1is optionally substituted Bn.

10. The method of any one of Claims 1-5, wherein R1is optionally substituted (C1- C6)alkyl (C6-C10)aryl.

11. The method of any one of Claims 1-5, wherein R1is optionally substituted -O-(C1- C6)alkyl.

12. The method of any one of Claims 1-5, wherein R1is optionally substituted (C1- C6)alkyl-O-(C1-C6)alkyl.

13. The method of any one of Claims 1-5, wherein R1is optionally substituted halo (C1- C6)alkyl.

14. The method of any one of Claims 1-5, wherein R1is optionally substituted hetero (C1- C6)alkyl.

15. The method of any one of Claims 1-5, wherein R1is optionally substituted (C1- C6)alkyl-C(=O)O(C1-C6)alkyl.

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

17. The method of any one of Claims 1-15, wherein Ar is optionally substituted (C5- C10)heteroaryl.

18. The method of Claim 16 or Claim 17, wherein R2is halo.

19. The method of Claim 16 or Claim 17, wherein R2is (C1-C6)alkyl.

20. The method of Claim 16 or Claim 17, wherein R2is -C(=O)O(C1-C6)alkyl.

21. The method of Claim 16 or Claim 17, wherein R2is NO2.

22. The method of Claim 16 or Claim 17, wherein R2is CN.

23. The method of Claim 16 or Claim 17, wherein R2is -O(C1-C6)alkyl.

24. The method of Claim 16 or Claim 17, wherein R2is -C(=O)H.

25. The method of Claim 16 or Claim 17, wherein R2is -C(=O)(C1-C6)alkyl.

26. The method of Claim 16 or Claim 17, wherein R2is CF3.

27. The method of Claim 16 or Claim 17, wherein R2is 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 of any one of Claims 1-31, wherein the base is KH2PO4.

33. The method of any one of Claims 1-31, wherein the base is34. The method of any one of Claims 1-31, wherein the base is35. The method of any one of Claims 1-31, wherein the base is36. The method of any one of Claims 1-31, wherein the base is37. The method of any one of Claims 1-31, wherein the base is38. The method of any one of Claims 1-31, wherein the base is39. The method of any one of Claims 1-31, wherein the base is40. The method of any one of Claims 1-31, wherein the base is41. The method of any one of Claims 1-31, wherein the base is42. The method of any one of Claims 1-31, wherein the base is43. The method of any one of Claims 1-31, wherein the base is44. The method of any one of Claims 1-31, wherein the base is45. The method of any one of Claims 1-44, wherein the oxidant is46. The method of any one of Claims 1-44, wherein the oxidant is47. The method of any one of Claims 1-44, wherein the oxidant is48. The method of any one of Claims 1-44, wherein the oxidant is49. The method of any one of Claims 1-44, wherein the oxidant is50. The method of any one of Claims 1-49, wherein the palladium source is51. The method of any one of Claims 1-49, wherein the palladium source is52. The method of 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 of 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 approximately 70 °C and approximately 140 °C.

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

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

60. The method of 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:-(4-(m ethoxy carbonyl)phenyl)-l-propylcy cl opentane-1 -carboxylic acid; -(4-nitrophenyl)- l -propylcyclopentane-l -carboxylic acid; -(4-isocyanophenyl)-l-propylcyclopentane-l-carboxylic acid; -(4-methoxyphenyl)-l-propylcyclopentane-l-carboxylic acid; -(4-formylphenyl)-l -propylcyclopentane- 1 -carboxylic acid; -(4-acetylphenyl)-l-propylcyclopentane-l-carboxylic acid; -propyl-3 -(4-(trifluoromethyl)phenyl)cyclopentane- 1 -carboxylic acid; -(4-fluorophenyl)-l-propylcyclopentane-l-carboxylic acid; -(4-chlorophenyl)- 1 -propylcyclopentane- 1 -carboxylic acid; -(4-bromophenyl)- 1 -propylcyclopentane- 1 -carboxylic acid; -(3-(methoxycarbonyl)phenyl)-l-propylcyclopentane-l-carboxylic acid; 3-(3-cyanophenyl)-l-propylcyclopentane-l-carboxylic acid; -(3-acetylphenyl)-l-propylcyclopentane-l-carboxylic acid; -(3-nitrophenyl)-l-propylcyclopentane-l-carboxylic acid; -(3-chlorophenyl)-l-propylcyclopentane-l-carboxylic acid; -(2-cyanophenyl)-l-propylcyclopentane-l-carboxylic acid; -(5-formylfuran-2-yl)-l-propylcyclopentane-l-carboxylic acid; -(5-acetylthiophen-2-yl)- 1 -propylcyclopentane- 1 -carboxylic acid; -(2-chloropyridin-4-yl)-l-propylcyclopentane-l-carboxylic acid; -(2-bromopyridin-4-yl)-l-propylcyclopentane-l-carboxylic acid; -(2,6-dichloropyridin-4-yl)-l-propylcyclopentane-l-carboxylic acid; -Propyl-3-(pyridin-4-yl)cyclopentane-l-carboxylic acid; -(2-methylbenzo[d]thiazol-6-yl)- 1 -propylcyclopentane- 1 -carboxylic acid; -(l-methyl-lH-indazol-5-yl)-l-propylcyclopentane-l-carboxylic acid; -Propyl-3-(l-tosyl-lH-indol-5-yl)cyclopentane-l-carboxylic acid;-3 -(4-(m ethoxy carbonyl)phenyl)- 1 -methylcyclopentane- 1 -carboxylic acid; -l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid; - 1 -benzyl-3 -(4-(m ethoxy carbonyl)phenyl)cy cl opentane- 1 -carboxylic acid; -3-(4-(methoxycarbonyl)phenyl)-l-(3-phenylpropyl)cyclopentane-l-carboxylic acid; 3-(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cyclopentane-l-carboxylic acid; -3 -(4-(m ethoxy carbonyl)phenyl)- 1 -phenylcyclopentane- 1 -carboxylic acid; -l-(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid; -3-(4-(methoxycarbonyl)phenyl)-l-propylcycloheptane-l-carboxylic acid; 3-(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cycloheptane-l-carboxylic acid;and-(4-(methoxycarbonyl)phenyl)-l-propylcyclooctane-l-carboxylic acid.

62. The method of any one of claims 1-5, wherein the product 6 is selected from the group consisting of: -3-(4-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid; -3-(4-cyanophenyl)-l-methylcyclopentyl)acetic acid; -l-methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; -l-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; -3-(4-formylphenyl)-l-methylcyclopentyl)acetic acid; -3-(4-benzoylphenyl)-l-methylcyclopentyl)acetic acid; -3-(4-acetylphenyl)-l-methylcyclopentyl)acetic acid; -3-(4-fluorophenyl)-l-methylcyclopentyl)acetic acid; -3-(3-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid; -3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid; -3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid; -3-(3-formylphenyl)-l-methylcyclopentyl)acetic acid;-l-methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; -3-(2-cyanophenyl)-l-methylcyclopentyl)acetic acid; -3-(5-formylfuran-2-yl)-l-methylcyclopentyl)acetic acid; )-3-(2-chloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; )-3-(5-acetylthiophen-2-yl)-l-methylcyclopentyl)acetic acid; )-l-methyl-3-(l-tosyl-lH-indol-5-yl)cyclopentyl)acetic acid; -3-(2,6-dichloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; -3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-l-methylcyclopentyl)acetic acid; -l-methyl-3-(2-methylbenzo[d]thiazol-6-yl)cyclopentyl)acetic acid; -l-methyl-3-(l-methyl-lH-indazol-5-yl)cyclopentyl)acetic acid; -l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; -3-(4-(m ethoxy carbonyl)phenyl)-l-propylcy cl opentyl)acetic acid; -3-(4-(m ethoxy carbonyl)phenyl)cy cl opentyl)acetic acid; and -3-(4-(methoxycarbonyl)phenyl)-l-phenylcyclopentyl)acetic acid.

63. The method of any one of claims 1-5, wherein the product 7 is selected from the group consisting of:(lA,35,4A)-3-(4-(methoxycarbonyl)phenyl)-4-(4-methoxyphenyl)-l-propylcyclopentane-l- carboxylic acid; -3-(4-methoxyphenyl)-4-(l-methyl-lH-indazol-5-yl)-l-propylcyclopentane-l-carboxylic acid; and-3-(2-chloropyridin-4-yl)-4-(4-methoxyphenyl)-l-propylcyclopentane-l- carboxylic acid.

64. A compound selected from the group consisting of:

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

66. A compound selected from the group consisting of: -3 -(4-(m ethoxy carbonyl)phenyl)- 1 -methylcyclopentane- 1 -carboxylic acid;-l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid;-benzyl-3 -(4-(m ethoxy carbonyl)phenyl)cy cl opentane- 1 -carboxylic acid; -(4-(m ethoxy carbonyl)phenyl)-l -(3 -phenylpropyl)cy cl opentane-1 -carboxylic acid; -(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cyclopentane-l-carboxylic acid; -(4-(m ethoxy carbonyl)phenyl)- 1 -phenylcyclopentane- 1 -carboxylic acid; -(4-chlorophenyl)-3-(4-(methoxycarbonyl)phenyl)cyclopentane-l-carboxylic acid; -(4-(methoxycarbonyl)phenyl)-l-propylcycloheptane-l-carboxylic acid; -(4-(methoxycarbonyl)phenyl)-l-(3-methoxypropyl)cycloheptane-l-carboxylic acid;and -(4-(methoxycarbonyl)phenyl)-l-propylcyclooctane-l-carboxylic acid.

67. A compound selected from the group consisting of: )-3-(4-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid; )-3-(4-cyanophenyl)-l-methylcyclopentyl)acetic acid; )-l-methyl-3-(4-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; )-l-methyl-3-(4-nitrophenyl)cyclopentyl)acetic acid; )-3-(4-formylphenyl)-l-methylcyclopentyl)acetic acid; )-3-(4-benzoylphenyl)-l-methylcyclopentyl)acetic acid; )-3-(4-acetylphenyl)-l-methylcyclopentyl)acetic acid; )-3-(4-fluorophenyl)-l-methylcyclopentyl)acetic acid; )-3-(3-(methoxycarbonyl)phenyl)-l-methylcyclopentyl)acetic acid; )-3 -(3 -acetylphenyl)- 1-methylcy cl opentyl)acetic acid; )-3-(3-acetylphenyl)-l-methylcyclopentyl)acetic acid; )-3-(3-formylphenyl)-l-methylcyclopentyl)acetic acid; )-l-methyl-3-(3-(trifluoromethyl)phenyl)cyclopentyl)acetic acid; )-3-(2-cyanophenyl)-l-methylcyclopentyl)acetic acid; )-3-(5-formylfuran-2-yl)- 1-methylcy cl opentyl)acetic acid;)-3-(5-acetylthiophen-2-yl)-l-methylcyclopentyl)acetic acid; )-3-(2-chloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; )-l-methyl-3-(l-tosyl-lH-indol-5-yl)cyclopentyl)acetic acid; -3-(2,6-dichloropyridin-4-yl)-l-methylcyclopentyl)acetic acid; -3-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-l-methylcyclopentyl)acetic acid; -l-methyl-3-(2-methylbenzo[d]thiazol-6-yl)cyclopentyl)acetic acid; -l-methyl-3-(l-methyl-lH-indazol-5-yl)cyclopentyl)acetic acid; -l-ethyl-3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; -3-(4-(methoxycarbonyl)phenyl)-l-propylcyclopentyl)acetic acid; -3-(4-(methoxycarbonyl)phenyl)cyclopentyl)acetic acid; and -3-(4-(methoxycarbonyl)phenyl)-l-phenylcyclopentyl)acetic acid.

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

69. A method of enantioselective remote y-C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

70. A method of enantioselective remote 5-C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

71. A method of enantioselective remote sequential y-methylene C-H arylation or heteroaryl ati on of free cycloalkane carboxylic acids according to the following reaction scheme:

72. Any compound or method as described herein.

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