SUBSTITUTED PYRROLIDINES AND THEIR USE

BACKGROUND

Technical Field

[0001] This invention relates to compounds that are modulators of the Cystic Fibrosis

Transmembrane Conductance Regulator (CFTR) protein, useful in treating diseases and conditions mediated and modulated by CFTR. This invention also relates to compositions containing compounds of the invention, processes for their preparation, and methods of treatment using them.

Description of Related Technology

[0002] Cystic fibrosis is the most common fatal genetic disease in humans, and affects -0.04% of white individuals. For example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective CF gene without apparent ill effects. However, individuals with two copies of the defective CF gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.

[0003] F508delCFTR, the most common CF mutation (present in at least 1 allele in -90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which protein in turn cannot exit the endoplasmic reticulum (ER) and traffic to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Indeed, even if F508delCFTR is allowed to reach the cell plasma membrane by low-temperature (27 °C) rescue where it can function as a cAMP- activated chloride channel, its activity is decreased significantly compared with WT-CFTR. Other mutations with lower incidence have also been identified that alter the channel regulation or the channel conductance.

[0004] In addition to cystic fibrosis, CFTR activity modulation may be beneficial for other diseases not directly caused by mutations in CFTR, such as, for example, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

[0005] Accordingly, there is a need for novel compounds able to modulate CFTR. In particular, the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis. The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.

SUMMARY

[0006] The present disclosure is directed to compounds having a structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of SO2R ⁶ , C(0)R ⁶ , C(0)OR ⁶ , and C(0)NR ⁷ R ⁸ ;

R ² is selected from the group consisting of C(0)OH or a bioisostere thereof;

R ³ is selected from the group consisting of Ci-C ₆ alkyl, C3-C6 cycloalkyl, 4-12 membered

heterocyclyl, and phenyl; wherein the R ³ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkoxy, OH, oxo, CN, NO2, F, Cl, Br, and I; wherein the R ³ C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and phenyl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, OH, oxo, CN, Br, and I;

R ^3A is selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and Ci-C ₆ haloalkyl;

wherein R ³ and R ^3A , together with the carbon to which they are attached, may form a

C ₃ -C ₆ cycloalkyl; wherein the C ₃ -C ₆ cycloalkyl formed from R ³ and R ^3A and the carbon to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, OH, oxo, CN, NO ₂ , F, Cl, Br, and I;

R ⁴ is selected from the group consisting of R ⁹ , C(0)R ⁹ , C(0)OR ⁹ , and C(O)NR ¹⁰ R ⁿ ;

R ⁵ is selected from the group consisting of 4-12 membered heterocyclyl, Ce-Cm membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, and C ₄ -C ₁₁ cycloalkenyl; wherein the R ⁵ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, and C ₄ -C ₁₁ cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I;

R ⁶ is selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R ⁶ Ci-C ₆ alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁵ , OR ¹⁵ , 0C(0)R ¹⁵ , SR ¹⁵ , NR ¹⁶ R ¹⁷ , NR ¹⁶ S0 ₂ R ¹⁵ , OH, CN, NO2, F, Cl, Br, and I; wherein the R ⁶ 6-l0 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁸ , OR ¹⁸ , C(0)R ¹⁸ , 0C(0)R ¹⁸ , C(0)0R ¹⁸ , S0 ₂ R ¹⁸ , C(0)NR ¹⁹ R ² °, NR ¹⁹ R ²⁰ ,

S0 ₂ NR ¹⁹ R ²⁰ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I;

R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁷ or R ⁸ Ci-C ₆ alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R ⁴⁵ , C(0)NH ₂ ,

C(0)NHCH ₃ , OH, OXO, CN, NO2, F, Cl, Br, and I; wherein each R ⁷ or R ⁸ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl, is optionally substituted with one or more substituents

independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, 6-10 membered aryl, oxo, OH, CN, NO2, F, Cl, Br, and I;

R ⁹ is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁹ Ci-C ₆ alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²¹ , OR ²¹ , SR ²¹ , C(0)R ²¹ , 0C(0)R ²¹ , C(0)0R ²¹ , C(0)NR ²² R ²³ , SO2R ²¹ , NR ²² R ²³ , NR ²² C(0)0R ²¹ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; wherein each R ⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ , C(0)0R ²⁴ , SO2R ²⁴ , NR ²⁵ R ²⁶ , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen, OH, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, C3-C11 cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein each R ¹⁰ or R ¹¹ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁷ , OR ²⁷ , C(0)R ²⁷ , 0C(0)R ²⁷ , C(0)0R ²⁷ , C(0)NR ²⁸ R ²⁹ , SO ₂ R ²⁷ , NR ²⁸ R ²⁹ , OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R ¹⁰ or R ¹¹ C3-C11 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ³⁰ , OR ³⁰ , C(0)R ³⁰ , OC(0)R ³⁰ , C(0)0R ³ °, SO2R ³⁰ , NR ³¹ R ³² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹² , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ¹² 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, OH, oxo, CN, NO2, F, Cl, Br, and I;

R ¹³ and R ¹⁴ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; wherein each R ¹³ or R ¹⁴ C 1 -C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkoxy, OH, oxo, CN, NO2, F, Cl, Br, and I;

R ¹⁵ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ¹⁵ Ci-C ₆ alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R ¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, oxo, OH, CN, NO2, F, Cl, Br, and i; R ¹⁶ and R ¹⁷ , at each occurrence, are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and 5-11 membered heteroaryl; wherein each R ¹⁶ or R ¹⁷ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, oxo, C(0)NR ³³ R ³⁴ , OH, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁸ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ¹⁸ Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, C ₆ -Cio membered aryl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, SO2NH2, OH, oxo, CN, NO2, F, Cl, Br, and I;

R ¹⁹ and R ²⁰ , at each occurrence, are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and C ₆ -Cio membered aryl; wherein each R ¹⁹ or R ²⁰ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C ₆ -Cio membered aryl, OH, CN, NO2, F, Cl, Br, and I;

R ²¹ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ²¹ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more R ³⁵ ; wherein each R ²¹ 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ³⁶ , OR ³⁶ , NR ³⁷ NR ³⁸ , OXO, OH, CN, N0 ₂ , F, Cl, Br, and I;

R ²² and R ²³ , at each occurrence, are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, 6-10 membered aryl, and 5-11 membered heteroaryl; wherein each R ²² or R ²³ Ci-C ₆ alkyl is optionally substituted with one or more R ⁴⁴ ; wherein each R ²² or R ²³ 6-10 membered aryl or 5-11 membered heteroaryl, is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkoxy, Ci-C ₆ alkoxy- OH, 5-6 membered heteroaryl, OH, oxo, CN, NO2, F, Cl, Br, and I; R ²⁴ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ - C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ²⁴ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ alkoxy, C ₃ -C ₁₁ cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ²⁵ and R ²⁶ are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ²⁷ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ²⁷ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO ₂ , F, Cl, Br, and I;

R ²⁸ and R ²⁹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ³⁰ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ³⁰ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO ₂ , F, Cl, Br, and I;

R ³¹ and R ³² , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ³³ and R ³⁴ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ³⁵ , at each occurrence, is each independently selected from the group consisting of 6-10

membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ³⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy;

R ³⁶ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ³⁶ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R ³⁶ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy;

R ³⁷ and R ³⁸ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ⁴⁴ , at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁴⁴ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy;

R ⁴⁵ , at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁴⁵ 6-10 membered aryl, 5-11 membered heteroaryl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ alkoxy, C ₃ -C ₁₁ cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO2, F, Cl, Br, and I;

with the proviso that when R ⁴ is R ⁹ ; and R ⁹ is 4-12 membered heterocyclyl, the 4-12 membered heterocyclyl is attached via a suitable carbon atom; and

with the proviso that the following compounds are excluded from the scope of formula (I): 3- /e/7-butyl-4- (2,5-dichlorobenzoyl)- 1 - (3, 5-dichlorobenzoyl )-5-phenyl pyrrol idine-2- carboxylic acid; l-benzoyl-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-5-phenylpyrro lidine-2- carboxylic acid; 3-/er/-butyl-4-(2-chlorobenzoyl)- l-(3,5-dichlorobenzoyl)-5- phenylpyrrolidine-2-carboxylic acid; 3-/er/-butyl-4-(2,4-dichlorobenzoyl)- 1-(3,5- dichlorobenzoyl)-5-phenylpyrrolidine-2-carboxylic acid; l-benzoyl-3-/er/-butyl-4-(2,4- dichlorobenzoyl)-5-phenylpyrrolidine-2-carboxylic acid; 3-/er/-butyl- l-(chloroacetyl)-4- [(2,4-dichlorophenyl)(hydroxy)methyl]-5-phenylpyrrolidine-2- carboxylic acid; 3-tert- butyl-l-(chloroacetyl)-4-(2,5-dichlorobenzoyl)-5-phenylpyrro lidine-2-carboxylic acid; 3- /er/-butyl-4-[(2,4-dichlorophenyl)(hydroxy)methyl]-l-(methox yacetyl)-5- phenylpyrrolidine-2-carboxylic acid; l-benzoyl-4-(2,5-dimethylfuran-3-carbonyl)-5-(4- fluorophenyl)-3-(4-methoxyphenyl)pyrrolidine-2-carboxylic acid; 3-/er/-butyl-4-(2- chlorobenzoyl)-l-(methoxyacetyl)-5-phenylpyrrolidine-2-carbo xylic acid; 3-/e/7-butyl- 1 - (methoxyacetyl)-4-(2-methoxybenzoyl)-5-phenylpyrrolidine-2-c arboxylic acid; 3-tert- butyl-4-(2, 5-dichlorobenzoyl)- l-(methoxyacetyl)-5-phenylpyrrolidine-2-carboxylic acid; and 3,5-bis(4-chlorophenyl)- 1 -(methoxyacetyl)-4-(thiophene-2-carbonyl)pyrrolidine-2- carboxylic acid.

[0007] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier. Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0008] These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the disclosure.

DETAILED DESCRIPTION

[0009] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt thereof,

[0010] wherein R ¹ , R ² , R ³ , R ^3A , R ⁴ , and R ⁵ ,are defined above in the Summary and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also described.

[0011] Compounds included herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.

Definitions

[0012] It is noted that, as used in this specification and the intended claims, the singular form “a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of the same or different compounds, reference to“a pharmaceutically acceptable carrier” refers to a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.

[0013] As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0014] The term“alkenyl” as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The term “C2-C6 alkenyl” means an alkenyl group containing 2-6 carbon atoms. Non-limiting examples of C2-C6 alkenyl include buta-l,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4- pentenyl, and 5-hexenyl.

[0015] The term“alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term“Ci-C ₆ alkoxy” as used herein, means a Ci-C ₆ alkyl group appended to the parent molecular moiety through an oxygen atom. Non limiting examples of alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, /e/7-butoxy, pentyloxy, and hexyloxy.

[0016] The term“Ci-C ₆ alkoxy-Ci-C ₆ alkyl” as used herein, means a Ci-C ₆ alkoxy group, as defined herein, appended to the parent molecular moiety through a Ci-C ₆ alkyl group, as defined herein. Non-limiting examples of Ci-C ₆ alkoxy-Ci-C ₆ alkyl include, but are not limited to, tert- butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

[0017] The term“Ci-C ₆ alkoxy-OH” as used herein, means a Ci-C ₆ alkoxy group, as defined herein, substituted on the Ci-C ₆ alkyl group with an -OH group.

[0018] The term“alkyl” as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix“C _x -C _y ,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example,“Ci-C ₆ alkyl” means an alkyl substituent containing from 1 to 6 carbon atoms and“C ₁ -C ₃ alkyl” means an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, /e/7-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, l-methylbutyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, l,l-dimethylpropyl, l,2-dimethylpropyl, 2,2- dimethylpropyl, l-methylpropyl, 2-methylpropyl, l-ethylpropyl, and l,2,2-trimethylpropyl. The terms“alkyl,”“Ci-C ₆ alkyl,”“C ₁ -C ₄ alkyl,” and“C ₁ -C ₃ alkyl” used herein are unsubstituted, unless otherwise indicated.

[0019] The term“Ci-C ₆ alkyl-6- 10 membered aryl” as used herein, means a Ci-C ₆ alkoxy group, as defined herein, appended to the parent molecular moiety through a Ci-C ₆ alkyl group, as defined herein. Non-limiting examples of Ci-C ₆ alkoxy-Ci-C ₆ alkyl include, but are not limited to, /e/7-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

[0020] The term“alkylene” or“alkylenyl” means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (Ci-C ₆ alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3 carbon atoms (C ₁ -C ₃ alkylenyl) or of 2 to 6 carbon atoms (C ₂ -C ₆ alkylenyl). Examples of Ci-C ₆ alkylenyl include, but are not limited to, -CH2-, -CH2CH2-, -C(CH3)2-CH ₂ CH ₂ CH2-, -C(CH ₃ )2CH ₂ CH ₂ , CH2CH2CH2CH2-, and - CH ₂ CH(CH ₃ )CH ₂ -.

[0021] The term“alkynyl” as used herein, means a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond. The term“C2-C6 alkynyl” as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of C2-C6 alkynyl include, but are not limited, to acetylenyl, l-propynyl, 2-prop ynyl, 3-butynyl, 2-pentynyl, and l-butynyl.

[0022] The term“aryl” as used herein, means a hydrocarbon ring radical containing carbon atoms, zero heteroatoms, and one or more aromatic rings. The aryl group may be a single-ring (monocyclic) or have two rings (bicyclic). The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system. The term“6-10 membered aryl,” as used herein, means a hydrocarbon ring radical containing 6-10 carbon atoms, zero heteroatoms, and one or more aromatic rings. The 6-10 membered aryl group may be a single-ring (monocyclic) or have two rings (bicyclic). Nonlimiting examples of the aryl groups include, include, but are not limited to, phenyl, indenyl,

tetrahydronaphthalenyl, dihydroindenyl (indanyl), naphthyl, and the like.

[0023] The term“bioisostere”, as used herein, means a moiety with substantially similar physical or chemical properties that impart similar biological properties to the compound having Formula (I). Examples of -C(0)OH bioisosteres include -P(0)(OH) ₂ , -P(0)(OH)(H),

-P(0)(0H)(0-C _I -C ₆ alkyl), -P(0)(CH ₃ )(0H), -B(OH) ₂ , -S0 ₃ H, -CH(OH)CF ₃ , -C(0)NH(0H), -C(0)NH(CN), -C(0)NHS0 ₂ R ^G3a , -S0 ₂ NHC(0)R ^G3a , -C(0)NHS0 ₂ NHR ^G3a , -C(0)NHS0 ₂ N(R ^G3a ) ₂ , -S0 ₂ NH ₂ , -S0 ₂ NHR ^G3a , -S0 ₂ N(R ^G3a ) ₂ , -C(0)NHS(0)(R ^G3a )=NC(0)R ^G3a ,

-C(0)NHS(0)(R ^G3a )=NR ^G3b ,

;

R ^G3a , at each occurrence, is independently selected from the group consisting of C1-G5 alkyl, Ci-Ce alkyl-0-Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, and G ^A ;

R ^G3b is selected from the group consisting of hydrogen, C1-G5 alkyl, C1-G5 haloalkyl and G ^A ;

G ^a , at each occurrence, is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, and heteroaryl; wherein each G ^A , cycloalkyl, cycloalkenyl, aryl, or heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 independently selected R ^u groups; R ^u , at each occurrence, is independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci-C ₆ haloalkyl, -CN, oxo, -NO2, -OR ^j , -0C(0)R ^k ,

-0C(0)N(R ^j ) ₂ , -S(0) ₂ R ^j , -S(0) ₂ N(R ^j ) ₂ , -C(0)R ^k , -C(0)0R ^j , -C(0)N(R ^j ) ₂ , -N(R ^j ) ₂ , -N(R ^j )C(0)R ^k , -N(R ^j )S(0) ₂ R ^k , -N(R ^j )C(0)0(R ^k ), and -N(R ^j )C(0)N(R ^j ) ₂ ;

R ^J , at each occurrence, is independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and Ci-C ₆ haloalkyl; and

R ^k , at each occurrence, is independently selected from the group consisting of Ci-C ₆ alkyl and Ci-C ₆ haloalkyl.

[0024] The term“carbonyl” as used herein means a -C(=0)- group.

[0025] The term“cyano” as used herein, means a -CN group.

[0026] The term“cycloalkenyl” or“cycloalkene” as used herein, means a non-aromatic hydrocarbon ring radical containing carbon atoms, zero heteroatoms, and one or more double bonds. The term“C ₄ -C ₁₁ cycloalkenyl” as used herein, means a non-aromatic hydrocarbon ring radical containing 4-11 carbon atoms, zero heteroatoms, and one or more double bonds. The cycloalkenyl group may be a single-ring (monocyclic) or have two or more rings (polycyclic or bicyclic). Nonlimiting examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, and cyclooctadienyl. The bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group, or a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge containing one, two, three, or four carbon atoms. Nonlimiting examples of the bicyclic cycloalkenyl groups include 4,5,6,7-tetrahydro-3a -indene,

octahydronaphthalenyl, 1 ,6-dihydro-pentalene, and bicyclo[2.2.l]hept-2-enyl. The monocyclic and bicyclic cycloalkenyl may be attached to the parent molecular moiety through any substitutable atom contained within the ring systems, and can be unsubstituted or substituted.

[0027] The term“cycloalkyl” or“cycloalkane” as used herein, means a carbocyclic ring radical containing zero heteroatoms, and zero double bonds. The term“C ₃ -C ₁₁ cycloalkyl” as used herein, means a hydrocarbon ring radical containing 3-11 carbon atoms, zero heteroatoms, and zero double bonds. The cycloalkyl group may be a single-ring (monocyclic) or have two or more rings

(polycyclic or bicyclic). Monocyclic cycloalkyl groups typically contain from 3 to 8 carbon ring atoms (C ₃ -C ₈ monocyclic cycloalkyl), and even more typically 3-6 carbon ring atoms (C ₃ -C ₆ monocyclic cycloalkyl). Nonlimiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups contain two or more rings, and bicyclic cycloalkyls contain two rings. In certain embodiments, the polycyclic cycloalkyl groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic cycloalkyl groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic cycloalkyl, one atom is common to two different rings. Spirocyclic cycloalkyl is exemplified by a monocyclic or a bicyclic cycloalkyl, wherein two of the substituents on the same carbon atom of the ring, together with said carbon atom, form a monocyclic cycloalkyl.

Nonlimiting examples of a spirocyclic cycloalkyl include spiro[2.5]octanyl and spiro[4.5]decanyl. The spirocyclic cycloalkyl groups of the invention can be appended to the parent molecular moiety through any substitutable carbon atom of the groups. In a bridged cycloalkyl, the rings share at least two non-adjacent atoms. Nonlimiting examples of bridged cycloalkyls include

bicyclo[l.l.l]pentanyl, bicyclo[2.2.2]octyl, bicyclo[3.2.l]octyl, bicyclo[3.l.l]heptyl,

bicyclo[2.2.l]heptyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.l]nonyl, and bicyclo[4.2.l]nonyl, tricyclo[3.3. 1 0 ⁷ ]hohn1 (octahydro-2,5-methanopentalenyl or noradamantyl),

tricyclo[3.3. 1.1 ⁷⁷ ]decyl (adamantyl), and tricyclo[4.3.l.l ^3,8 ]undecyl (homoadamantyl). In a fused ring cycloalkyl, the rings share one common bond. Nonlimiting examples of fused-ring cycloalkyl include decalin (decahydronaphthyl), bicyclo[3.l.0]hexanyl, and bicyclo[2.2.0]octyl.

[0028] The term“halo” or“halogen” as used herein, means Cl, Br, I, and F.

[0029] The term“haloalkoxy” as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term“Ci-C ₆ haloalkoxy” means a Ci-C ₆ alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen.

[0030] The term“haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term“Ci-C ₆ haloalkyl” means a Ci-C ₆ alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. The term“C ₁ -C ₃ haloalkyl” means a C ₁ -C ₃ alkyl group, as defined herein, in which one, two, three, four, or five hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,

pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

[0031] The term“heteroaryl” as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by heteroatom independently selected from the group consisting of O, N, and S. The five-membered ring contains two double bonds. The five-membered ring may contain one heteroatom selected from O, N, or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Nonlimiting examples of monocyclic heteroaryl include furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, l,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, l,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Nonlimiting examples of bicyclic heteroaryl groups include 4H-furo[3,2-b]pyrrolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4 /)-yl, 6,7- dihydro-pyrazolo[ 1 ,5-a]pyrazin-5(4//)-yl, 6,7-dihydro- 1 ,3-benzothiazolyl, imidazo[ 1 ,2- _< r/]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 4, 5,6,7- tetrahydropyrazolo[l,5-a]pyridinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,

thiazolo[5,4-/ ]pyridin-2-yl, thiazolo[5,4- _< i]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be alkylated. The monocyclic and bicyclic heteroaryl groups of the invention can be substituted or unsubstituted and are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring systems.

[0032] The term“heterocycle” or“heterocyclic” or“heterocyclyl” as used herein, means a hydrocarbon ring radical wherein at least one carbon atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. The term“4-12 membered heterocyclyl” as used herein, means a hydrocarbon ring radical of 4-12 carbon ring atoms wherein at least one carbon atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. The heterocycle ring may be a single ring (monocyclic) or have two or more rings (bicyclic or polycyclic). In certain embodiments, the monocyclic heterocycle is a four-, five-, six-, seven-, or eight-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. In certain embodiments, the monocyclic heterocycle is a 4-7 membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s). A four-membered monocyclic heterocycle contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. A five-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S.

Nonlimiting examples of five-membered monocyclic heterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Nonlimiting examples of 5-membered monocyclic heterocyclic groups include l,3-dioxolanyl,

tetrahydrofuranyl, dihydrofuranyl, tetrahydro thienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and thiazolidinyl. A six-membered monocyclic heterocycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered monocyclic heterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Nonlimiting examples of six-membered monocyclic heterocycles include dihydropyranyl, l,4-dioxanyl, l,3-dioxanyl, l,4-dithianyl,

hexahydropyrimidine, morpholinyl, l,4-dihydropyridinyl, piperazinyl, piperidinyl,

tetrahydropyranyl, l,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-membered monocyclic heterocycles contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Nonlimiting examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, l,4-diazepanyl, dihydropyranyl, l,3-dioxanyl, l,3-dioxolanyl, l,3-dithiolanyl, l,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. Polycyclic heterocycle groups contain two or more rings, and bicyclic heterocycles contain two rings. In certain embodiments, the polycyclic heterocycle groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic heterocycle groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic heterocycle, one atom is common to two different rings.

Non limiting examples of the spirocyclic heterocycle include 6-oxaspiro[2.5]octanyl, 2- azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl, 2-azaspiro[3.5]nonyl, 2- azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl, 5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl, 2-oxa-6- azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8- azaspiro[4.5]decyl, l-oxa-7-azaspiro[4.4]nonyl, l-oxa-7-azaspiro[3.5]nonyl, l-oxa-8- azaspiro[4.5]decyl, l-oxa-3,8-diazaspiro[4.5]decyl, l-oxa-4,9-diazaspiro[5.5]undecyl, 2-oxa-7- azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl, 7-oxa-2- azaspiro[3.5]nonyl, 8-oxa-2-azaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, l,4-dioxa-8- azaspiro[4.5]decyl, l,3,8-triazaspiro[4.5]decyl. In a fused ring heterocycle, the rings share one common bond. Examples of fused bicyclic heterocycles are a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle. Examples of fused bicyclic heterocycles include, but are not limited to, 1,2- dihydrophthalazinyl, 3,4-dihydro-2H-benzo[/ ][ 1 ,4]dioxepinyl, chromanyl, chromenyl,

isochromanyl, 2,3-dihydrobenzo[/ ][ 1 ,4]dioxinyl, isoindolinyl, 2, 3-dihydrobenzo[/ ] thienyl, hexahydro- 177-cyc lopenta[c]furanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexyl, benzopyranyl, benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro- 1 /7-indolyl, 3,4-dihydroisoquinolin- 2(l//)-yl, 2,3,4,6-tetrahydro- 17/-pyrido[ 1 ,2- _< r/]pyrazin-2-yl, hexahydropyrano[3,4-/ ][ 1 ,4]oxazin- l(5H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(l//)-yl, hexahydrocyclopenta[c]pyrrol-3a(l//)-yl, hexahydro-l//-oxazolo[3,4-a]pyrazinyl, octahydropyrrolo[3,4-h][l,4]oxazinyl,

octahydroimidazo[ 1 ,5-a]pyrazinyl, octahydropyrrolo[ 1 ,2-a]pyrazinyl, octahydro- l//-pyrrolo[3,2- c]pyridinyl, and octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the rings share at least two non-adjacent atoms. Examples of such bridged heterocycles include, but are not limited to, 8- oxabicyclo[3.2.l]octanyl, 7-oxabicyclo[2.2.l]heptanyl, azabicyclo[2.2.l]heptyl (including 2- azabicyclo[2.2.l]hept-2-yl), 8-azabicyclo[3.2.l]oct-8-yl, octahydro-2,5-epoxypentalene, 8-oxa-3- azabicyclo[3.2.l]octyl, hexahydro- 1 H- 1 ,4-methanocyclopenta[r]furan, aza-admantane

(l-azatricyclo[3.3.l.l ^3,7 ]decane), and oxa-adamantane (2-oxatricyclo[3.3.l.l ^3,7 ]decane). The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1- dioxidotetrahydro thienyl, l,l-dioxido-l,2-thiazolidinyl, l,l-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally be quaternized. Non limiting examples of the polycyclic heterocycle include 6,7-dihydro-[l,3]dioxolo[4,5-/]benzofuranyl. The monocyclic, bicyclic, polycyclic, and spirocyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.

[0033] The term“heteroatom” as used herein, means a nitrogen, oxygen, and sulfur. [0034] The term“hydroxyl” or“hydroxyl” as used herein, means an -OH group.

[0035] The term“hydroxyalkyl” as used herein, means an alkyl group, as defined herein, which is substituted by an -OH group substituent. Representative, non-limiting examples of alkoxy include hydroxymethyl, l-hydroxyethyl, 2-hydroxyethyl, l-hydroxypropyl, 2-hydroxypropyl, and 3 -hydroxypropyl .

[0036] The term“oxo” as used herein, means a =0 group.

[0037] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix“C _x -C _y ” or“C _x-y ,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “Ci-C ₆ alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-C6 cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.

[0038] Where a group is a divalent group, the group may be attached in any order to the two groups to which it is attached. By way of example, when W and V are attached by the divalent group -CH2O- this will be understood to include W-CH2O-V and V-CH2O-W.

[0039] As used herein, the term“radiolabel” refers to a compound of the invention in which at least one of the atoms is a radioactive atom or radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons. Examples of such radioactive atoms include, but are not limited to, ³ H (tritium), ¹⁴ C, ⁿ C, ¹⁵ 0, ¹⁸ F, ³⁵ S, ¹²³ I, and ¹²⁵ I.

[0040] If a moiety is described as“substituted,” a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety. Thus, for example, a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).

[0041] If a moiety is described as being“optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.

[0042] The term“subject” is defined herein to refer to humans. The terms“human,”“patient,” and“subject” are used interchangeably herein.

[0043] The terms“treat,”“treating,” and“treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In one embodiment,“treat,”“treating,” and “treatment” refer to slowing the progression of disease or disorder.

[0044] The phrase“therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent or treatment in a particular subject or subject population.

[0045] As used herein,“Class I mutation(s)” refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane. In particular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+lG>T (62l+lG>T), or c.579+lG>T (7ll+lG>T) mutation. More particularly, Class I mutation(s) refers to G542X; or W 1282X mutations.

[0046] As used herein,“Class II mutation(s)” refers to mutations which affect protein maturation. These lead to the production of a CFTR protein that cannot be correctly folded and/or trafficked to its site of function on the apical membrane. In particular, Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asnl303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations.

[0047] As used herein,“Class III mutation(s)” refers to mutations which alter the regulation of the CFTR channel. The mutated CFTR protein is properly trafficked and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel. In particular, Class III mutation(s) refers to p.Gly55lAsp (G551D), G551S, R553G, G1349D, S1251N, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.

[0048] As used herein,“Class IV mutation(s)” refers to mutations which affect chloride conductance. The CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a“gating defect” (most are missense mutations located within the membrane- spanning domain). In particular, Class IV mutation(s) refers to p.Argll7His (R117H), R347P, or р.Arg334Trp (R334W) mutations.

[0049] As used herein,“Class V mutation(s)” refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a“conductance defect” (for example partially aberrant splicing mutations or inefficient trafficking missense mutations). In particular, Class V mutation(s) refers to c.l2lO-l2T[5] (5T allele), c.S3l40-26A>G (3272-26A>G), с.3850-2477C>T (3849+l0kbC>T) mutations.

[0050] As used herein,“Class VI mutation(s)” refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery. In particular, Class VI mutation(s) refers to Rescued F508del, l20del23, N287Y, 4326dellTC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.

Compounds

[0051] The present disclosure provides compounds of formula (I), and pharmaceutically acceptable salt thereof:

wherein

R ¹ is selected from the group consisting of S0 ₂ R ⁶ , C(0)R ⁶ , C(0)OR ⁶ , and C(0)NR ⁷ R ⁸ ;

R ² is selected from the group consisting of C(0)OH or a bioisostere thereof;

R ³ is selected from the group consisting of Ci-C ₆ alkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and phenyl; wherein the R ³ C ₁ -G ₅ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkoxy, OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; wherein the R ³ C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and phenyl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, OH, oxo, CN, Br, and I;

R ^3A is selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and Ci-C ₆ haloalkyl; wherein R ³ and R ^3A , together with the carbon to which they are attached, may form a C3-C6 cycloalkyl; wherein the C3-C6 cycloalkyl formed from R ³ and R ^3A and the carbon to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ⁴ is selected from the group consisting of R ⁹ , C(0)R ⁹ , C(0)0R ⁹ , and C(O)NR ¹⁰ R ⁿ ;

R ⁵ is selected from the group consisting of 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, and C ₄ -C ₁₁ cycloalkenyl; wherein the R ⁵ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, and C ₄ -C ₁₁ cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I;

R ⁶ is selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R ⁶ Ci-C ₆ alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁵ , OR ¹⁵ , 0C(0)R ¹⁵ , SR ¹⁵ , NR ¹⁶ R ¹⁷ ,

NR ^{l 6} S0 ₂ ¹⁵ , OH, CN, NO2, F, Cl, Br, and I; wherein the R ⁶ 6-l0 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁸ , OR ¹⁸ , C(0)R ¹⁸ , 0C(0)R ¹⁸ , C(0)0R ¹⁸ , SO2R ¹⁸ , C(0)NR ¹⁹ R ²⁰ , NR ¹⁹ R ²⁰ , S0 ₂ NR ¹⁹ R ²⁰ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I;

R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁷ or R ⁸ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R ⁴⁵ , C(0)NH ₂ , C(0)NHCH ₃ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; wherein each R ⁷ or R ⁸ 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁

cycloalkenyl, or 4-12 membered heterocyclyl, is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C , haloalkyl, 6-10 membered aryl, oxo, OH, CN, N0 ₂ , F, Cl, Br, and i;

R ⁹ is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁹ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²¹ , OR ²¹ , SR ²¹ , C(0)R ²¹ , OC(0)R ²¹ , C(0)OR ²¹ , C(0)NR ²² R ²³ , S0 ₂ R ²¹ , NR ²² R ²³ , NR ²² C(0)0R ²¹ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; wherein each R ⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ , C(0)0R ²⁴ , S0 ₂ R ²⁴ , NR ²⁵ R ²⁶ , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen, OH, Ci-Ce alkyl, Ci-C ₆ alkoxy, C3-C11 cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein each R ¹⁰ or R ¹¹ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁷ , OR ²⁷ , C(0)R ²⁷ , 0C(0)R ²⁷ , C(0)0R ²⁷ , C(0)NR ²⁸ R ²⁹ , S0 ₂ R ²⁷ , NR ²⁸ R ²⁹ , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; wherein each R ¹⁰ or R ¹¹ C3-C11 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ³⁰ , OR ³⁰ , C(0)R ³ °, 0C(0)R ³ °, C(0)0R ³ °, S0 ₂ R ³ °, NR ³¹ R ³² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹² , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ¹² 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹³ and R ¹⁴ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; wherein each R ¹³ or R ¹⁴ C i -C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkoxy, OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁵ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ¹⁵ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo,

CN, N0 ₂ , F, Cl, Br, and I; wherein each R ¹⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, oxo, OH, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁶ and R ¹⁷ , at each occurrence, are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and 5-11 membered heteroaryl; wherein each R ¹⁶ or R ¹⁷ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, oxo, C(0)NR ³³ R ³⁴ , OH, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁸ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ¹⁸ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, C ₆ -Cio membered aryl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, S0 ₂ NH ₂ , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I;

R ¹⁹ and R ²⁰ , at each occurrence, are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and C6-C10 membered aryl; wherein each R ¹⁹ or R ²⁰ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C ₆ -Cio membered aryl, OH, CN, N0 ₂ , F, Cl, Br, and I;

R ²¹ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ²¹ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl is optionally substituted with one or more R ³⁵ ; wherein each R ²¹ 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ³⁶ , OR ³⁶ , NR ³⁷ NR ³⁸ , oxo, OH, CN, N0 ₂ , F, Cl, Br, and I;

R ²² and R ²³ , at each occurrence, are each independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, 6-10 membered aryl, and 5-11 membered heteroaryl; wherein each R ²² or R ²³ Ci-C ₆ alkyl is optionally substituted with one or more R ⁴⁴ ; wherein each R ²² or R ²³ 6-10 membered aryl, or 5-11 membered heteroaryl, is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkoxy, Ci-C ₆ alkoxy-OH, 5-6 membered heteroaryl, OH, oxo, CN, NO2, F, Cl, Br, and I;

R ²⁴ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ²⁴ Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ alkoxy, C ₃ - C ₁₁ cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO2, F, Cl, Br, and I;

R ²⁵ and R ²⁶ are each independently selected from the group consisting of hydrogen and

Ci-C ₆ alkyl;

R ²⁷ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ²⁷ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO ₂ , F, Cl, Br, and I;

R ²⁸ and R ²⁹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ³⁰ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ³⁰ Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -Cio membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO ₂ , F, Cl, Br, and I;

R ³¹ and R ³² , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ³³ and R ³⁴ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ³⁵ , at each occurrence, is each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ³⁵ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy;

R ³⁶ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ³⁶ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R ³⁶ 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy;

R ³⁷ and R ³⁸ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl;

R ⁴⁴ , at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁴⁴ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy;

R ⁴⁵ , at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ⁴⁵ of 6-10 membered aryl, 5-11 membered heteroaryl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ alkoxy, C3-C11 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO2, F, Cl, Br, and i;

with the proviso that when R ⁴ is R ⁹ ; and R ⁹ is 4-12 membered heterocyclyl, the 4-12

membered heterocyclyl is attached via a suitable carbon atom; and

with the proviso that the following compounds are excluded from the scope of formula (I):

3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(3,5-dichlorobenzo yl)-5-phenylpyrrolidine-2- carboxylic acid;

l-benzoyl-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-5-phenylpy rrolidine-2-carboxylic acid;

3-/er/-butyl-4-(2-chlorobenzoyl)-l-(3,5-dichlorobenzoyl)- 5-phenylpyrrolidine-2-carboxylic acid;

3-/er/-butyl-4-(2,4-dichlorobenzoyl)-l-(3,5-dichlorobenzoyl) -5-phenylpyrrolidine-2- carboxylic acid;

l-benzoyl-3-/er/-butyl-4-(2,4-dichlorobenzoyl)-5-phenylpy rrolidine-2-carboxylic acid;

3-/er/-butyl-l-(chloroacetyl)-4-[(2,4-dichlorophenyl)(hyd roxy)methyl]-5-phenylpyrrolidine-

2-carboxylic acid;

3-/er/-butyl-l-(chloroacetyl)-4-(2,5-dichlorobenzoyl)-5-phen ylpyrrolidine-2-carboxylic acid;

3-/er/-butyl-4-[(2,4-dichlorophenyl)(hydroxy)methyl]-l-(meth oxyacetyl)-5- phenylpyrrolidine-2-carboxylic acid;

l-benzoyl-4-(2,5-dimethylfuran-3-carbonyl)-5-(4-fluorophenyl )-3-(4- methoxyphenyl)pyrrolidine-2-carboxylic acid;

3-/er/-butyl-4-(2-chlorobenzoyl)-l-(methoxyacetyl)-5-phenylp yrrolidine-2-carboxylic acid;

3-/ _< ° r/-butyl- 1 -( methoxyacetyl )-4-(2-methoxybenzoyl )-5-phenyl pyrrol idine-2-carboxylic acid;

3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(methoxyacetyl)-5-phe nylpyrrolidine-2-carboxylic acid; and

3,5-bis(4-chlorophenyl)-l-(methoxyacetyl)-4-(thiophene-2-car bonyl)pyrrolidine-2- carboxylic acid.

[0052] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where

R ¹ is selected from the group consisting of S0 ₂ R ⁶ , C(0)R ^6A , C(0)0R ⁶ , and C(0)NR ⁷ R ⁸ ;

R ^6A is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R ⁶ C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁵ , OR ¹⁵ , OC(0)R ¹⁵ , SR ¹⁵ , NR ¹⁶ R ¹⁷ , NR ^{l 6} S0 ₂ ¹⁵ , OH, CN, NO2, F, Cl, Br, and I; wherein the R ⁶ 6-l0 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹⁸ , OR ¹⁸ , C(0)R ¹⁸ , OC(0)R ¹⁸ , C(0)OR ¹⁸ , SO2R ¹⁸ , C(0)NR ¹⁹ R ²⁰ , NR ¹⁹ R ²⁰ , S0 ₂ NR ¹⁹ R ²⁰ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I;

R ⁴ is selected from the group consisting of R ⁹ , C(0)R ^9A , C(0)OR ⁹ , and C(O)NR ¹⁰ R ⁿ ;

R ^9A is selected from the group consisting of Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R ^9A Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²¹ , OR ²¹ , SR ²¹ , C(0)R ²¹ , OC(0)R ²¹ , C(0)OR ²¹ , C(0)NR ²² R ²³ , SO ₂ R ²¹ , NR ²² R ²³ , NR ²² C(0)0R ²¹ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; wherein each R ^9A 5-11 membered heteroaryl, C ₃ -C ₁₁ cycloalkyl, C ₄ -C ₁₁ cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ , C(0)0R ²⁴ , SO2R ²⁴ , NR ²⁵ R ²⁶ , OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R ^9A 6-10 membered aryl is

R ^9B is selected from the group consisting of hydrogen, R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ ,

C(0)0R ²⁴ , SO2R ²⁴ , NR ²⁵ R ²⁶ , OH, OXO, CN, N0 ₂ , F, Br, and I;

R ^9C is selected from the group consisting of hydrogen, R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ ,

C(0)0R ²⁴ , SO2R ²⁴ , NR ²⁵ R ²⁶ , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I;

R ⁵ is selected from the group consisting of 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, C ₃ -C ₁₁ cycloalkyl, and C ₄ -C ₁₁ cycloalkenyl; wherein the R ⁵ C ₆ -Cio membered aryl, is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2,

Cl, Br, and I; wherein the R ⁵ 4-12 membered heterocyclyl, C ₃ -C ₁₁ cycloalkyl, and C ₄ -C ₁₁ cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ ,

NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and

the remaining variables are as defined for formula (I).

[0053] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; and the remaining variables are as defined for formula (I).

[0054] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl which is optionally substituted with Ci-C ₆ alkoxy; and the remaining variables are as defined for formula (I).

[0055] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl which is optionally substituted with Ci-C ₆ alkoxy; R ^3A is selected from the group consisting of hydrogen and C 1 -C ₆ alkyl; wherein R ³ and R ^3A , together with the carbon to which they are attached, may form a C3-C6 cycloalkyl; R ⁵ is phenyl; and the remaining variables are as defined for formula (I).

[0056] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁵ is phenyl; and the remaining variables are as defined for formula (I).

[0057] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is phenyl; and the remaining variables are as defined for formula (I).

[0058] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is phenyl; R ⁹ is 6-10 membered aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ , C(0)0R ²⁴ , SO2R ²⁴ , NR ²⁵ R ²⁶ , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0059] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/ -butyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is phenyl; R ⁹ is 6-10 membered aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , OH, CN, F, Cl, and Br; and the remaining variables are as defined for formula (I).

[0060] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/ -butyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is phenyl; R ⁹ is 6-10 membered aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , OH, CN, F, Cl, and Br; R ²⁴ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, 6-10 membered aryl, and C3-C11 cycloalkyl; wherein each R ²⁴ Ci-C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ alkoxy, C3-C11 cycloalkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, OH, and F; and the remaining variables are as defined for formula (I).

[0061] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e _/7 -butyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is phenyl; and the remaining variables are as defined for formula (I).

[0062] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e _/7 -butyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is phenyl; R ⁹ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, and 5-11 membered heteroaryl; wherein each R ⁹ Ci-C ₆ alkyl, or C2-C6 alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²¹ , OR ²¹ , SR ²¹ , C(0)R ²¹ , 0C(0)R ²¹ , C(0)0R ²¹ ,

C(0)NR ²² R ²³ , SO2R ²¹ , NR ²² R ²³ , NR ²² C(0)0R ²¹ , OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R ⁹ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ , OR ²⁴ , C(0)R ²⁴ , 0C(0)R ²⁴ , C(0)0R ²⁴ , SO2R ²⁴ , NR ²⁵ R ²⁶ , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0063] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is phenyl; R ⁹ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, and 5-11 membered heteroaryl; wherein each R ⁹ Ci-C ₆ alkyl, or C2-C6 alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²¹ , OR ²¹ , SR ²¹ , SO2R ²¹ , NR ²² R ²³ , NR ²² C(0)0R ²¹ , and OH; and wherein each R ⁹ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ and Cl; and the remaining variables are as defined for formula (I).

[0064] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is phenyl; R ⁹ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl and C2-C6 alkenyl; wherein each R ⁹ Ci-C ₆ alkyl, or C2-C6 alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R ²¹ , OR ²¹ , SR ²¹ , SO2R ²¹ , NR ²² R ²³ , NR ²² C(0)0R ²¹ , and OH; R ²¹ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl; wherein each R ²¹ Ci-C ₆ alkyl is optionally substituted with one or more R ³⁵ ; wherein each R ²¹ 6-10 membered aryl, 5-11 membered heteroaryl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents

independently selected from the group consisting of R ³⁶ , OR ³⁶ , NR ³⁷ NR ³⁸ , oxo, CN, F, and Cl; R ³⁵ , at each occurrence, is 6-10 membered aryl; wherein each R ³⁵ 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C ₆ haloalkyl and Ci-C ₆ alkoxy; R ³⁶ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, 6-10 membered aryl, C3-C11 cycloalkyl, and 4-12 membered heterocyclyl; wherein each R ³⁶ C _I -C ₆ alkyl is optionally substituted with one or more substituents independently selected from the group consisting of F and OH; wherein each R ³⁶ 6-10 membered aryl is optionally substituted with one or more substituents Ci-C ₆ haloalkyl; and the remaining variables are as defined for formula (I).

[0065] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is phenyl; R ⁹ is 5-11 membered heteroaryl; and wherein each R ⁹ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ and Cl; and the remaining variables are as defined for formula (I).

[0066] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is phenyl; R ⁹ is 5-11 membered heteroaryl; and wherein each R ⁹ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ²⁴ and Cl; R ²⁴ , at each occurrence, is each independently selected from the group consisting of Ci-C ₆ alkyl, 6-10 membered aryl, and C3-C11 cycloalkyl; wherein each R ²⁴ 6-10 membered aryl, is optionally substituted with one or more substituents independently selected from the group consisting of C1-G5 alkyl, C1-G5 haloalkyl, C1-G5 alkoxy, F, Cl, and Br; and the remaining variables are as defined for formula (I).

[0067] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is C(0)OR ^9; R ⁵ is phenyl; and the remaining variables are as defined for formula (I).

[0068] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is /e/7-butyl; R ^3A is hydrogen; R ⁴ is C(0)OR ^9; R ⁵ is phenyl; R ⁹ is C1-G5 alkyl; wherein each R ⁹ C1-G5 alkyl is optionally substituted with one or more substituents R ²¹ ; R ²¹ is 6-10 membered aryl; and the remaining variables are as defined for formula (I).

[0069] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is a bioisostere of C(0)OH; wherein the bioisostere is -C(0)NHS0 ₂ R ^G3a ;

R ^G3a , at each occurrence, is independently selected from the group consisting of C1-G5 alkyl, Ci-Ce alkyl-O-Ci-Ce alkyl, Ci-C ₆ haloalkyl, and G ^A ;

G ^a , at each occurrence, is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, and heteroaryl; wherein each G ^A cycloalkyl, cycloalkenyl, aryl, or heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 independently selected R ^u groups;

R ^u , at each occurrence, is independently selected from the group consisting of Ci-C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci-C ₆ haloalkyl, -CN, oxo, -NO2, -OR ^j , -0C(0)R ^k ,

-0C(0)N(R ^j ) ₂ , -S(0) ₂ R ^j , -S(0) ₂ N(R ^j ) ₂ , -C(0)R ^k , -C(0)0R ^j , -C(0)N(R ^j ) ₂ , -N(R ^j ) ₂ , -N(R ^j )C(0)R ^k , -N(R ^j )S(0) ₂ R ^k , -N(R ^j )C(0)0(R ^k ), and -N(R ^j )C(0)N(R ^j ) ₂ ;

R ^J , at each occurrence, is independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and Ci-C ₆ haloalkyl; and

R ^k , at each occurrence, is independently selected from the group consisting of Ci-C ₆ alkyl and Ci-C ₆ haloalkyl.

[0070] In one embodiment, compounds of the present disclosure, and pharmaceutically acceptable salts thereof, are selected from the group consisting of rac-(2R,3S,4R,5S)-3-tert-buty\-l- (cyclopentylacetyl)-4-(2,5-dichlorobenzoyl)-5-phenylpyrrolid ine-2-carboxylic acid; rac- (2R,33',4R,53 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(2,5-dichloro benzoyl)-5-phenylpyrrolidine- 2-carboxylic acid; rac-(2R,3SAR,5S)- 1 -benzoyl-3-/e/ -butyl-4-(2,5-dichlorobenzoyl)-/V- (methanesulfonyl)-5-phenylpyrrolidine-2-carboxamide; rac-(2R,3S,5S)-3-tert-b\xty\-\- (cyclopentanecarbonyl)-4-(2,5-dichlorobenzoyl)-5-phenylpyrro lidine-2-carboxylic acid; rac- (2R,3S,· 4R,5S)- l-(bicyclo[ 1.1. l]pentane- l-carbonyl)-3-/er/-butyl-4-(2, 5-dichlorobenzoyl)-5- phenylpyrrolidine-2-carboxylic acid; mc-(2R,33',4R,53 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4- (2,5-difluorobenzoyl)-5-phenylpyrrolidine-2-carboxylic acid; mc-(2R,3SAR,5S)-3-tert-b\xty\A-(2,5- dichlorobenzoyl)-l-(oxane-4-carbonyl)-5-phenylpyrrolidine-2- carboxylic acid; rac-(2R,3SAR,5S)-

1 -(bicyclo[3.1.0] hexane-6-carbonyl ₎ -3- _/ er _/ -butyl-4-(2, 5-dichlorobenzoyl ₎ -5-phenyl pyrrol idine-2- carboxylic acid; mc-(2R,33 ^, ,4R,53 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(5-fluoro-2- methoxybenzoyl)-5-phenylpyrrolidine-2-carboxylic acid; mc-(2R,33',4R,53 ^, )-3-/er/-butyl-4-(5- chloro-2-methoxybenzoyl)-l-(cyclohexanecarbonyl)-5-phenylpyr rolidine-2-carboxylic acid; rac- (2R,33 ^, ,43 ^, ,53 ^, )-3-/er/-butyl-4-[l-(5-chloro-2-methoxyphenyl)ethenyl] -l-(cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid; mc-(2R,33',4R,53 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2- methoxy-5-(trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-ca rboxylic acid; rac-(2R,3S AR,5S)-3- /er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(cyclohexanecarbo nyl)-A/-(methanesulfonyl)-5- phenylpyrrolidine-2-carboxamide; mc-(2R,3R,4R,53')-4-(5-chloro-2-methoxybenzoyl)-l- (cyclohexanecarbonyl)-3-(2-methoxypropan-2-yl)-5-phenylpyrro lidine-2-carboxylic acid; rac- (2R,33 ^, ,4R,53 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(l5',4 3 ^, )-4-methoxycyclohexane-l- carbonyl]-5-phenylpyrrolidine-2-carboxylic acid; rac-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2- methoxybenzoyl)-l-(3-methoxy-2,2-dimethylpropanoyl)-5-phenyl pyrrolidine-2-carboxylic acid; rac-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(lr,4i ?)-4-methoxycyclohexane-

1 -carbonyl] -5-phenylpyrrolidine-2-carboxylic acid; mc-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2- methoxybenzoyl)-l-(oxane-4-carbonyl)-5-phenylpyrrolidine-2-c arboxylic acid; rac-(2R,3S ,4R,5S)- 3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(li?,3i?)-3-me thoxycyclohexane-l-carbonyl]-5- phenylpyrrolidine-2-carboxylic acid; mc-(2i?,33',4i?,53 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2- hydroxy-5-(trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-ca rboxylic acid; (2S,3R,4S,5R)-3-tert- butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy-5-(trifluoromethy l)benzoyl]-5-phenylpyrrolidine-2- carboxylic acid; rac-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(l3 ^, ,33 ^, )-3- methoxycyclohexane-l-carbonyl]-5-phenylpyrrolidine-2-carboxy lic acid; rac-(2R,3S ,4R,5S)-3-tert- butyl- 1 -(cyclohexanecarbonyl)-/V-(methanesulfonyl)-4-[2-methoxy-5-( trifluoromethyl)benzoyl]-5- phenylpyrrolidine-2-carboxamide; (23 ^, ,3i?,43',5i?)-3-/er/-butyl-4-(5-chloro-2-methoxybenzoy l)- 1 - (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic acid; 1 - { (2.V)- 1 - [(benzyloxy)carbonyl]pyrrolidine-2-carbonyl}-3-/er/-butyl-4- (5-chloro-2-methoxybenzoyl)-5- phenylpyrrolidine-2-carboxylic acid; mc-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-[5-chloro-2- (difluoromethoxy)benzoyl]-l-(cyclohexanecarbonyl)-5-phenylpy rrolidine-2-carboxylic acid; rac- (2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(23 ^, )-l-

(methoxycarbonyl)pyrrolidine-2-carbonyl]-5-phenylpyrrolid ine-2-carboxylic acid; (2S,3R,4R,5R)-3- /°/7-butyl-4- [ 1 -(5-chloro-2-methoxyphenyl)ethenyl] - 1 -(cyclohexanecarbonyl)-5 -phenylpyrrolidine-

2-carboxylic acid; rac-(2R ,3R ,4S ,5S)-4-[ 1 -(5-chloro-2-methoxyphenyl)ethenyl]-3-(2- methoxypropan-2-yl)- l-(2-methyloxane-3-carbonyl)-5-phenylpyrrolidine-2-carboxyli c acid; rac- (2i?,3i?,43',53 ^, )-4-[l-(5-chloro-2-methoxyphenyl)ethenyl]-l-(2-methoxy cyclohexane-l-carbonyl)-3- (2-methoxypropan-2-yl)-5-phenylpyrrolidine-2-carboxylic acid; rac-(2R,3S,4R,5S)-3-tert-buty\-4- [5-chloro-2-(2-hydroxyethoxy)benzoyl]-l-(cyclohexanecarbonyl )-5-phenylpyrrolidine-2-carboxylic acid; rac-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[di(pro pan-2-yl)carbamoyl]- 5-phenylpyrrolidine-2-carboxylic acid; mc-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2- methoxybenzoyl)-5-phenyl-l-{ [(propan-2-yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid; propan- 2-yl mc-(2i?,33',4i?,53 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-2- [(methanesulfonyl)carbamoyl]-5-phenylpyrrolidine-l-carboxyla te; rac-(2R,3R,4R,5S)-4- [(benzyloxy)carbonyl]-l-[di(propan-2-yl)carbamoyl]-3-methyl- 5-phenylpyrrolidine-2-carboxylic acid; mc-(4i?,63',7i?)-7-[(benzyloxy)carbonyl]-5-[di(propan-2-yl)c arbamoyl]-6-phenyl-5- azaspiro[2.4]heptane-4-carboxylic acid; rac-(2i?,33,4i?,53)-4-[(benzyloxy)carbonyl]-3-/er/-butyl-l- [di(propan-2-yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylic acid; rac-(2i?,33,4i?,53)-3-/er/-butyl- l-(cyclohexanecarbonyl)-4-[(i?)-(2,5-dichlorophenyl)(hydroxy )methyl]-5-phenylpyrrolidine-2- carboxylic acid; rac-(2i?,3i?,4i?,53)-4-[(benzyloxy)methyl]-l-[di(propan-2-yl )carbamoyl]-3-methyl- 5-phenylpyrrolidine-2-carboxylic acid; rac-(2i?,3i?,4i?,53)-l-[di(propan-2-yl)carbamoyl]-3-methyl- 4-(phenoxymethyl)-5-phenylpyrrolidine-2-carboxylic acid; rac-(2i?,3i?,4i?,53)-l-[di(propan-2- yl)carbamoyl]-3-methyl-5-phenyl-4-({ [5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-2- carboxylic acid; rac-(2i?,3i?,4i?,53)-4-[(5-chloro-2-methoxyphenoxy)methyl]-l -[di(propan-2- yl)carbamoyl]-3-methyl-5-phenylpyrrolidine-2-carboxylic acid; rac-(2R,3RAS,5S)- l -[di(propan-2- yl)carbamoyl]-3-methyl-4-({ [6-methyl-4-(trifluoromethyl)pyridin-2-yl]amino}methyl)-5- phenylpyrrolidine-2-carboxylic acid; rac-(2R,3RAS,5S)- 1 -[di(propan-2-yl)carbamoyl]-4-( { [6- methoxy-4-(trifluoromethyl)pyridin-2-yl]amino}methyl)-3-meth yl-5-phenylpyrrolidine-2- carboxylic acid; rac-(2R, 3RAS, 53)- l-[di(propan-2-yl)carbamoyl]-4-({ [2-(2-hydroxyethoxy)-5- (trifluoromethyl)pyridin-3-yl]amino}methyl)-3-methyl-5-pheny lpyrrolidine-2-carboxylic acid; rac- (2i?,33,4i?,53)-4-[5-(2-bromo-6-methoxyphenyl)-l,3,4-oxadiaz ol-2-yl]-3-/er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic acid; rac-(2i?,33,4i?,53)-3-/er/-butyl-l- (cyclohexanecarbonyl)-4-[3-(2-methoxy-6-methylphenyl)-l,2,4- oxadiazol-5-yl]-5- phenylpyrrolidine-2-carboxylic acid; (23, 33,43, 5i?)- l-[di(propan-2-yl)carbamoyl]-3-methyl-5- phenyl-4-{ l-[4-(trifluoromethyl)phenyl]-l//-l,2,3-triazol-4-yl}pyrroli dine-2-carboxylic acid; rac- (2i?,33,4i?,53)-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-{ [2-methoxy-5-

(trifbioromethyl)phenoxy] methyl} -5 -phenylpyrrolidine-2-carboxylic acid; rac-(2R,3S AR,5S)-3-tert- butyl-l-(cyclohexanecarbonyl)-4-({ [6-methyl-4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-5- phenylpyrrolidine-2-carboxylic acid; (23,33,43,5/i)-/V ² -(6-aminopyridine-2-sulfonyl)-3-methyl-4- { [3-(2-methylpropoxy)phenoxy]methyl}-5-phenyl-/V ¹ ,/V ¹ -di(propan-2-yl)pyrrolidine-l,2- dicarboxamide; (23 ^, ,33 ^, ,43 ^, ,5/^)-/V ² -(cyclopiOpanesulfonyl)-3-methyl-4-{ [3-(2- methylpropoxy)phenoxy]methyl}-5-phenyl-/V ¹ ,/V ¹ -di(propan-2-yl)pyrrolidine-l, 2-dicarboxamide; rac-(2R,3S S,5S)-3-tert-buty\- 1 -(cyclohexanecarbonyl)-5-phenyl-4-( { (2L -2-[2- (trifluoromethyl)phenyl]pyrrolidin-l-yl}methyl)pyrrolidine-2 -carboxylic acid; and rac- (23,33,43,53)-3-/e/7-butyl- 1 -(cyclohexanecarbonyl)-5-phenyl-4-( { (2R)-2-\2- (trifluoromethyl)phenyl]pyrrolidin-l-yl}methyl)pyrrolidine-2 -carboxylic acid.

[0071] In one embodiment, compounds of the present disclosure, and pharmaceutically acceptable salts thereof, are selected from the group consisting of Examples 4 through 57, 1-1 through 1-52, 1-54, 1-56 through 1-62, II- 1 through 11-794, 11-796 through 11-800, 11-802 through II- 815, 11-818 through 11-863.

[0072] The following compounds are known and explicitly excluded from formula (I): 3-tert- butyl-4-(2,5-dichlorobenzoyl)-l-(3,5-dichlorobenzoyl)-5-phen ylpyrrolidine-2-carboxylic acid; 1- benzoyl-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-5-phenylpyrroli dine-2-carboxylic acid; 3-/er/-butyl-4- (2-chlorobenzoyl)-l-(3,5-dichlorobenzoyl)-5-phenylpyrrolidin e-2-carboxylic acid; 3-/er/-butyl-4- (2,4-dichlorobenzoyl)-l-(3,5-dichlorobenzoyl)-5-phenylpyrrol idine-2-carboxylic acid; l-benzoyl-3- /er/-butyl-4-(2,4-dichlorobenzoyl)-5-phenylpyrrolidine-2-car boxylic acid; 3-/c/7-butyl- 1 - (chloroacetyl)-4-[(2,4-dichlorophenyl)(hydroxy)methyl]-5-phe nylpyrrolidine-2-carboxylic acid; 3- /er/-butyl-l-(chloroacetyl)-4-(2,5-dichlorobenzoyl)-5-phenyl pyrrolidine-2-carboxylic acid; 3-tert- butyl-4-[(2,4-dichlorophenyl)(hydroxy)methyl]-l-(methoxyacet yl)-5-phenylpyrrolidine-2- carboxylic acid; l-benzoyl-4-(2,5-dimethylfuran-3-carbonyl)-5-(4-fluorophenyl )-3-(4- methoxyphenyl)pyrrolidine-2-carboxylic acid; 3-/er/-butyl-4-(2-chlorobenzoyl)-l-(methoxyacetyl)- 5-phenylpyrrolidine-2-carboxylic acid; 3-/er/-butyl- l-(methoxyacetyl)-4-(2-methoxybenzoyl)-5- phenylpyrrolidine-2-carboxylic acid; 3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(methoxyacetyl)-5- phenylpyrrolidine-2-carboxylic acid; and 3,5-bis(4-chlorophenyl)- l-(methoxyacetyl)-4-(thiophene- 2-carbonyl)pyrrolidine-2-carboxylic acid.

[0073] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; and the remaining variables are as defined for formula (I).

[0074] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; and the remaining variables are as defined for formula (I).

[0075] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; and the remaining variables are as defined for formula (I).

[0076] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R ⁴ is C(0)R ⁹ , and the remaining variables are as defined for formula (I).

[0077] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; and the remaining variables are as defined for formula (I). [0078] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0079] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0080] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0081] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is CO(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0082] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0083] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0084] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0085] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0086] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0087] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0088] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0089] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0090] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0091] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0092] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0093] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0094] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0095] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is CO(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C i -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0096] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0097] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C i -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0098] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0099] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0100] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0101] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0102] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0103] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0104] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C ₃ -C ₆ cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0105] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R ⁴ is C(0)0R ⁹ , and the remaining variables are as defined for formula (I).

[0106] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; and the remaining variables are as defined for formula (I).

[0107] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0108] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I). [0109] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)0H; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0110] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is CO(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0111] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0112] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0113] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0114] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0115] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0116] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)0H; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0117] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0118] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0119] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0120] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0121] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0122] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH2, C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0123] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C ₃ -C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C ₃ -C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0124] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C0(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0125] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0126] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0127] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0128] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0129] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C6-C10 membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0130] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0131] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)OR ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0132] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0133] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(0)0R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0134] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R ⁴ is C(O)NR ¹⁰ R ⁿ , and the remaining variables are as defined for formula (I).

[0135] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; and the remaining variables are as defined for formula (I).

[0136] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0137] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0138] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0139] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is CO(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I). [0140] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)0H; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0141] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0142] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0143] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0144] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0145] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0146] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0147] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0148] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0149] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0150] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0151] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH2, C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0152] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, NO2, F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I). [0153] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C0(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0154] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0155] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹

4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0156] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0157] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵

5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0158] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0159] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹

4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0160] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents

independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and

5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0161] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents

independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0162] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is C(O)NR ¹⁰ R ⁿ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents

independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0163] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R ⁴ is R ⁹ , and the remaining variables are as defined for formula (I).

[0164] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; and the remaining variables are as defined for formula (I).

[0165] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0166] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0167] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)0H; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0168] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C0(0)R ⁶ ; R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0169] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)0H; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0170] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I). [0171] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0172] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0173] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)OR ⁶ ; R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0174] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0175] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0176] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)OH; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0177] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)0H; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0178] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)0H; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0179] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)OH; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).

[0180] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, OXO, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0181] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0182] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C0(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0183] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is C ₆ -Cio membered aryl, wherein the R ⁵ C ₆ -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0184] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0185] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0186] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0187] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 5-11 membered heteroaryl; wherein the R ⁵ 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0188] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-Ce alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , C 1 -C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0189] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0190] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)0R ⁶ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C ₆ -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0191] In one embodiment, compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R ¹ is C(0)NR ⁷ R ⁸ ; R ² is C(0)NHS0 ₂ R ³⁹ ; R ³ is Ci-C ₆ alkyl; R ^3A is hydrogen; R ⁴ is R ⁹ ; R ⁵ is 4-12 membered heterocyclyl; wherein the R ⁵ 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R ¹² , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ C(0)R ¹² , OH, oxo, CN, N0 ₂ , F, Cl, Br, and I; R ³⁹ is selected from the group consisting of NR ⁴⁰ R ⁴¹ , Ci-C ₆ alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R ³⁹ Ci-C ₆ alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR ⁴² R ⁴³ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy and phenyl; and wherein the R ³⁹ 4-12 membered heterocyclyl, C ₆ -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH ₂ , Ci-C ₆ alkyl, Ci-C ₆ alkoxy, and Ci-C ₆ hydroxyalkyl; wherein R ⁴⁰ and R ⁴¹ , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl; and wherein R ⁴² and R ⁴³ , at each occurrence, are each independently Ci-C ₆ alkyl; and the remaining variables are as defined for formula (I).

[0192] Compounds of the invention were named using Name 2016.1.1 (File Version N30E41, Build 86668, 25 May, 2016) naming algorithm by Advanced Chemical Development, Inc., or Struct=Name naming algorithm as part of CHEMDRAW ^® ULTRA v. 12.0.2.1076 or Professional Version 15.0.0.106.

[0193] Compounds of the present disclosure may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are“R” or“5” depending on the configuration of substituents around the chiral carbon atom. The terms“R” and“5” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure.

Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or

diastereomers. Individual stereoisomers of compounds of the present disclosure may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art.

[0194] Compounds of the present disclosure may exist as cis or trans isomers, wherein substituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans). For example, cyclobutane may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers. Individual cis or trans isomers of compounds of the present disclosure may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and Irons isomers.

[0195] It should be understood that the compounds of the present disclosure may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the present disclosure.

[0196] The present disclosure includes pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as ² H and ³ H, carbon, such as ⁿ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ Cl, fluorine, such as ¹⁸ F, iodine, such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ 0, ¹⁷ 0 and ¹⁸ 0, phosphorus, such as ³² P, and sulfur, such as ³⁵ S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-l4, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ⁿ C, ¹⁸ F, ¹⁵ 0 and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Pharmaceutical Compositions

[0197] This disclosure also provides for pharmaceutical compositions comprising a

therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0198] In one embodiment, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.

[0199] In another embodiment, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. The additional therapeutic agents may be selected from the group consisting of CFTR modulators and CFTR amplifiers. In other embodiments, the additional therapeutic agents are CFTR modulators. In a particular embodiment, the other therapeutic agent is a cystic fibrosis treatment agent.

[0200] In another embodiment, the additional therapeutic agent(s) are one potentiator, and one or more additional correctors. In another embodiment, the additional therapeutic agent(s) is selected from the group consisting of CFTR modulators and CFTR amplifiers. In another embodiment, the other therapeutic agent(s) is a CFTR modulator. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

[0201] Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451, GLPG3067, GLPG1837, PTI-808, V-(3- carbamo T5,5,7,7-tetrameth T5,7-dihydro-4/7-thieno[2,3-r]pyran-2-yl)- 1 /7-pyrazole-5- carboxamide, and 3-amino-/V-[(25 ^, )-2-hydroxypropyl]-5-{ [4-

(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide. Examples of potentiators are also disclosed in publications: W02005120497, WO2008147952, W02009076593, W02010048573, W02006002421, WO2008147952, W02011072241, WO2011113894, WO2013038373,

WO2013038378, WO2013038381, WO2013038386, W02013038390, WO2014180562,

WO2015018823, WO2014/180562, WO2015018823, WO 2016193812 and W02017208115.

[0202] In one embodiment, the potentiator can be selected from the group consisting of Ivacaftor (VX-770, V-(2,4-di-/er/-butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquino line-3- carboxamide); GLPG1837; GLP-2451; PTI-808; CTP-656; NVS-QBW251; FD1860293;

GLPG3067; 2-(2-fhiorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4//-th ieno[2,3-c]pyran-3- carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydiO-5/7-thieno[2 ,3-r]pyran-2-yl)- 1 H- pyrazole-5-carboxamide; 2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4//-t hieno[2,3- c]pyran-3-carboxamide; 2-(l-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5, 7-dihydro- 4/7-thieno[2,3-r]pyran-3-carboxamide; 5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7- dihydiO-4/7-thieno[2,3-r]pyran-3-carboxamide; 2-(2-hydroxy-2-methylpropanamido)-5, 5,7,7- tetramethyl-5,7-dihydi _O -4/7-thieno[2,3-r]pyran-3-carboxamide; 2-(l-

(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetrameth yl-5,7-dihydro-4//-thieno[2,3- c]pyran-3-carboxamide; 2-(3-hydroxy-2,2-dimethylpropanamido)-5, 5, 7, 7-tetramethyl-5, 7-dihydro- 4/7-thieno[2,3-r]pyran-3-carboxamide; V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4/7- thieno[2,3-c]pyran-2-yl)-5-methyl-l//-pyrazole-3-carboxamide ; /V-(3-carbamoyl-5,5,7,7- tetramethyl-5,7-dihydro-4/7-thieno[2,3-r]pyran-2-yl)-5 -cyclopropyl- 1 /7-pyrazole-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4//-thieno[2 ,3-r]pyran-2-yl)-5- isopropyl- 1 H- pyrazole-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4//-thieno[2 ,3-c]pyran-

2-yl -5-(ti ifl uoio methyl - 1 /7-pyrazole-3-carboxamide; 5-/er/-butyl-iV-(3-carbamo yl-5, 5,7,7- tetramethyl-5,7-dihydro-4/7-thieno[2,3-r]pyran-2-yl)- 1 /7-pyrazole-3-carboxamide; /V-(3-carbamoyl- 5,5,7,7-tetramethyl-5,7-dihydro-4//-thieno[2,3-c]pyran-2-yl) -5-ethyl-l//-pyrazole-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4//-thieno[2 ,3-r]pyran-2-yl)-3-ethyl-4-methyl- 1 H- pyrazole-5-carboxamide; 2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4// - thieno[2,3-c]pyran-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4//-thieno[2 ,3- c]pyran-2-yl)-4-chloro-l//-pyrazole-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7- dihydro-4//-thieno[2,3-c]pyran-2-yl)-l,4,6,7-tetrahydropyran o[4,3-c]pyrazole-3-carboxamide; 4- bromo-/V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4/7-th ieno[2,3-r]pyran-2-yl)- 1 /7-pyrazole-

3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4//-thieno[2 ,3-c]pyran-2-yl)-4- chloro-5-methyl- 1 /7-pyrazole-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4//- thieno[2,3-c]pyran-2-yl)-4-methyl-l//-pyrazole-3-carboxamide ; 2-(2-hydroxy-3,3- dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4//-thie no[2,3-c]pyran-3-carboxamide; 2-[(2- hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4//-th ieno[2,3-c]pyran-3-carboxamide; 5- (2-methoxy-ethoxy)- 17/-pyrazole-3-carboxylic acid (3-carbamo yl-5, 5,7, 7-tetramethyl-4, 7-dihydro- 5//-thieno[2,3-r]pyran-2-yl)-amide; /V-(3-carbamoyl -5,5,7, 7-tetramethyl-4//-th ieno[2,3-r] pyran-2- yl)-4-(3-methoxypropyl)-l//-pyrazole-3-carboxamide; /V-(3-carbamoyl-5,5,7,7-tetramethyl-4/7- thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-l//-pyrazole-3-ca rboxamide; 2-[[(25)-2-hydroxy-3,3- dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4/7-thieno[2,3- r]pyran-3-carboxamide; 2-[[(2i?)-2- hydi _O xy-3,3-diinethyl-butanoyl]aimino]-5,5,7,7-tetrainethyl -4/7-thieno[2,3-r]pyran-3-carboxamide;

2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tet ramethyl-4//-thieno[2,3-r]pyran-3- carboxamide; [5-[(3-carbamoyl-5, 5,7,7 -tetramethyl-4//-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol- l-yl]methyl dihydrogen phosphate; [3-[(3-carbamo yl-5, 5,7, 7-tetramethyl-4//-thieno[2,3-c]pyran-2- yl)carbamoyl]pyrazol-l-yl]methyl dihydrogen phosphate; /V-(3-carbamoyl-5,5,7,7-tetramethyl-4/7- thieno[2,3-c]pyran-2-yl)-4-(l,4-dioxan-2-yl)-l//-pyrazole-3- carboxamide; 5,5,7,7-tetramethyl-2- [[(25 ^, )-3,3,3-trifhioro-2-hydroxy-2-methyl-propanoyl]amino]- 4//-thieno[2,3-c]pyran-3- carboxamide; 2-[[(25 ^, )-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4//-th ieno[2,3-c]pyran-3- carboxamide; 3-amino-/V-(2-hydroxy-2-methylpropyl)-5-{ [4- (trifluoromethoxy)phenyl] sulfonyl }pyridine-2-carboxamide; 3-amino-/V- [(4-hydroxy- 1 - methylpiperidin-4-yl)methyl]-5-{ [4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; 3- am ino-/V-(3-hydroxy-2, 2-dimethyl propyl )-5- { [4-(trifluoromethoxy)phenyl] sulfonyl }pyridine-2- carboxamide; 3-amino-5-[(4-fluorophenyl)sulfonyl]-/V-[(l-hydroxycycloprop yl)methyl]pyridine-2- carboxamide; 3-amino-5-[(4-fluorophenyl)sulfonyl]-/V-[(2i?)-3,3,3-trifluo ro-2- hydroxypropyl]pyridine-2-carboxamide; 3-amino-5-[(3-fluorophenyl)sulfonyl]-/V-(2-hydroxy-2- methylpropyl)pyridine-2-carboxamide; 3-amino-/V-[2-(cyclopropylamino)-2-oxoethyl]-5-{ [4- (trifluoromethoxy)phenyl] sulfonyl }pyridine-2-carboxamide; (3-amino-5-{ [4- (trifluoromethoxy)phenyl] sulfonyl }pyridin-2-yl)(azetidin-l-yl)methanone; (3-amino-5-{ [4- (trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxyme thyl)azetidin-l-yl]methanone; (3- amino-5-{ [4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroa zetidin-l-yl)methanone; 3- am ino-/V-[(2/^)-2-hydiOxy-3-methoxypropyl] -5- { [4-(trifluoromethyl)phenyl] sulfonyl }pyridine-2- carboxamide; (3-amino-5-{ [2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)( 3- hydroxyazetidin-l-yl)methanone; (3-amino-5-{ [2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2- yl)(3,3-difluoroazetidin-l-yl)methanone; rac-3-amino-/V-[(3i?,45 ^, )-4-hydroxytetrahydro-2//-pyran- 3-yl]-5-{ [2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; 3-amino-5-[(4,4- difluoropiperidin-l-yl)sulfonyl]-A/-(3,3,3-trifluoro-2-hydro xypropyl)pyridine-2-carboxamide; (3- amino-5-{ [2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy -3- (trifluoromethyl)azetidin-l-yl]methanone; 3-amino-/V-(2-hydroxy-4-methylpentyl)-5- { [4- (trifluoromethoxy)phenyl] sulfonyl }pyridine-2-carboxamide; (3-amino-5-{ [4- (trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-m ethylazetidin-l-yl)methanone; 3- amino-A/-(3,3,3-trifluoro-2-hydroxypropyl)-5-{ [4-(trifluoromethyl)piperidin-l-yl] sulfonyl Jpyridine-

2-carboxamide; 3-amino-/V-[2-hydroxy-l-(4-methoxyphenyl)ethyl]-5-{ [4- (trifluoromethoxy)phenyl] sulfonyl }pyridine-2-carboxamide; 3-amino-5-[(3,3-difluoroazetidin-l- yl)sulfonyl]-/V-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2- carboxamide; 3-amino-5-{ [2-fluoro-4- (trifluoromethyl)phenyl] sulfonyl} -N- [(23 ^, )-2-hydroxypropyl]pyridine-2-carboxamide; 3-amino-5- { [2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-/V-[(2i?)-2-hy droxy-3-methoxypropyl]pyridine-2- carboxamide; 3-amino-/V-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{ [4- (trifluoromethyl)phenyl] sulfonyl }pyridine-2-carboxamide; (3-amino-5-{ [4- (trifluoromethyl)phenyl] sulfonyl }pyridin-2-yl) [3-hydroxy-3-(trifluoromethyl)azetidin- 1 - yl]methanone; 3-amino-5- { [2-fluoiO-4-(trifluoiOinethyl)phenyl] sulfonyl }-/V-[(3/^)-tetrahydrofuran-

3-ylmethyl]pyridine-2-carboxamide; (3-amino-5-{ [2-fluoro-4- (trifluoromethyl)phenyl] sulfonyl }pyridin-2-yl) [3-hydroxy-3-(trifluoromethyl)azetidin- 1 - yl]methanone; 3-amino-5- { [2-fluoro-4-(trifluoromethyl)phenyl] sulfonyl }-/V-[(3.V)-tetrahydiOfuran-

3-ylmethyl]pyridine-2-carboxamide; 3-amino-5-{ [2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}- /V-[(3.S')-tetrahydrofuran-3-yl methyl] pyridine-2-carboxamide; 3-amino-/V-[2-hydroxy-3-(2,2,2- trifluoroethoxy)propyl]-5-{ [4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide; 3-amino- /V-(3-/e/ -butoxy-2-hydroxypropyl)-5-{ [2-fluoro-4-(trifluoromethyl)phenyl] sulfonyl }pyridine-2- carboxamide; [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(triflu oromethyl)azetidin-l- yl]methanone; { 3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl} [3-hydroxy-3- (trifbioromethyl)azetidin-l-yl]methanone; and 3-amino-/V-[(23 ^, )-2-hydroxy propyl] -5- { [4- (trifluoromethoxy)phenyl] sulfonyl }pyridine-2-carboxamide.

[0203] Non-limiting examples of correctors include Lumacaftor (VX-809), l-(2,2-difluoro-l,3- benzodioxol-5-yl)-/V-{ l-[(2i?)-2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methyl propan-2-yl)- l//-indol-5-yl]cyclopropanecarboxamide (VX-661), VX-983, GLPG2851, GLPG2222, GLPG2665, GLPG2737, GLPG3221, PTI-801, VX-152, VX-440, VX-445, VX-659, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in WO2016069757, WO2016069891, W02017009804, W02017060874, W02017060873, WO2017187321 and U.S. Patent Application Serial No. 15/723896, 15/726075 and PCT Patent Application No.

PCT/IB2017/058179.

[0204] In one embodiment, the corrector(s) can be selected from the group consisting of Lumacaftor (VX-809); 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-/V-{ l-[(2Z?)-2,3-dihydroxypropyl]-6- fhioro-2-(l-hydroxy-2-methylpropan-2-yl)-l//-indol-5-yl}cycl opropanecarboxamide (VX-661); PTI-801; VX-983; GLPG2665; GLPG2851; GLPG2222; GLPG2737; GLPG3221; VX-152; VX- 440; VX-659; VX-445; FDL169; FDL304; FD2052160; FD2035659; 3-[(2Z?,4Z?)-4-({ [l-(2,2- difhioro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2//-chromen- 2-yl]benzoic acid; 3-[(2Z?,4Z?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2//-chromen-2-yl] benzoic acid; 3-[(2//,4//)-4-( { [ 1 - (2,2-difluoro- 1, 3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino)-6-methyl-3, 4-dihydro-2/7- chromen-2-yl] benzoic acid; 3-[(2Z?,4Z?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2//-chro men-2-yl]benzoic acid; 3-[(2Z?,4Z?)-

4-({ [l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)-6-methoxy-3,4-dihydro- 2//-chromen-2-yl]benzoic acid; 3-[(2i?,4i?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihyd ro-2//-chromen-2- yl]cyclohexanecarboxylic acid; 3-[(2L',4L ^> )-4-( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(difhioromethoxy)-3,4-dihyd ro-2//-chromen-2-yl]benzoic acid;

3-[(2i?,4i?)-4-({ [l-(2,2-difhioro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)-7-methoxy- 3,4-dihydro-2//-chromen-2-yl]cyclohexanecarboxylic acid; 3-[(2L',4L ^> )-4-( { [ 1 -(2,2-difluoro- 1 ,3- benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fhioro-3,4-di hydro-2//-chromen-2-yl]benzoic acid; 3-({3-[(2i?,4i?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)-7- methyl-3,4-dihydro-2//-chromen-2-yl]benzoyl} amino)- l-methylcyclopentanecarboxylic acid; 3- [(2i?,4i?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)-7-methyl-3,4- dihydiO-2/7-chroinen-2-yl] -A/- [(2/^)-2, 3-dihydroxy propyl] benzamide; 3-[(2i?,4i?)-4-({ [l-(2,2- difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl }amino)-7-(2-methoxyethoxy)-3,4-dihydro-2//- chromen-2-yl] benzoic acid; 3-[(2i?,4i?)-7-(benzyloxy)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2//-chromen-2-yl] benzoic acid; 3-[(2i?,4i?)-4-({ [1- (2, 2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-(2-fbioroethoxy)-3, 4-dihydro- 2//-chromen-2-yl]benzoic acid; 3-[(2R,4R)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl } am ino)-7-(trifluoiOinethyl)-3,4-dihydiO-2/7-chiOinen-2-yl] benzoic acid; 3- [(2i?,4i?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)-7- (trifluoiOinethyl)-3,4-dihydiO-2/7-chiOinen-2-yl]cyclohexane carboxylic acid; 4-[(2i?,4i?)-4-({ [l- (2,2-difhioro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amin o)-7-methoxy-3,4-dihydro-2//- chromen-2-yl] benzoic acid; 3-[(2R,4R)-4-({ [l-(2,2-difhioro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl } ami no)-8-fluoiO-3,4-dihydiO-2/7-chromen-2-yl] benzoic acid; 4-[(2i?,4i?)-

4-({ [l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)-3,4-dihydro-2//-chromen-

2-yl]benzoic acid; 4-[(2i?,4i?)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihyd ro-2//-chromen-2-yl]benzoic acid; mc-3-[(2i?,45 ^, )-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a mino)tetrahydro- 2//-pyran-2-yl]benzoic acid; rac-4-[(2R,4S)-4-({ [1 -(2,2-difluoro- 1, 3-benzodioxol-5- yl)cyclopropyl]carbonyl } am ino)tetrahydiO-2/7-pyran-2-yl] benzoic acid; 3-[(25',4L ^> )-4-( { [ 1 -(2,2- difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl } am ino)tetrahydi _O -2/7-pyran-2-yl] benzoic acid;

3-[(2/^,45')-4-( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl }amino)tetrahydro-2/7- pyran-2-yl]benzoic acid; rac-3-[(2R,4S,6S)-4-({ [ 1 -(2,2-difluoro- 1, 3-benzodioxol-5- yl)cyclopropyl]carbonyl } am ino)-6-phenyltetrahydro-2/7-pyran-2-yl] benzoic acid; 3-[(25,4i?,6i?)-4- ( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopiOpyl]carbonyl }amino)-6-phenyltetrahydro-2/7- pyran-2-yl]benzoic acid; 3-[(2R,4S,6S)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl } am ino)-6-phenyltetrahydro-277-pyran-2-yl] benzoic acid; 4-[(2//43')-4- ( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl }amino)tetrahydro-277-pyran-2- yl]benzoic acid; 3-cyclobutyl-4- [4- (morpholin-4-yl)piperidin- 1 -yl] - 1 -phenyl- 177-pyrazolo [3 ,4- / ]pyridine-6-carboxylic acid; 3-cyclobutyl- l-phenyl-4-{ 4-[(pyrrolidin- l-yl)methyl]piperidin- l-yl}- l/7-pyrazolo[3,4-h]pyridine-6-carboxylic acid; 5-[(27?,47?)-4-{ [(77?)-2,2-difhioro-7-methyl-6,7- dihydro-2/7-furo [2,3-/] [ 1 ,3]benzodioxole-7 -carbonyl] amino } -7 -methoxy-3 ,4-dihydro-2/7- 1 - benzopyran-2-yl]pyrazine-2-carboxylic acid; 6-[(2i?,4i?)-4-{ [(7 ?)-2,2-difluoro-7-methyl-6,7- dihydro-277-furo[2,3-/][l,3]benzodioxole-7-carbonyl]amino}-7 -(trifhioromethoxy)-3,4-dihydro-277- l-benzopyran-2-yl]pyridine-3-carboxylic acid; //Y/ns-4-[(23 ^, ,43 ^, )-4-{ [(7/^)-2,2-difluoiO-7-methyl-6,7- dihydro-2/7-furo[2,3-/][l,3]benzodioxole-7-carbonyl]amino}-7 -(trifhioromethoxy)-3,4-dihydro-2/7- l-benzopyran-2-yl]cyclohexane-l-carboxylic acid; 6-[(2/?,47?)-7-(difhioromethoxy)-4-{ [(77?)-2,2- difhioro-7-methyl-6,7-dihydro-277-furo[2,3-/][l,3]benzodioxo le-7-carbonyl]amino}-3,4-dihydro- 2/7- 1 -benzopyran-2-yl]pyridine-3-carboxylic acid; /rans-4-[(23 ^, ,43 ^, )-4- { [(7/^)-2,2-difluoiO-7-methyl- 6,7-dihydro-277-furo[2,3-/][l,3]benzodioxole-7-carbonyl]amin o}-7-methoxy-3,4-dihydro-2/7-l- benzopyran-2-yl]cyclohexane-l-carboxylic acid; ethyl //Y/ns-4-[(23 ^, ,43 ^, )-7-(difluoiOinethoxy)-4- { [(7/?)-2,2-difhioro-7-methyl-6,7-dihydro-2/7-furo[2,3-/][l,3 ]benzodioxole-7-carbonyl]amino}-3,4- dihydro-277- l-benzopyran-2-yl]cyclohexane-l-carboxylate; r .s-4-[(2/7,4/7 -4- { [(7/7 -2,2-difluoi o-7- methyl-6,7-dihydro-2/7-furo[2,3-/][l,3]benzodioxole-7-carbon yl]amino}-7-(trifhioromethoxy)-3,4- dihydro-277- l-benzopyran-2-yl]cyclohexane-l-carboxylic acid; lrans-4-[(2SAS)-7- (difhioromethoxy)-4-{ [(7/?)-2,2-difhioro-7-methyl-6,7-dihydro-2/7-furo[2,3-/][l,3 ]benzodioxole-7- carbonyl] amino } -3 ,4-dihydro-277- 1 -benzopyran-2-yl] cyclohexane- 1 -carboxylic acid; 1 -[(2R,4R)-4- { [(77?)-2,2-difluoro-7-methyl-6,7-dihydro-277-furo[2,3-/][l,3 ]benzodioxole-7-carbonyl]amino}-7- (trifhioromethoxy)-3,4-dihydro-277-l-benzopyran-2-yl]cyclopr opane-l -carboxylic acid; trans-4- [(27?,47?)-4-{ [(55 ^, )-2,2-difhioro-5-methyl-6,7-dihydro-2/7,5/7-indeno[5,6 -<7][l,3]dioxole-5- carbonyl] amino } -7-(trifluoromethoxy)-3 ,4-dihydro-277- 1 -benzopyran-2-yl] cyclohexane- 1 - carboxylic acid; trans-4-[(2R,4R)-4-{ [(55 ^, )-2,2-difhioro-5-methyl-6,7-dihydro-277,577-indeno[5,6 - d] [ 1 ,3] dioxole-5-carbonyl] amino } -7 -methoxy-3 ,4-dihydro-277- 1 -benzopyran-2-yl] cyclohexane- 1 - carboxylic acid; trans-4-[(2R,4R)-4-{ [(77?)-2,2-difluoro-7-methyl-6,7-dihydro-277-furo[2,3- /][l,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro- 277-l-benzopyran-2- yl] cyclohexane- 1 -carboxylic acid; /r _< ms-4-[(2//4A ^> )-7-(difluoiOiuethoxy)-4-{ [(7/?)-2,2-difluoro-7- methyl-6,7-dihydro-277-furo[2,3-/][l,3]benzodioxole-7-carbon yl]amino}-3,4-dihydro-277-l- benzopyran-2-yl]cyclohexane-l-carboxylic acid; and /r _< r//7.v-4-[(2/7,477 -4- { [(7/7 -2,2-difluoi o-7- methyl-6, 7-dihydro-2/7-furo[2, 3-/] [l,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3, 4- dihydro-2/7- 1 -benzopyran-2-yl] cyclohexane- 1 -carboxylic acid.

[0205] In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifiers are PTI130 and PTI-428. Examples of amplifiers are also disclosed in WO2015138909 and WO2015138934.

[0206] In one embodiment, the additional therapeutic agent is a CFTR stabilizer. CFTR stabilizers enhance the stability of corrected CFTR that has been treated with a corrector, corrector/ potentiator or other CFTR modulator combination(s). An example of a CFTR stabilizer is cavosonstat (N91115). Examples of stabilizers are also disclosed in W02012048181.

[0207] In one embodiment, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in W02009074575 and W02013043720; and US Patent No. US8,999,976.

[0208] In one embodiment, the ENaC inhibitor is VX-371.

[0209] In one embodiment, the ENaC inhibitor is SPX-101 (S18).

Methods of Use

[0210] Compounds of the invention are useful as modulators of CFTR. Thus, the compounds and compositions are particularly useful for treating or lessening the severity or progression of a disease, disorder, or a condition where hyperactivity or inactivity of CFTR is involved.

Accordingly, the invention provides a method for treating cystic fibrosis in a subject, wherein the method comprises the step of administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a preferred embodiment thereof as set forth above, with or without a pharmaceutically acceptable carrier. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

[0211] One embodiment is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.

[0212] This invention also is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III,

IV, V, and/or VI mutation.

[0213] The present compounds or pharmaceutically acceptable salts thereof may be administered as the sole active agent or it may be co-administered with other therapeutic agents.

The term“co-administered” means the administration of two or more different therapeutic agents to a subject in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus co-administration involves administration at the same time of a single pharmaceutical composition comprising two or more therapeutic agents or administration of two or more different compositions to the same subject at the same or different times.

[0214] In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or two CFTR modulators and one CFTR amplifier.

In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator, one or more correctors, and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention or

pharmaceutically acceptable salts thereof may be co-administered with one potentiator.

[0215] The following Examples may be used for illustrative purposes and should not be deemed to narrow the scope of the present disclosure.

General Synthesis

[0216] Those skilled in the art will recognize that the molecules claimed in this disclosure may be synthesized using a varitey of standard organic chemistry tansformations. While not intended to be exhaustive, representative synthetic organic tranformations which can be used to prepare compounds of the invention are included below.

[0217] Optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

[0218] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the present disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art. Synthesis of the compounds of the present disclosure can be accomplished by methods analogous to those described in the synthetic schemes described herein and in specific examples.

[0219] Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0220] Many of the compounds of the present disclosure have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling.

[0221] It can be appreciated that the synthetic schemes and specific examples as illustrated in the Examples section are illustrative and are not to be read as limiting the scope of the present disclosure as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

Schemes

[0222] The compounds of the present disclosure can be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared. The compounds of this disclosure can be prepared by a variety of synthetic procedures. Representative procedures are shown in, but are not limited to, Schemes 1-10.

Scheme 1

(1-1) (1-2) (1-3)

[0223] As shown in Scheme 1, core compounds of formula (1-3) can be prepared from compounds of formula (1-2). Compounds of formula (1-2), wherein R ^2A is typically Ci-C ₆ alkyl and R ⁵ is as described herein, can be treated first with lithium bromide, followed by compounds of formula (1-1) in the presence of a base such as, but not limited to, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), triethylamine, or potassium carbonate in a solvent such as but not limited to toluene or tetrahydrofuran to provide a racemic mixture of compounds of formula (1-3). The reaction is typically performed at a reduced temperature, such as -78 °C, before quenching with aqueous saturated ammonium chloride.

[0224] Alternatively, a mixture of compounds of formula (1-3) and ((£)-l-(2-methoxy-5- (trifluoromethyl)phenyl)-4,4-dimethylpent-2-en-l-one, wherein R ² is typically Ci-C ₆ alkyl and R ⁵ is as described herein, can be treated with acetyl(oxo) silver in the presence of molecular sieves and a base such as, but not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, or potassium carbonate in a solvent such as but not limited to toluene or tetrahydrofuran to provide a racemic mixture of core compounds of formula (1-3). The reaction is typically performed in an ice bath before warming to room temperature and quenching with aqueous saturated aqueous ammonium chloride. Compounds (1-3) may be obtained as a mixture or may be separated by precipitation or chromato graphy.

Scheme 2

[0225] As shown in Scheme 2, specific examples of compounds of formula (1-1) include enones of formula (2-3). Enones of formula (2-3) can be prepared via aldol condensation of compounds of formula (2-1) where R ⁹ is as defined for fomula (I) with compounds of formula (2-2) to provide compounds of formula (2-3). Examples of aldol condensation conditions include treating compounds of formula (2-1) with a base such as potassium hydroxide in a suitable solvent such as methanol, followed by addition of an aldehyde of formula (2-2). The aldol condensation reaction is typically performed at a suitable temperature, typically ranging from 0-50 °C. Alternatively, enones of formula (2-3) can be prepared by coupling acid chlorides of formula (2-4) where R ⁹ is as defined for fomula (I) with suitable compounds such as and including organotin compounds of formula (2- 5). Organotin compounds of formula (2-5) can be treated with acid chlorides of formula (2-4) in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(0). Co-catalysts such as tri(2- furyl)phosphine may be employed. The coupling reaction is performed in a suitable solvent including, but not limited to tetrahydrofuran at a suitable temperature, which may be an elevated temperature such as 60 °C.

Scheme 3

racemic mixture racemic mixture racemic mixture

(1-3) (3-2) (3-3) [0226] As shown in Scheme 3, compounds of formula (3-3) can be prepared from compounds of formula (1-3). Carboxylic acids of formula (3-1B) where R ^1A is R ⁶ , OR ⁶ , or NR ⁷ R ⁸ as defined in formula (I), can be coupled with amine cores of formula (1-3) to provide compounds of formula (3- 2). Examples of conditions known to generate compounds of formula (3-2) from a mixture of a carboxylic acid and an amine include, but are not limited to, adding a coupling reagent such as, but not limited to, l-chloro-/V,/V,2-trimethylprop-l-en-l -amine (Ghosez reagent), N-( 3- dimethylaminopropyl)-/V-ethylcarbodiimide or 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, ED AC or EDCI) or the corresponding hydrochloride salt, l,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1), /V-[(dimethylamino)- 1 H- 1 ,2,3- triazolo-[4,5-/ ]pyridin- 1 -ylmethylene]-/V-methylmethanaminium hexafluorophosphate N- oxide or 2-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate or 1- [bis(dimethylamino)methylene]- 1 H- \ ,2,3-tnazolo[4,5-/ ]pyndinium 3-oxid hexafluorophosphate (HATU), 0-(benzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium tetrafluoroborate (TBTU), 2-( 1 H- benzo[ _< i][l,2,3]triazol-l-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (HBTU), and 2,4,6-tripropyl- 1,3, 5, 2, 4, 6-trioxatriphosphinane 2,4,6-trioxide (T3P®). The coupling reagents may be added as a solid, a solution, or as the reagent bound to a solid support resin. In addition to the coupling reagents, auxiliary-coupling reagents may facilitate the coupling reaction. Auxiliary coupling reagents that are often used in the coupling reactions include but are not limited to 4- (dimethylamino)pyridine (DMAP), l-hydroxy-7-azabenzotriazole (HO AT) and 1- hydroxybenzotriazole (HOBT). The reaction may be carried out optionally in the presence of a base such as, but not limited to, triethylamine, /V,/V-diisopropylethylamine or pyridine. The coupling reaction may be carried out in solvents such as, but not limited to, tetrahydrofuran, N,N- dimethylformamide, /V,/V-di methyl acetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate. The reactions may be carried out at ambient temperature or heated. The heating can be accomplished either conventionally or with microwave irradiation.

[0227] Alternatively, carboxylic acids of formula (3-1B) can be converted to the corresponding acid chlorides of formula (3-1 A) where R ^1A is R ⁶ , OR ⁶ , or NR ⁷ R ⁸ as defined in formula (I), by reaction with thionyl chloride, PCE, PCI5, cyanuric chloride, oxalyl chloride, or 1 -chloro-/V,/V,2- trimethylprop-l-en-l -amine. The reactions with thionyl chloride and oxalyl chloride can be catalyzed with /V,/V-di methyl form amide at ambient temperature in a solvent such as

dichloromethane. The resultant acid chlorides of formula (3-1 A) (or commercially available acid chlorides of formula (3-1 A)) can then be treated with core amines of formula (1-3) optionally in the presence of a base such as a tertiary amine base such as but not limited to triethylamine or /V,/V- diisopropylethylamine or an aromatic base such as pyridine, at room temperature or heated in a solvent such as dichloro methane to provide compounds of formula (3-2).

[0228] Esters of formula (3-2) can be hydrolyzed in an aqueous hydroxide solution to provide acids of formula (3-3) which are representative of Formula (I). The reaction may be performed in a solvent such as but not limited to methanol, tetrahydrofuran, or mixtures thereof, and may be performed at ambient temperature or an elevated temperature. Alternatively, for acid sensitive esters of formula (3-2) such as /e/7-butyl ester, hydrolysis can be accomplished by treating the former with an acid such as, but not limited to, trifluoroacetic acid. The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, dichloromethane.

Compounds (3-3) may be obtained as a mixture or may be separated by precipitation or

chromatography.

Scheme 4

racemic mixture racemic mixture

(3-3) (4-1)

[0229] As shown in Scheme 4, compounds of formula (4-1) can be prepared from compounds of formula (3-3). Carboxylic acids of formula (3-3) can be coupled with methanesulfonamide to provide compounds of formula (4-1). Examples of conditions known to generate compounds of formula (4-1) from a mixture of a carboxylic acid and methanesulfonamide, include but are not limited to, adding a coupling reagent such as di( 1 //-imidazol- 1 -yljmethanone. The reaction may be carried out in the presence of a base such as, but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and in solvents such as, but not limited to dichloromethane, and l,2-dichloroethane. The reaction is typically performed at elevated temperature, such as 42 °C.

Scheme 5

racemic mixture racemic mixture

(5-2) (5-3)

[0230] Scheme 5 depicts examples of ways to diversify the substituents on the pyrrolidine ring, specifically the R ⁴ substituent. Compounds of formula (5-3) which are representative of Formula (I) can be prepared from compounds of formula (1-2). Compounds of formula (1-2), wherein R ² is typically Ci-C ₆ alkyl and R ⁵ is as described herein, can be treated first with lithium bromide, followed by compounds of formula (2-3) in the presence of a base such as, but not limited to, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, or potassium carbonate in a solvent such as but not limited to toluene, or tetrahydrofuran to provide a racemic mixture of compounds of formula (5-1). The reaction is typically performed at a reduced temperature, such as -78 °C, before quenching with aqueous saturated ammonium chloride. Compounds of formula (5-1) can be transformed to compounds of formula (5-2) using compounds (3-1 A) or (3-1B) as discussed for Scheme 3. Esters of formula (5-2) can be hydrolyzed to compounds of formula (5-3) using methods as described for Scheme 3.

Scheme 6

racemic mixture racemic mixture racemic mixture

(5-2) (6-1) (6-2)

[0231] Scheme 6 depicts further examples of ways to diversify R ⁴ substituents on the pyrrolidine ring. Compounds of formula (6-2) can be prepared from compounds of formula (5-2). Compounds of formula (5-2) can be treated with sodium borohydride to afford compounds of formula (6-1).

The reaction is typically performed at a reduced temperature such as 0 °C or below, in a solvent such as, but not limited to, ethanol, methanol and the like. Other methods which are known to one skilled in the art for reducing ketones to the corresponding alcohol can likewise be utilized. Esters of formula (6-1) can be hydrolyzed to compounds of formula (6-2) which are representative of compounds for Formula (I), using methods as described for Scheme 3.

Scheme 7

racemic mixture racemic mixture

(7-1) (1-2) (7-2) (7-3)

racemic mixture racemic mixture racemic mixture

(7-4) (7-5) (7-6)

[0232] Alternatively, hydroxymethyl R ⁴ substituents on the pyrrolidine ring can be synthesized as shown in Scheme 7. Compounds of formula (7-6) can be prepared from compounds of formula (7-1). Compounds of formula (7-1) where R ^4b is typically substituted or unsubstituted alkyl or cycloalkyl are commercially available or can be synthesized by methods known to one skilled in the art. Compounds of formula (7-1) can be coupled with compounds of formula (1-2) to afford compounds of formula (7-2) by methods discussed above for Scheme 1 for the coupling of compounds of formula (1-1) with those of formula (1-2). Compounds of formula (7-2) can be hydrolyzed to the corresponding carboxylic acid of formula (7-4) by methods known to one skilled in the art. When R ^4b is benzyl, the benzyl group can selectively be removed using hydrogenation conditions. Typical catalysts for hydrogenation include, but are not limited to 10% Pd/C catalyst in a solvent including for example, tetrahydrofuran, or ethyl acetate. The hydrogenation reaction is performed under pressure, such as 15-50 psi H ₂ pressure in a pressure bottle.

[0233] Compounds of formula (7-6) can be prepared from compounds of formula (7-4).

Compounds of formula (7-4) can be treated with isobutyl chloroformate or ethyl chloroformate in the presence of a base including, for example, /V-methyl morpholine or triethylamine. The reaction is performed in a suitable solvent such as for example, tetrahydrofuran, typically at a temperature < 0 °C. Sodium borohydride is added to afford primary alcohols of formula (7-5). Esters of formula (7-5) can be hydrolyzed to compounds of formula (7-6) which are representative of compounds for Formula (I), using methods as described for Scheme 3.

Scheme 8

racemic mixture racemic mixture racemic mixture

(7-5) (8-1) (8-2)

[0234] Primary alcohols of formula (7-5) can be further diversified to ethers, esters, sulfonate, and the like by methods known to one skilled in the art. For example, as illustrated in Scheme 8, compounds of formula (8-2) can be prepared from compounds of formula (7-5). For example, compounds of formula (7-5) can be treated with a nucleophile in the presence of a phosphine such as, and including tributyl phosphine and a coupling agent such as, and including (TGΐ-L^,L^,L^,/n ² - tetramethyldiazene-l, 2-dicarboxamide (TMAD) or diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) under Mitsunobu conditions. Nucleophiles include for example a substituted or unsubstituted phenol to form an ether of formula (8-1). The reaction is performed in a suitable solvent such as, and including tetrahydrofuran, at elevated temperature, for example 50 °C. Esters of formula (8-1) can be hydrolyzed to compounds of formula (8-2) which are representative of compounds for Formula (I), using methods as described for Scheme 3.

Scheme 9

racemic mixture racemic mixture racemic mixture

racemic mixture racemic mixture

(9-3) (9-4)

[0235] As shown in Scheme 9, aminomethyl compounds of formula (9-3) can be prepared from hydroxymethyl compounds of formula (7-5). Compounds of formula (7-5) can be treated with methanesulfonyl chloride in the presence of a suitable base including, but not limited to

triethylamine. The reaction is typically performed at a reduced temperature such as 0 °C or below, in a solvent such as, but not limited to, dichloromethane. Mesylates of formula (9-1) can be treated with sodium azide typically at an elevated temperature such as 65 °C, in a solvent such as, but not limited to, /V,/V-dimethylformamide to afford compounds of formula (9-2). Azides of formula (9-2) can be reduced with triphenylpho spine typically at an elevated temperature such as 50 °C, in a solvent such as, but not limited to, tetrahydrofuran to afford compounds of formula (9-3). Esters of formula (9-3) can be hydrolyzed to compounds of formula (9-4) which are representative of compounds for Formula (I), using methods as described for Scheme 3.

Scheme 10 racemic mixture racemic mixture racemic mixture

(9-3) (10-2) (10-3)

[0236] Additional compounds of varying R ⁴ substituent can be prepared by functionalizing the amino group of compounds of formula (9-3) by methods known to one skilled in the art. For example, compounds of formula (10-2) can be prepared by coupling compounds of formula (10-1), where X is I, Br, Cl or triflate, and R ²² is as defined in formula (I), with amines compounds of formula (9-3) under Buchwald-Hartwig amination conditions known to those skilled in the art and widely available in the literature. The reaction typically requires the use of a base, catalyst, and optionally, a ligand. Examples of bases include, but are not limited to, potassium carbonate, potassium /-butoxide, sodium /-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride. Examples of catalysts include, but are not limited to, dichloro[4,5-dichloro-l,3-bis(2,6-di-3- pentylphenyl)imidazol-2-ylidene] (3-chloropyridyl)palladium(II) (PEPPSTIPentCl), chloro-(2- dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) - methyl- /-butyl ether adduct (RuPhos palladacycle), tetrakis(triphenylphosphine)nickel(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane,

tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. Examples of optional ligands include, but are not limited to, XPhos (2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl), BINAP (2,2'-bis(diphenylphosphino)-l,r-binaphthyl), DPPF (I,G- bis(diphenylphosphino)ferrocene), and Xantphos (4,5-bis(diphenylphosphino)-9,9- dimethylxanthene). The reaction may be conducted in a solvent such as, but not limited to, water, dioxane, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide, dimethoxyethane, N,N- dimethylformamide, toluene, ethanol, tetrahydrofuran, and the like or mixtures thereof. The reaction may be conducted at ambient or elevated temperatures, and optionally in a microwave oven. Esters of formula (10-2) can be hydrolyzed to compounds of formula (10-3) which are representative of compounds for Formula (I), using methods as described for Scheme 3. EXAMPLES

[0237] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0238] Common abbreviations well known to those with ordinary skills in the synthetic art which are used throughout: dba fordibenzylideneaceton; DBU for l,8-diazabicyclo(5.4.0)undec-7- ene or 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine; DCE for l,2-dichloroethane; DCM for dichloromethane; Dess Martin periodinane for 1 , 1 , 1 -tris(acetyloxy)- 1 k ⁵ ,2-benziodoxol-3( 17/)-one; DIEA for /V,/V-diisopropylethylamine; DME for l,2-dimethoxyethane; DMF for /V,/V- dimethylformamide; DMSO for dimethyl sulfoxide; EA or EtOAc for ethyl acetate; EDC for 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide; HATU for ( 1 -[bis(dimethylamino)methylene]- 1 H- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HOBt for hydroxybenzotriazole; MeOH for methanol; MTBE for methyl /e/7-butyl ether; Pd-PEPPSTIPentCl complex for dichloro[4,5-dichloro-l,3-bis(2,6-di-3-pentylphenyl)imidazol -2-ylidene](3- chloropyridyl)palladium(II); TBAF for tetra-n-butylammonium fluoride; TEA for triethylamine; TFA for trifluoroacetic acid; THF for tetrahydrofuran; and XANTPHOS for 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene.

[0239] Other abbreviations well known to those with ordinary skills in the art which are used throughout: atm for atmospheres of gas pressure; ESI for electrospray ionization; g for gram; h for hour or hours; HPLC for high performance liquid chromatography; LC/MS or LCMS for liquid chromatography - mass spectrometry; pL for microliter; pm for micrometer; mg for milligram; min for minute; mL for milliliter; mmol for millimoles; MS for mass spectrum; NMR for nuclear magnetic resonance; psi for pounds per square inch; rt for room temperature; SFC for supercritical fluid chromatography; and UPLC ^® or UHPLC for Ultra High Performance Liquid Chromatography.

[0240] All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 pm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). ¹ H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz), an Agilent 400 MHz NMR spectrometer or a 500 MHz spectrometer. Chemical shifts (d) for ¹ H NMR spectra were reported in parts per million (ppm) relative to tetramethylsilane (d 0.00) or the appropriate residual solvent peak, i.e. CHC (d 7.27), as internal reference. Multiplicities were given as singlet (s), doublet (d), doublet of doublets of doublets (ddd), doublet of doublets of doublets of doublets (dddd), doublet of doublets of quartets (ddq), doublet of doublets of triplets (ddt), doublet of quartets (dq), doublet of triplets of doublets (dtd), heptet (hept), triplet (t), triplet of doublets of doublets (tdd), triplet of quartets (tq), quartet (q), quartet of doublets (qd), quartet of triplets (qt), quintuplet (quin), multiplet (m) and broad (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 50 mm L, Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30 mm L, or Waters Xterra® MS 5 pm C18, 100 x 4.6 mm. The methods were using either acetonitnle/H ₂ 0 gradients (H ₂ 0 contains either 0.1% TFA or 0.1% NH ₃ ) or CH3OH/H2O gradients (H ₂ 0 contains 0.05% TFA). Microwave heating was performed with a Biotage® Initiator.

[0241] Racemic mixtures were separated on an Agilent HP 1100 system with UV detection. Column used: Chiralpak® IA (10 x 250 mm, 5 pm). Solvents used: Ao-propyl alchohol and tert- butyl methyl ether. Enantiomeric purity was determined on an Agilent HP 1100 system with UV detection. Column used: Chiralpak® IA (4.6 x 250 mm, 5pm). Solvents used were A - propyl alchohol and /e/7-butyl methyl ether.

Reverse phase purification methods

Prep LC/MS Method TFA8

[0242] Samples were purified by reverse phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (50 mm x 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 35% A, 0.5- 8.0 minute linear gradient 35-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-35% A, 9.1- 10 minute 35% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method TFA 11

[0243] Samples were purified by reverse phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 mih 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-1.0 minute 5% A, 1.0- 8.5 minute linear gradient 5-100% A, 8.5-11.5 minute 100% A, 11.5-12.0 minute linear gradient 95- 5% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

Prep LC/MS Method AA9

[0244] Samples were purified by reverse phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) was used, at a flow rate of 50 mL/minute (0-1.0 minute 5% A, 1.0- 8.5 minute linear gradient 5-100% A, 8.5-11.5 minute 100% A, 11.5-12.0 minute 95-5% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[0245] Stereochemistry of final compounds was arbitrarily assigned in some cases, based on the order of elution and/or activity with respect to existing analogs.

Example 1

rac-(2i?,35 ^, ,4i?,55 ^, )-l-benzoyl-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-5-phe nylpyrrolidine-2- carboxylic acid

Example 1A

/e/7-butyl [(7f)-benzylideneamino] acetate

[0246] A slurry of glycine /e/7-butyl ester hydrochloride (10.04 g, 59.9 mmol),

dichloromethane (100 mL), benzaldehyde (6.07 mL, 59.9 mmol), triethylamine (8.35 mL, 59.9 mmol), and magnesium sulfate (14.42 g, 120 mmol) was stirred at room temperature. After 19 h, the slurry was filtered, concentrated, toluene added (30 mL), and filtered again. The filtrate was concentrated to a minimal volume, pipet filtered through a kimwipe with minimal toluene rinse, then concentrated, giving the title compound (11.429 g, 52.1 mmol, 87 % yield). ¹ H NMR (400 MHz, DMSO-ifc) d 8.34 (d, /= 1.3 Hz, 1H), 7.76 (dd, /= 7.5, 2.1 Hz, 2H), 7.54 - 7.39 (m, 3H), 4.31 (d, /= 1.3 Hz, 2H), 1.44 (s, 9H); MS (ESI+) m/z 220 (M+H) ⁺ .

Example 1B

(£ ^’ )-l-(2,5-dichlorophenyl)-4,4-dimethylpent-2-en-l-one

[0247] A solution of 2',5'-dichloroacetophenone (3.3 mL, 22.90 mmol) and

trimethylacetaldehyde (5.29 mL, 47.9 mmol) in methanol (115 mL) at 0 °C was treated with potassium hydroxide (4.58 mL, 4.58 mmol) and the reaction allowed to warm to ambient temperature. The reaction was stirred for 72 h. The solvent was removed in vacuo and the reaction diluted with water (95 mL) and neutralized with 1 M aqueous HC1 (4.6 mL). The reaction was extracted with methyl /e/7-butyl ether (3 x 100 mL) and the extracts dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude material was purified using an 80 g silica gel cartridge with a gradient of 5-40% methyl /e/7-butyl ether/heptanes over 30 minutes to give the title compound (3.06 g, 11.90 mmol, 52.0 % yield). ^X H NMR (501 MHz, DMSO-tfc) d 7.62 - 7.55 (m, 3H), 6.66 (d, / = 16.1 Hz, 1H), 6.33 (d, / = 16.1 Hz, 1H), 1.07 (s, 9H); MS (ESI+) m/z 258 (M+H) ⁺ .

Example 1C

rac-(2R,3S,4R,5S)-tert-buty\ 3- ₍ 7er/-butyl )-4-(2, 5-dichlorobenzoyl )-5 -phenyl pyrrol idine-2- carboxylate

[0248] A solution of Example 1A (1.312 g, 5.98 mmol), tetrahydrofuran (29.9 mL), and lithium bromide (5.98 mL, 8.97 mmol) was cooled to <-70 °C and Example 1B (1.539 g, 5.98 mmol) and DBU (1.082 mL, 7.18 mmol) were added at < -70 °C. After 90 minutes, the reaction was at -20 °C. The reaction was allowed to warm to 5 °C and was at this temperature for 1 h. Added saturated aqueous NH ₄ Cl (15 mL), methyl /e/7-butyl ether (100 mL), and water (15 mL), separated the layers, dried (Na ₂ S0 ₄ ) the organic layer, concentrated, and a solid was observed. Added heptane (~20 mL) and triturated then heated until everything dissolved, then let cool overnight. A precipitate formed, which was filtered, and washed with 20 mL more heptane to give the title compound (2.22 g, 4.66 mmol, 78 % yield). ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.41 (dd, / = 8.6, 2.5 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.22 - 7.08 (m, 3H), 7.06 (d, / = 2.4 Hz, 1H), 4.42 (dd, J= 10.6, 7.3 Hz, 1H), 4.26 (dd, / = 7.4, 3.5 Hz, 1H), 3.61 (dd, / = 8.7, 6.6 Hz, 1H), 3.14 (dd, /= 10.6, 8.7 Hz, 1H), 2.68 (dd, / = 6.6, 3.5 Hz, 1H), 1.47 (s, 9H), 0.94 (s, 9H); MS (ESI+) m/z 477 (M+H) ⁺ .

Example 1D

rac-(2R,3S ,4R,5S)-tert-buty\ l-benzoyl-3-(/er/-butyl)-4-(2,5-dichlorobenzoyl)-5-phenylpyr rolidine-

2-carboxylate

[0249] A solution of Example 1C (216 mg, 0.453 mmol) and triethylamine (0.126 mL, 0.907 mmol) in dichloromethane (2.0 mL) at 25 °C was treated dropwise with benzoyl chloride (76 mg, 0.544 mmol). After 1 h, the reaction was quenched with 10 drops of 1N aqueous ammonium hydroxide and the solvent removed under a stream of nitrogen. The crude material was purified using 5-50-% methyl /e/7-butyl ether/heptanes to give the title compound (208 mg, 0.358 mmol,

79 % yield). NMR (400 MHz, DMSO -de) d 7.40 - 7.13 (m, 9H), 6.99 (q, 7= 6.8, 6.2 Hz, 3H), 6.91 (d, 7 = 2.4 Hz, 1H), 5.56 (d, 7 = 10.0 Hz, lH), 4.7l (dd, 7 = 10.1, 4.5 Hz, 1H), 4.44 (d, 7= 3.6 Hz, 1H), 3.10 (t, 7 = 4.0 Hz, 1H), 1.51 (s, 9H), 1.00 (s, 9H); MS (ESI-) m/z 584 (M-H) .

Example 1E

rac-(2R,35,4R,55)-l-benzoyl-3-/er/-butyl-4-(2,5-dichlorobenz oyl)-5-phenylpyrrolidine-2- carboxylic acid

[0250] Example 1D (100 mg, 0.172 mmol) was dissolved in trifluoro acetic acid (0.5 mL). After 30 minutes, the solvent was removed under a stream of nitrogen and the crude material triturated with diethyl ether and «-heptane to give the title compound (83 mg, 0.158 mmol, 92 % yield). ^l H NMR (400 MHz, DMSO -de) d 7.33 (dd, 7= 8.6, 2.6 Hz, 1H), 7.30 - 7.12 (m, 8H), 6.98 (pt, 7 = 6.2, 1.8 Hz, 3H), 6.89 (d, 7= 2.5 Hz, 1H), 5.54 (d, 7= 10.0 Hz, 1H), 4.69 (dd, 7= 10.1, 4.7 Hz, 1H), 4.50 (d, 7 = 3.8 Hz, 1H), 3.17 (t, 7 = 4.2 Hz, 1H), 0.99 (s, 9H); the COOH (exchangeable) proton does not appear in the ^X H NMR; MS (ESI+) m/z 524 (M+H) ⁺ .

Example 2

(25.35.45.55)- 1 -benzoyl -3-/er/-butyl -4-(2, 5-dichlorobenzoyl )-5-phenyl pyrrol idine-2-carboxylic acid

[0251] The product of Example 1 (43 mg) was purified by chiral supercritical fluid chromatography [Whelk-01 (5,5) column, gradient of 5-50% methanol (containing 0.1% diethylamine)-C0 ₂ over 10 minutes, flow rate 3 mL/minute, pressure 150 bar] to obtain the crude title compound as the first eluting peak (5.57 min). The resulting sample was dissolved in ethyl acetate (5 mL), washed with aqueous 1 N HC1 and brine, and concentrated to afford the title compound (19 mg, 99% ee). ^l H NMR (400 MHz, DMSO-7 ₆ ) d 7.37 - 7.11 (m, 9H), 7.04 - 6.94 (m, 4H), 5.58 (d, 7= 10.0 Hz, 1H), 4.73 (dd, 7= 10.1, 4.4 Hz, 1H), 4.47 (s, 1H), 3.66 (s, 1H), 1.00 (s, 9H). MS (ESI+) m/z 524 (M+H) ⁺ .

Example 3

(25.35.45.55)-l-benzoyl-3-/er/-butyl-4-(2,5-dichlorobenzoyl) -5-phenylpyrrolidine-2-carboxylic acid

[0252] The product of Example 1 (43 mg) was purified by chiral supercritical fluid chromatography [Whelk-Ol (S,S) column, gradient of 5-50% methanol (containing 0.1% diethylamine)-C0 ₂ over 10 minutes, flow rate 3 mL/minute, pressure 150 bar] to obtain the crude title compound as the second eluting peak (6.67 min). The resulting sample was dissolved in ethyl acetate (5 mL), washed with aqueous 1 N HC1 and brine, and concentrated to afford the title compound (20 mg, 97% ee). The absolute chemistry was confirmed by X-ray analysis. ¹ H NMR (400 MHz, DMSO-ifc) d 7.37 - 7.11 (m, 9H), 7.04 - 6.94 (m, 4H), 5.58 (d, J= 10.0 Hz, 1H), 4.73 (dd, / = 10.1, 4.4 Hz, 1H), 4.47 (s, 1H), 3.15 (t, / = 4.0 Hz, 1H), 1.00 (s, 9H). MS (ESI+) m/z 524 (M+H) ⁺ .

Example 4

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclopentylacetyl)-4-(2,5-dichlorobe nzoyl)-5-phenylpyrrolidine-

2-carboxylic acid

Example 4A

rac-tert- butyl (2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclopentylacetyl)-4-(2,5-dichlorobe nzoyl)-5- phenylpyrrolidine-2-carboxylate

[0253] A solution of Example 1C (82 mg, 0.172 mmol) and triethylamine (48.0 pL, 0.344 mmol) in dichloromethane (861 pL) at 25 °C was treated with cyclopentylacetyl chloride (25.5 pL, 0.189 mmol) dropwise. After 1 h, the reaction was quenched with 4 drops of ammonium hydroxide and the solvent removed under a stream of nitrogen. The crude material and purified using 5-50-% methyl /e/7-butyl ether/heptanes to give the title compound (99 mg, 0.169 mmol, 98 % yield). ¹ H NMR (400 MHz, DMSO -de) d 7.44 - 7.28 (m, 4H), 7.15 - 7.05 (m, 3H), 6.98 (s, 1H), 5.49 (d, J =

9.9 Hz, 1H), 4.66 (dd, J = 9.8, 5.2 Hz, 1H), 4.51 (d, / = 4.4 Hz, 1H), 3.06 (t, J = 4.6 Hz, 1H), 2.07 (ddt, / = 20.7, 13.9, 6.8 Hz, 2H), 1.99 - 1.84 (m, 1H), 1.63 (tt, /= 13.4, 6.2 Hz, 1H), 1.52 (s, 9H), 1.46 - 1.30 (m, 5H), 0.99 (s, 9H), 0.92 - 0.79 (m, 2H); MS (ESI-) m/z 584 (M-H) .

Example 4B

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclopentylacetyl)-4-(2,5-dichlorobe nzoyl)-5-phenylpyrrolidine-

2-carboxylic acid

[0254] Example 4A (20 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and warmed to 40 °C. After 30 minutes, the solvent was removed under a stream of nitrogen and the crude material triturated with water to give the title compound (17 mg, 0.032 mmol, 94 % yield). ^l n NMR (400 MHz, DMSO -de) d 7.43 - 7.30 (m, 4H), 7.12 - 7.05 (m, 3H), 6.97 (d, /= 2.7 Hz, 1H), 5.51 (d, J= 9.9 Hz, 1H), 4.67 (dd, J= 10.0, 5.3 Hz, 1H), 4.57 (d, /= 4.4 Hz, 1H), 3.14 (t, /= 4.9 Hz, 1H), 2.15 (dd, / = 14.9, 6.8 Hz, 1H), 2.06 (p, /= 7.1 Hz, 1H), 2.00 - 1.87 (m, 1H), 1.71 - 1.58 (m, 1H), 1.55 (q, 7= 7.0, 6.6 Hz, 1H), 1.39 (ttd, 7 = 11.9, 8.4, 7.6, 4.4 Hz, 4H), 0.99 (s, 10H), 0.85 (dd, J = 12.8, 6.4 Hz, 1H); the COOH (exchangeable) proton does not appear in the ^X H NMR; MS (ESI-) m/z 528 (M-H) .

Example 5

/g/G-(2L ^> ,3.n,4L ^> ,55 ^, )-3-/ _< ° r/-butyl- 1 -(cyclohexanecarbonyl)-4-(2,5-dichlorobenzoyl)-5- phenylpyrrolidine-2-carboxylic acid

[0255] The title compound was prepared following steps from Example 1D to Example 1E, substituting cyclohexanecarbonyl chloride for benzoyl chloride. ¹ H NMR (400 MHz, 120 °C, DMS0-7 ₆ :D ₂ 0 = 9: 1 (v/v)) d 7.54 - 7.25 (m, 4H), 7.20 - 7.12 (m, 3H), 6.94 (s, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.84 - 4.69 (m, 1H), 4.64 (d, 7 = 4.4 Hz, 1H), 3.30 - 3.23 (m, 1H), 3.21 - 3.16 (m, 1H), 2.34 - 2.16 (m, 1H), 1.77 - 1.65 (m, 2H), 1.59 - 1.42 (m, 2H), 1.42 - 0.57 (m, 14H); MS (APCI+) m/z 529.7 (M+H) ⁺ .

Example 6

rac-(2R,35 ^, ,4R,55 ^, )-l-benzoyl-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-/V-(m ethanesulfonyl)-5- phenylpyrrolidine-2-carboxamide

[0256] A solution of Example 1E (50 mg, 0.095 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (34.3 mg, 0.212 mmol) in l,2-dichloroethane (1 mL) was stirred 2 h at 42 °C. To this mixture was added methanesulfonamide (27.2 mg, 0.286 mmol) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2- a]azepine (DBU, 0.043 mL, 0.286 mmol). DBU was dried with powdered 4A molecular sieves at 42 °C for 2 h prior to usage) and the solution was stirred for 2 h. The reaction was diluted with ethyl acetate (6 mL) and washed with 1 N aqueous HC1 (10 mL) then saturated aqueous NaCl. Dried with Na ₂ S0 ₄ and concentrated leaving 63 mg crude solid which was purified via a 12 g silica gel cartridge with a gradient of 0-5 % methanol/dichloromethane over 20 minutes to give 55 mg crude product and then it was further purified by reverse-phase preparative HPLC on a

Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0- 12.0 minutes linear gradient 95-10% A to give the title compound (23 mg, 0.038 mmol, 40.1 % yield). ^l H NMR (400 MHz, DMSO -d ₆ ) d 12.19 (s, 1H), 7.61 - 7.55 (m, 1H), 7.52 (dd, J = 8.5, 2.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 2H), 7.03 - 6.77 (m, 7H), 5.39 (d, J = 9.9 Hz, 1H), 4.76 (t, J= 10.2 Hz, 1H), 4.59 (d, J = 8.6 Hz, 1H), 3.28 (m, 1H), 3.23 (s, 3H), 0.93 (s, 9H); MS (ESI-) m/z 601 (M+H) ⁺ . Example 7

mc-(2i?,36 ^, ,56 ^, )-3-/er/-butyl-l-(cyclopentanecarbonyl)-4-(2,5-dichlor obenzoyl)-5-phenylpyrrolidine-

2-carboxylic acid

[0257] The title compound was prepared following steps from Example 1D to Example 1E, substituting cyclopentanecarbonyl chloride for benzoyl chloride. ¹ H NMR (400 MHz, 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.52 - 7.25 (m, 4H), 7.20 - 7.05 (m, 3H), 6.91 (s, 1H), 5.55 (d, J = 9.9 Hz, 1H), 4.69 (dd, 7 = 10.0, 5.1 Hz, 1H), 4.62 (d, 7= 4.3 Hz, 1H), 3.26 - 3.18 (m, 1H), 3.16 - 3.11 (m, 1H), 2.77 - 2.57 (m, 1H), 1.84 - 1.67 (m, 1H), 1.64 - 1.23 (m, 6H), 1.00 (s, 9H); MS (APCI+) m/z 516.0 (M+H) ⁺ .

Example 8

rac-(2R,3SAR,5S) 1 -(bicyclo[ 1. 1.1 (pentane- 1 -carbonyl)-3- _/ e _/7 -butyl-4-(2,5-dichloi _O benzoyl)-5- phenylpyrrolidine-2-carboxylic acid

[0258] The title compound was prepared following steps from Example 1D to Example 1E, substituting bicyclo[l.l.l]pentane-l-carbonyl chloride for benzoyl chloride. ¹ H NMR (400 MHz, 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.52 - 7.25 (m, 4H), 7.20 - 7.05 (m, 3H), 6.91 (s, 1H), 5.55 (d, 7 = 9.9 Hz, 1H), 4.69 (dd, 7 = 10.0, 5.1 Hz, 1H), 4.62 (d, 7= 4.3 Hz, 1H), 3.26 - 3.18 (m, 1H), 3.16 - 3.11 (m, 1H), 2.77 - 2.57 (m, 1H), 1.84 - 1.67 (m, 1H), 1.64 - 1.23 (m, 6H), 1.00 (s, 9H);

MS (APCI+) m/z 516.0 (M+H) ⁺ .

Example 9

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(2,5-difluoro benzoyl)-5- phenylpyrrolidine-2-carboxylic acid

Example 9A

rac-tert- butyl (2R,35,4R,55 ^, )-3-/er/-butyl-4-(2,5-difluorobenzoyl)-5-phenylpyrroli dine-2- carboxylate

[0259] The title compound was prepared following steps from Example 1B to Example 1C, substituting 2',5'-difluoroacetophenone for 2',5'-dichloroacetophenone in Example 1B. ¹ H NMR: (400 MHz, CDCb): d 7.10-7.12 (d, 7= 8.0 Hz, 2H), 7.01-7.07 (m, 3H), 6.91-6.96 (m, 1H), 6.83-6.89 (m, 1H), 6.69-6.74 (m, 1H), 4.53 (d, 7 = 8.0 Hz, 1H), 4.88 (dd, 7 = 4.0 Hz, 8.0 Hz, 1H), 3.69 (d, 7 = 8.0 Hz, 1H), 3.09 (brs, 1H), 2.85 (dd, 7 = 4.0 Hz, 8.0 Hz, 1H), 1.56 (s, 9H), 1.03 (s, 9H); MS (ESI+) m/z 444.3 (M+H) ⁺ .

Example 9B

rac-tert- butyl (2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(2,5-difluoro benzoyl)-5- phenylpyrrolidine-2-carboxylate

[0260] A solution of Example 9A (50 mg, 0.113 mmol) and triethylamine (0.031 mL, 0.225 mmol) in dichloromethane (0.5 mL) at 25 °C was treated with cyclohexanecarbonyl chloride (0.019 mL, 0.141 mmol) dropwise, stirred for 2 h, diluted with methyl /e/7-butyl ether (20 mL), washed with saturated aqueous NaHCCh (5 mL) and with 1 N aqueous NH ₄ OH (1 mL) solution, dried over sodium sulfate, filtered, concentrated to give a yellow oil. The crude material was chromatographed on a 12 g column eluting with a gradient of 0-2% methanol/dichloromethane over a period of 20 minutes to provide the title compound (48 mg, 0.087 mmol, 77 % yield). NMR (400 MHz, DMSO-ifc) d 7.35 (bs, 2H), 7.26 (ddd, / = 11.5, 7.4, 3.5 Hz, 1H), 7.15 (ddd, J= 10.7, 9.0, 4.3 Hz, 1H), 7.08 - 7.00 (m, 3H), 6.80 (d, / = 9.1 Hz, 1H), 5.54 (d, / = 10.1 Hz, 1H), 4.50 (dd, / = 10.1, 5.6 Hz, 1H), 4.46 (d, / = 5.0 Hz, 1H), 3.05 (t, / = 5.3 Hz, 1H), 2.16 (s, 1H), 1.64 (d, / = 10.3 Hz, 2H), 1.52 (s, 9H), 1.49 - 1.38 (m, 3H), 1.26 (td, / = 11.8, 8.3 Hz, 1H), 1.09 (d, / = 20.0 Hz, 4H), 0.96 (s, 9H); MS (ESI+) m/z 552 (M-H) .

Example 9C

_/g/G -(2L ^> ,3.n,4L ^> ,55 ^, ₎ -3- _/< ° r _/ -butyl- 1 -(cyclohexanecarbonyl ₎ -4-(2,5-difluorobenzoyl ₎ -5- phenylpyrrolidine-2-carboxylic acid

[0261] To Example 9B (47 mg, 0.085 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.082 mL, 1.061 mmol) and the mixture was stirred at 44 °C for 4 h. The solvent was removed in vacuo and the resulting solid was chromatographed using a 12 g silica gel cartridge with a gradient of 1-10% methanol/dichloromethane over a period of 12 minutes to give the title compound (36 mg, 0.072 mmol, 85 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 7.36 (bs, 2H), 7.27 (tt, /= 7.7, 3.6 Hz, 1H), 7.15 (ddd, J= 10.7, 9.1, 4.3 Hz, 1H), 7.07 - 7.01 (m, 3H), 6.82 (dq, / = 8.9, 4.4, 3.9 Hz, 1H), 5.56 (d, / = 10.1 Hz, 1H), 4.53 (d, / = 5.0 Hz, 1H), 4.52 - 4.48 (m, 1H), 3.13 (t, /= 5.4 Hz, 1H), 2.18 (d, / = 15.8 Hz, 1H), 1.66 (d, / = 12.6 Hz, 2H), 1.47 (d, / = 12.7 Hz, 2H), 1.32 - 1.20 (m, 2H), 1.08 (td, /= 13.3, 12.6, 7.2 Hz, 3H), 0.96 (d, /= 1.0 Hz, 9H), 0.73 (bs, 1H); MS (ESI+) m/z 498 (M+H) ⁺ .

Example 10

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(oxane-4-carb onyl)-5-phenylpyrrolidine-

2-carboxylic acid

[0262] The title compound was prepared following steps from Example 1D to Example 1E, substituting tetrahydro-2//-pyran-4-carbonyl chloride for benzoyl chloride. ¹ H NMR (400 MHz, 120 °C, DMS0-i/ ₆ :D ₂ 0 = 9:1 (v/v)) d 7.47 - 7.30 (m, 4H), 7.20 - 7.07 (m, 3H), 6.90 (s, 1H), 5.59 (d, / = 10.0 Hz, 1H), 4.69 (dd, / = 10.4, 5.3 Hz, 1H), 4.62 (d, / = 4.3 Hz, 1H), 3.80 (dt, /= 11.3, 3.5 Hz, 1H), 3.70 - 3.52 (m, 1H), 3.28 - 3.13 (m, 2H), 3.01 - 2.74 (m, 1H), 2.60 - 2.34 (m, 2H), 1.61 - 1.50 (m, 2H), 1.50 - 1.25 (m, 1H), 1.00 (s, 9H); MS (APCI+) m/z 532.4 (M+H) ⁺ .

Example 11

rac-(2R,3SAR-,5S) 1 -(bicyclo[3.1.0]hexane-6-carbonyl)-3-/i77-butyl-4-(2,5-dichl orobenzoyl)-5- phenylpyrrolidine-2-carboxylic acid

[0263] The title compound was prepared following steps from Example 1D to Example 1E, substituting bicyclo[3.1 0]hexane-6-carbonyl chloride for benzoyl chloride. ¹ H NMR (400 MHz, 120 °C, DMS0-J ₆ :D ₂ 0 = 9:1 (v/v)) d 7.45 - 7.24 (m, 4H), 7.17 - 7.05 (m, 3H), 6.89 (d, J= 2.5 Hz, 1H), 5.60 (d, / = 9.9 Hz, 1H), 4.71 (dd, / = 10.0, 4.9 Hz, 1H), 4.61 (d, /= 4.3 Hz, 1H), 3.18 - 3.09 (m, 1H), 1.76 - 1.53 (m, 3H), 1.51 - 1.32 (m, 3H), 1.24 - 1.11 (m, 1H), 1.09 - 0.90 (m, 10H), 0.83 - 0.52 (m, 1H); MS (APCI+) m/z 528.4 (M+H) ⁺ .

Example 12

/g/G-(2L ^> ,3.n,4L ^> ,55 ^, )-3-/ _< ° r/-butyl- 1 -(cyclohexanecarbonyl)-4-(5-fluoro-2-methoxybenzoyl)-5- phenylpyrrolidine-2-carboxylic acid

Example 12A

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-(5-fluoro-2-methoxybenzoyl)-5-phenylp yrrolidine-2- carboxylate

[0264] The title compound was prepared following steps from Example 1B to Example 1C, substituting l-(5-fluoro-2-methoxyphenyl)ethanone for 2',5'-dichloroacetophenone in Example 1B. MS (ESI+) m/z 456.7 (M+H) ⁺ .

Example 12B

rac-tert- butyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(5-fluoro-2-m ethoxybenzoyl)-

5-phenylpyrrolidine-2-carboxylate

[0265] A solution of Example 12A (50 mg, 0.110 mmol) and triethylamine (0.031 mL, 0.220 mmol) in dichloromethane (0.5 mL) at 25 °C was treated with cyclohexanecarbonyl chloride (0.018 mL, 0.137 mmol) dropwise, stirred for 2 h, diluted with dichloromethane (1 mL), washed with saturated aqueous NaHCCh (1 mL) and with 10% aqueous NH ₄ OH (1 mL) solution to convert any left over acid chloride to the coresponding amide, dried over sodium sulfate, filtered, concentrated to give a yellow oil. The crude material was chromatographed on a 12 g silica gel cartridge eluting with a gradient of 0-70% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the title compound (58 mg, 0.103 mmol, 93 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 7.32 (s, 2H), 7.14 (td, J= 8.5, 8.0, 3.3 Hz, 1H), 7.05 (d, /= 5.7 Hz, 4H), 6.27 (s, 1H), 5.43 (d, / = 10.0 Hz, 1H), 4.77 (dd, / = 10.0, 5.9 Hz, 1H), 4.50 - 4.39 (m, 1H), 3.90 (s, 3H), 3.03 (t, /= 5.3 Hz, 1H), 2.16 (s, 1H), 1.64 (d, / = 10.1 Hz, 2H), 1.51 (s, 9H), 1.46 (m, 1H), 1.27 (d, / = 11.0 Hz, 2H), 1.07 (s, 4H), 0.95 (s, 9H), 0.84 (d, / = 7.5 Hz, 1H); MS (ESI-) m/z 564 (M-H) .

Example 12C

/g/G-(2L ^> ,3.n,4L ^> ,55 ^, )-3-/ _< ° r/-butyl- 1 -(cyclohexanecarbonyl)-4-(5-fluoro-2-methoxybenzoyl)-5- phenylpyrrolidine-2-carboxylic acid

[0266] To Example 12B (57 mg, 0.101 mmol) was added trifluoroacetic acid (0.311 mL, 4.04 mmol) and the mixture was stirred at 24 °C for 2 h. The solvent was removed in vacuo and the resulted solid was chromatographed using a 12 g silica gel cartridge with a gradient of 0-6% methanol/dichloromethane over a period of 20 minutes to give the title compound (50 mg, 0.098 mmol, 97 % yield). ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.32 (bs, 2H), 7.15 (td, / = 8.4, 8.0, 3.3 Hz, 1H), 7.10 - 6.93 (m, 4H), 6.29 (d, / = 9.1 Hz, 1H), 5.46 (d, / = 10.1 Hz, 1H), 4.77 (dd, / = 10.1, 6.1 Hz, 1H), 4.54 - 4.48 (m, 1H), 3.90 (s, 3H), 3.15 - 3.07 (m, 1H), 2.17 (m, 1H), 1.71 - 1.59 (m, 2H), 1.46 (m, 2H), 1.26 (m, 2H), 1.17 - 1.01 (m, 3H), 0.96 (s, 9H), 0.80 (bs, 1H); MS (ESI-) m/z 508 (M- H)-.

Example 13

mc-(2i?,35',4i?,55 ^, )-3-(/er/-butyl)-4-(5-chloro-2-methoxybenzoyl)-l-(cycl ohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

Example 13A

(£)- 1 -(5-chloro-2-methoxyphenyl)-4,4-dimethylpent-2-en- 1 -one

[0267] A solution of l-(5-chloro-2-methoxyphenyl)ethanone (3.48 mL, 29.0 mmol) and trimethylacetaldehyde (4.75 mL, 43.7 mmol) in methanol (29.0 mL) was treated with potassium hydroxide (1.628 g, 29.0 mmol) and heated at 50 °C overnight. The solvent was removed in vacuo and the reaction was diluted with water (100 mL) and neutralized with 1 M aqueous HC1 (30 mL).

A yellow oil separated. The crude oil was purified using a 240 g silica gel cartridge with a gradient of 5-40% methyl /e/7-butyl ether/heptanes over 40 minutes to give the title compound (5.533 g, 21.89 mmol, 75 % yield). ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.51 (dd, J= 8.9, 2.8 Hz, 1H), 7.34 (d, /= 2.7 Hz, 1H), 7.15 (d, J= 8.9 Hz, 1H), 6.68 (d, J= 15.9 Hz, 1H), 6.45 (d, /= 15.9 Hz, 1H), 3.79 (s, 3H), 1.03 (s, 9H). MS (ESI+) m/z 253 (M+H) ⁺ .

Example 13B

rac-tert- butyl (2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-5-phenylp yrrolidine-2- carboxylate

[0268] A solution of Example 1A (1.909 g, 8.70 mmol) tetrahydrofuran (39.6 mL), and lithium bromide (7.91 mL, 11.87 mmol) was cooled to < -70 °C and a solution of Example 13A' (2.00 g, 7.91 mmol) in tetrahydrofuran (10 mL) was added followed by dropwise addition of

2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine (DBU, 1.431 mL, 9.50 mmol) at < -70 °C. The reaction was allowed to warm to 5 °C and was maintained at about this temperature for 1 h.

Saturated aqueous NH ₄ Cl (25 mL), methyl /e/7-butyl ether (150 mL), and water (25 mL) were added. The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to give a solid. Hexane (40 mL), heptane (40 mL) and ethyl acetate (10 mL) were added and heated to reflux. All the solid dissolved. The solution was cooled overnight, then filtered and washed with heptane (10 mL) to give the title compound (3.065 g, 6.49 mmol, 82 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 7.32 (dd, J= 8.9, 2.8 Hz, 1H), 7.15 - 7.03 (m, 5H), 7.00 (d, 7 = 8.9 Hz, 1H), 6.34 (d, 7= 2.8 Hz, 1H), 4.49 - 4.35 (m, 2H), 3.85 (s, 3H), 3.55 (t, 7= 7.6 Hz, 1H), 3.02 (t, J= 9.2 Hz, 1H), 2.76 (dd, 7= 7.1, 3.8 Hz, 1H), 1.48 (s, 9H), 0.95 (s, 9H). MS (ESI+) m/z 473 (M+H) ⁺ .

Example 13C

rac-tert- butyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(cycloh exanecarbonyl)-

5-phenylpyrrolidine-2-carboxylate

[0269] A solution of Example 13B (50 mg, 0.106 mmol) and triethylamine (0.030 mL, 0.212 mmol) in dichloromethane (0.5 mL) at 25 °C was treated dropwise with cyclohexanecarbonyl chloride (0.018 mL, 0.132 mmol), stirred for 2 h, then diluted with dichloromethane (1 mL). The organic layer was washed with saturated aqueous NaHCCh (1 mL), then with 10% aqueous NH ₄ OH (1 mL) solution, dried over sodium sulfate, filtered, and concentrated to give a yellow oil. The crude material was chromatographed on a 12 g silica gel cartridge eluting with a gradient of 0-70% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the title compound (61 mg, 0.105 mmol, 99 % yield). ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.39 - 7.24 (m, 3H), 7.06 (q, 7= 9.0, 8.0 Hz, 4H), 6.38 (s, 1H), 5.42 (d, J= 10.0 Hz, 1H), 4.75 (dd, 7 = 10.1, 5.6 Hz, 1H), 4.44 (d, 7= 4.9 Hz, 1H), 3.90 (s, 3H), 3.01 (t, 7 = 5.2 Hz, 1H), 2.12 (d, J = 23.6 Hz, 1H), 1.63 (d, 7 = 9.4 Hz, 2H), 1.51 (s, 9H), 1.43 (m, 1H), 1.25 (s, 2H), 1.09 (d, 7 = 20.0 Hz, 3H), 0.96 (s, 9H), 0.84 (q, 7 = 6.3 Hz, 2H); MS (ESI-) m/z 580 (M-H) .

Example 13D

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(cycloh exanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid [0270] To Example 13C (60 mg, 0.103 mmol) was added trifluoroacetic acid (0.318 mL, 4.13 mmol) and the mixture was stirred at 24 °C for 2 h. The solvent was removed in vacuo and the resulting solid was chromatographed using a 12 g silica gel cartridge with a gradient of 0-6% methanol/dichloromethane over a period of 20 minutes to give the title compound (43 mg, 0.082 mmol, 79 % yield). ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.33 (dt, /= 9.8, 3.5 Hz, 3H), 7.06 (s, 4H), 6.40 (s, 1H), 5.45 (d, / = 10.1 Hz, 1H), 4.75 (dd, / = 10.1, 5.8 Hz, 1H), 4.51 (d, /= 4.8 Hz, 1H),

3.91 (s, 3H), 3.10 (t, / = 5.4 Hz, 1H), 2.16 (bs, 1H), 1.64 (m, 2H), 1.46 (m, 2H), 1.26 (m, 2H), 1.17 - 1.01 (m, 3H), 0.96 (s, 9H), 0.74 (bs, 1H); MS (ESI-) m/z 524 (M-H) .

Example 14

rac-(2R,3S,4S,5S)-tert-buty\ 3-(/er/-butyl)-4-(l-(5-chloro-2-methoxyphenyl)vinyl)-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

Example 14A

rac-(2R,3S,4S,5S)-tert-buty\ 3-(/er/-butyl)-4-(l-(5-chloro-2-methoxyphenyl)vinyl)-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

[0271] Methyltriphenylphosphonium bromide (145 mg, 0.405 mmol) was suspended in 1.5 mL of toluene and potassium 2-methylpropan-2-olate (1 M solution in tetrahydrofuran, 0.385 mL, 0.385 mmol) was added dropwise. The resulting yellow solution was stirred for 30 min at rt, at which point Example 13C (118 mg, 0.203 mmol) was added to the vial as a solution in toluene (1 mL).

The reaction was stirred at ambient temperature. After 16 h, the reaction was loaded directly onto a 12 g silica gel column and eluted with 0-20% ethyl acetate/heptanes over 20 min to give the title compound (111 mg). MS (ESI+) 524 (M-/er/-butyl) ⁺ , 580 (M+H) ⁺ , 602 (M+Na) ⁺ .

Example 14B

rac-(2R,35 ^, ,45 ^, ,55 ^, )-3-/er/-butyl-4-[l-(5-chloro-2-methoxyphenyl)ethenyl] -l-(cyclohexanecarbonyl)-

5-phenylpyrrolidine-2-carboxylic acid

[0272] A solution of Example 14A (26 mg, 0.045 mmol) was treated with trifluoroacetic acid, and stirred at ambient temperature for 30 minutes. The reaction was concentrated and

chromatographed using a 4 g silica gel cartridge with a 3:1:4 ethyl acetate/ethanol/heptanes solvent system over 15 minutes to give 17 mg of impure product. This product was precipitated from ethyl acetate/heptane to give the title compound (12 mg, 0.023 mmol, 51.1 % yield). Ή NMR (400 MHz, DMSO-ifc) d 12.15 (s, 1H), 7.39 - 7.29 (m, 4H), 7.18 - 7.10 (m, 4H), 6.91 (d, / = 8.8 Hz,

1H), 6.14 - 6.08 (m, 1H), 5.22 (d, J = 9.5 Hz, 1H), 4.48 (d, / = 5.2 Hz, 1H), 3.92 (dd, J = 9.5, 7.2 Hz, 1H), 3.78 (s, 3H), 2.29 - 2.18 (m, 1H), 1.71 - 1.57 (m, 3H), 1.54 - 1.38 (m, 3H), 1.33 - 1.19 (m, 1H), 1.20 - 1.01 (m, 3H), 0.99 (s, 9H), 0.82 - 0.64 (m, 1H); MS (ESI-) m/z 522 (M-H) .

Example 15

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy-5- (trifluoromethyl)benzoyl]-

5-phenylpyrrolidine-2-carboxylic acid

Example 15A

(E)- 1 -(2-methoxy-5-(trifluoromethyl)phenyl)-4,4-dimethylpent-2-en - 1 -one

[0273] To l-(2-methoxy-5-(trifluoromethyl)phenyl)ethanone (4.86 g, 22.28 mmol in methanol (50 mL) was added pivalaldehyde (4.90 mL, 44.6 mmol). The mixture was cooled in an ice bath, potassium hydroxide (1.250 g, 22.28 mmol) added in portions, and then stirred at room temperature overnight. Solvent was removed under pressure and the residue dissolved in ethyl acetate (100 mL), washed with 1N HC1, then brine, dried over MgS0 ₄ , and concentrated. The residue was purified via chromatography on an 80 g silica gel cartridge, eluting with ethyl acetate in heptane at 0-30% gradient to yield the title compound (5.6 g, 88 % yield). MS (APCI+), m/z 287 (M+H) ⁺ .

Example 15B

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-[2-methoxy-5-(trifluoromethyl)benzoyl ]-5- phenylpyrrolidine-2-carboxylate

[0274] To a solution of Example 1A (1.5 g, 6.84 mmol) and Example 15A (1.958 g, 6.84 mmol) in toluene (30 mL) was added acetyl(oxo)silver (1.713 g, 10.26 mmol) and 3A molecular sieves (1 g). The reaction mixture was cooled to 0 °C in an ice-bath and well stirred. Triethylamine (1.907 mL, 13.68 mmol) was added slowly. After stirringlO minutes at 0 °C, the reaction was allowed to warm to room temperature and stirred for another 4 h. LC/MS indicated conversion was complete. Saturated aqueous ammonium chloride (10 mL) was added. The precipitate was filtered off and the residue was extracted with ether. The combined organic fractions were dried over MgS0 ₄ , and concentrated. Purification was performed via chromatography on a 40 g silica gel cartridge eluting with ethyl acetate in heptane at 0-50% gradient to yield the title compound (1.25 g, 36.1 % yield). NMR (501 MHz, CDCb) d 7.43 (dd, / = 8.7, 2.4 Hz, 1H), 7.10 - 6.95 (m, 5H), 6.92 - 6.77 (m, 2H), 4.49 (d, / = 1.3 Hz, 2H), 3.89 (s, 3H), 3.70 (d, J = 6.3 Hz, 1H), 3.13 (s, 1H), 2.82 (dt, / = 6.1, 1.4 Hz, 1H), 1.57 (s, 9H), 1.06 (s, 9H); MS (ESI+) m/z 506 (M+H) ⁺ .

Example 15C

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy-5- (trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-carboxylate

[0275] To the solution of Example 15B (1.2 g, 2.374 mmol) and triethylamine (0.498 mL, 3.56 mmol) in dichloromethane (40 mL) cooled in an ice bath was slowly added cyclohexanecarbonyl chloride (0.413 mL, 3.09 mmol). The mixture was stirred at 0 °C for 30 minutes and warmed to room temperature and stirred for another 1 h. Dichloromethane (20 mL) was added. The mixture was washed with saturated NaHCCL, then brine, dried over MgS0 ₄ , and concentrated. Purification was performed via chromatography on an 80 g silica gel cartridge eluting with 0-40 % ethyl acetate in heptane to provide the title compound (1.30 g, 89 % yield). ¹ H NMR (501 MHz, CDCL) d 7.55 (dd, / = 8.6, 2.4 Hz, 1H), 7.36 (dd, / = 6.5, 2.9 Hz, 2H), 7.13 (dd, / = 4.9, 1.9 Hz, 3H), 6.99 (t, / = 2.5 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 5.25 (d, J = 10.0 Hz, 1H), 4.79 (dd, J = 10.0, 6.4 Hz, 1H),

4.57 (d, / = 5.8 Hz, 1H), 3.99 (s, 3H), 3.15 (t, / = 6.1 Hz, 1H), 2.09 - 1.99 (m, 1H), 1.77 (dt, / = 22.1, 12.4 Hz, 2H), 1.58 (s, 9H), 1.50 - 1.40 (m, 3H), 1.37 (dt, / = 13.4, 3.5 Hz, 1H), 1.23 - 1.13 (m, 2H), 1.07 (s, 1H), 1.02 (s, 9H), 0.93 - 0.87 (m, 1H); MS (ESI+-) m/z 616 (M+H) ⁺ .

Example 15D

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy-5- (trifluoromethyl)benzoyl]-

5-phenylpyrrolidine-2-carboxylic acid

[0276] The mixture of Example 15C (80 mg, 0.130 mmol) in trifluoroacetic acid (1.5 mL) was stirred at room temperature overnight. Purification was performed via chromatography, eluting with ethyl acetate/methanol (9:1) in heptane at 0-60% gradient to yield the title compound (66 mg, 91 % yield). ^l H NMR (400 MHz, CDCL) d 7.64 (dd, /= 8.6, 2.4 Hz, 1H), 111 (d, /= 7.2 Hz, 3H), 7.08 - 6.90 (m, 4H), 5.40 (d, /= 9.6 Hz, 1H), 4.79 - 4.60 (m, 2H), 4.04 (s, 3H), 3.96 - 3.80 (m, 1H), 2.34 - 2.22 (m, 1H), 1.54 (dd, /= 24.5, 12.0 Hz, 3H), 1.27 (d, / = 11.4 Hz, 2H), 1.17 (s, 2H), 0.96 (s, 9H), 0.91 - 0.70 (m, 3H); MS (ESI+) m/z 560 (M+H) ⁺ .

Example 16

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(cycloh exanecarbonyl)-/V- (methanesulfonyl)-5-phenylpyrrolidine-2-carboxamide

[0277] A solution of Example 13D (100 mg, 0.190 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (68.4 mg, 0.422 mmol) in l,2-dichloroethane (1.5 mL) was stirred 2 h at 42 °C. To this mixture was added methanesulfonamide (54.2 mg, 0.570 mmol) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2- a]azepine (DBU, 0.086 mL, 0.570 mmol). DBU was dried with powdered 4A molecular sieves at 42 °C for 2 h prior to usage. The solution was stirred for 2 h. The reaction was diluted with ethyl acetate (6 mL) and washed with 1 N aqueous HC1 (10 mL), then saturated aqueous NaCl, dried with Na ₂ S0 ₄ , and concentrated leaving 93 mg crude solid which was purified via a 12 g silica gel cartridge with a gradient of 0-7% methanol/dichloromethane over 20 minutes to give the title compound (82 mg, 0.136 mmol, 71.5 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 11.26 (s, 1H), 7.45 (dd, 7 = 9.0, 2.8 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.19 - 7.08 (m, 4H), 6.67 (d, 7= 2.8 Hz, 1H), 5.48 (d, 7 = 9.9 Hz, 1H), 4.71 (t, J = 9.9 Hz, 1H), 4.47 (d, 7 = 7.9 Hz, 1H), 3.97 (s, 3H), 3.42 (dd, 7 = 10.0, 7.9 Hz, 1H), 3.17 (s, 3H), 2.26 - 2.13 (m, 1H), 1.68 (t, 7= 15.7 Hz, 2H), 1.46 (d, 7 = 13.0 Hz, 1H), 1.39 - 1.23 (m, 2H), 1.21 - 0.94 (m, 3H), 0.91 (s, 9H), 0.76 (d, 7 = 10.7 Hz, 1H), 0.65 (d, 7 = 13.1 Hz, 1H); MS (ESI-) m/z 601 (M-H) .

Example 17

mc-(2i?,3i?,4i?,55 ^, )-4-(5-chloro-2-methoxybenzoyl)-l-(cyclohexanecarbonyl )-3-(2-methoxypropan-

2-yl)-5-phenylpyrrolidine-2-carboxylic acid

Example 17 A

5-chloro-2-methoxybenzoyl chloride

[0278] 5-Chloro-2-methoxybenzoic acid (15 g, 80 mmol) was dissolved in thionyl chloride (20 mL) and the resulting solution was heated to 75 °C for 1 h. The solution was cooled to room temperature, volatiles were removed in vacuo and the resulting residue was azeotroped with toluene (2 x 20 mL). The resulting solid was used without additional purification. MS (ESI+) m/z 202 (M+H, methyl ester).

Example 17B

(3£ ^’ )-2-methyl-4-(tributylstannyl)but-3-en-2-ol

[0279] Bis(triphenylphosphine)palladium(II) dichloride (1.022 g, 1.456 mmol) and 2- methylbut-3-yn-2-ol (3.53 mL, 36.4 mmol) were dissolved in tetrahydrofuran (72.8 mL) and tributyltin hydride (36.4 mL, 36.4 mmol) was added as a solution in cyclohexane over 2 min via syringe. The reaction mixture was stirred for 30 min at room temperature then concentrated in vacuo and the residue was loaded onto a 220 g silica gel column and eluted with 0:100 to 20:80 methyl /er/-butyl ether/heptanes over 20 min to afford the title compound (4.47 g). ¹ H NMR (501 MHz, CDCb) d 6.11 (d, 7= 3.7 Hz, 2H), 1.54 - 1.44 (m, 6H), 1.36 - 1.26 (m, 6H), 1.3 (s, 6H), 0.89 (td, 7= 7.7, 1.5 Hz, 15H); MS (DCI+) m/z 376.1 (M+NH ₄ -H ₂ 0) ⁺ .

Example 17C

(2£)-l-(5-chloro-2-methoxyphenyl)-4-hydroxy-4-methylpent-2- en-l-one

[0280] Example 17B (7 g, 18.66 mmol) was dissolved in tetrahydrofuran (141 mL). Tri(2- furyl)phosphine (0.158 g, 0.678 mmol) and Pd ₂ (dba) ₃ (155 mg, 0.17 mmol) were added, followed by addition of Example 17A (3.48 g, 16.96 mmol) as a solution in tetrahydrofuran (1 mL). The reaction was heated to 60 °C for 1 h then cooled to room temperature, concentrated in vacuo, and loaded onto a 120 g silica gel column and eluted with 10:90 to 60:40 ethyl acetate:heptanes over 20 min to give the title compound (3.98 g). ^X H NMR (400 MHz, DMSO-tfc) d 7.55 (dd, J= 8.9, 2.8 Hz, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.20 (d, 7 = 8.9 Hz, 1H), 6.75 (d, J = 15.7 Hz, 1H), 6.65 (d, J =

15.7 Hz, 1H), 4.95 (s, 1H), 3.83 (s, 3H), 1.24 (s, 6H); MS (ESI+) m/z 237.1 (M-OH) ⁺ .

Example 17D

(2£ ^’ )-l-(5-chloro-2-methoxyphenyl)-4-methoxy-4-methylpent- 2-en-l-one

[0281] Example 17C (1.4 g, 5.50 mmol) was dissolved in /V,/V-dimethylformaiuide (2 mL).

The solution was cooled to < 5 °C in an ice bath before sodium hydride (0.440 g, 10.99 mmol) was added in one portion. The resulting slurry was stirred for 1 min before adding iodomethane (1.718 mL, 27.5 mmol). The thin suspension was stirred for 5 min in the ice bath then warmed to room temperature for 10 min. The vial was recooled to < 5 °C and slowly quenched with saturated ammonium chloride then extracted with methyl /e/7-butyl ether (3 x 20 mL). The combined extracts were washed with water and brine then dried over sodium sulfate, concentrated, and purified via flash chromatography, eluting with 0:100 to 50:50 ethyl acetate:heptanes over 20 min on an 80 g silica gel column to give the title compound (1.05 g). ¹ H NMR (500 MHz, CDCE) d 7.50 (d, J =

2.7 Hz, 1H), 7.39 (dd, J = 8.8, 2.7 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 2.3 Hz, 2H), 3.85 (s, 3H), 3.23 (s, 3H), 1.35 (s, 6H); MS (ESI+) m/z 236.9 (M-HOMe) ⁺ .

Example 17E

rac-tert- butyl (2R,3R,4R,55')-4-(5-chloro-2-methoxybenzoyl)-3-(2-methoxypro pan-2-yl)-5- phenylpyrrolidine-2-carboxylate

[0282] Example 1A (1408 mg, 6.42 mmol) was dissolved in tetrahydrofuran (3 mL) and the solution was cooled to -78 °C. A solution of lithium bromide (4.28 mL, 6.42 mmol) was added, followed by addition of Example 17D (1150 mg, 4.28 mmol) in tetrahydrofuran (13 mL).

2,3,4,6,7,8,9, l0-octahydropyrimido[l,2-fl]azepine (5.56 mL, 5.56 mmol) solution in tetrahydrofuran was added dropwise, and a yellow suspension resulted. After 30 min at -78 °C, the starting material had been consumed as indicated by LC/MS. The flask was warmed to 0 °C before diluting with methyl /e/7-butyl ether (30 mL), adding saturated ammonium chloride (10 mL), and stirring for 10 min at rt. The layers were separated, and the organic layer was concentrated in vacuo and loaded onto a 12 g silica gel column, eluting with 0:100 to 100:0 methyl /e/7-butyl ether/heptanes over 20 min to give 780 mg of the title compound. ¹ H NMR (400 MHz, CDCI ₃ ) d 7.13 (dd, J= 8.8, 2.7 Hz, 1H), 7.06 (t, 7= 2.1 Hz, 5H), 6.66 (d, 7 = 8.8 Hz, 1H), 6.56 (d, 7 = 2.7 Hz, 1H), 4.61 (d, 7 = 1.5 Hz, 2H), 3.87 (d, 7 = 6.3 Hz, 1H), 3.80 (s, 3H), 3.24 (s, 3H), 3.02 (dt, 7= 6.3, 1.5 Hz, 1H), 1.56 (s, 9H), 1.29 (d, /= 6.2 Hz, 6H); MS (ESI+) m/z 488.0 (M+H) ⁺ .

Example 17F

rac-(2i?,3i?,4i?,56')-4-(5-chloro-2-methoxybenzoyl)-l-(cy clohexanecarbonyl)-3-(2-methoxypropan-

2-yl)-5-phenylpyrrolidine-2-carboxylic acid

[0283] Example 17E (30 mg, 0.061 mmol) was dissolved in tetrahydrofuran (0.615 mL) and triethylamine (0.013 mL, 0.092 mmol) was added, followed by cyclohexanecarbonyl chloride (8.19 pL, 0.068 mmol). The reaction was stirred for 1 h at room temperature, at which point complete conversion to the amide was observed by LC/MS. Trifluoro acetic acid (0.1 mL, 1.298 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and loaded onto a 4 g silica gel column then eluted with 0:100 to 100:0 ethyl acetate:heptanes over 20 min to give the title compound (24 mg). ¹ H NMR (400 MHz,

DMSO -de, 120 °C) d 7.47 - 7.19 (m, 3H), 7.17 - 6.94 (m, 4H), 6.51 (s, 1H), 5.46 (d, / = 9.9 Hz, 1H), 4.78 (dd, / = 9.9, 6.8 Hz, 1H), 4.59 (d, / = 5.4 Hz, 1H), 3.92 (d, / = 1.6 Hz, 3H), 3.41 - 3.30 (m, 1H), 3.11 (s, 3H), 2.20 (s, 1H), 1.66 (d, /= 11.3 Hz, 2H), 1.47 (s, 2H), 1.28 (d, /= 11.8 Hz,

2H), 1.20 (s, 3H), 1.15 (s, 4H), 1.13 - 0.96 (m, 4H); MS (ESI+) m/z 542.3 (M+H) ⁺ .

Example 18

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(l,s', 45 ^, )-4-methoxycyclohexane- l-carbonyl]-5-phenylpyrrolidine-2-carboxylic acid

Example 18A

rac-tert- butyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(lr,4i ?)-4- methoxycyclohexane-l-carbonyl]-5-phenylpyrrolidine-2-carboxy late

[0284] A solution of Example 13B (100 mg, 0.212 mmol) and triethylamine (89 pL, 0.636 mmol) in dichloromethane (942 pL) at 25 °C was treated with drop wise addition of 4- methoxycyclohexanecarbonyl chloride (94 mg, 0.530 mmol) as a solution in dichloromethane (0.2 mL), stirred for 20 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to give the title compound (91 mg, 0.149 mmol, 70.2 % yield) as the first eluting compound. ¹ H NMR (400 MHz, DMSO-tfc) d 7.32 (td, ./ = 7.7, 6.5, 2.5 Hz, 3H), 7.05 (q, J= 8.8, 8.1 Hz, 4H), 6.39 (s, 1H), 5.43 (d, / = 10.1 Hz, 1H), 4.74 (dd, J= 10.0, 5.7 Hz, 1H), 4.45 (d, / = 5.0 Hz, 1H), 3.90 (s, 3H), 3.21 (d, / = 6.2 Hz, 1H), 3.12 (s, 3H), 3.03 (t, / = 5.4 Hz, 1H), 2.26 - 2.13 (m, 1H), 1.84 - 1.74 (m, 1H), 1.69 - 1.51 (m, 2H), 1.51 (s, 9H), 1.42 - 1.32 (m, 1H), 1.32 - 1.18 (m, 2H), 0.96 (s, 9H), 0.91 - 0.77 (m, 2H). MS (ESI-) m/z 610 (M- H)-.

Example 18B

rac-(2i?,3 S ^, ,4/?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(l,s', 4S ^, )-4-methoxycyclohexane- l-carbonyl]-5-phenylpyrrolidine-2-carboxylic acid

[0285] Example 18A (50 mg, 0.082 mmol) was treated with trifluoro acetic acid (363 m L) and after 20 minutes, concentrated under a stream of nitrogen. The crude material purified using a 12 g silica gel cartridge eluting with a 3: 1:4 ethyl acetate\ethanol\heptanes solvent system over a period of 20 minutes to give the title compound (37 mg, 0.067 mmol, 81 % yield). ¹ H NMR (400 MHz, DMSO-ifc) d 7.39 - 7.26 (m, 3H), 7.13 - 6.98 (m, 4H), 6.40 (s, 1H), 5.45 (d, J = 10.0 Hz, 1H), 4.74 (dd, J = 10.1, 5.9 Hz, 1H), 4.51 (d, / = 4.9 Hz, 1H), 3.91 (s, 3H), 3.26 - 3.18 (m, 1H), 3.12 (s, 3H), 2.24 (s, 1H), 1.85 - 1.75 (m, 1H), 1.67 - 1.52 (m, 2H), 1.39 (dd, / = 12.6, 4.1 Hz, 1H), 1.33 - 1.21 (m, 2H), 1.20 - 1.03 (m, 1H), 0.96 (s, 9H), 0.90 - 0.72 (m, 2H). MS (ESI-) m/z 554 (M-H) .

Example 19

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(3-meth oxy-2,2- dimethylpropanoyl)-5-phenylpyrrolidine-2-carboxylic acid

Example 19A

rac-tert- butyl (2i?,35 ^, ,4i?,55')-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l -(3-methoxy-2,2- dimethylpropanoyl)-5-phenylpyrrolidine-2-carboxylate

[0286] A solution of Example 13B (100 mg, 0.212 mmol) and triethylamine (89 pL, 0.636 mmol) in dichloromethane (942 pL) at 25 °C was treated with dropwise addition of 3-methoxy-2,2- dimethylpropanoyl chloride (80 mg, 0.530 mmol) as a solution in dichloromethane (0.2 mL), stirred for 30 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen. The resulting product purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the title compound (0.117 g, 0.200 mmol, 94 % yield). MS (ESI+) m/z 587 (M+H) ⁺ .

Example 19B

mc-(2i?,35 ^, ,4i?,55')-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l -(3-methoxy-2,2- dimethylpropanoyl)-5-phenylpyrrolidine-2-carboxylic acid

[0287] Example 19A (50 mg, 0.085 mmol) was treated with trifluoro acetic acid (379 pL) and after 20 minutes, LC/MS showed the desired mass. The reaction was concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a 3: 1:4 ethyl

acetate\ethanol\heptanes solvent system over a period of 20 minutes to give the title compound (37 mg, 0.070 mmol, 82 % yield). (400 MHz, DMSO -de) d 7.38 - 7.30 (m, 3H), 7.08 (d, J = 8.9 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.53 (d, /= 2.8 Hz, 1H), 5.70 (d, / = 10.0 Hz, 1H), 4.82 (d, /= 4.7 Hz, 1H), 4.63 (dd, / = 9.9, 5.9 Hz, 1H), 3.94 (s, 3H), 3.29 (s, 2H), 3.19 (s, 3H), 3.09 (t, / = 5.4 Hz, 1H), 1.08 (s, 3H), 1.02 (s, 3H), 0.96 (s, 9H); MS (ESI-) m/z 528 (M-H) .

Example 20

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(lr,4R )-4-methoxycyclohexane- l-carbonyl]-5-phenylpyrrolidine-2-carboxylic acid

Example 20A

rac-tert- butyl (2/^35, 4A ^> ,5.S ^, )-3-/e/7-but T4-(5-chloiO-2-methoxybenzoyl)- 1 -[( l y,4.S')-4- methoxycyclohexane-l-carbonyl]-5-phenylpyrrolidine-2-carboxy late

[0288] A solution of Example 13B (100 mg, 0.212 mmol) and triethylamine (89 pL, 0.636 mmol) in dichloromethane (942 pL) at 25 °C was treated with drop wise addition of 4- methoxycyclohexanecarbonyl chloride (94 mg, 0.530 mmol) as a solution in dichloromethane (0.2 mL), stirred for 20 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the title compound (28 mg, 0.046 mmol, 21.59 % yield) as the second eluting compound. ¹ H NMR (400 MHz, DMSO-tfc) d 7.38 - 7.25 (m, 3H), 7.13 - 7.00 (m, 4H), 6.38 (s, 1H), 5.43 (d, J = 10.0 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.45 (d, / = 4.9 Hz, 1H), 3.91 (s, 3H), 3.13 (s, 3H), 1.98 - 1.89 (m, 1H), 1.74 - 1.66 (m, 1H), 1.51 (s,

9H), 1.33 - 1.23 (m, 3H), 1.22 - 1.04 (m, 4H), 0.96 (s, 9H), 0.89 - 0.81 (m, 2H); MS (ESI-) m/z 610 (M-H) ^~ . The trans-stereochemistry of the cyclohexane ring in the second-eluting structure was confirmed by X-ray.

Example 20B

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(lr,4R )-4-methoxycyclohexane- l-carbonyl]-5-phenylpyrrolidine-2-carboxylic acid

[0289] Example 20A (28 mg, 0.046 mmol) was treated with trifluoro acetic acid (203 pL) and after 20 minutes, LC/MS showed desired mass. The reaction was concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a 3:1:4 ethyl

acetate\ethanol\heptanes solvent system over a period of 20 minutes to give the title compound (17 mg, 0.031 mmol, 66.8 % yield). ^l H NMR (400 MHz, DMSO -de) d 7.41 - 7.28 (m, 3H), 7.13 - 7.00 (m, 3H), 6.39 (s, 1H), 5.45 (d, / = 10.1 Hz, 1H), 4.81 - 4.68 (m, 1H), 4.50 (d, / = 4.9 Hz, 1H), 3.91 (s, 3H), 3.20 - 3.09 (m, 4H), 2.26 - 2.07 (m, 1H), 1.99 - 1.88 (m, 1H), 1.77 - 1.64 (m, 2H), 1.35 - I.25 (m, 3H), 1.21 - 1.02 (m, 2H), 0.96 (s, 9H), 0.89 - 0.74 (m, 2H); MS (ESI-) m/z 554 (M-H) .

Example 21

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(oxane- 4-carbonyl)-5- phenylpyrrolidine-2-carboxylic acid

Example 21 A

rac-tert- butyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(oxane- 4-carbonyl)-5- phenylpyrrolidine-2-carboxylate

[0290] To tetrahydro-2/7-pyran-4-carboxylic acid (0.3 g, 2.305 mmol) in dichloromethane (2 mL) was added half of a solution of oxalyl dichloride (0.581 mL, 6.86 mmol) in dichloromethane (1 mL) followed by 4 drops of /V,/V-dimethylformamide. The reaction bubbled vigorously, then the remainder of the oxalyl chloride solution was added dropwise. The reaction was stirred for 2 h, the solvent was removed under a stream of nitrogen, then chased with dichloromethane (2 x 1 mL), dried under a stream of nitrogen, and stored under vacumn overnight to give 150 mg oily product. This reagent (0.05 g, 0.338 mmol) was added to a mixture Example 13B (0.12 g, 0.254 mmol) and triethylamine (0.089 mL, 0.635 mmol) in 1 mL of dichloromethane. After 2 h, the mixture was quenched with saturated aqueous sodium bicarbonate, the aqueous layer removed, the resulting oil dissolved in dichloromethane and purified using a 12 g silica gel cartridge with 10-100% ethyl acetate/heptanes in 20 min to give the title compound (106 mg, 0.181 mmol, 71.4 % yield). Ή

NMR (400 MHz, DMSO -de) d 7.39 - 7.26 (m, 3H), 7.13 - 6.99 (m, 4H), 6.38 (s, 1H), 5.47 (d, J = 10.1 Hz, 1H), 4.76 (dd, / = 10.0, 5.7 Hz, 1H), 4.46 (d, / = 4.9 Hz, 1H), 3.91 (s, 3H), 3.78 (d, / =

II.5 Hz, 1H), 3.58 (s, 1H), 3.15 (s, 1H), 3.03 (t, / = 5.3 Hz, 1H), 2.47 - 2.34 (m, 2H), 1.51 (m,

10H), 1.42 - 1.28 (m, 2H), 0.96 (s, 9H); 0.81 (bs, 1H); MS (ESI+) m/z 582 (M-H) .

Example 21B

rac-(2R,35 ^, ,4R,55 ^, )-3-(/er/-butyl)-4-(5-chloro-2-methoxybenzoyl)-5-pheny l-l-(tetrahydro-2//-pyran-

4-carbonyl)pyrrolidine-2-carboxylic acid

[0291] To Example 21A (103 mg, 0.176 mmol) was added trifluoroacetic acid (0.621 mL, 8.06 mmol) and the mixture was stirred at 24 °C for 2 h. The solvent was removed in vacuo and the resulting solid was chromatographed using a 12 g silica gel cartridge with a gradient of 0-6% methanol/dichloromethane over a period of 20 minutes to give the title compound (88 mg, 0.167 mmol, 95 % yield). ^l H NMR (400 MHz, DMSO -de) d 7.34 (dd, /= 9.0, 2.8 Hz, 3H), 7.13 - 6.99 (m, 4H), 6.39 (s, 1H), 5.49 (d, /= 10.1 Hz, 1H), 4.76 (dd, / = 10.1, 5.7 Hz, 1H), 4.53 (d, / = 4.9 Hz, 1H), 3.91 (s, 3H), 3.77 (dt, / = 11.2, 3.5 Hz, 1H), 3.59 (bs, 1H), 3.25 - 3.07 (m, 4H), 1.52 (dd, / = 8.1, 3.7 Hz, 2H), 1.37 (bs, 1H), 0.97 (s, 9H), 0.81 (bs,lH); MS (ESI+) m/z 526 (M-H) .

Example 22

rac-(2i?,35',4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(li?,3 i?)-3-methoxycyclohexane- l-carbonyl]-5-phenylpyrrolidine-2-carboxylic acid

[0292] A solution of Example 13B (100 mg, 0.212 mmol) and triethylamine (89 pL, 0.636 mmol) in dichloromethane (942 pL) at 25 °C was treated with dropwise addition of 3- methoxycyclohexanecarbonyl chloride (94 mg, 0.530 mmol) as a solution in dichloromethane (0.2 mL) and stirred for 20 minutes. The reaction was quenched with 2 drops of methanol, concentrated under a stream of nitrogen, and purified using a 12 g silica gel cartridge eluting with a gradient of 5- 100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the rac-tert- butyl (2i?,35',4i?,55 ^, )-3-tert-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(3-meth oxycyclohexane-l-carbonyl)- 5-phenylpyrrolidine-2-carboxylate as the first eluting compound. MS (EST) m/z 610 (M-H) . This material (19 mg, 0.031 mmol) was treated with trifluoroacetic acid (138 pL) at 25 °C and stirred for 20 minutes, then concentrated under a stream of nitrogen and precipitated with heptane and two drops of ethyl acetate to give the title compound (13 mg, 0.023 mmol, 75 % yield). Structure confirmed by X-ray diffraction. ^X H NMR (400 MHz, DMSO-tfc) d 7.39 - 7.25 (m, 3H), 7.10 - 7.00 (m, 4H), 6.41 (s, 1H), 5.44 (d, / = 10.0 Hz, 1H), 4.74 (dd, / = 10.0, 5.6 Hz, 1H), 4.51 (d, 7 = 4.6 Hz, 1H), 3.91 (s, 3H), 3.34 - 3.26 (m, 1H), 3.23 (s, 3H), 3.10 - 3.03 (m, 1H), 2.62 - 2.53 (m, 1H), 2.26 - 2.11 (m, 1H), 1.85 - 1.71 (m, 1H), 1.66 - 1.55 (m, 1H), 1.48 - 1.37 (m, 2H), 1.37 - 1.20 (m, 3H), 0.96 (s, 9H). MS (ESI-) m/z 554 (M-H) .

Example 23

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-hydroxy-5- (trifluoromethyl)benzoyl]-

5-phenylpyrrolidine-2-carboxylic acid

[0293] A solution of Example l5C (l.l8 g, 1.916 mmol) and tetrabutylammonium iodide (2.124 g, 5.75 mmol) in dichloromethane (60 mL) was cooled to -20 °C in a dry ice bath was treated with trichloroborane (0.674 g, 5.75 mmol). The reaction mixture was stirred at -20 °C for 30 minutes, and allowed to warm to rt for 30 minutes. LC/MS indicated the conversion was complete, and de-methyl by-product was also detected. The reaction mixture was poured in cold water (50 mL) slowly and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine and concentrated. The residue was purified via chromatography on a 120 g silica gel cartridge, eluting with ethyl acetate/methanol (9:1) in heptane at 0-60% gradient to yield the second eluent as the title compound (30 mg, 2.87 % yield). ¹ H NMR (501 MHz, CDCE) d 11.85 (s, 1H), 8.19 - 7.92 (m, 1H), 7.71 (dd, 7 = 8.8, 2.1 Hz, 1H), 7.17 (dd, J= 5.0, 2.0 Hz, 3H), 6.99 (dd, J = 7.7, 2.2 Hz, 3H), 5.49 (d, 7 = 9.8 Hz, 1H), 4.80 (d, J= 6.7 Hz, 1H), 4.45 (t, J= 9.2 Hz, 1H), 3.93 (dd, 7 = 8.6, 6.6 Hz, 1H), 2.35 - 2.23 (m, 1H), 1.85 (d, 7= 11.8 Hz, 2H), 1.60 (m, 2H), 1.45 (s, 1H), 1.35 - 1.08 (m, 4H), 1.00 (s, 9H), 0.76 (td, 7 = 16.8, 15.0, 11.2 Hz, 1H); MS (ESI+) m/z 546 (M+H) ⁺ .

Example 24

(25 ^, ,3L ^> ,4.n,5L ^> )-3-/ _< ° r/-butyl- 1 -(cyclohexanecarbonyl)-4-[2-methoxy-5-(trifluoromethyl)benzo yl]-5- phenylpyrrolidine-2-carboxylic acid

Example 24A

(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy-5- (trifluoromethyl)benzoyl]-5- phenylpyrrolidine-2-carboxylic acid

[0294] Example 24A was isolated as the first eluting peak from the purification of Example 23 (570 mg, 53.1 % yield). ^l H NMR (400 MHz, CDCE) d 7.64 (dd, J= 8.6, 2.4 Hz, 1H), 111 (d, 7 = 7.2 Hz, 3H), 7.08 - 6.90 (m, 4H), 5.40 (d, 7 = 9.6 Hz, 1H), 4.79 - 4.60 (m, 2H), 4.04 (s, 3H), 3.96 - 3.80 (m, 1H), 2.34 - 2.22 (m, 1H), 1.54 (dd, 7 = 24.5, 12.0 Hz, 3H), 1.27 (d, J= 11.4 Hz, 2H), 1.17 (s, 2H), 0.96 (s, 9H), 0.91 - 0.70 (m, 3H); MS (ESI+) m/z 560 (M+H) ⁺ .

Example 24B

(25 ^, ,3R,45 ^, ,5R)-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy -5-(trifluoromethyl)benzoyl]-5- phenylpyrrolidine-2-carboxylic acid

[0295] Example 24A was separated via chiral supercritical fluid chromatography. The preparative supercritical fluid chromatography was performed on a THAR/Waters SFC 80 system running under SuperChrom software control. The preparative supercritical fluid chromatography system was equipped with an 8-way preparative column switcher, CO2 pump, modifier pump, automated back pressure regulator (ABPR), UV detector, and 6-position fraction collector. The mobile phase comprised of supercritical CO2 supplied by a dewar of bone-dry non-certified CO2 pressurized to 350 psi with a modifier of isopropyl alcohol at a flow rate of 70 g/min. The column was at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was loaded into the modifier stream in 2 mL (130 mg) injections. The mobile phase was held isocratically at 25% CosolvenkCCE. Fraction collection was time and/or threshold triggered. The instrument was fitted with a Regis Whelk-0 (S, S) column with dimensions 21 mm i.d. x 250 mm length with 5 pm particles. Peak A eluted at 4.6 minutes and Peak B eluted at 6.2 minutes. The title compound is the first eluting peak (102 mg, 29.1 % yield). ¹ H NMR (400 MHz, CDCE) d 7.63 (dd, J= 8.8, 2.5 Hz, 1H), 7.23 - 7.10 (m, 3H), 7.07 - 6.91 (m, 4H), 5.39 (d, / = 9.6 Hz, 1H), 4.77 - 4.63 (m, 2H), 4.08 - 3.97 (s, 3H), 3.91 (dd, / = 8.8, 6.4 Hz, 1H), 2.28 (tt, / = 11.6, 3.2 Hz, 1H), 1.82 - 1.75 (m, 2H), 1.61 - 1.45 (m, 3H), 1.33 - 1.23 (m, 1H), 1.15 (dtd, / = 19.0, 8.1, 3.8 Hz, 2H), 1.05 (d, /= 6.1 Hz, 1H), 0.97 (s, 9H), 0.81 (s, 1H); MS (ESI+) m/z 560 (M+H) ⁺ . The second eluting peak is Example 11-189.

Example 25

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(l5 ^, ,35 ^, )-3-methoxycyclohexane- l-carbonyl]-5-phenylpyrrolidine-2-carboxylic acid

[0296] A solution of Example 13B and triethylamine (89 pL, 0.636 mmol) in dichloromethane (942 pL) at 25 °C was treated with dropwise addition of 3-methoxycyclohexanecarbonyl chloride (94 mg, 0.530 mmol) as a solution in dichloromethane (0.2 mL), stirred for 20 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide rac-tert- butyl (2A ^> ,3.S ^, ,4A ^> ,5.S ^, )-3- _/ e _/7 -butyl-4-(5-chloi _O -2- methoxybenzoyl)- 1 -(3-methoxycyclohexane- 1 -carbonyl)-5 -phenylpyrrolidine-2-carboxylate as the second eluting compound. MS (EST) m/z 610 (M-H) . This material, rac-tert- butyl (2R,3S,4R,5S)- 3-/e/7-but T4-(5-chloro-2-methoxybenzoyl)- 1 -(3-methoxycyclohexane- 1 -carbonyl)-5- phenylpyrrolidine-2-carboxylate (53 mg, 0.087 mmol) was treated with trifluoroacetic acid (385 pL) at 25 °C overnight. The reaction was concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide the title compound (12 mg, 0.019 mmol, 22.43 % yield).

The structure was determined by X-ray diffraction. ¹ H NMR (400 MHz, DMSO-tfc) d 7.41 - 7.28 (m, 3H), 7.13 - 7.01 (m, 4H), 6.44 (s, 1H), 5.40 (d, /= 10.1 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.49 (d, J = 5.0 Hz, 1H), 3.92 (s, 3H), 3.44 (s, 1H), 3.19 (s, 3H), 3.18 - 3.09 (m, 1H), 1.78 (d, /= 13.7 Hz,

1H), 1.62 (d, / = 12.9 Hz, 1H), 1.42 (t, /= 12.6 Hz, 1H), 1.32 - 1.21 (m, 3H), 1.23 - 1.02 (m, 1H), 0.96 (s, 9H), 0.89 - 0.76 (m, 2H). MS (ESI-) m/z 554 (M-H) .

Example 26

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-/V-(methanesulf onyl)-4-[2-methoxy-5- (trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-carboxamide

[0297] Example 24A (87 mg, 0.155 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (55.5 mg,

0.342 mmol) in l,2-dichloroethane (1.5 mL) was stirred at 42 °C for 2 h, and then

methanesulfonamide (44.4 mg, 0.466 mmol) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine, (1 M in tetrahydrofuran, 0.5 mL, 71.0 mg, 0.466 mmol) was added. The reaction was concentrated and the residue purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm

100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to yield the title compound (15 mg, 15.15 % yield. ^X H NMR (400 MHz, CDCb) d 10.25 (s, 1H), 7.64 (dd, J = 8.7, 2.4 Hz, 1H), 7.22 - 7.15 (m, 3H), 7.04 - 6.90 (m, 4H), 5.38 (d, J = 9.5 Hz, 1H), 4.70 - 4.61 (m, 2H), 4.04 (s, 3H), 3.94 (s, 1H), 3.27 (s, 3H), 2.29 (t, J = 11.6 Hz, 1H), 1.90 (s, 3H), 1.54 (d, / = 21.5 Hz, 3H), 1.29 - 1.12 (m, 3H), 0.96 (s, 9H), 0.78 (s, 1H), MS(ESI+): m/z = 637 (M+H) ⁺ .

Example 27

(25 ^, ,3R,45 ^, ,5R)-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(cyc lohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

[0298] Example 13D (195 mg) was separated by chiral preparative supercritical fluid chromatography using a CHIRALPAK IA, column size 30 x 250 mm, 5 micron, serial Number: IA00SALC002-812121, using a concentration of 50 mg/mL in methanol at a flow rate of 49 g/min C0 ₂ to provide 75 mg of the title compound. Retention time (chiral supercritical fluid

chromatography) = 7.0 min. ^l H NMR (400 MHz, CDCb) d 7.35 (dd, J = 8.8, 2.7 Hz, 1H), 7.23 - 7.13 (m, 3H), 6.96 (dd, / = 7.0, 2.3 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.79 (d, / = 2.7 Hz, 1H), 5.46 (d, / = 9.6 Hz, 1H), 4.68 (d, / = 6.8 Hz, 1H), 4.62 (t, / = 9.5 Hz, 1H), 3.98 (s, 3H), 3.94 (dd, / = 9.5, 6.8 Hz, 1H), 2.32 (tt, / = 11.7, 3.2 Hz, 1H), 1.88 - 1.75 (m, 2H), 1.65 - 1.46 (m, 3H), 1.36 - 1.14 (m, 3H), 1.04 (d, / = 13.5 Hz, 1H), 0.93 (s, 9H), 0.90 - 0.74 (m, 1H). MS (ESI-) 524 (M-H) . Structure was confirmed by X-ray diffraction.

Example 28

l-{ (25 ^, )-l-[(benzyloxy)carbonyl]pyrrolidine-2-carbonyl}-3-/er /-butyl-4-(5-chloro-2- methoxybenzoyl)-5-phenylpyrrolidine-2-carboxylic acid

[0299] A solution of (5)-benzyl 2-(chlorocarbonyl)pyrrolidine-l-carboxylate was prepared by treating (5 ^, )-l-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (0.451 g, 1.809 mmol) in dichloromethane (9 mL) with /V,/V-dimethylformamide (0.014 mL, 0.181 mmol) followed by oxalyl chloride (0.475 mL, 5.43 mmol) and stirred at ambient temperature for 30 min. The mixture was concentrated and azeotroped with dichloromethane (2 x 2 mL) to provide the desired product. This material was taken up in dichloromethane (2 mL) and added dropwise to a solution of Example 13B (400 mg, 0.847 mmol) and triethylamine (354 pL, 2.54 mmol) in dichloromethane (3766 pL) at 25 °C. The reaction was stirred for 30 minutes, then quenched with 5 drops of methanol and of saturated aqueous sodium bicarbonate (0.5 mL), concentrated under a stream of nitrogen, and purified using a 40 g silica gel cartridge eluting with a gradient of 5-100% ethyl acetate\heptanes over a period of 40 minutes to provide rar-OS'-benzyl 2-((25 ^, ,3R,45 ^, ,5R)-2-(/er/-butoxycarbonyl)-3- (7er/-butyl)-4-(5 -chloro-2-methoxybenzoyl)-5 -phenylpyrrolidine- 1 -carbonyl)pyrrolidine- 1 - carboxylate (30 mg, 0.043 mmol). This product was treated with trifluoroacetic acid (0.3 mL) at 25 °C was stirred for 20 minutes, then concentrated under a stream of nitrogen, and

chromatographed using a 4 g silica gel cartridge with a ethyl acetate/ethanol/heptanes solvent system to give the title compound (24 mg, 0.037 mmol, 87 % yield). ¹ H NMR (400 MHz, DMSO- de) d 7.48 - 7.24 (m, 8H), 7.17 - 7.04 (m, 4H), 6.53 (s, 1H), 5.83 - 5.50 (m, 1H), 5.16 - 4.97 (m, 2H), 4.79 - 4.62 (m, 1H), 4.51 (d, / = 6.0 Hz, 1H), 4.31 - 4.14 (m, 1H), 3.91 (s, 3H), 3.32 (td, /= 6.9, 2.9 Hz, 2H), 3.13 (t, / = 6.6 Hz, 1H), 1.90 - 1.69 (m, 1H), 1.59 - 1.42 (m, 1H), 1.34 - 1.12 (m, 1H), 0.91 (s, 9H), 0.88 - 0.77 (m, 1H); MS (ESI+) m/z 647 (M+H) ⁺ .

Example 29

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-[5-chloro-2-(difluoromethoxy)benzoyl] -l-(cyclohexanecarbonyl)-

5-phenylpyrrolidine-2-carboxylic acid

Example 29A

1 - (5-chloro-2- (difluoromethoxy)phenyl)ethanone

[0300] Potassium hydroxide (13.1 g, 234.0 mmol) was suspended in a mixture of acetonitrile (15 mL) and water (15 mL) and cooled to approximately -20 °C. l-(5-chloro-2-hydroxyphenyl) ethanone (2.0 g, 11.7 mmol) was added dropwise, followed by diethyl (bromodifluoromethyl) phosphonate (4.16 mL, 23.4 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3 x 30 mL), and then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by silica gel column on eluent (petroleum ether/ethyl acetate = 100/1) to afford the title compound (1.1 g, 4.99 mmol, 42.6 % yield). ¹ H NMR (400 MHz, CDCL) d 7.65 (d, /= 2.4 Hz, 1H), 7.38-7.41 (m, 1H), 7.08 (d, J= 8.8 Hz, 1H), 6.51 (t, J = 72.8 Hz, 1H), 2.55 (s, 3H).

Example 29B

rac- (2R,3S ,4R,5S)-tert-buty\ 3-(/er/-butyl)-4-(5-chloro-2-(difluoromethoxy)benzoyl)- 1- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

[0301] The title compound was prepared following the procedure of Example 1B and Example 1C, substituting Example 29 A for 2',5'-dichloroacetophenone in Example 1B. ¹ H NMR (400 MHz, CDCb) d 7.41-7.51 (m, 3H ), 6.61-7.13 (m, 6H), 5.53 (d, J= 10.0 Hz, 1H), 4.66 (s, 1H), 4.46 (d, 7 = 6.0 Hz, 1H), 3.02 (d, J= 8.0 Hz, 1H), 1.98-2.09 (m, 1H), 1.65-1.83 (m, 4H), 1.59 (s, 9H), 1.18-1.44 (m, 5H), 0.98 (s, 9H), 0.78 (s, 1H), 0.50 (s, 1H).; MS (ESI+) m/z 618 (M+H) ⁺ .

Example 29C

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-[5-chloro-2-(difluoromethoxy)benzoyl] -l-(cyclohexanecarbonyl)-

5-phenylpyrrolidine-2-carboxylic acid

[0302] Example 29B (25 mg, 0.040 mmol) was treated with trifluoro acetic acid (0.3 mL) at 25 °C and stirred for 20 minutes. The reaction was concentrated under a stream of nitrogen and purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10- 95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to afford the title compound (11.7 mg, 0.021 mmol, 51.5 % yield). ^X H NMR (400 MHz, CDCE) d 7.39 (dd, J= 8.8, 2.7 Hz, 1H), 7.19 (qd, 7 = 8.7, 7.8, 3.7 Hz, 3H), 7.04 (d, 7 = 8.8 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.88 - 6.42 (m, 2H), 5.51 (d, 7 = 9.7 Hz, 1H), 4.74 (d, 7 = 6.1 Hz, 1H), 4.54 (dd, 7= 9.7, 8.4 Hz, 1H), 3.93 (dd, 7 = 8.4, 6.1 Hz, 1H), 2.33 (tt, 7= 11.5, 3.3 Hz, 1H), 1.80 (d, 7 = 12.1 Hz, 2H), 1.65 - 1.45 (m, 3H), 1.36 - 1.07 (m, 4H), 0.96 (s, 9H), 0.90 - 0.72 (m, 1H); MS (ESI+) m/z 562 (M+H) ⁺ .

Example 30

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(25 ^, )-l- (methoxycarbonyl)pyrrolidine-2-carbonyl]-5-phenylpyrrolidine -2-carboxylic acid

Example 30 A

rac-(R)-benzyl 2-((25 ^, ,3R,45 ^, ,5R)-2-(/er/-butoxycarbonyl)-3-(/er/-butyl)-4-(5-chlor o-2- methoxybenzoyl)-5-phenylpyrrolidine-l-carbonyl)pyrrolidine-l -carboxylate

[0303] A solution of (5 ^, )-l-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (0.451 g, 1.809 mmol) in dichloromethane (9 mL) was treated with /V,/V-dimethylformamide (0.014 mL, 0.181 mmol) followed by oxalyl chloride (0.475 mL, 5.43 mmol) and stirred at ambient temperature for 30 minutes. The mixture was concentrated and azeotroped with dichloromethane (2 x 2 mL) to provide (5)-benzyl 2-(chlorocarbonyl)pyrrolidine-l-carboxylate, which was taken up in

dichloromethane (2 mL) and added dropwise to a solution of Example 13B (400 mg, 0.847 mmol) and triethylamine (354 pL, 2.54 mmol) in dichloromethane (3.7 mL) at 25 °C. The reaction was stirred for 30 minutes, then quenched with 5 drops of methanol and saturated aqueous sodium bicarbonate (0.5 mL), concentrated under a stream of nitrogen, and purified using a 40 g silica gel cartridge eluting with a gradient of 5-100% ethyl acetate\heptanes over a period of 40 minutes to provide the title compound 0.246 g (0.35 mol, 41%). MS (ESI-) m/z 703 (M-H) .

Example 30B

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-5-phenyl- l-[(25')- pyrrolidine-2-carbonyl]pyrrolidine-2-carboxylate— hydrogen chloride)

[0304] Into a glass tube reactor was charged Example 30A (202 mg, 0.287 mmol), 5% Pd/C (101 mg, 0.287 mmol), tetrahydrofuran (2.02 mL) and 4 M HC1 in dioxane (0.206 mL, 0.824 mmol). The reactor was purged with H ₂ and stirred at room temperature under 60 psig of hydrogen (g) for 2 h. The reaction was filtered and the solvent was removed in vacuo to give 175 mg (96%) of the title compound. MS (ESI+) m/z 569 (M+H) ⁺ .

Example 30C

rac-(2Z?,35 ^, ,4Z?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(25 ^, )-l- (methoxycarbonyl)pyrrolidine-2-carbonyl]-5-phenylpyrrolidine -2-carboxylic acid

[0305] To a solution of Example 30B (25 mg, 0.041 mmol) in dichloromethane (0.3 mL) at 25 °C was added triethylamine (30 m L, 0.215 mmol) followed by methyl carbonochloridate (8 pL, 0.104 mmol). The reaction was stirred for 20 minutes, the solvent removed, and the residue purified using a 4 g silica gel cartridge with a gradient of 5-100% ethyl acetate\heptanes over 20 minutes to give 17 mg (0.027 mmol, 65% yield) of the desired ester. The ester was treated with trifluoroacetic acid (0.3 mL). After 20 minutes, the solvent was removed and the crude material chromatographed using a 4 g silica gel cartridge with an ethyl acetate\ethanol\heptane solvent system to give the title compound (13 mg, 0.023 mmol, 55.1 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 7.43 - 7.29 (m, 3H), 7.15 - 7.05 (m, 5H), 6.54 (s, 1H), 5.76 - 5.61 (m, 1H), 4.79 (t, / = 8.3 Hz, 1H), 4.55 (d, /= 5.6 Hz, 1H), 4.25 - 4.10 (m, 1H), 3.97 (s, 3H), 3.56 (s, 3H), 3.35 - 3.24 (m, 2H), 3.12 (t, / = 6.1 Hz,

1H), 1.84 - 1.67 (m, 1H), 1.55 - 1.39 (m, 1H), 0.96 (s, 9H), 0.90 - 0.75 (m, 1H); MS (ESI+) m/z 571 (M+H) ⁺ .

Example 31

(25 ^, ,3i?,4i?,5i?)-3-/er/-butyl-4-[l-(5-chloro-2-methoxyphe nyl)ethenyl]-l-(cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

Example 31A

rac-tert- butyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(cycloh exanecarbonyl)-

5-phenylpyrrolidine-2-carboxylate [0306] Example 13B (140 mg, 0.297 mmol) was dissolved in dichloromethane (1 mL).

Triethylamine (0.062 mL, 0.445 mmol) was added, followed by cyclohexanecarbonyl chloride (47.8 mg, 0.326 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was loaded directly onto a 12 g silica gel column and was eluted with 0:100 to 100:0 ethyl acetate:heptanes over 20 min to give the title compound. (170 mg, 98% yield). ¹ H NMR (400 MHz, CDCb) d 7.44 - 7.35 (m, 2H), 7.27 (d, J= 5.6 Hz, 1H), 7.23 - 7.13 (m, 2H), 7.08 - 7.01 (m, 1H), 6.81 (d, / = 8.8 Hz, 1H), 6.53 (d, / = 2.7 Hz, 1H), 5.27 (d, / = 9.9 Hz, 1H), 4.75 (dd, / = 9.9, 6.9 Hz, 1H), 4.54 (d, / = 6.1 Hz, 1H), 3.93 (s, 3H), 3.14 (d, / = 6.4 Hz, 1H), 2.06 (tt, / = 11.6, 3.3 Hz, 1H), 1.82-0.78 (m, 11H), 1.58 (s, 9H), 1.00 (s, 9H); MS (ESI+) m/z 581.9 (M+H) ⁺ .

Example 31B

rac-tert- butyl (2A ^> ,3.S ^, ,4.S ^, ,5.S ^, )-3-/e/7-butyl-4-[ 1 -(5-chloro-2-methoxyphenyl)ethenyl]- 1 - (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

[0307] Methyltriphenylphosphonium bromide (145 mg, 0.405 mmol) was suspended in toluene (1.5 m) and potassium 2-methylpropan-2-olate (1 M solution in tetrahydrofuran, 0.385 mL, 0.385 mmol) was added dropwise. The resulting solution was stirred for 30 min at room temperature, then Example 31A (118 mg, 0.203 mmol) was added as a solution in toluene (1 mL). The reaction was stirred at room temperature. After 16 h, the reaction was complete as indicated by TLC. The reaction mixture was loaded directly onto a 12 g silica gel column and eluted with 0:100 to 20:80 ethyl acetate:heptanes over 20 min to give the title compound (111 mg, 94%). ¹ H NMR (400 MHz, CDCE) d 7.47 (dd, /= 6.8, 2.8 Hz, 2H), 7.27 - 7.21 (m, 3H), 7.13 (dd, J = 8.7, 2.7 Hz, 2H), 6.74 (d, J= 8.7 Hz, 1H), 6.24 (d, /= 2.7 Hz, 1H), 5.09 (d, J= 9.3 Hz, 1H), 4.97 (s, 1H), 4.80 (s, 1H), 4.43 (d, / = 6.8 Hz, 1H), 3.88 (d, / = 9.0 Hz, 1H), 3.82 (s, 3H), 2.76 (dd, / = 8.8, 6.8 Hz, 1H), 2.18 - 2.08 (m, 1H), 1.78-0.79 (m, 9H), 1.54 (s, 9H), 1.04 (s, 9H); MS (ESI+) m/z 580.1 (M+H) ⁺ .

Example 31C

(25 ^, ,3R,4R,5R)-3-/er/-butyl-4-[l-(5-chloro-2-methoxyphenyl )ethenyl]-l-(cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

[0308] Example 31B (123 mg, 0.212 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.25 mL, 3.24 mmol) was added. The reaction was stirred for 1 h at room temperature, and was complete as indicated by LC/MS. The solvent was removed in vacuo, and the residue was azeotroped with dichloromethane (2 x 10 mL) in vacuo to give the crude product, which was purified via Chiral supercritical fluid chromatography, eluting on a 21 x 250 mm, 5 micron Chiralcel OJ-H column with a sample concentration of 30 mg/mL in 1:1 methanohDMSO and an eluent composition of 15% methanol in C0 ₂ . The first eluting peak was Example 11-254 (11 mg) and the second-eluting peak was Example 31 (12.8 mg). ^X H NMR (400 MHz, DMSO-tfc) d 7.40 - 7.29 (m, 2H), 7.19 - 7.08 (m, 4H), 6.91 (d, 7 = 8.8 Hz, 1H), 6.10 (d, / = 2.7 Hz, 1H), 5.21 (d, J= 9.6 Hz, 1H), 4.93 (d, J= 9.1 Hz, 2H), 4.47 (s, 1H), 3.95 - 3.87 (m, 1H), 3.77 (s, 3H), 2.33 - 2.20 (m, 2H), 1.63 (d, / = 10.1 Hz, 2H), 1.49 - 1.33 (m, 3H), 1.33 - 1.03 (m, 6H), 0.99 (s, 9H); MS (ESI+) m/z 524.3 (M+H) ⁺ .

Example 32

mc-(2i?,3i?,45',55 ^, )-4-[l-(5-chloro-2-methoxyphenyl)ethenyl]-3-(2-methoxy propan-2-yl)-l-(2- methyloxane-3-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid

Example 32A

5-chloro-2-methoxybenzoyl chloride

[0309] 5-Chloro-2-methoxybenzoic acid (15 g, 80 mmol) was dissolved in thionyl chloride (20 mL) and the resulting solution was heated to 75 °C for 1 h. The reaction was cooled to room temperature. Volatiles were removed in vacuo and azeotroped with toluene two times. The resulting solid was used without additional purification.

Example 32B

₍ 7f ₎ -2-methyl-4-(tnbutylstannyl ₎ but-3-en-2-ol

[0310] Bis(triphenylphosphine)palladium(II) dichloride (1.022 g, 1.456 mmol) and 2- methylbut-3-yn-2-ol (3.53 mL, 36.4 mmol) were dissolved in tetrahydrofuran (72.8 mL) and tri-n- butyltin hydride (36.4 mL, 36.4 mmol) was added as a solution in cyclohexane over 2 min via syringe. An exotherm to about 35 °C occurred during the addition. The reaction was allowed to cool to room temperature, stirred for 30 min, then concentrated in vacuo and purified using a 220 g silica gel column (0-20% methyl /e/7-butyl ether/heptanes over 20 min) to afford the title compound (4.47 g).

Example 32C

(2£ ^’ )-l-(5-chloro-2-methoxyphenyl)-4-hydroxy-4-methylpent- 2-en-l-one

[0311] Example 32B (7 g, 18.66 mmol) was dissolved in tetrahydrofuran (141 mL). Tri(2- furyl)phosphine (0.158 g, 0.678 mmol) and Pd ₂ (dba) ₃ (155 mg, 0.17 mmol) were added, followed by addition of 5-chloro-2-methoxybenzoyl chloride (3.48 g, 16.96 mmol) as a solution in tetrahydrofuran (1 mL). The reaction was heated to 60 °C for 1 h. The reaction was cooled to room temperature, concentrated in vacuo and purified using a 120 g silica gel column (10-60% ethyl acetate/heptanes over 20 min, then 10 min at 60% ethyl acetate/heptanes) to afford the title compound (3.98 g), which was stored in the freezer when not in use.

Example 32D

(E)- 1 -(5-chloro-2-methoxyphenyl)-4-methoxy-4-methylpent-2-en- 1 -one

[0312] Example 32C (1.4 g, 5.50 mmol) was dissolved in /V,/V-dimethylformaiuide (2 mL).

The solution was cooled to < 5 °C in an ice bath before sodium hydride (0.440 g, 10.99 mmol) was added in one portion. The reaction was stirred for 1 min (yellow-orange suspension) before iodomethane (1.718 mL, 27.5 mmol) added. The reaction was stirred for 5 min in the ice bath, then warmed to room temperature for 10 min. The reaction was recooled to < 5 °C, and quenched slowly with saturated ammonium chloride, then extracted with methyl /e/7-butyl ether. The combined extracts were washed with water, then brine, dried over sodium sulfate, concentrated, and purified using an 80 g silica gel column (0-50% ethyl acetate/heptanes over 20 min) to give the title compound (1.05 g). ^l H NMR (500 MHz, CDCE) d 7.54 (d, /= 2.7 Hz, 1H), 7.43 (dd, /= 8.8, 2.7 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.79 (d, / = 2.3 Hz, 2H), 3.89 (s, 3H), 3.26 (s, 3H), 1.38 (s, 6H). MS (APCI+) m/z 268.8 (M+H) ⁺ .

Example 32E

rac-(2R,3R,4R,5S)-tert-buty\ 4-(5-chloro-2-methoxybenzoyl)-3-(2-methoxypropan-2-yl)-5- phenylpyrrolidine-2-carboxylate

[0313] Example 1A (1408 mg, 6.42 mmol) was dissolved in tetrahydrofuran (3 mL) and the solution was cooled to -78 °C. A solution of lithium bromide (4.28 mL, 6.42 mmol) was added, followed by addition Example 32D (1150 mg, 4.28 mmol) in tetrahydrofuran (13 mL).

2,3,4,6,7,8,9,lO-Octahydropyrimido[l,2-fl]azepine (5.56 mL, 5.56 mmol) solution was added dropwise, and a yellow suspension resulted. After 30 min at -78 °C, the starting material had been consumed, and clean conversion to the desired product had occurred. The reaction was warmed to 0 °C before diluting with methyl /e/7-butyl ether, adding saturated ammonium chloride, and stirring 10 min at room temperature. The layers were separated, and the organic phase was concentrated and purified using a 12 g silica gel column (0-100% methyl /e/7-butyl ether/heptanes gradient over 20 min) to give the title compound (1.54 g). ^X H NMR (400 MHz, CDCE) d 7.12 (dd, J= 20.6, 1.9 Hz, 6H), 6.69 (d, / = 8.8 Hz, 1H), 6.59 (d, / = 2.7 Hz, 1H), 4.64 (d, / = 1.5 Hz, 2H), 3.90 (d, / = 6.3 Hz, 1H), 3.83 (s, 3H), 3.26 (s, 3H), 3.05 (dt, / = 6.2, 1.5 Hz, 1H), 1.59 (s, 9H), 1.32 (d, / = 6.3 Hz, 6H); MS (APCI+) m/z 488.0 (M+H) ⁺ .

Example 32F

rac-(2R,3R,4S ,5S)-tert-buty\ 4-(l-(5-chloro-2-methoxyphenyl)vinyl)-3-(2-methoxypropan-2-y l)-5- phenylpyrrolidine-2-carboxylate

[0314] Example 32E (1.54 g, 3.16 mmol) was dissolved in toluene (5 mL). In a separate flask, methyltriphenylphosphonium bromide (1.691 g, 4.73 mmol) was suspended in toluene and potassium 2-methylpropan-2-olate (4.42 mL, 4.42 mmol) was added dropwise. The resulting yellow suspension was stirred for 16 h. The reaction was filtered through a one inch silica pad using a fritted funnel, eluting with 50% methyl /e/7-butyl ether/heptanes. Concentrated fractions containing product were purified using a 40 g silica gel column (10-30% methyl /e/7-butyl

ether/heptanes gradient over 15 min) to give the title compound (1.315 g). ^X H NMR (400 MHz, CDCb) d 7.22 - 6.93 (m, 6H), 6.61 (d, 7= 8.8 Hz, 1H), 5.78 (d, 7 = 2.6 Hz, 1H), 5.37 (s, 1H), 5.04 (s, 1H), 4.44 (d, J = 6.8 Hz, 1H), 3.86 (d, J = 6.5 Hz, 1H), 3.75 (s, 3H), 3.70 (dd, J = 6.8, 2.6 Hz, 1H), 3.28 (s, 3H), 2.78 (dd, J = 6.6, 2.6 Hz, 1H), 1.57 (s, 9H), 1.35 (d, J = 14.4 Hz, 6H); MS (APCI+) m/z 486.0 (M+H) ⁺ .

Example 32G

rac-(2i?,3i?,45',55 ^, )-4-[l-(5-chloro-2-methoxyphenyl)ethenyl]-3-(2-methoxy propan-2-yl)-l-(2- methyloxane-3-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0315] In a 4 mL vial was added 2-methyl tetrahydiO-2/7-pyran-3-carboxylic acid (0.468 mL, 0.187 mmol) and l-chloro-/V,/V,2-trimethylprop-l-en-l -amine (0.025 mL, 0.187 mmol) in dichloromethane (1 mL) to give a colorless solution at room temperature. The reaction was stirred at room temperature for 15 min. Example 32L (45.5 mg, 0.094 mmol) was added in 1:1

tetrahydrofuran/pyridine and stirred overnight. The solvent was removed under a stream of nitrogen. Trifluoroacetic acid (1 mL) was added and reaction stirred at rt for 2 h. Trifluoroacetic acid was removed under a stream of nitrogen, and residue reconstituted in 1:1 DMSO/methanol and purified via preparative reverse phase HPLC/MS method TLA8 to afford the title compound (35.5 mg, 68% yield). NMR (400 MHz, 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.43 - 7.31 (m, 2H), 7.22 - 7.13 (m, 4H), 7.01 - 6.87 (m, 1H), 6.41 - 6.09 (m, 1H), 5.22 (dd, J = 24.8, 9.3 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.86 - 4.71 (m, 1H), 4.66 - 4.54 (m, 1H), 4.01 - 3.86 (m, 1H), 3.85 - 3.78 (m, 3H), 3.77 - 3.59 (m, 2H), 3.35 - 3.21 (m, 1H), 3.18 - 3.11 (m, 4H), 2.72 - 2.53 (m, 1H), 1.92 - 0.61 (m, 13H); MS (APCI+) m/z 556.1 (M+H) ⁺ .

Example 33

rac-(2R AR AS AS )-4-[ 1 -(5-chloro-2-methoxyphenyl)ethenyl]- 1 -(2-methoxycyclohexane- 1 - carbonyl)-3-(2-me\thoxypropan-2-yl)-5-phenylpyrrolidine-2-ca rboxylic acid

[0316] The title compound was prepared according to Example 32, substituting 2- methoxycyclohexanecarboxylic acid for 2-methyltetrahydro-2 -pyran-3-carboxylic acid. ¹ H NMR (400 MHz, 120 °C, DMS0-d ₆ :D ₂ 0 = 9:1 (v/v)) d 7.45 - 7.09 (m, 7H), 6.99 - 6.92 (m, 1H), 6.42 - 6.18 (m, 1H), 5.40 - 5.13 (m, 1H), 5.04 - 4.53 (m, 3H), 3.98 - 3.70 (m, 4H), 3.27 - 3.10 (m, 6H), 3.00 - 2.53 (m, 2H), 2.11 - 0.75 (m, 14H); MS (APCI+) m/z 570.1 (M+H) ⁺ .

Example 34

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-[5-chloro-2-(2-hydroxyethoxy)benzoyl] -l-(cyclohexanecarbonyl)-

5-phenylpyrrolidine-2-carboxylic acid

Example 34A

1 - (5-chloro-2- (2-hydroxyethoxy)phenyl)ethanone

[0317] l,3-Dioxolan-2-one (1.032 g, 11.72 mmol) was added to a solution of l-(5-chloro-2- hydroxyphenyl)ethanone (1 g, 5.86 mmol) and potassium carbonate (1.620 g, 11.72 mmol) in N,N- dimethylformamide (10 mL). The reaction mixture was stirred at 100 °C for 15 h. Ice water (50 mL) was added. The mixture was extracted with dichloromethane (2 x 50 mL), and the organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude was purified by column chromatography (1:5 ethyl acetate/petroleum ether) to afford the title compound (1.05 g, 4.65 mmol, 79 % yield). MS (ESI+) m/z 215.7 (M+H) ⁺ .

Example 34B

(2 E)- 1 - [5-chloro-2- (2-hydroxyethoxy)phenyl] -4,4-dimethylpent-2-en- 1 -one

[0318] Potassium hydroxide (0.392 g, 6.99 mmol) was added to a solution of Example 34A (1 g, 4.66 mmol) and pivalaldehyde (1.204 g, 13.98 mmol) in methanol (10 mL) at 0 °C. The reaction mixture was warmed to 50 °C and stirred at this temperature for 15 h. Methanol was evaporated and the residue was suspended in ice water (100 mL). The mixture was neutralized with 2 M HC1 (2.33 mL) and extracted with dichloromethane (2 x 100 mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude was purified by column chromatography (1/5 ethyl acetate/petroleum ether) to afford the title compound (0.76 g, 2.285 mmol, 49.0 % yield). MS (ESI+) m/z 283.7 (M+H) ⁺ .

Example 34C

(2 E)- 1 -[2-(2- { [/e/7-butyl(di methyl )silyl] oxy } ethoxy)-5-chlorophenyl] -4,4-dimethylpent-2-en- 1 -one

[0319] To a solution of Example 34B (1.127 g, 3.99 mmol) and /e/7-butylchlorodi methyl si lane (0.721 g, 4.78 mmol) in /V,/V-d i meth y 1 f o rm am i de (15 mL) was added 1 //-imidazole (0.678 g, 9.96 mmol). The reaction was stirred at rt for 5 h, then added to water (100 mL), and the aqueous layer extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried (Na ₂ S0 ₄ ), concentrated, and then purified by column chromatography(ethyl acetate/petroleum ether=l/l00) to afford the title compound (0.95 g, 2.273 mmol, 57.0 % yield). NMR (400 MHz, CDCb) d 7.46 (d, 7=2.4 Hz, 1H), 7.34 (dd, 7=8.8Hz, 2.8Hz, 1H), 6.93 (d, 7=8.8 Hz, 1H), 6.86-6.82 (m, 1H), 6.61-6.57 (m, 1H), 4.07 (t, 7=5.4 Hz, 2H), 3.93 (t, 7=5.6 Hz, 2H), l.l0(s, 9H), 0.87(s, 9H), 0.05 (s, 6H); MS (ESI+) m/z 397.7 (M+H) ⁺ .

Example 34D

rac-tert- butyl (2A ^> ,3.S ^, ,4/ri5.S ^, )-3-/e/7-butyl-4-[2-(2-{ [/e/7-butyl (dimethyl )silyl]oxy}ethoxy)-5-chlorob enzoyl]-5-phenylpyrrolidine-2-carboxylate

[0320] A solution of Example 1A (0.758 g, 3.11 mmol) and lithium bromide (0.312 g, 3.59 mmol) in tetrahydrofuran (15 mL) was cooled to -78 °C. Example 34C (0.95 g, 2.393 mmol) in tetrahydrofuran (5 mL) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine (0.546 g, 3.59 mmol) was added drop wise at -78 °C. The reaction was stirred at-78 °C for 6 h, then the reaction was added to saturated aqueous ammonium chloride (100 mL), and the aqueous layer extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried (Na ₂ S0 ₄ ), and concentrated to afford a solid. Ethyl acetate and petroleum ether were added to the solid, and the mixture filtered and dried to afford the title compound (1.4 g, 2.044 mmol, 85 % yield). MS (ESI+) m/z 616.7 (M+H) ⁺ .

Example 34E

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-[2-(2-{ [/er/-butyl(dimethyl)silyl]oxy}ethoxy)-5-chlorob enzoyl]-l-(cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carbox ylate

[0321] Cyclohexaneearbonyl chloride (0.328 g, 2.236 mmol) was added to a solution of Example 34D (1.06 g, 1.720 mmol) and triethylamine (0.261 g, 2.58 mmol) in dichloromethane (15 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h, and then ice water (100 mL) was added. The mixture was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCCh, washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated to afford the title compound (1.1 g, 1.438 mmol, 84 % yield). MS (ESI+) m/z 726.7 (M+H) ⁺ .

Example 34L

(2R,3S ,4R,5S)-tert-buty\ 3-(/er/-butyl)-4-(5-chloro-2-(2-hydroxyethoxy)benzoyl)-l-(cy clohexanecar bonyl)-5-phenylpyrrolidine-2-carboxylate

[0322] 2N HC1 in methanol (20 mL) was added to a solution of Example 34E (1.6 g, 2.202 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at rt for 8 h, the water (50 mL) was added. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography (1/1 ethyl acetate/petroleum ether) to afford the title compound (1.2216 g, 1.975 mmol, 90 % yield). ^X H NMR (400 MHz, CDCL) d 7.35-6.66(m, 8H), 5.73-5.42(m, 1H), 4.76-3.92(m, 6H), 3.33-3.13 (m, 1H), 2.31-2.02 (m, 1H), 1.68-0.94 (m,

10H), 1.49 (s, 9H), 0.94 (s, 3H), 0.90 (s, 6H); MS (ESI+) m/z 726.7 (M+H) ⁺ .

Example 34G

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-[5-chloro-2-(2-hydroxyethoxy)benzoyl] -l-(cyclohexanecarbonyl)-

5-phenylpyrrolidine-2-carboxylic acid

[0323] A mixture of Example 34F (100 mg, 0.163 mmol) in 4 M HC1 in dioxane (4 mL) was stirred at room temperature overnight. Solvent was removed and the residue purified via HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0- 1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to yield title compound (73 mg, 80 % yield). ¹ H NMR (400 MHz, DMSO-rL) d 12.48 (s, 1H), 7.44 (d, 7 = 4.3 Hz, 2H), 7.41 (dd, 7 = 8.9, 2.9 Hz, 1H), 7.11 (d, 7= 9.0 Hz, 1H), 7.05 (q, 7 = 2.9 Hz, 3H), 6.68 (d, 7 = 2.8 Hz, 1H), 5.69 (d, 7 = 10.1 Hz, 1H), 5.01 (dd, 7 = 10.1, 6.9 Hz, 2H), 4.37 (d, 7 = 6.0 Hz, 1H), 4.27 (dd, 7 = 6.5, 3.6 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.00 - 3.81 (m, 2H), 3.02 (t, 7= 6.4 Hz, 1H), 2.18 - 2.03 (m, 1H), 1.61 (t, 7= 12.8 Hz, 3H), 1.40 (d, 7= 11.5 Hz, 1H), 1.26 (d, 7 = 13.7 Hz, 1H), 1.17 (t, 7= 11.2 Hz, 1H), 0.98 (s, 2H), 0.89 (s, 9H), 0.66 (d, 7 = 12.7 Hz, 1H), 0.40 (q, 7 = 13.0 Hz, 1H); MS (ESI+) m/z 556 (M+H) ⁺ .

Example 35

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[di(pro pan-2-yl)carbamoyl]-5- phenylpyrrolidine-2-carboxylic acid

Example 35 A

rac-tert- butyl (2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[di(pro pan-2- yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylate

[0324] A solution of Example 13B (50 mg, 0.106 mmol) and triethylamine (0.030 mL, 0.212 mmol) in dichloromethane (0.5 mL) at 25 °C was treated with diisopropylcarbamoyl chloride (21.67 mg, 0.132 mmol), heated to 45 °C and stirred for 16 h. The reaction was directly chromatographed on a 12 g silica gel cartridge, eluting with a gradient of 0-70% methyl /er/-butyl ether/heptanes over a period of 20 minutes to provide the title compound (48 mg, 0.080 mmol, 76 % yield). ¹ H NMR (400 MHz, CDCl ₃ ) d 7.30 - 7.26 (m, 2H), 7.22 (dd, J= 8.8, 2.7 Hz, 1H), 7.11 - 7.03 (m, 3H), 6.77 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 5.50 (d, J = 9.8 Hz, 1H), 4.59 (d, J = 5.0 Hz, 1H), 4.54 (dd, 7 = 9.8, 6.2 Hz, 1H), 3.90 (s, 3H), 3.73 (h, 7 = 6.7 Hz, 2H), 3.21 (t, 7 = 5.6 Hz, 1H), 1.58 (s,

9H), 1.18 (d, 7 = 6.7 Hz, 6H), 1.13 (d, 7 = 6.6 Hz, 6H), 0.96 (s, 9H); MS (ESI+) m/z 597 (M-H) .

Example 35B

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[di(pro pan-2-yl)carbamoyl]-5- phenylpyrrolidine-2-carboxylic acid

[0325] To Example 35A (42 mg, 0.070 mmol) was added trifluoroacetic acid (0.324 mL, 4.21 mmol) and the mixture was stirred at 25 °C for 4 h. The solvent was removed in vacuo and the resulting oil was chromatographed using a 4 g silica gel cartridge eluting with a gradient of 0-80% methyl /e/7-butyl ether/heptanes over a period of 20 minutes. The product containing fractions were combined and chromatographed again on 12 g silica gel cartridge with a gradient of 0-6% methanol/dichloromethane over a period of 20 minutes to give the title compound (22 mg, 0.041 mmol, 57.8 % yield). ^l H NMR (400 MHz, CDCI3) d 12.90 (bs, 1H), 7.34 - 7.28 (m, 1H), 7.16 (dt, J = 5.5, 1.4 Hz, 3H), 7.08 - 6.99 (m, 2H), 6.90 (dd, 7 = 2.8, 1.2 Hz, 1H), 6.82 (dd, 7= 8.8, 1.2 Hz,

1H), 5.23 (d, 7 = 8.5 Hz, 1H), 4.61 - 4.52 (m, 1H), 4.36 (dd, 7 = 5.2, 1.2 Hz, 1H), 3.90 (d, 7 = 1.2 Hz, 3H), 3.73 (p, 7 = 6.5 Hz, 2H), 3.49 (t, 7 = 5.9 Hz, 1H), 1.24 (dd, 7 = 6.7, 1.2 Hz, 6H), 1.20 (dd, 7= 6.7, 1.2 Hz, 6H), 1.02 (d, 7 = 1.3 Hz, 9H); MS (ESI-) m/z 541 (M-H) .

Example 36

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-5-phenyl- l-{ [(propan-2- yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid

Example 36 A

rac-2-tert-buty\ l-propan-2-yl (2i?,35',4i?,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-5- phenylpyrrolidine- 1 ,2-dicarboxylate

[0326] Example 13B (102.0 mg, 0.216 mmol) was dissolved in dichloromethane (1 mL).

Triethylamine (80 pL, 0.574 mmol) was added followed by isopropyl chloroformate solution (1 M in dichloromethane, 280 pL, 0.28 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction was concentrated and purified by reverse phase HPLC purification, ammonium acetate method. Samples were purified by preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5- 100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to afford the title compound (87.7 mg, 73%). NMR (400 MHz, DMSO -de) d 7.30 (dd, 7 = 8.9, 2.8 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.07 - 6.96 (m, 4H), 6.36 (dd, 7 = 2.9, 1.3 Hz, 1H), 5.21 (d, 7 = 10.2 Hz, 1H), 4.70 (dd, 7 = 10.1, 5.5 Hz, 1H), 4.60 (p, J= 6.2 Hz, 1H), 4.28 (d, J= 4.7 Hz, 1H), 3.89 (s, 3H), 3.02 (t, J = 5.1 Hz, 1H), 1.52 (s, 9H), 1.04 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H), 0.87 (d, J = 6.2 Hz, 3H); MS (ESI+) m/z 502 (M-tBu+H) ⁺ .

Example 36B

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-5-phenyl- l-{ [(propan-2- yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid

[0327] Example 36A (84.7 mg, 0.152 mmol) was dissolved in dichloromethane (1 mL).

Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added and the reaction was stirred at ambient temperature for 1 h. The reaction was concentrated and purified by reverse phase purification: Samples were purified by preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5- 11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to afford the title compound (51.8 mg, 68%). ^l H NMR (400 MHz, DMSO -de, 120 °C) d 7.32 (dd, J= 8.9, 2.8 Hz, 1H), 7.28 - 7.19 (m,

2H), 7.07 - 6.95 (m, 4H), 6.38 (d, 7= 2.6 Hz, 1H), 5.22 (d, 7 = 10.2 Hz, 1H), 4.71 (dd, 7 = 10.2, 5.8 Hz, 1H), 4.65 - 4.54 (m, 1H), 4.34 (d, 7 = 5.0 Hz, 1H), 3.90 (s, 3H), 3.08 (t, 7= 5.3 Hz, 1H), 1.04 (d, 7 = 6.2 Hz, 3H), 0.96 (s, 9H), 0.86 (d, 7 = 6.2 Hz, 3H); MS (ESI+) m/z 502 (M+H) ⁺ .

Example 37

propan-2-yl rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-2- [(methanesulfonyl)carbamoyl]-5-phenylpyrrolidine-l-carboxyla te

[0328] Example 36 (201.1 mg, 0.401 mmol) and 1 , 1 '-carbonyldiimidazole (142.7 mg, 0.880 mmol) were dissolved in dichloromethane (4 mL) and stirred at 40 °C for 2 h. 1,8- diazabicyclo[5.4.0]undec-7-ene (183.6 mg, 1.206 mmol) and methanesulfonamide (119.6 mg, 1.257 mmol) were added and the reaction was stirred for an additional 2 h at 40 °C. The reaction was diluted with dichloromethane (50 mL) and washed with aqueous 1 N HC1 (2 x 35 mL) and brine (50 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to give a solid. The residue was purified by silica gel chromatography (25 g column, 10% ethyl acetate in

dichloromethane) to afford the product (126.5 mg, 55%). ¹ H NMR (400 MHz, DMSO-de, 120 °C) d 7.41 (dd, 7 = 8.9, 2.8 Hz, 1H), 7.23 (dd, 7= 7.4, 2.3 Hz, 2H), 7.12 (d, 7 = 8.9 Hz, 1H), 7.10 - 7.02 (m, 3H), 6.60 (dd, 7 = 2.8, 0.9 Hz, 1H), 5.23 (d, 7 = 10.1 Hz, 1H), 4.71 - 4.64 (m, 1H), 4.64 - 4.55 (m, 1H), 4.35 (d, 7= 7.7 Hz, 1H), 3.95 (d, 7 = 0.9 Hz, 3H), 3.40 (dd, 7 = 9.6, 7.7 Hz, 1H), 3.21 (d, J = 0.9 Hz, 3H), 1.08 (dd, J= 6.2, 0.9 Hz, 3H), 0.92 (d, 7 = 1.0 Hz, 9H), 0.85 (d, 7 = 6.2 Hz, 3H); MS (ESI+) m/z 579 (M+H) ⁺ ; MS (ESI-) m/z 577 (M+H) ⁺ .

Example 38

mc-(2i?,3i?,4i?,55')-4-[(benzyloxy)carbonyl]-l-[di(propan-2- yl)carbamoyl]-3-methyl-5- phenylpyrrolidine-2-carboxylic acid

[0329] The title compound was prepared according to Example 36B, substituting Example 51C for Example 36A. ^l H NMR (400 MHz, 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.48 - 7.38 (m, 2H), 7.38 - 7.27 (m, 3H), 7.27 - 7.11 (m, 5H), 4.83 (d, 7 = 8.0 Hz, 1H), 4.81 - 4.77 (m, 2H), 4.35 (d, 7 = 11.0 Hz, 1H), 3.54 (hept, 7= 6.7 Hz, 2H), 2.74 - 2.58 (m, 1H), 1.26 - 1.11 (m, 4H), 1.05 (d, 7 = 6.6 Hz, 6H), 0.94 (d, J = 6.7 Hz, 6H). MS (APCI+) m/z 467.5 (M+H) ⁺ .

Example 39

mc-(4i?,65',7i?)-7-[(benzyloxy)carbonyl]-5-[di(propan-2-yl)c arbamoyl]-6-phenyl-5- azaspiro[2.4]heptane-4-carboxylic acid

Example 39 A

[2-(benzyloxy)-2-oxoethyl] (triphenyl)phosphanium bromide

[0330] A mixture of benzyl bromoacetate (6.6ml, 42.1 mmol) and triphenylphosphine (11.58 g, 44.2 mmol) in toluene (200 mL) was stirred at room temperature for 3 days. The precipitate was collected by filtration and washed with diethyl ether to afford the title compound (20g, 40.3 mmol, 96 % yield). MS (ESI+) m/z 411 (M-80+l) ⁺ .

Example 39B

[(benzyloxy)carbonyl](triphenylphosphaniumyl)methanide

[0331] A solution of Example 39A (2.00 g, 4.07 mmol) and NaOH (0.081 g, 2.035 mmol) in methylene chloride (20 mL) was stirred at 25 °C for 1 hour. The mixture was diluted with methylene chloride (50 mL), and washed with water (30 mL). The organic layer was separated and concentrated to give the title compound (1.5 g, 3.25 mmol, 80 % yield). ¹ H NMR: (400 MHz, CDCE): d ppm 7.60-7.65 (m, 6H), 7.51-7.54 (m, 4H), 7.42-7.46 (m, 6H), 7.20 (s, 4H), 5.00 (s, 2H), 2.96 (s, 1H) ; MS (ESI+) m/z 411.1 (M+H) ⁺ .

Example 39C

1 -ethoxycyclopropan- 1 -ol

[0332] A solution of [(l-ethoxycyclopropyl)oxy](trimethyl)silane (1.499 mL, 7.46 mmol), a drop of hydrogen chloride (7.16 mg, 0.075 mmol) in methanol (6 mL) was stirred at 25 °C for 16 hours. The mixture was concentrated to give the title compound (0.5 g, 4.90 mmol, 65.6 % yield). ^l H NMR: (400 MHz, CDCb) d 3.76 (q, /= 8 Hz, 2H), 1.22 (t, / = 8 Hz, 4H), 0.93-0.95 (m, 4H).

Example 39D

benzyl 2-cyclopropylideneacetate

[0333] To a solution of Example 39B (5 g, 11.57 mmol) and benzoic acid (0.601 g, 4.92 mmol) in toluene (50 mL) at 80 °C was added Example 39C (1.391 g, 11.57 mmol). The mixture was stirred at 80 °C for 5 hours and then concentrated. The residue was purified by column

chromatography (on silica gel, eluted with 5% ethyl acetate/hexane) to give the title compound (1.3 g, 5.66 mmol, 48.9 % yield). MS (ESI+) 189.2 m/z (M+H) ⁺ .

Example 39E

rac-7-benzyl 4-/e/7-butyl (4i?,65',7i?)-6-phenyl-5-azaspiro[2.4]heptane-4,7-dicarboxyl ate

[0334] To a mixture of Example 1A (1.966 g, 7.17 mmol) and lithium bromide (0.747 g, 8.61 mmol) in tetrahydrofuran (20 mL) at -70 °C was added Example 39D (1.8 g, 7.17 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (1.62 mL, 10.76 mmol). After stirred for 30 minutes at -78 °C, the mixture was warmed to 0 °C for 45 minutes and then at 25 °C for 2 hours. LCMS showed complete conversion to the desired product. The reaction was quenched with saturated aq NH ₄ Cl (10 mL) and water (10 mL). The mixture was extractecd with methylene chloride (30 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and conentrated. The residue was purified by preparative HPLC (Instrument: Gilson 281; Column: Xbridge 21.2 x 250mm cl8, 10 pm; Mobile Phase: A: water (10 mmol/L NH ₄ HC0 ₃ ) B: Acetonitrile; Gradient: 55-65% B in 10 minutes, stop at 15 minutes; Flow Rate (mL/minute): 25.00; Detective Wavelength (nm): 214) to give the title compound (251 mg, 0.616 mmol, 8.59 % yield). ^X H NMR: (400 MHz, CDCb): d ppm 7.23-7.34 (m, 8H), 6.98-7.01 (m, 2H), 4.67-4.79 (m, 3H), 3.68 (s, 1H), 2.9l(d, / = 8 Hz, 1H), 1.49 (s, 9H), l.05-l.08(m, 1H), 0.92-0.95(m, 1H), 0.77-0.79(m, 1H), 0.60-0.63 (m, 1H) ; MS (ESI) m/z 408.2 (M+H) ⁺ .

Example 39F

rac-7-benzyl 4-/e/7-butyl (4R,65',7R)-5-[di(propan-2-yl)carbamoyl]-6-phenyl-5- azaspiro[2.4]heptane-4,7-dicarboxylate

[0335] The title compound was prepared following the method of Example 51C, substituting Example 39E for Example 51B.

Example 39G

rac- (4R,65,7R)-7 - [(benzyloxy)carbonyl] -5- [di(propan-2-yl)carbamoyl] -6-phenyl-5 - azaspiro[2.4]heptane-4-carboxylic acid

[0336] The title compound was prepared according to Example 36B, substituting Example 39F for Example 36A. ^l H NMR (400 MHz, 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.52 (dd, 7 = 6.5, 2.9 Hz, 2H), 7.36 - 7.11 (m, 8H), 5.22 (d, 7 = 7.9 Hz, 1H), 4.85 (d, 7 = 12.8 Hz, 1H), 4.70 (d, 7 = 12.5 Hz, 1H), 4.41 (s, 1H), 3.70 (h, 7 = 6.7 Hz, 2H), 3.41 (d, 7 = 7.9 Hz, 1H), 1.15 (d, 7 = 6.4 Hz, 2H), 1.06 (dd, 7 = 6.6, 0.9 Hz, 6H), 1.00 (dd, 7 = 6.7, 0.9 Hz, 6H), 0.79 - 0.74 (m, 2H); MS (APCI+) m/z 479.5 (M+H) ⁺ .

Example 40

rac-(2R,35 ^, ,4R,55 ^, )-4-[(benzyloxy)carbonyl]-3-/er/-butyl-l-[di(propan-2- yl)carbamoyl]-5- phenylpyrrolidine-2-carboxylic acid

Example 40A

rac-4-benzyl 2-/e/7-butyl (2R,3S,4R,5S)-3-tert-buty\- l-[di(propan-2-yl)carbamoyl]-5- phenylpyrrolidine-2,4-dicarboxylate

[0337] A solution of Example 50B (1.5 g, 3.43 mmol) and triethylamine (0.956 mL, 6.86 mmol) in dichloromethane (8.57 mL) at 25 °C was treated with diisoprop ylcarbamoyl chloride (0.701 g, 4.29 mmol), heated to 48 °C and stirred for 16 h. The reaction was directly loaded and chromatographed on a 40 g silica gel cartridge, eluting with a gradient of 0-60% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide the title compound (1.9 g, 3.36 mmol, 98 % yield). ^l H NMR (400 MHz, CDCE) d 7.44 - 7.38 (m, 2H), 7.31 - 7.26 (m, 3H), 7.25 - 7.16 (m, 3H), 7.05 - 6.99 (m, 2H), 5.12 (d, 7= 9.5 Hz, 1H), 4.77 (d, 7= 6.5 Hz, 1H), 4.58 (d, 7= 12.1 Hz, 1H), 4.47 (d, 7 = 12.1 Hz, 1H), 3.66 (p, 7 = 6.7 Hz, 2H), 3.37 (dd, 7= 9.5, 8.4 Hz, 1H), 3.08 (dd, 7= 8.4, 6.4 Hz, 1H), 1.52 (s, 9H), 1.16 (d, 7 = 6.6 Hz, 6H), 1.07 (d, 7 = 6.6 Hz, 6H), 0.92 (s, 9H); MS (ESI+) m/z 565 (M+H) ⁺ .

Example 40B

mc-(2R,35',4R,55 ^, )-4-((benzyloxy)carbonyl)-3-(/er/-butyl)-l-(diisopropy lcarbamoyl)-5- phenylpyrrolidine-2-carboxylic acid

[0338] To Example 40A (50 mg, 0.089 mmol) was added trifluoroacetic acid (0.307 mL, 3.98 mmol) and the mixture was stirred at 25 °C for 4 h. The solvent was removed in vacuo and the resulting oil was chromatographed using a 4 g silica gel cartridge eluting with a gradient of 0-70% methyl /er/-butyl ether/heptanes over a period of 20 minutes. The combined product fractions were chromatographed again on 12 g silica gel cartridge with a gradient of 0-6%

methanol/dichloromethane over a period of 20 minutes to give to give the title compound (26 mg, 0.051 mmol, 57.7 % yield). NMR (501 MHz, CDCb) d 12.77 (s, 1H), 7.32 - 7.22 (m, 8H), 7.04 - 6.96 (m, 2H), 5.15 (d, / = 8.2 Hz, 1H), 4.77 - 4.62 (m, 2H), 4.43 (d, J= 5.4 Hz, 1H), 3.65 (p, / = 6.7 Hz, 2H), 3.45 - 3.30 (m, 2H), 1.22 (d, / = 6.6 Hz, 6H), 1.18 (d, / = 6.7 Hz, 6H), 0.99 (s, 9H);

MS (ESI-) m/z 507 (M-H) .

Example 41

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[(R)-(2,5- dichlorophenyl)(hydroxy)methyl]-5-phenylpyrrolidine-2-carbox ylic acid

[0339] A solution of Example 5 (99 mg, 0.187 mmol) in methanol (933 pL) at -15 °C was treated with sodium borohydride (17.65 mg, 0.467 mmol) and stirred for 15 minutes. The reaction was quenched with 5 drops of saturated aqueous ammonium chloride, the solvent removed under a stream of nitrogen and the crude material filtered and washed with water to give a solid. The solid was chromatographed using a 12 g silica gel cartridge with an ethyl aceate\ethanol\heptanes solvent system to give the title compound (60 mg, 0.113 mmol, 60.4 % yield). Ή NMR (400 MHz, DMSO-ifc) d 7.49 (s, 2H), 7.21 (d, J= 8.4 Hz, 1H), 7.11 - 6.97 (m, 4H), 6.76 (s, 1H), 5.11 (d, / =

9.6 Hz, 1H), 4.83 (d, J= 6.0 Hz, 1H), 4.42 (s, 1H), 3.30 (t, /= 7.8 Hz, 1H), 2.29 - 2.21 (m, 1H), 1.63 - 1.54 (m, 3H), 1.51 - 1.37 (m, 2H), 1.25 (s, 2H), 1.15 (t, / = 10.9 Hz, 1H), 1.09 - 0.99 (m, 1H), 0.95 - 0.79 (m, 12H). MS (ESI+) m/z 532 (M+H) ⁺ .

Example 42

mc-(2R,3R,4R,55')-4-[(benzyloxy)methyl]-l-[di(propan-2-yl)ca rbamoyl]-3-methyl-5- phenylpyrrolidine-2-carboxylic acid

Example 42A

benzyl (2£ ^’ )-but-2-enoate

[0340] A solution of crotonic acid (4.494 g, 52.2 mmol) in anhydrous /V,/V-dimethylformamide (30 mL) was cooled with a water ice bath, treated with potassium carbonate (5.53 g, 40.0 mmol) and swirled. Benzyl bromide (5.95 mL, 50.0 mmol) was added dropwise with swirling of the thick suspension. After several minutes the reaction mixture was removed from the bath and stirred almost two days. Methyl /e/7-butyl ether (45 mL) was added and the solids were removed by filtration and rinsed with methyl /e/7-butyl ether. The filtrate was washed twice with dilute aqueous NaHCCh and once with brine, dried (Na ₂ S0 ₄ ), filtered and concentrated to afford 8.64 g of the title compound. ^l H NMR (400 MHz, CDCb) d 1.88 (dd, /= 6.9, 1.7 Hz, 3H), 5.17 (s, 2H), 5.89 (dq, J = 15.5, 1.7 Hz, 1H), 7.02 (dq, /= 15.5, 6.9 Hz, 1H), 7.28 - 7.39 (m, 5H). MS (DCI) m/z = 194 (M+NH ₄ ) ⁺ . Example 42B

rac-4-benzyl 2-/e/7-butyl (2i?,3i?,4i?,53 ^, )-3-methyl-5-phenylpyrrolidine-2,4-dicarboxylate

[0341] A 1.5 M solution of lithium bromide in tetrahydrofuran (64.0 mL, 96 mmol) was added to a solution of Example 1A (13.92 g, 57.1 mmol) in anhydrous tetrahydrofuran (130 mL), and the resulting mixture was cooled with a dry ice / acetone bath. A solution of Example 42A (11.22 g, 63.6 mmol) in tetrahydrofuran (30 mL) was added slowly, followed by dropwise addition of 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-fl]azepine (11.50 mL, 76 mmol). DBU formed frozen beads in the reaction solution, which very slowly dissolved and colored the solution yellow. After the reaction mixture had stirred for 1 h near -78 °C, the dry ice was removed from the bath and the bath was permitted to warm to -15 °C over 90 minutes and then on to 0 °C over another 90 minutes. The bath was removed, the reaction mixture was stirred at room temperature for 15 minutes and saturated aqueous NH ₄ Cl (150 mL) was added, with a methyl /e/7-butyl ether (100 mL) rinse. The biphasic mixture was stirred thoroughly and then diluted with brine (100 mL). The aqueous phase was separated and extracted twice with methyl /e/7-butyl ether, and the combined organic phases were washed with brine, dried (Na ₂ S0 ₄ ), and concentrated to a syrup which was loaded and chromatographed on a 80 g silica gel cartridge eluting with a gradient of 0-90% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide the crude product, which was dissolved into heptane and placed in the freezer for over 1 h to induce precipitation. The biphasic mixture was swirled for a while, resulting in additional precipitation, a process which was accelerated with brief sonication. Then, the suspension was aged for over 1 h, and the precipitate collected by filtration, rinsed with heptane and dried under vacuum to give the title compound (11.4 g, 28.8 mmol, 50.5 % yield). ^l H NMR (400 MHz, CDCL) d 7.40 - 7.21 (m, 8H), 7.06 (ddd, J = 4.0, 3.0, 2.2 Hz, 2H), 4.74 (d, J = 12.2 Hz, 1H), 4.61 (d, J = 8.6 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 3.41 (d, J = 9.0 Hz, 1H), 3.06 (t, / = 8.4 Hz, 1H), 2.83 (s, 1H), 2.68 (tq, / = 8.6, 6.7 Hz, 1H), 1.54 (s, 9H), 1.25 (d, / = 6.6 Hz, 3H), MS (ESI+) m/z 396 (M+H) ⁺ .

Example 42C

rac-4-benzyl 2-/e/7-butyl (2R,3R,4R,5S)- l-[di(propan-2-yl)carbamoyl]-3-methyl-5- phenylpyrrolidine-2,4-dicarboxylate

[0342] A solution of Example 42B (5.6 g, 14.16 mmol) and triethylamine (3.95 mL, 28.3 mmol) in dichloromethane (8 mL) at 25 °C was treated with diisopropylcarbamoyl chloride (2.66 g, 16.28 mmol), amd stirred for 20 min at rt, then heated to 50 °C for 16 h. The reaction was washed with 10% aqueous NH ₄ OH and the organic layer was concentrated to an oil which was loaded and chromatographed on a 80 g column eluting with a gradient of 0-50% methyl /e/7-butyl ether /heptanes over a period of 20 min to provided the title compound (7.30 g, 13.97 mmol, 99 % yield). ^l H NMR (400 MHz, CDCb) d 7.50 - 7.40 (m, 2H), 7.37 (dd, /= 5.0, 1.9 Hz, 2H), 7.32 - 7.23 (m, 4H), 7.19 (dd, / = 6.7, 2.9 Hz, 2H), 4.90 - 4.76 (m, 3H), 4.61 (d, J= 10.8 Hz, 1H), 3.55 (h, /= 6.7 Hz, 2H), 3.05 (dd, / = 12.1, 7.9 Hz, 1H), 2.78 (ddt, /= 17.0, 12.3, 6.3 Hz, 1H), 1.56 (s, 9H), 1.25 (d, / = 6.3 Hz, 3H), 1.17 (d, / = 6.6 Hz, 6H), 1.02 (d, / = 6.7 Hz, 6H); MS (ESI+) m/z 523 (M+H) ⁺ .

Example 42D

rac-(25 ^, ,3Z?,4Z?,5Z?)-5-(/er/-butoxycarbonyl)-l-[di(propan-2-y l)carbamoyl]-4-methyl-2- phenylpyrrolidine-3-carboxylic acid

[0343] Example 42C (7.29 g, 13.95 mmol) and ethyl acetate (140 mL) were added to 10% Pd/C, dry (1.484 g, 1.395 mmol) in a 250 mL stainless steel pressure bottle and shaken for 16 h at 50 psi and ambient temperature. The reaction was filtered and the solvent was evaporated leaving crude solid which was purified via a 24 g silica gel cartridge with a gradient of 0-10 %

methanol/dichloromethane over 20 minutes to give the title compound (2.87 g, 6.64 mmol, 47.6 % yield). ^l H NMR (400 MHz, CDCb) d 7.55 - 7.43 (m, 2H), 7.30 (d, /= 7.1 Hz, 3H), 4.81 (d, /= 7.8 Hz, 1H), 4.62 (d, / = 10.7 Hz, 1H), 3.56 (p, / = 6.6 Hz, 2H), 3.01 (dd, / = 12.1, 7.8 Hz, 1H), 2.69 (ddd, J = 12.3, 10.7, 6.1 Hz, 1H), 1.56 (s, 9H), 1.26 (d, / = 6.3 Hz, 3H), 1.17 (d, / = 6.5 Hz, 6H), 1.03 (d, / = 6.6 Hz, 6H); MS (ESI+) m/z 433 (M+H) ⁺ .

Example 42E

rac-tert- butyl (2R,3R,4R,55')-l-[di(propan-2-yl)carbamoyl]-4-(hydroxymethyl )-3-methyl-5- phenylpyrrolidine-2-carboxylate

[0344] To a solution of Example 42D (1.00 g, 2.312 mmol) in tetrahydrofuran (7.2 mL) at - 10 °C (ice/acetone) was added /V-methyl morpholine (0.280 mL, 2.54 mmol). To this solution was added slowly isobutyl chloroformate (0.334 mL, 2.54 mmol). After 30 minutes, the mixture was filtered into a solution of sodium borohydride (0.175 g, 4.62 mmol) in water (1.4 mL) at 0 °C and warmed to 10 °C. After 40 minutes, the mixture was quenched via addition of saturated solution of aqueous NH ₄ Cl (25 mL). The reaction mixture was diluted with dichloromethane (50 mL) and the organics separated, filtered and the solvent removed. The crude material was purified with a 12 g silica gel cartridge using a gradient of 0-100 % ethyl acetate/heptane over 30 min to give the title compound (814 mg, 1.945 mmol, 84 % yield). ^X H NMR (501 MHz, CDCb) d 7.66 - 7.59 (m, 2H), 7.41 - 7.34 (m, 2H), 7.33 - 7.27 (m, 1H), 4.76 (d, / = 6.5 Hz, 1H), 4.59 (d, / = 9.6 Hz, 1H), 3.59 (p, J= 6.6 Hz, 4H), 3.11 (s, 1H), 2.20 (ddd, / = 6.2, 4.6, 2.9 Hz, 2H), 1.57 (s, 9H), 1.25 (d, / = 5.7 Hz, 3H), 1.18 (d, / = 6.6 Hz, 6H), 1.06 (d, / = 6.7 Hz, 6H); MS (ESI+) m/z 419 (M+H) ⁺ .

Example 42F

mc-(3i?,4i?,56 ^, )-4-((benzyloxy)methyl)-l-(diisopropylcarbamoyl)-3-met hyl-5-phenylpyrrolidine-2- carboxylic acid

[0345] To a solution of Example 42E (50 mg, 0.119 mmol) and (bromomethyl)benzene (24.52 mg, 0.143 mmol) in /V,/V-d i meth y 1 f o rm am i de (0.239 mL) was added sodium hydride (7.17 mg,

0.179 mmol). The reaction was stirred at room temperature for 2 h, then the mixture was quenched via addition of saturated solution of aqueous NH ₄ Cl. The crude material was purified with a 12 g silica gel cartridge using a gradient of 0-10 % methanol/dichloromethane over 12 min to give the crude /e/7-butyl ester (20 mg) as an oil. This oil was treated with 2,2,2-trifluoroacetic acid (0.368 mL, 4.78 mmol) and stirred for 2 h at room temperature and purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to obtain title compound (6 mg, 0.013 mmol,

11.10 % yield). NMR (501 MHz, CDCE) d 7.44 - 7.38 (m, 2H), 7.38 - 7.31 (m, 8H), 4.89 (d, J = 7.3 Hz, 1H), 4.60 (d, / = 9.8 Hz, 1H), 4.48 (bs, 1H), 4.34 (q, / = 11.5 Hz, 2H), 3.52 (p, / = 6.6 Hz, 2H), 3.37 (dd, / = 9.5, 3.8 Hz, 1H), 2.68 (t, / = 9.7 Hz, 1H), 2.45 (ddd, / = 12.1, 9.7, 6.0 Hz, 1H), 2.36 (dddd, / = 11.8, 10.1, 7.3, 3.8 Hz, 1H), 1.17 (d, / = 6.3 Hz, 3H), 1.15 (d, / = 3.2 Hz, 6H), 1.14 (d, / = 3.1 Hz, 6H); MS (ESI+) m/z 453 (M+H) ⁺ .

Example 43

mc-(2i?,3i?,4i?,55')-l-[di(propan-2-yl)carbamoyl]-3-methyl-4 -(phenoxymethyl)-5- phenylpyrrolidine-2-carboxylic acid

Example 43A

rac-(2R,3R,4R,5S)-tert-butyl l-(diisopropylcarbamoyl)-3-methyl-4-(phenoxymethyl)-5- phenylpyrrolidine-2-carboxylate

[0346] The Example 42E (52 mg, 0.124 mmol) was azeotroped with toluene before combining with tributylphosphine (0.037 mL, 0.149 mmol), and phenol (10.52 mg, 0.112 mmol) in

tetrahydrofuran (0.597 mL). (/f)-A ^/l ,/V ^l ,/V ² ,/V ² -tetramethyldiazene- 1 ,2-dicarboxamide (TMAD) (25.7 mg, 0.149 mmol) was added all at once at room temperature while stirring vigorously, the reaction turned from lighter yellow to clear color. The reaction was warmed to 50 °C. After 2 h, more (£)- N ¹ , N ¹ , N ² ,/V ² -tetramethyldiazene-l, 2-dicarboxamide (TMAD) (25.7 mg, 0.149 mmol) and tributylphosphine (0.037 mL, 0.149 mmol) were added and the reaction heated at 50 °C for 2 h longer. The solvent was removed under a stream of nitrogen. The crude material was purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0- 10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to afford the title compound (31 mg, 0.063 mmol, 50.4 % yield). ^l H NMR (501 MHz, CDCL) d 7.54 (s, 1H), 7.30 - 7.19 (m, 6H), 7.00 - 6.94 (m, 1H), 6.83 - 6.77 (m, 2H), 4.88 (d, / = 7.5 Hz, 1H), 4.67 (d, / = 9.8 Hz, 1H), 3.72 (dd, / = 9.4, 4.2 Hz, 1H), 3.62 (p, /= 6.7 Hz, 2H), 3.21 (t, /= 9.6 Hz, 1H), 2.53 (dddd, /= 11.7,

9.7, 7.4, 4.2 Hz, 1H), 2.23 (ddq, / = 12.6, 9.8, 6.4 Hz, 1H), 1.57 (s, 9H), 1.31 (d, 7 = 6.4 Hz, 3H), 1.19 (d, / = 6.6 Hz, 6H), 1.09 (d, / = 6.7 Hz, 6H); MS (ESI+) m/z495 (M+H) ⁺ .

Example 43B

rac-(2R,3RAR 5S) 1 -(di i sopropylcarbamoyl )-3-methyl-4-( phenoxymethyl )-5-phenyl pyrrol idine-2- carboxylic acid

[0347] To Example 43A (30 mg, 0.061 mmol) was added trifluoroacetic acid (0.257 mL, 3.34 mmol) and the mixture was stirred at 25 °C for 2 h. The solvent was removed in vacuo and the resulting oil was chromatographed using a 12 g silica gel cartridge eluting with a gradient of 0-8% methanol/dichloromethane over a period of 20 minutes to give the title compound (21 mg, 0.048 mmol, 79 % yield). ^l H NMR (400 MHz, CDCL) d 11.47 (bs, 1H), 7.31 - 7.19 (m, 7H), 7.00 - 6.91 (m, 1H), 6.79 (dt, J= 8.0, 1.0 Hz, 2H), 4.95 (d, /= 7.1 Hz, 1H), 4.63 (d, / = 9.6 Hz, 1H), 3.77 (dd, J = 9.5, 3.7 Hz, 1H), 3.50 (p, / = 6.7 Hz, 2H), 3.19 (t, /= 9.6 Hz, 1H), 2.64 - 2.43 (m, 2H), 1.20 (d, J = 6.1 Hz, 3H), 1.17 (d, / = 6.7 Hz, 6H), 1.13 (d, / = 6.6 Hz, 6H); MS (ESI+) m/z 439 (M+H) ⁺ .

Example 44

mc-(2R,3R,4R,55')-l-[di(propan-2-yl)carbamoyl]-3-methyl-5-ph enyl-4-({ [5- (trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-2-carbo xylic acid

Example 44A

rac-tert- butyl (2R,3R,4R,55)- l-[di(propan-2-yl)carbamoyl]-3-methyl-5-phenyl-4-({ [5- (trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-2-carbo xylate

[0348] Example 42E (50 mg, 0.119 mmol) was azeotroped with toluene before combining with tributylphosphine (0.035 mL, 0.143 mmol), and 5-(trifluoromethyl)pyridin-2-ol (19.48 mg, 0.119 mmol) in tetrahydrofuran (0.4 mL). (/f)-A ^/l ,/V ^l ,/V ² ,/V ² -tetramethyldiazene- 1 ,2-dicarboxamide (TMAD) (24.68 mg, 0.143 mmol) was added all at once at room temperature while stirring vigorously, the reaction turned from lighter yellow to clear color, and was warmed to 50 °C. After 1 h, tributylphosphine (0.01 mL, 0.041 mmol) and TMAD (8 mg, 0.046 mmol) were added, and the reaction stirred at 50 °C for 1 h longer. The solvent was removed under a stream of nitrogen and the resulting crude material was purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A,

0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to affod the title compound (30 mg, 0.053 mmol, 44.6 % yield). ¹ H NMR (500 MHz, CDCL) d 7.56 - 7.52 (m, 2H), 7.42 (dd, / = 9.6, 2.7 Hz, 1H), 7.39 (dd, /= 7.9, 6.6 Hz, 2H), 7.36 - 7.31 (m, 1H), 6.83 (s, 1H), 6.61 (d, / = 9.6 Hz, 1H), 5.17 (d, /= 7.8 Hz, 1H), 4.24 (d, / = 6.3 Hz, 1H), 3.77 (dd, J = 13.7, 6.2 Hz, 1H), 3.68 (hept, J = 6.7 Hz, 2H), 3.41 (dd, J = 13.7, 5.7 Hz,

1H), 2.75 - 2.67 (m, 1H), 2.54 (h, / = 6.6 Hz, 1H), 1.57 (s, 9H), 1.21 (d, / = 6.6 Hz, 3H), 1.18 (d, J = 6.7 Hz, 6H), 1.15 (d, / = 6.6 Hz, 6H); MS (ESI-) m/z 564 (M-H) .

Example 44B

rac-(2R,3RAR-,5S) 1 -[di(propan-2-yl)carbamoyl]-3-methyl-5-phenyl-4-( { [5- (trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-2-carbo xylic acid

[0349] To Example 44A (0.029 g, 0.051 mmol) was added trifluoroacetic acid (0.218 mL, 2.83 mmol) and the mixture was stirred at 25 °C for 2 h. The solvent was removed in vacuo and the resulting oil was chromatographed using a 4 g silica gel cartridge eluting with a gradient of 0-10% methanol/dichloromethane over a period of 20 minutes to the title compound (21 mg, 0.041 mmol, 80 % yield). ^l H NMR (400 MHz, CDCL) d 8.38 (d, /= 2.4 Hz, 1H), 7.80 (dd, J= 8.8, 2.5 Hz, 1H), 7.27 - 7.15 (m, 5H), 6.81 (d, /= 8.7 Hz, 1H), 4.90 (d, /= 7.2 Hz, 1H), 4.64 (d, /= 9.6 Hz, 1H), 4.21 (dd, / = 11.0, 3.9 Hz, 1H), 3.61 (dd, /= 11.1, 9.3 Hz, 1H), 3.52 (p, /= 6.7 Hz, 2H), 2.62 (ddd, / = 12.0, 9.6, 6.1 Hz, 1H), 2.57 - 2.46 (m, 1H), 1.25 (d, /= 6.2 Hz, 3H), 1.15 (d, /= 6.8 Hz, 6H), 1.13 (d, / = 6.6 Hz, 6H); MS (ESI-) m/z 506 (M-H) .

Example 45

mc-(2R,3R,4R,55')-4-[(5-chloro-2-methoxyphenoxy)methyl]-l-[d i(propan-2-yl)carbamoyl]-3- methyl-5-phenylpyrrolidine-2-carboxylic acid

Example 45 A

rac-tert- butyl (2R,3R,4R,55')-4-[(5-chloro-2-methoxyphenoxy)methyl]-l-[di(p ropan-2- yl)c arb amoyl] - 3 -methyl- 5 -phenylpyrrolidine-2-carboxylate

[0350] Example 42E (100 mg, 0.239 mmol) was azeotroped with toluene before combining with tributylphosphine (0.071 mL, 0.287 mmol), and 5-chloro-2-methoxyphenol (37.9 mg, 0.239 mmol) in tetrahydrofuran (0.8 mL). (/7)-A ^/l ,A ^/l ,A ^/2 ,A ^/2 -tetramethyldiazene- 1 ,2-dicarboxamide (TMAD) (49.4 mg, 0.287 mmol) was added all at once at room temperature while stirring vigorously, the reaction turned from lighter yellow to clear in color, and warmed to 50 °C. After 1 h, tributylphosphine (0.02 mL, 0.082 mmol) and TMAD (16 mg, 0.092 mmol) were added, and the reaction stirred at 50 °C for 1 h longer. The solvent was removed under a stream of nitrogen and the resulted crude material was purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A,

0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to give the title compound (71 mg, 0.127 mmol, 53.2 % yield). ¹ H NMR (400 MHz, CDCL) d 7.57 - 7.52 (m, 2H), 7.28 - 7.19 (m, 3H), 6.90 (dd, 7= 8.6, 2.4 Hz, 1H), 6.82 (d, J =

8.5 Hz, 1H), 6.59 (d, 7= 2.3 Hz, 1H), 4.90 (d, 7= 7.5 Hz, 1H), 4.65 (d, 7= 10.0 Hz, 1H), 3.90 (s, 3H), 3.75 (dd, 7 = 9.5, 4.2 Hz, 1H), 3.59 (hept, 7 = 6.7 Hz, 2H), 3.17 (d, 7 = 9.8 Hz, 1H), 2.68 - 2.54 (m, 1H), 2.20 (ddt, 7 = 16.0, 12.3, 6.4 Hz, 1H), 1.56 (s, 9H), 1.29 (d, 7 = 6.3 Hz, 3H), 1.17 (d, 7 =

6.7 Hz, 6H), 1.07 (d, 7 = 6.7 Hz, 6H); MS (ESI+) m/z 559 (M+H) ⁺ .

Example 45B

mc-(2i?,3i?,4i?,55 ^, )-4-[(5-chloro-2-methoxyphenoxy)methyl]-l-[di(propan-2 -yl)carbamoyl]-3- methyl-5-phenylpyrrolidine-2-carboxylic acid

[0351] Example 45A (0.070 g, 0.125 mmol) was added trifluoroacetic acid (0.530 mL, 6.88 mmol) and the mixture was stirred at 25 °C for 2 h. The trifluoroacetic acid was removed in vacuo and the resulting oil was chromatographed using a 4 g silica gel cartridge eluting with a gradient of 0-10% methanol/dichloromethane over a period of 20 minutes to give the title compound (46 mg, 0.091 mmol, 73.0 % yield). ^l H NMR (400 MHz, CDCL) d 7.27 - 7.22 (m, 5H), 6.91 (dd, 7= 8.6, 2.4 Hz, 1H), 6.82 (d, 7= 8.7 Hz, 1H), 6.60 (d, 7 = 2.4 Hz, 1H), 5.01 (d, 7 = 6.4 Hz, 1H), 4.62 (d, 7 =

9.6 Hz, 1H), 3.90 (s, 3H), 3.83 (dd, 7 = 9.4, 3.0 Hz, 1H), 3.50 (hept, 7= 6.7 Hz, 2H), 3.12 (t, 7= 9.6 Hz, 1H), 2.66 - 2.52 (m, 2H), 1.20 (d, 7 = 5.8 Hz, 3H), 1.17 (d, 7 = 6.7 Hz, 6H), 1.13 (d, 7 = 6.6 Hz, 6H); MS (ESI-) m/z 501 (M-H) .

Example 46

rac-(2R,3R, 45,55')- l-[di(propan-2-yl)carbamo yl]-3-methyl-4-({ [6-methyl-4- (trifluoromethyl)pyridin-2-yl]amino}methyl)-5-phenylpyrrolid ine-2-carboxylic acid

Example 46A rac-tert- butyl (2i?,3i?,4/?,55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-{ [(methane )oxy]methyl}-3-methyl-5- phenylpyrrolidine-2-carboxylate

[0352] To the solution of Example 42E (1 g, 2.389 mmol) and triethylamine (0.666 mL, 4.78 mmol) in dichloromethane (1.062 mL) at 0 °C was added dropwise methanesulfonyl chloride (0.279 mL, 3.58 mmol) and the reaction mixture was stirred overnight while the ice bath warmed to rt.

The solvent was removed, and the residue partitioned between ethyl acetate and water. The organic phase was washed with sodium bicarbonate (20 mL), dried with sodium sulfate and concentrated to yield the crude title compound (1.15 g, 2.315 mmol, 97 % yield). ¹ H NMR (400 MHz, CDCb) d 7.55 - 7.49 (m, 2H), 7.37 (ddd, /= 7.7, 6.4, 1.4 Hz, 2H), 7.33 - 7.30 (m, 1H), 4.78 (d, / = 7.5 Hz, 1H), 4.63 - 4.58 (m, 1H), 4.01 (dd, / = 10.1, 4.6 Hz, 1H), 3.58 (p, /= 6.7 Hz, 2H), 3.51 (t, /= 9.5 Hz, 1H), 2.90 (d, / = 1.2 Hz, 3H), 2.50 - 2.39 (m, 1H), 2.29 - 2.18 (m, 1H), 1.56 (s, 9H), 1.27 (d, / = 6.4 Hz, 3H), 1.17 (d, / = 6.6 Hz, 6H), 1.06 (d, / = 6.7 Hz, 6H); MS (ESI+) m/z 497 (M+H) ⁺ .

Example 46B

rac-tert- butyl (2i?,3i?,45',55 ^, )-4-(azidomethyl)-l-[di(propan-2-yl)carbamoyl]-3-methy l-5- phenylpyrrolidine-2-carboxylate

[0353] To a solution of Example 46A (1.15 g, 2.315 mmol) in /V,/V-dimethylformamide (6 mL) was added sodium azide (1.054 g, 16.21 mmol). The reaction mixture was stirred at 65 °C for 16 h. The reaction was cooled to 0 °C, partitioned between ethyl acetate (20 mL) and water (30 mL). The organic layer was washed with brine, and concentrated in vacuo. The resulting oil was purified using a 24 g silica gel cartridge with a gradient of 0-40% ethyl acetate/heptanes over 20 min to give the titile compound (1 g, 2.254 mmol, 97 % yield). ^X H NMR (501 MHz, CDCb) d 7.55 - 7.51 (m, 2H), 7.39 - 7.34 (m, 2H), 7.32 - 7.26 (m,l2H), 4.73 (d, / = 6.6 Hz, 1H), 4.58 (d, / = 9.0 Hz, 1H), 3.58 (hept, / = 6.7 Hz, 2H), 3.22 (dd, / = 12.5, 4.0 Hz, 1H), 2.57 (dd, / = 12.5, 9.5 Hz, 1H), 2.21 - 2.09 (m, 2H), 1.56 (d, / = 0.5 Hz, 9H), 1.24 (d, / = 5.8 Hz, 3H), 1.17 (d, / = 6.6 Hz, 6H), 1.07 (d, J = 6.7 Hz, 6H); MS (HTP-LC/MS) m/z 444 (M+H) ⁺ .

Example 46C

rac-tert- butyl (2R,3R,45',55 ^, )-4-(aminomethyl)-l-[di(propan-2-yl)carbamoyl]-3-methy l-5- phenylpyrrolidine-2-carboxylate

[0354] Example 46B (100 mg, 0.225 mmol) was dissolved in tetrahydrofuran (0.9 mL), water (0.100 mL) and triphenylphosphine (71.0 mg, 0.271 mmol) was added, and the reaction heated at 50 °C for 9 h. Dried sample with a stream of N ₂ and purified using a 12 g silica gel cartridge eluting with a 3:1:4 ethyl acetate/ethanol/heptane solvent system to provide the title compound (60 mg, 0.144 mmol, 63.7 % yield). NMR (400 MHz, CDCb) d 7.63 - 7.52 (m, 2H), 7.33 (t, 7 = 7.4 Hz, 2H), 7.25 (d, J = 7.3 Hz, 1H), 4.72 (d, J = 7.4 Hz, 1H), 4.53 (d, J = 9.8 Hz, 1H), 3.56 (p, J = 6.7 Hz, 2H), 2.67 - 2.58 (m, 1H), 2.15 (ddt, 7 = 12.7, 9.6, 6.3 Hz, 1H), 2.03 - 1.89 (m, 1H), 1.54 (s, 9H), 1.21 (d, 7 = 6.3 Hz, 3H), 1.14 (d, J = 6.6 Hz, 6H), 1.04 (d, 7 = 6.7 Hz, 6H); MS (ESI+) m/z 4l8 (M+H) ⁺ .

Example 46D

rac-tert- butyl (2i?,3i?,45',55 ^, )-l-[di(propan-2-yl)carbamoyl]-3-methyl-4-({ [6-methyl-4- (trifluoromethyl)pyridin-2-yl]amino}methyl)-5-phenylpyrrolid ine-2-carboxylate

[0355] Example 46C (60 mg, 0.144 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (56.2 mg, 0.287 mmol), cesium carbonate (117 mg, 0.359 mmol), XANTPHOS (8.31 mg, 0.014 mmol), and Pd ₂ (dba) ₃ (6.58 mg, 7.18 m mol) were weighed into a microwave vial. Toluene (3.0 mL) was sparged with nitrogen and then added to the solids, and the resulting suspension was sparged with N ₂ for 5 min. The vial was sealed and heated to 140 °C in a heating block for 20 h. The reaction was then cooled to room temperature, removed the solvent and loaded the resulting suspension onto a 12 g silica gel column and eluted with 3:1:4 acetate/ethanol/heptanes over 20 min to give the title compound. MS (ESI+) m/z 577 (M+H) ⁺ .

Example 46E

rac-(2R,3R S.,5S)- 1 -[di(propan-2-yl)carbamoyl]-3-methyl-4-( { [6-methyl-4- (trifluoromethyl)pyridin-2-yl]amino}methyl)-5-phenylpyrrolid ine-2-carboxylic acid

[0356] Example 46D (34 mg, 0.059 mmol) was treated with trifluoroacetic acid (0.3 mL).

After 30 minutes, the solvent was removed, and the resulting suspension loaded onto a 12 g silica gel column and eluted with 3:1:4 acetate/ethanol/heptanes over 20 min to give the title compound (17 mg, 0.033 mmol, 55.4 % yield). ^l H NMR (501 MHz, CDCb) d 7.32 (q, 7= 6.2 Hz, 5H), 6.64 (d, 7 = 1.3 Hz, 1H), 6.17 (s, 1H), 4.98 (d, 7 = 7.5 Hz, 1H), 4.54 (d, 7 = 8.2 Hz, 1H), 3.52 (p, 7 = 6.6 Hz, 2H), 3.07 (dt, 7 = 13.4, 4.3 Hz, 1H), 2.72 (dt, 7 = 16.5, 7.4 Hz, 2H), 2.48 (s, 3H), 2.38 (d, 7 =

9.0 Hz, 1H), 1.25 (d, 7 = 6.5 Hz, 3H), 1.20 (d, 7 = 6.7 Hz, 6H), 1.10 (d, 7 = 6.6 Hz, 6H); MS (ESI+) m/z 521 (M+H) ⁺ .

Example 47

mc-(2R,3R,45 ^, ,55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [6-methoxy-4-(trifluoromethyl)pyridin-2- yl]amino}methyl)-3-methyl-5-phenylpyrrolidine-2-carboxylic acid

Example 47 A

rac-tert- butyl (2R,3R,45 ^, ,55)- l-[di(propan-2-yl)carbamoyl]-4-({ [6-methoxy-4- (trifluoromethyl)pyridin-2-yl]amino}methyl)-3-methyl-5-pheny lpyrrolidine-2-carboxylate

[0357] Example 46C (50 mg, 0.120 mmol), 2-chloro-6-methoxy-4-(trifluoromethyl)pyridine (50.7 mg, 0.239 mmol), cesium carbonate (117 mg, 0.359 mmol), 2-chloro-6-methoxy-4- (trifluoromethyl)pyridine (50.7 mg, 0.239 mmol), and Pd-PEPPSI-IPentCl complex (4.7 mg, 5.46 m mol) were weighed into a 4 mL vial and put under nitrogen. l,2-Dimethoxyethane (2.0 mL) was added under nitrogen. The vial was sealed and heated to 80 °C in a heating block for 2.5 h, then cooled to room temperature. The solvent was removed under a stream of nitrogen and loaded directly onto a 12 g silica gel column and eluted with 0-100% ethyl acetate/heptanes over 20 min to give the title compound (16 mg, 0.027 mmol, 22.55 % yield). ¹ H NMR (400 MHz, CDCE) d 7.56 - 7.51 (m, 2H), 7.38 - 7.30 (m, 3H), 6.20 (s, 1H), 5.85 (s, 1H), 4.73 (d, J = 12 Hz, 1H), 4.56 (d, 7 = 9.2 Hz, 1H), 4.05 (d, 7 = 8.2 Hz, 1H), 3.85 (s, 3H), 3.60 (p, 7 = 6.6 Hz, 2H), 3.15 (dt, 7 = 13.5, 3.6 Hz, 1H), 2.85 (dt, 7 = 14.7, 8.1 Hz, 1H), 2.39 - 2.14 (m, 2H), 1.56 (s, 9H), 1.29 (d, 7= 2.0 Hz, 3H), 1.17 (d, 7 = 6.7 Hz, 6H), 1.06 (d, 7 = 6.7 Hz, 6H); MS (ESI+) m/z 593 (M+H) ⁺ .

Example 47B

mc-(2i?,3i?,45 ^, ,55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [6-methoxy-4-(trifluoromethyl)pyridin-2- yl]amino}methyl)-3-methyl-5-phenylpyrrolidine-2-carboxylic acid

[0358] Example 47A (16 mg, 0.027 mmol) was treated with trifluoro acetic acid (0.3 mL) and after 30 minutes the solvent was removed. The resulting suspension was loaded onto a 4 g silica gel column and eluted with 3:1:4 acetate/ethanol/heptanes over 20 min to give the title compound (14 mg, 0.026 mmol, 97 % yield). ^l H NMR (400 MHz, CDCE) d 7.34 - 7.28 (m, 3H), 7.26 - 7.21 (m, 2H), 6.16 (d, 7 = 1.1 Hz, 1H), 5.98 (s, 1H), 5.08 (d, 7 = 7.4 Hz, 1H), 4.51 (d, 7 = 7.9 Hz, 1H), 3.94 (s, 3H), 3.49 (hept, 7 = 6.6 Hz, 2H), 3.04 (dd, 7 = 13.0, 4.6 Hz, 1H), 2.72 (dq, 7= 14.4, 6.8 Hz, 1H), 2.57 (dd, 7 = 13.0, 9.5 Hz, 1H), 2.52 - 2.40 (m, 1H), 1.25 - 1.18 (m, 9H), 1.07 (d, 7 = 6.6 Hz, 6H); MS (ESI+) m/z 537 (M+H) ⁺ .

Example 48

mc-(2R,3R,45',55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [2-(2-hydroxyethoxy)-5- (trifluoromethyl)pyridin-3-yl]amino}methyl)-3-methyl-5-pheny lpyrrolidine-2-carboxylic acid

Example 48A

2-{ [3-bromo-5-(trifluoromethyl)pyridin-2-yl]oxy}ethan- l-ol

[0359] To a 20 mL vial containing 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (1.00 g, 3.84 mmol) and ethylene glycol (2.141 mL, 38.4 mmol) was added potassium hydroxide (0.517 g, 9.22 mmol). The reaction was heated at 60 °C for 18 h. The reaction was poured into ice (20 mL) and washed with water (10 mL) and stirred vigorously until all the ice melted. The resulting solid was filtered and washed with ice water to give the title compound (1.086 g, 2.85 mmol, 74.2 % yield). ^l n NMR (500 MHz, CDCb) d 8.38 (dq, /= 1.9, 1.0 Hz, 1H), 8.07 (dd, /= 2.2, 0.6 Hz, 1H), 4.65 - 4.56 (m, 2H), 4.09 - 3.98 (m, 2H), 2.48 (s, 1H); MS (ESI+) m/z 286 (M+H) ⁺ .

Example 48B

rac-tert- butyl (2R,3R,4S,5S)- l-[di(propan-2-yl)carbamoyl]-4-({ [2-(2-hydroxyethoxy)-5- (trifluoromethyl)pyridin-3-yl]amino}methyl)-3-methyl-5-pheny lpyrrolidine-2-carboxylate

[0360] Example 46C (115 mg, 0.275 mmol), cesium carbonate (278 mg, 0.853 mmol),

Example 48A (117 mg, 0.409 mmol), and Pd-PEPPSTIPentCl complex (22.4 mg, 0.026 mmol) were weighed into a 4 mL vial and put under nitrogen. Degassed l,2-dimethoxyethane (2.0 mL) was added to the dry reagents and the reaction was degassed with nitrogen for 5 minutes. The vial was sealed and heated to 110 °C in a heating block for 1 h, then cooled to room temperature. The solvent was removed under a stream of nitrogen and loaded directly onto a 24 g silica gel column and eluted with 5-100% ethyl acetate/heptanes over 20 min to give the title compound (42 mg,

0.067 mmol, 24.49 % yield). ^l H NMR (400 MHz, CDCb) d 7.69 (dt, /= 2.1, 1.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.34 - 7.27 (m, 3H), 6.50 (d, / = 2.0 Hz, 1H), 4.79 - 4.70 (m, 1H), 4.60 - 4.54 (m,

3H), 4.08 (dd, / = 8.3, 3.5 Hz, 1H), 4.00 (t, /= 4.3 Hz, 2H), 3.60 (p, /= 6.7 Hz, 2H), 2.90 (dt, / = 12.9, 3.0 Hz, 1H), 2.58 (dt, /= 12.7, 8.2 Hz, 1H), 2.28 (dt, / = 10.8, 4.7 Hz, 2H), 1.61 (s, 4H), 1.55 (s, 9H), 1.16 (d, / = 6.6 Hz, 6H), 1.04 (d, / = 6.7 Hz, 6H); MS (ESI+) m/z 623 (M+H) ⁺ .

Example 48C

rac-(2R,3R,45',55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [2-(2-hydroxyethoxy)-5- (trifluoromethyl)pyridin-3-yl]amino}methyl)-3-methyl-5-pheny lpyrrolidine-2-carboxylic acid

[0361] Example 48B (42 mg, 0.067 mmol) was treated with trifluoroacetic acid (0.3 mL) and after 15 minutes the solvent was removed. The resulting suspension was loaded onto a 4 g silica gel column and eluted with ethyl acetate/ethanol/heptanes over 20 min to give the title compound (21.8 mg, 0.038 mmol, 57.0 % yield). ^l H NMR (501 MHz, CDCb) d 7.72 (dt, /= 2.2, 1.2 Hz, 1H), 7.44 - 7.24 (m, 5H), 6.50 (d, / = 2.1 Hz, 1H), 4.99 (d, / = 7.5 Hz, 1H), 4.65 - 4.54 (m, 2H), 4.52 (d, / = 7.4 Hz, 1H), 4.10 - 3.96 (m, 2H), 3.55 (hept, / = 6.7 Hz, 2H), 2.92 (dd, / = 13.4, 5.3 Hz, 1H), 2.79 (dt, J = 8.6, 6.7 Hz, 1H), 2.59 (dd, /= 13.5, 8.5 Hz, 1H), 2.39 (qd, / = 8.4, 5.3 Hz, 1H), 1.26 (d, / = 6.6 Hz, 3H), 1.22 (d, / = 6.6 Hz, 6H), 1.10 (d, / = 6.6 Hz, 6H); MS (ESI+) m/z 567 (M+H) ⁺ .

Example 49

rac-(2R,35 ^, ,4R,55 ^, )-4-[5-(2-bromo-6-methoxyphenyl)-l,3,4-oxadiazol-2-yl] -3-/er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic acid

Example 49A

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(hydrazinecar bonyl)-5- phenylpyrrolidine-2-carboxylate

[0362] To a solution of 50D (229 mg, 0.50 mmol) in acetonitrile (2 mL) and N,N- dimethylformamide (2 mL) at room temperature were added hydroxybenzotriazole (81 mg, 0.60 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (115 mg, 0.60 mmol). The mixture was stirred for 1 h and hydrazine hydrate (48 pL, 1.00 mmol) was added. The mixture was stirred at room temperature for 1 h. Water and dichloromethane were added and the organic phase was separated and dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered and dried in vacuo to afford the title compound (207 mg, 88%). LC/MS (ESI+) m/z 472.5 (M+H) ⁺ .

Example 49B

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-4-[2-(2-bromo-6-methoxybenzoyl)hydrazinecarbonyl]-3- /er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

[0363] To a solution of 2-bromo-6-methoxy-benzoic acid (79 mg, 0.34 mmol) and 1- [bis(dimethylamino)methylene]- 1 H- \ ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 130 mg, 0.34 mmol) in anhydrous dichloromethane (3 mL) was added NN- diisopropylethylamine (119 m L, 0.68 mmol). The mixture was stirred at room temperature for 10 minutes and Example 49A (160 mg, 0.34 mmol) was added. The resulting mixture was stirred for 72 h at rt. Water was added and the organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel

(dichloromethane/methanol 100/0 to 97/3) to afford the title compound (210 mg, 90%). LC/MS (ESI+) m/z 684.5 - 686.5 (M+H) ⁺ .

Example 49C

rac-tert- butyl (2i?,35',4i?,55 ^, )-4-[5-(2-bromo-6-methoxyphenyl)-l,3,4-oxadiazol-2-yl] -3-/er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylate

[0364] /V,/V-Diisopropylethylamine (53 pL, 0.30 mmol) and 4-methylbenzenesulfonyl chloride (58 mg, 0.30 mmol) were added to a solution of Example 49B (105 mg, 0.15 mmol) in acetonitrile. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel

(dichloromethane/methanol 100/0 to 97/3) to afford the title compound (50 mg, 37%). LC/MS (ESI+) m/z 666.5-668.4 (M+H) ⁺ .

Example 49D

rac-(2R,35 ^, ,4R,55 ^, )-4-[5-(2-bromo-6-methoxyphenyl)-l,3,4-oxadiazol-2-yl] -3-/er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0365] Trifluoroacetic acid (750 m L) was added to a solution of Example 49C (50 mg, 0.075 mmol) in dichloromethane. The mixture was stirred for 2 h, the solvent was removed under vacuum and the residue diluted with dichloromethane and neutralized with a saturated NaHCCh solution. The organic phase was dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure to afford the title compound (45 mg, 99%). ^X H NMR (400 MHz, CDCb) d 7.33 (t, J = 8.2 Hz, 1H), 7.16 - 7.27 (m, 4H), 7.07 (d, 7 = 6.8 Hz, 2H), 6.86 (d, 7 = 8.4 Hz, 1H), 5.59 (d, 7 = 9.3 Hz, 1H), 4.74 (d, 7 = 7.9 Hz, 1H), 4.37 (dd, 7 = 11.8, 9.4 Hz, 1H), 3.84 (dd, 7 = 11.9, 7.9 Hz, 1H), 3.67 (s, 3H), 2.26 - 2.37 (m, 1H), 1.87 (d, J = 11.2 Hz, 2H), 1.51 - 1.68 (m, 3H), 1.09 - 1.38 (m, 5H),

0.95 (s, 9H). LC/MS (ESI+) m/z 610.3-612.3 (M+H) ⁺ .

Example 50

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[3-(2-methoxy -6-methylphenyl)-l,2,4- oxadiazol-5-yl]-5-phenylpyrrolidine-2-carboxylic acid

Example 50 A

benzyl (27, ^’ )-4, 4-dimethyl pent-2-enoate

[0366] A solution of benzyl 2-bromoacetate (43.8 g, 191 mmol) and triethyl phosphite (34.9 g, 210 mmol) was heated to 80 °C for 3 h, allowing the ethyl bromide to escape via a N ₂ flush. The reaction was cooled to 25 °C, tetrahydrofuran (300 mL) was added to the above solution and cooled further to < 0 °C. NaH (5.51 g, 229 mmol) was added portionwise at < 0 °C, then warmed to 25 °C and stirred 30 min. Pivalaldehyde (16.47 g, 191 mmol) was added to the reaction at < 0 °C and stirred for 5 min. The mixture was washed with saturated NH ₄ Cl (200 mL), methyl /e/7-butyl ether (500 mL) and water (100 mL) and separated the organic layers, dried over Na ₂ S0 ₄ and concentrated to give the title compound (34 g, 81 %), which was used directly without further purification. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 7.44 - 7.24 (m, 5H), 6.93 (d, 7=15.9 Hz, 1H), 5.76 (d, 7=15.9 Hz, 1H), 5.12 (s, 2H), 1.02 (s, 9H).

Example 50B

rac-(2R,3S ,4R,55)-4-benzyl 2-/e/7-butyl 3-/er/-butyl-5-phenylpyrrolidine-2,4-dicarboxylate

[0367] A solution of Example 1A (34 g, 155 mmol) in tetrahydrofuran (600 mL) was cooled to < -70 °C. Example 50A (33.8 g, 155 mmol), 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine (23.37 mL, 155 mmol) and lithium bromide (13.47 g, 155 mmol) were added at < -70 °C and then warmed slowly to 25 °C. The reaction was stirred at 25 °C for 1 h. The mixture was washed with saturated NH ₄ Cl (500 mL), methyl /e/7-butyl ether (500 mL) and water (500 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated to give a crude yellow solid. The solid was stirred in petroleum ether (600 mL) for 12 h and filtered to provide title compound (22.5 g, 33.2 %). ¹ H NMR (400 MHz, DMSO-ifc) d 7.37 - 7.19 (m, 8 H), 7.02 - 6.90 (m, 2H), 4.68 (d, 7=12.3 Hz, 1H), 4.42 (d, 7=12.3 Hz, 1H), 4.31 (dd, 7=8.4, 9.7 Hz, 1H), 3.51 (t, 7=8.4 Hz, 1H), 3.21 (dd, 7=4.4, 7.9 Hz, 1H), 3.08 (t, 7=9.9 Hz, 1H), 2.56 (dd, 7=4.4, 7.5 Hz, 1H), 1.44 (s, 9H), 0.92 (s, 9H). MS (ESI+) m/z 438.2 (M+H) ⁺ .

Example 50C

rac-4-benzyl 2-/e/7-butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-phenylpyrroli dine-

2,4-dicarboxylate

[0368] A solution of Example 50B (2.37 g, 5.42 mmol) and triethylamine (1.510 mL, 10.83 mmol) in dichloromethane (50 mL) under N ₂ was cooled to 0 °C, treated drop wise with

cyclohexanecarbonyl chloride (0.949 mL, 7.04 mmol), and stirred at 0 °C for 30 minutes. The reaction was stirred at room temperature for 90 minutes, then treated with 37 % aqueous ammonium hydroxide solution (1.443 mL, 13.71 mmol), stirred for 5 minutes, concentrated without heating on rotovap, and partitioned between /e/7-butyl methyl ether (100 mL) and saturated aqueous NaHCCh solution (~ 25 mL). The /e/7-butyl methyl ether layer was washed with brine, dried (MgS0 ₄ ), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 10 % to 30 % ethyl acetate in heptanes to provide the title compound (2.95 g, 5.39 mmol, 99 % yield). ¹ H NMR (400 MHz, DMSO, 120 °C) d 7.63 - 7.57 (m, 2H), 7.33 - 7.19 (m, 6H), 7.11 - 7.07 (m, 2H), 5.44 (d, 7 = 10.0 Hz, 1H), 4.62 (d, 7 = 12.4 Hz, 1H), 4.41 - 4.36 (m, 2H), 3.63 (dd, 7 = 7.0, 10.0 Hz, 1H), 2.88 - 2.84 (m, 1H), 2.25 - 2.14 (m, 1H), 1.73 - 1.65 (m, 2H), 1.55 - 1.44 (m, 11H), 1.35 - 1.24 (m, 2H), 1.19 - 1.05 (m, 4H), 0.96 (s, 9H); MS (ESI+) m/z 548 (M+H) ⁺ .

Example 50D

rac-(25 ^, ,3R,45 ^, ,5R)-5-(/er/-butoxycarbonyl)-4-/er/-butyl-l-(cyclohexa necarbonyl)-2- phenylpyrrolidine-3-carboxylic acid

[0369] To a solution of intermediate Example 50C (1.77 g, 3.23 mmol) in methanol (30 mL) under N ₂ was added Pd on charcoal 10% (340 mg, 0.32 mmol). The solution was then degassed, flushed with H ₂ and stirred at room temperature overnight. The reaction mixture was then filtered on Celpure ^® diatomite filter aid, washed with methanol, and the filtrate was concentrated in vacuo to deliver the title compound as a solid which was used directly in the next step without further purification.

Example 50E

/V-hydroxy-2-methoxy-6-methyl-benzamidine

[0370] A suspension of 2-bromo-6-methoxy-benzonitrile (455 mg, 2.14 mmol), hydroxylamine hydrochloride (297 mg, 4.28 mmol) and Na ₂ C0 ₃ (454 mg, 4.28 mmol) in EtOH (10 mL) was heated to reflux for 96 h. The inorganic solids were removed by filtration and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (KP-NH column (Biotage), dichloromethane/methanol 100/0 to 99/1). The product fractions were combined and concentrated to dryness to afford the title compound as a solid (300 mg, 57%). LC/MS (ESI+) m/z 245.1 - 247.1 (M+H) ⁺ .

Example 50F

rac-tert- butyl (2 /,3.V,4 /,5.V)-4-[( { (Z)-[amino(2-methoxy-6- methylphenyl)methylidene]amino}oxy)carbonyl]-3-tert-butyl-l- (cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylate

[0371] To a stirred solution of Example 50D (92 mg, 0.20 mmol) and (1- [bis(dimethylamino)methylene]- 1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (76 mg, 0.20 mmol) in anhydrous dichloromethane (2 mL) was added /V,/V-diisopropylethylamine (70 pL, 0.40 mmol). The mixture was stirred at room temperature for 10 minutes and Example 50E (36 mg, 0.20 mmol) was added. The resulting mixture was stirred overnight at rt. LC/MS showed full conversion. Water was added and the organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 100/0 to 96/4). The product fractions were combined and concentrated to dryness to afford the title compound (90 mg, 72%). LC/MS (ESI+) m/z 620.5 (M+H) ⁺ .

Example 50G

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[3-(2-methoxy -6- methylphenyl)-l,2,4-oxadiazol-5-yl]-5-phenylpyrrolidine-2-ca rboxylate

[0372] Tetra-n-butylammonium fluoride (1.0 M in tetrahydrofuran, 30 pL, 0.03 mmol) was added to a solution of Example 50F (90 mg, 0.14 mmol) in tetrahydrofuran (3 mL). The mixture was stirred for 2 h at rt. LC/MS seemed to show racemization of starting material. More tetra-n- butylammonium fluoride was added (0.8 eq) and the mixture was stirred overnight at rt, followed by addition of more tetra-n-butylammonium fluoride (1.0 eq) and the mixture kept stirring at room temperature overnight. LC/MS showed a mixture of two compounds with the expected mass. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel (dichloromethane/methanol 100/0 to 98/2) to afford the title compound (22 mg, 26%). LC/MS (ESI+) m/z 602.6 (M+H) ⁺ .

Example 5 OH

rac-(2R,3S,4R,5S ₎ -3- _l er _l -bu _. y\- 1 -(cyclohexanecarbonyl ₎ -4-[3-(2-methoxy-6-methyl-phenyl ₎ - ] ,2,4- oxadiazol-5-yl]-5-phenyl-pyrrolidine-2-carboxylic acid

[0373] Trifluoroacetic acid (500 m L) was added to a solution of Example 50G (22 mg, 0.036 mmol) in dichloromethane (1 mL). The mixture was stirred for 1 h at rt. The solvent was removed under vacuum and the residue diluted with dichloromethane and neutralized with a saturated NaHCCh solution. The organic phase was dried over Na ₂ S0 ₄ , filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (dichloromethane/methanol 100/0 to 95/5) to afford the title compound (12 mg, 61%). ^X H NMR (300 MHz, CDCb) d 7.19 - 7.36 (m,

4H), 7.06 - 7.18 (m, 2H), 6.77 (d, / = 8.4 Hz, 1H), 6.82 (d, / = 7.7 Hz, 1H), 5.58 (d, / = 9.3 Hz,

1H), 4.75 (d, 7 = 7.8 Hz, 1H), 4.26 (dd, / = 11.4, 9.3 Hz, 1H), 3.97 (dd, /= 11.7, 7.8 Hz, 1H), 3.72 (s, 3H), 2.32 (t, J = 11.5 Hz, 1H), 1.91 (s, 3H), 1.72 - 1.88 (m, 2H), 1.57 (d, J= 14.3 Hz, 3H), 1.08 - 1.43 (m, 5H), 0.95 (s, 9H); LC/MS (ESI+) m/z 546.7 (M+H) ⁺ .

Example 51

(25, 35, 45, 5// ₎ - 1 -[di( propan-2-yl /carbamoyl] -3-methyl -5-phenyl -4- { l-[4-(trifluoromethyl)phenyl]- l//-l,2,3-triazol-4-yl}pyrrolidine-2-carboxylic acid

Example 51A

benzyl (2£)-but-2-enoate

[0374] To a solution of (£)-but-2-enoic acid (50 g, 290 mmol) in /V,/V-dimethylformamide (250 mL) was added potassium carbonate (80 g, 580 mmol). The mixture was stirred at 20 °C for 1 h and then bromomethyl benzene (99 g, 290 mmol) was added into the reaction. The resulting mixture was stirred at 20 °C for 12 h. One more vial was set up as described above. After reaction, both of these reactions were combined and filtered to remove potassium carbonate. The filtrate solvent was poured into water (1 L) and extracted with ethyl acetate (2 x 1 L). The combined organic layers were washed with (2 x 1 L), dried over sodium sulfate (20 g), filtered and

concentrated under reduced pressure to give the title compound (169 g, yield 83%). ¹ H NMR (400 MHz, DMSO -de) d 7.50 - 7.22 (m, 5H), 7.02 - 6.86 (m, 1H), 6.01 - 5.87 (m, 1H), 5.14 (s, 2H), 1.89 - 1.81 (m, 3H).

Example 51B

rac-4-benzyl 2-/e/7-butyl (2i?,3i?,4i?,55 ^, )-3-methyl-5-phenylpyrrolidine-2,4-dicarboxylate

[0375] A solution of Example 1 A (44 g, 200 mmol) in tetrahydrofuran (350 mL) was cooled to -70 °C, then Example 51A (35 g, 200 mmol), 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine (36 g, 240 mmol) and lithium bromide (26 g, 300 mmol) were added into the reaction. The resulting reaction mixture was allowed to warm to 25 °C and stirred for 12 h. Three more vials were set up as described above. After reaction, all four reactions were combined and poured into saturated NH ₄ Cl (1.5 L) and extracted with ethyl acetate (3 x 1.5 L). The combined organic layers were washed with brine (2 x 2 L), dried over sodium sulfate (30 g), filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel with the eluent of 10: 1 petroleum ethenethyl acetate to give the title compound (183 g, yield 58%). ¹ H NMR (400 MHz, methanol-cU) d 7.35 - 7.20 (m, 8H), 7.02 (dd, 7=2.9, 6.4 Hz, 2H), 4.71 (d, 7=12.3 Hz, 1H), 4.60 - 4.52 (m, 2H), 3.42 - 3.34 (m, 1H), 3.09 (dd, 7=6.8, 8.2 Hz, 1H), 2.70 - 2.58 (m, 1H), 1.54 (s, 9H), 1.30 - 1.23 (m, 3H).

Example 51C

rac-4-benzyl 2-/e/7-butyl (2i?,3i?,4i?,55 ^, )-l-[di(propan-2-yl)carbamoyl]-3-methyl-5-phenylpyrrol idin e-2,4-dicarboxylate

[0376] To a solution of Example 51B (61 g, 154 mmol) in dichloromethane (500 mL) was added diisopropylcarbamic chloride (28 g, 170 mmol) and triethylamine (19 g, 185 mmol). The reaction was stirred at 25 °C for 12 h. Two vials were set up as described above. After reaction, all these reactions were combined and poured into saturated NaHCCh (1 L). The mixture was separated and the aqueous layer was extracted with dichloromethane (1.5 L). The combined organic layers were washed with brine (2 x 1.5 L), dried over sodium sulfate (50 g), filtered and

concentrated under reduced pressure to give the title compound (210 g, yield 80%). ¹ H NMR (400 MHz, methanol-d ₄ ) d 7.44 - 7.39 (m, 2H), 7.38 - 7.31 (m, 3H), 7.30 - 7.20 (m, 5H), 4.91 - 4.84 (m, 3H), 4.45 (d, 7=11.0 Hz, 1H), 3.65 - 3.51 (m, 2H), 3.14 - 3.02 (m, 1H), 2.75 - 2.59 (m, 1H), 1.55 (s, 9H), 1.22 - 1.19 (m, 3H), 1.12 (d, 7=6.6 Hz, 6H), 1.02 (d, 7=6.6 Hz, 6H).

Example 51D

rac-(25 ^, ,3R,4R,5R)-5-(/er/-butoxycarbonyl)-l-[di(propan-2-yl)c arbamoyl]-4-methyl-2-phenylpyrroli dine-3-carboxylic acid

[0377] To a solution of Example 51C (42 g, 80 mmol) in tetrahydrofuran (800 mL) was added Pd/C (10 g, 10%). The mixture was stirred under 15 psi of hydrogen in a balloon at 25 °C for 2 h. Four vials were set up as described above. After reaction, all five reactions were combined and filtered to remove Pd/C. The filtrate solvent was concentrated under reduced pressure to give the title compound (150 g, yield 88%). ^l H NMR (400 MHz, CDCb) d 7.49 - 7.41 (m, 2H), 7.29 - 7.20 (m, 3H), 4.81 - 4.72 (m, 1H), 4.60 - 4.53 (m, 1H), 3.52 (spt, 7=6.6 Hz, 2H), 3.03 - 2.90 (m, 1H),

2.72 - 2.54 (m, 1H), 1.59 - 1.44 (m, 9H), 1.21 (d, 7=6.2 Hz, 3H), 1.12 (d, 7=6.6 Hz, 6H), 0.98 (d, 7=6.6 Hz, 6H).

Example 51E

rac-tert- butyl (2//, 3//, 4//, 55 ₎ - 1 -[di(propan-2-yl /carbamoyl] -4-(hydi _O xymethyl ₎ -3-methyl-5-phenylp yrrolidine-2-carboxylate

[0378] A solution of Example 51D (50 g, 116 mmol) in tetrahydrofuran (375 mL) was cooled to -10 °C and then /V-methyl morpholine (12.9 g, 127 mmol) and isobutyl carbonochloridate (13.4 g, 127 mmol) were added into the reaction. The resulting mixture was stirred at -10 °C for 30 min and then filtered. The filtrate was added dropwise into a mixture of sodium borohydride (8.8 g, 232 mmol) in water (100 mL) below 0 °C. The reaction was allowed to warm to 10 °C and stirred for 50 min. Two more vials were set up as described above. All three reactions were combined and poured into saturated NH ₄ Cl (2 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 1 L). The combined organic layers were washed with brine (2 x 2 L), dried over sodium sulfate (50 g), filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel with the eluent of 5:1 petroleum ethenethyl acetate to give the title compound (95 g, yield 65%). ¹ H NMR (400 MHz, DMSO-r/e) d 7.56 - 7.44 (m, 2H), 7.32 - 7.28 (m, 2H), 7.25 - 7.21 (m, 1H), 4.74 - 4.72 (m, 1H), 4.47 - 4.46 (m, 1H), 4.32 - 4.29 (m, 1H), 3.53 - 3.47 (m, 2H), 3.15 - 3.12 (m, 1H), 2.68 - 2.66 (m, 1H), 1.99 - 1.87 (m, 2H), 1.46 (s, 9H), 1.12-1.05 (d, 7=6.4 Hz, 3H), 1.05-1.03 (d, 7=6.8 Hz, 6H), 0.97-0.95 (d, 7=6.8 Hz, 6H).

Example 51F

/e/ -butyl (2R,3R,4R,55)-l-[di(propan-2-yl)carbamoyl]-4-(hydroxymethyl) -3-methyl-5-phenylpyrro lidine-2-carboxylate

[0379] Example 51E (90 g, 215 mmol) was purified by supercritical fluid chromatography (SFC) using Thar analytical SFC, Chiralcel OD column (3 3pm, 0.46cm id x lOcm L) eluting with a gradient of B (isopropyl alcohol) in A (liquid CO2) from 5% to 40% in 5 minutes at a flow rate of 4.0 mL/min, with system back pressure set at 100 bar, resulting in the title compound as the first eluting peak. ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.52 (d, 7=7.5 Hz, 2H), 7.32 - 7.25 (m, 2H), 7.25 - 7.18 (m, 1H), 4.70 (d, 7=7.1 Hz, 1H), 4.47 (t, 7=4.4 Hz, 1H), 4.28 (d, 7=9.7 Hz, 1H), 3.55 - 3.42 (m, 2H), 3.16 - 3.06 (m, 1H), 2.70 - 2.59 (m, 1H), 2.02 - 1.91 (m, 1H), 1.91 - 1.80 (m, 1H), 1.43 (s, 9H), 1.09 (d, 7=6.2 Hz, 3H), 1.01 (d, 7=6.6 Hz, 6H), 0.94 (d, 7=6.6 Hz, 6H); MS (ESI+) m/z 419.2 (M+H) ⁺ .

Example 51G

/e/7-butyl (25,35,45,55)- l -[di(propan-2-yl)carbamoyl]-4-(hydiOxymethyl)-3-methyl-5-phe nyl pyrrol idine-2-carboxylate

[0380] Isolated as the second eluting peak in the chromatography method described in Example 51F: ^l H NMR (400 MHz, DMSO-7 ₆ ) d 7.55 (d, 7=7.1 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.27 - 7.20 (m, 1H), 4.73 (d, 7=7.1 Hz, 1H), 4.49 (t, 7=4.4 Hz, 1H), 4.31 (d, 7=9.7 Hz, 1H), 3.50 (spt, 7=6.5 Hz,

2H), 3.14 (td, 7=4.5, 10.5 Hz, 1H), 2.75 - 2.62 (m, 1H), 2.06 - 1.94 (m, 1H), 1.94 - 1.81 (m, 1H), 1.46 (s, 9H), 1.11 (d, 7=6.2 Hz, 3H), 1.04 (d, 7=6.6 Hz, 6H), 0.99 - 0.92 (m, 6H); MS (ESI+) m/z 419.2 (M+H) ⁺ .

Example 51H

/e/ -butyl (2S,3S,4S,5R) 1 -(di isopropyl carbamoyl )-4-formyl-3-methyl -5-phenyl -pyrrol idine-2- carboxylate

[0381] Example 51G (1.026 g, 2.451 mmol) was dissolved in dichloromethane (70 mL) and cooled at 0 °C, Dess Martin periodinane (1.091 g, 2.573 mmol) was added and the mixture was slowly warmed to room temperature overnight. The reaction mixture was quenched with saturated NaHCCh aqueous solution and extracted with dichloromethane. The organic layer was separated using phase separator, concentrated to dryness, and the residue was purified by flash

chromatography on silica gel (ethyl acetate/heptane 5/95 to 20/80) to give the title compound (1 g, 97%). ^l H NMR (400 MHz, CDCE) d 8.99 (d, 7= 3.1 Hz, 1H), 7.49 (d, 7= 7.5 Hz, 2H), 7.36 (dd, 7 = 7.1, 8.2 Hz, 2H), 7.30 - 7.24 (m, 1H), 5.15 (d, 7 = 8.1 Hz, 1H), 4.44 (d, 7 = 8.2 Hz, 1H), 3.60 (quin, 7 = 6.7 Hz, 2H), 2.96 - 2.84 (m, 1H), 2.83 - 2.75 (m, 1H), 1.55 (s, 9H), 1.23 (d, 7= 6.6 Hz, 3H), 1.18 (d, 7 = 6.6 Hz, 6H), 1.08 (d, 7 = 6.6 Hz, 6H). LC/MS (ESI+) m/z 417.4 (M+H) ⁺ .

Example 511

_/ e _/ 7-butyl (25,35,55)- 1 -[di(propan-2-yl /carbamoyl] -4-ethynyl-3-methyl-5-phenyl pyrrol idine-2- carboxylate

[0382] To a solution of Example 5lH(l00 mg, 0.24 mmol) in methanol (5 mL) were successively added dimethyl (l-diazo-2-oxopropyl)phosphonate (55 mg, 0.29 mmol) and K2CO3 (66 mg, 0.48 mmol) at rt. Reaction mixture was stirred at room temperature for 20 h, with monitoring by ultra high performance liquid chromatography. Reaction mixture was quenched with NH4CI saturated aqueous solution and extracted with dichloromethane. The organic layer was separated using phase separator, concentrated to dryness, and the residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 5/95 to 25/75) to give the title compound as a mixture of 2 diastereomers used as such in the next step (90 mg, 2 co-eluting spots, assuming epimerization at C4, one peak in LC/MS (ESI+) m/z 413.4 (M+H) ⁺ ). ¹ H NMR (400 MHz, CDCI3) d 7.60 (d, 7 = 7.1 Hz, 2H), 7.22 - 7.29 (m, 2H), 7.11 - 7.22 (m, 1H), 4.99 (d, 7 = 6.6 Hz, 1H), 4.13 (d, J= 5.1 Hz, 1H), 3.52 (quin, 7 = 6.7 Hz, 2H), 2.86 (td, 7 = 6.1, 2.4 Hz, 1H), 2.25 - 2.41 (m, 1H), 2.15 (d, 7 = 2.4 Hz, 1H), 1.44 (s, 9H), 1.19 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 6.6 Hz, 6H), 1.08 (d, 7 = 6.8 Hz, 6H).

Example 51J

/e/7-butyl (25, 35, 45, 5//)- 1 -[di(piOpan-2-yl)carbamoyl]-3-methyl-5-phenyl-4-{ l-[4- (trifluoromethyl)phenyl] - 1H- 1 ,2,3-triazol-4-yl }pyrrolidine-2-carboxylate

[0383] Example 511 (45 mg, 0.109 mmol) and l-azido-3-(trifluoromethyl)benzene (218 m L, 0.109 mmol) were added to a mixture of /e/7-butanol (1 mL) and water (1 mL). Sodium ascorbate (1 M in water, 11 pL, 0.01 mmol) and CuS0 ₄ -5H ₂ 0 (one crystal, 0.01 eq) were added. The reaction mixture was stirred at room temperature for 24 h. Reaction was quenched with saturated NaHCCh aqueous solution and diluted with dichloromethane. The organic layers were collected using phase separator, concentrated to dryness, and the residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 5/95 to 60/40) as the first eluting peak to give the title compound (8 mg). ^l n NMR (400 MHz, CDCb) d 7.74 (m, 2H), 7.58 (m, 2H), 7.09 - 7.23 (m, 5H), 6.57 (s, 1H), 4.81 - 4.87 (m, 2H), 3.69 (dd, J= 12.4, 7.7 Hz, 1H), 3.60 (quin, 7= 6.6 Hz, 2H), 2.53 (ddd, 7 = 12.5, 10.3, 6.4 Hz, 1H), 1.57 (s, 9H), 1.15 - 1.23 (m, 9H), 1.04 (d, 7= 6.8 Hz, 6H). LC/MS (ESI+) m/z 600.5 (M+H) ⁺ .

Example 51K

/e/7-butyl (25,35,45,55)- 1 - [di(propan-2-yl /carbamoyl] -3-methyl-5-phenyl-4-{ l-[4- (trifluoromethyl)phenyl] - 1H- 1 ,2,3-triazol-4-yl }pyrrolidine-2-carboxylate

[0384] Example 51K was isolated from the product mixture of Example 51 J as the second eluting peak during the flash column chromatography (18 mg). ¹ H NMR (400 MHz, CDCb) d 8.16 (s, 1H), 7.95 (m, 2H), 7.80 (m, 2H), 7.68 (d, 7 = 7.3 Hz, 2H), 7.34 - 7.41 (m, 2H), 7.25 - 7.31 (m, 1H), 4.83 (d, 7 = 2.7 Hz, 1H), 4.55 (d, 7 = 9.0 Hz, 1H), 3.71 (dd, 7 = 5.9, 2.9 Hz, 1H), 3.58 - 3.68 (m, 2H), 2.72 - 2.83 (m, 1H), 1.56 (s, 9H), 1.25 (d, 7 = 6.6 Hz, 6H), 1.03 (d, 7 = 6.6 Hz, 6H), 0.97 (d, 7 = 6.8 Hz, 3H). LC/MS (ESI+) m/z 600.5 (M+H) ⁺ .

Example 51L

(2S,3S,4S, 5R)-1- [di(prop an-2- yl)c arb amoyl] - 3 -methyl- 5 -phenyl-4- { 1 - [4- (trifluoromethyl)phenyl] - l/7-l,2,3-triazol-4-yl}pyrrolidine-2-carboxylic acid

[0385] Example 51J (8 mg) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (250 pL) was added and the reaction mixture was stirred at room temperature for 20 h. Monitoring by ultra high performace liquid chromatography showed complete conversion. The reaction mixture was concentrated and purified by flash chromatography on silica gel

(dichloromethane/methanol 100/0 to 90/10) to give the title compound (3 mg). LC/MS (ESI+) m/z 544.4 (M+H) ⁺ .

Example 52

/g/G-(2//,3.n,4//,5.n)-3-/ _< ° r/-butyl- 1 -(cyclohexanecarbonyl)-4-{ [2-methoxy-5- (trifluoromethyl)phenoxy] methyl } -5 -phenylpyrrolidine-2-carboxylic acid

Example 52 A

rac-tert- butyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(hydroxymethy l)-5- phenylpyrrolidine-2-carboxylate

[0386] To a solution of Example 50D (675.1 mg, 1.475 mmol) in tetrahydrofuran (6 mL) at 0 °C (ice/water bath) was added /V-methylmorpholine (199.4 mg, 1.971 mmol). To this solution was added slowly isobutyl chloroformate (289.5 mg, 2.120 mmol). After 30 minutes, the mixture was filtered into a solution of sodium borohydride (163.7 mg, 4.33 mmol) in water (2 mL) at 0 °C. After 30 minutes, the mixture was quenched via addition of a saturated solution of NH ₄ Cl (10 mL). The reaction mixture was diluted with dichloromethane (50 mL) and the organic layer separated, dried over Na ₂ S0 ₄ , filtered, and the solvent removed. The crude material was purified with a 25 g silica gel cartridge using a a gradient of 5-10% ethyl aceate in dichloromethane over 20 min to give the title compound (560 mg, 99%). ^l H NMR (400 MHz, DMSO -de, 120 °C) d 7.55 (s, 2H), 7.24 (dt, 7 = 26.1, 7.2 Hz, 3H), 5.15 (d, 7= 8.8 Hz, 1H), 4.41 (d, 7= 2.4 Hz, 1H), 3.78 - 3.62 (m, 1H), 3.30 - 3.11 (m, OH), 2.90 (d, 7= 12.6 Hz, 3H), 2.72 - 2.54 (m, 2H), 2.34 (s, 1H), 2.10 (s, 1H), 1.72 - 1.54 (m, 4H), 1.54 - 1.40 (m, 10H), 1.30 - 1.13 (m, 2H), 1.13 - 1.01 (m, OH), 0.95 (d, 7= 5.2 Hz, 9H); MS (ESI+) m/z 444 (M+H) ⁺ .

Example 52B

rac-(2Z?,35 ^, ,4Z?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-{ [2-methoxy-5- (trifluoromethyl)phenoxy] methyl } -5 -phenylpyrrolidine-2-carboxylic acid [0387] Example 52A (45.0 mg, 0.101 mmol) was azeotroped with toluene (3 x 1 mL) before combining with tri-n-butyl phosphine (43.6 mg, 0.216 mmol), and 5-chloro-2-methoxyphenol (33.0 mg, 0.172 mmol) in tetrahydrofuran (1 mL). (/f)-A ^/l ,A ^/l ,A ^/2 ,A ^/2 -tetramethyldiazene- 1 ,2- dicarboxamide (TMAD, 37.6 mg, 0.218 mmol) was added all at once at ambient temperature while stirring vigorously. The reaction was heated to 50 °C for 16 h. Methanol (0.5 mL) was added to the reaction, which was then concentrated. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at ambient temperature for 20 h. The reaction was concentrated and purified by reverse phase purification. Samples were purified by preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5- 12.0 min linear gradient 95-5% A) to afford the title compound (22.5 mg, 40%). ¹ H NMR (400 MHz, DMSO-ifc, 120 °C) d 7.63 (d, 7 = 7.5 Hz, 2H), 7.28 (t, 7 = 7.5 Hz, 2H), 7.23 - 7.12 (m, 2H), 7.03 (d, 7 = 8.5 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 5.33 (d, 7 = 9.1 Hz, 1H), 4.54 (d, 7 = 2.4 Hz, 1H), 3.75 (s, 3H), 3.61 (t, 7 = 9.7 Hz, 1H), 3.26 (dd, 7 = 9.7, 5.6 Hz, 1H), 3.05 (q, 7 = 8.5 Hz, 1H), 2.43 (s, 1H), 2.16 (s, 1H), 1.64 (d, 7 = 9.8 Hz, 2H), 1.47 (s, 2H), 1.31 - 1.13 (m, 3H), 1.06 (s, 2H), 1.00 (s, 9H), 0.70 (s, 1H); MS (ESI+) m/z 562 (M+H) ⁺ .

Example 53

rac-(2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-({ [6-methyl-4-(trifluoromethyl)pyridin- 2-yl]oxy}methyl)-5-phenylpyrrolidine-2-carboxylic acid

[0388] Example 52A (43.4 mg, 0.098 mmol) was azeotroped with toluene (3 x 1 mL) before combining with tri-n-butyl phosphine (40.0 mg, 0.198 mmol), and 6-methyl-4- (trifluoromethyl)pyridin-2-ol (48.6 mg, 0.274 mmol) in tetrahydrofuran (1 mL). (E)-N ^l N ^l N ² N ² - tetramethyldiazene-l, 2-dicarboxamide (TMAD, 37.3 mg, 0.217 mmol) was added all at once at ambient temperature while stirring vigorously. The reaction was heated to 50 °C for 16 h.

Methanol (0.5 mL) was added to the reaction, which was then concentrated. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at ambient temperature for 18 h. The reaction was concentrated and purified by reverse phase purification. Samples were purified by preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1%

trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to afford the title compound (23.2 mg, 43%). ^X H NMR (400 MHz, DMSO-tfc, 120 °C) d 7.62 (d, J = 7.5 Hz, 2H), 7.20 (t, / = 7.5 Hz, 2H), 7.10 (t, / = 7.3 Hz, 1H), 6.95 (s, 1H), 6.54 (s, 1H), 5.29 (d, / = 9.2 Hz, 1H), 4.55 (d, / = 2.4 Hz, 1H), 3.93 - 3.77 (m, 2H), 3.11 - 3.01 (m, 1H), 2.36 - 2.28 (m, 4H), 2.22 - 2.08 (m, 1H), 1.63 (d, / = 9.7 Hz, 2H), 1.46 (s, 2H), 1.31 - 1.13 (m, 2H), 1.08 (d, / = 26.3 Hz, 2H), 0.96 (s, 9H), 0.70 (s, 2H).); MS (ESI+) m/z 547 (M+H) ⁺ .

Example 54

(2.S ^, ,3.S ^, ,4.S ^, ,5/^)-/V ² -(6-aminopyi idine-2-sulfonyl)-3-methyl-4- { [3-(2- methylpropoxy)phenoxy] methyl} -5-phenyl-iV ¹ , N ¹ -di(propan-2-yl)pyrrolidine-l, 2-dicarboxamide

Example 54 A

3-isobutoxyphenol

[0389] To a suspension of resorcinol (2.040 g, 18.53 mmol) and potassium carbonate (2.67 g, 19.32 mmol) in /V,/V-dimethylformamide (12 mL) was added l-iodo-2-methylpropane (2.139 mL, 18.53 mmol). The reaction was stirred at room temperature for 72 h. The reaction was diluted with methyl /e/7-butyl ether and saturated aqueous ammonium chloride. The organic layer was separated, washed with water, then washed with brine, and dried over sodium sulfate, and concentrated. The crude material was chromatographed using an 80 g silica gel cartridge with a gradient of 5-50% ethyl acetate/hexanes over 40 minutes to give the title compound (0.569 g, 3.42 mmol, 18.48 % yield). ^l H NMR (400 MHz, CDCb) d 7.13 (t, / = 8.5 Hz, 1H), 6.50 (ddd, / = 8.2, 2.2, 1.0 Hz, 1H), 6.45 - 6.38 (m, 2H), 4.85 (d, / = 0.8 Hz, 1H), 3.70 (d, / = 6.5 Hz, 2H), 2.08 (dp, J = 13.3, 6.7 Hz, 1H), 1.03 (d, / = 6.7 Hz, 6H).

Example 54B

/e/7-butyl (2S,3S,4S,5R)- l-[di(propan-2-yl)carbamoyl]-3-methyl-4-{ [3-(2- methylpropoxy)phenoxy] methyl } -5-phenylpyrrolidine-2-carboxylate

[0390] Example 51G (0.5 g, 1.195 mmol) was azeotroped with toluene before combining with tributylphosphine (0.354 mL, 1.433 mmol), and Example 54A (0.196 mL, 1.195 mmol) in tetrahydrofuran (3 mL). (/f)-A ^/l ,/V ^l ,/V ² ,/V ² -tetramethyldiazene- 1 ,2-dicarboxamide (TMAD) (0.247 g, 1.433 mmol) was added all at once at room temperature while stirring vigorously. The reaction turned from clear color to lighter yellow with precipitation. The reaction was warmed to 50 °C. After 1 h, tributylphosphine (0.1 mL, 0.4 mmol) and TMAD (80 mg, 0.46 mmol) were added, and the reaction stirred at 50 °C for 1 h. The solvent was removed under a stream of nitrogen and the resulting crude material was loaded and chromatographed on a 12 g column eluting with a gradient of 0-40% ethyl acetate/heptanes over a period of 10 minutes to give the title compound (421 mg, 0.743 mmol, 62.2 % yield). NMR (501 MHz, DMSO -de) d 7.48 (dd, 7= 7.9, 1.5 Hz, 2H), 7.28 -

7.17 (m, 3H), 7.08 (t, 7 = 8.2 Hz, 1H), 6.45 (ddd, J= 8.3, 2.3, 0.8 Hz, 1H), 6.38 - 6.29 (m, 2H), 4.80 (d, J = 7.6 Hz, 1H), 4.34 (d, J = 9.8 Hz, 1H), 3.71 - 3.62 (m, 3H), 3.50 (p, J = 6.6 Hz, 2H), 3.08 (t, J = 9.6 Hz, 1H), 2.36 (dtd, J = 12.2, 8.7, 4.6 Hz, 1H), 2.15 - 2.04 (m, 1H), 2.00 - 1.90 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.6 Hz, 6H), 0.97 (d, J = 6.7 Hz, 6H), 0.95 - 0.87 (m, 6H); MS (ESI+) m/z 567 (M+H) ⁺ .

Example 54C

(25 ^, ,35',45 ^, ,5i?)-l-(diisopropylcarbamoyl)-4-((3-isobutoxyphenoxy) methyl)-3-methyl-5- phenylpyrrolidine-2-carboxylic acid

[0391] To Example 54B (420 mg, 0.741 mmol) was added trifluoroacetic acid (3.058 mL, 39.7 mmol) and the mixture was stirred at 25 °C for 6 h. Trifluoroacetic acid was removed in vacuo.

The resulting oil was chromatographed using a 40 g silica gel cartridge eluting with a gradient of 0- 10% methanol/dichloromethane over a period of 20 minutes to give crude product (440 mg) which was purified by reverse-phase preparative HPLC on a Phenomenex ^® Luna ^® C8(2) 5 pm 100A AXIA™ column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A to give the title compound (0.215 g, 0.421 mmol, 56.8 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 12.54 (s, 1H), 7.55 (dd, J = 7.8, 1.7 Hz, 2H), 7.27 - 7.17 (m, 3H), 7.10 (t, J = 8.2 Hz, 1H), 6.47 (dd, 7 = 8.2, 2.2 Hz, 1H), 6.38 - 6.35 (m, 1H), 6.34 (t, 7 = 2.3 Hz, 1H), 4.80 (d, 7 = 7.4 Hz, 1H), 4.41 (d, 7 = 10.2 Hz, 1H), 3.74 - 3.64 (m, 3H), 3.51 (p, 7 = 6.6 Hz, 2H), 3.10 (t, 7= 9.6 Hz, 1H), 2.37 (ddt, 7 = 12.3, 7.7, 4.5 Hz, 1H), 2.17 - 2.05 (m, 1H), 1.97 (dt, 7= 13.3, 6.7 Hz, 1H), 1.21 (d, 7 = 6.3 Hz, 3H), 1.04 (d, 7 = 6.5 Hz, 6H), 0.98 (d, 7 = 6.7 Hz, 6H), 0.96 (d, 7 = 6.7 Hz, 6H); MS (APCI+) m/z 511 (M+H) ⁺ .

Example 54D

(2.S ^, ,3.S ^, ,4.S ^, ,5/^)-/V ² -(6-aminopyridine-2-sulfonyl)-3-methyl-4-{ [3-(2- methylpropoxy)phenoxy]methyl}-5-phenyl-/V ¹ 7V ¹ -di(propan-2-yl)pyrrolidine-l, 2-dicarboxamide

[0392] A solution of Example 54C (100 mg, 0.196 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (95 mg, 0.587 mmol) in l,2-dichloroethane (1 mL) was stirred 6 h at 45 °C. To this mixture was added 6-aminopyridine-2-sulfonamide (40.7 mg, 0.235 mmol) and 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-fl]azepine (DBU, 0.059 mL, 0.392 mmol). DBU was dried with powdered 4A molecular sieves at 45 °C for 2 h prior to usage. The solution was stirred for 16 h at 45 °C, then acidified with 1 N aqueous HC1 (1.2 mL) to pH 6. The organic layer was directly loaded onto a 12 g silica gel cartridge and eluted with a gradient of 0-100 % ethyl acetate/heptanes over 8 minutes to give the title compound (36 mg, 0.054 mmol, 27.6 % yield). ¹ H NMR (400 MHz, DMSO-tfc) d 12.25 (s, 1H), 7.68 (d, 7 = 6.8 Hz, 2H), 7.29 (t, 7 = 7.8 Hz, 1H), 7.11 (d, 7 = 6.6 Hz, 3H), 7.10 - 7.02 (m, 1H), 6.97 (d, 7 = 7.3 Hz, 1H), 6.42 (dd, 7= 8.2, 2.7 Hz, 2H), 6.27 - 6.17 (m, 2H), 6.00 (s, 2H), 5.01 (d, 7 = 6.8 Hz, 1H), 4.00 (d, 7 = 5.9 Hz, 1H), 3.64 (dd, 7 = 11.2, 6.5 Hz, 5H), 3.10 (t, 7= 8.9 Hz, 1H), 2.25 (d, 7 = 6.3 Hz, 2H), 2.04 - 1.88 (m, 1H), 1.18 (d, 7 = 5.5 Hz, 3H), 1.05 (d, 7 = 6.5 Hz, 6H), 0.97 (dd, 7 = 9.3, 6.6 Hz, 12H); MS (APCI+) m/z 666 (M+H) ⁺ .

Example 55

(2.V, 3.V, 4.V,5/< ^> )-/V ² -(cyclop _iO panesulfonyl)-3- _i uethy 1-4- { [3-(2-methyl propoxyjphenoxy] methyl }_5_ phenyl-iV ¹ , N ^l -di(propan-2-yl)pyrrolidine-l, 2-dicarboxamide

[0393] A solution of Example 54C (60 mg, 0.117 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (57.2 mg, 0.352 mmol) in l,2-dichloroethane (0.5 mL) was stirred for 5 h at 45 °C. To this mixture was added cyclopropanesulfonamide (17.08 mg, 0.141 mmol) and 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-fl]azepine (DBU, 0.035 mL, 0.235 mmol). DBU was dried with powdered 4A sieves at 45 °C for 2 h prior to usage. The solution was stirred for 16 h, then acidified with 1 N aqueous HC1 (0.75 mL) to pH 5. The organic layer was directly loaded onto a 12 g silica gel cartridge and eluted with a gradient of 0-100 % ethyl acetate/heptanes over 20 minutes to give the title compound (22 mg, 0.036 mmol, 30.5 % yield). ^X H NMR (400 MHz, DMSO-tfc) d 11.92 (s,

1H), 7.74 (d, 7 = 7.3 Hz, 2H), 7.33 - 7.18 (m, 3H), 7.09 (t, 7 = 8.2 Hz, 1H), 6.46 (dd, 7 = 8.0, 2.3 Hz, 1H), 6.34 - 6.30 (m, 1H), 6.29 (t, 7= 2.3 Hz, 1H), 4.95 (d, 7 = 7.6 Hz, 1H), 4.33 (d, 7 = 9.2 Hz, 1H), 3.73 - 3.64 (m, 3H), 3.56 - 3.45 (m, 2H), 3.12 (t, 7= 9.2 Hz, 1H), 3.00 (m, 1H), 2.42 (m, 1H), 2.22 (d, 7 = 8.3 Hz, 1H), 1.96 (hept, 7 = 6.7 Hz, 1H), 1.14 (d, 7 = 6.5 Hz, 3H), 1.03 (dd, 7 = 6.6, 2.5 Hz, 12H), 0.95 (d, 7 = 6.7 Hz, 6H), 0.87 - 0.80 (m, 4H); MS (APCI+) m/z 614 (M+H) ⁺ .

Example 56

/7/r-(25, 35, 4.n,55)-3-/ _< ° /7-butyl- 1 -(cyclohexanecarbonyl)-5-phenyl-4-( { (25)-2-[2- (trifluoromethyl)phenyl]pyrrolidin-l-yl}methyl)pyrrolidine-2 -carboxylic acid

Example 56 A

(£)-ethyl 2-(benzylideneamino)acetate

[0394] A slurry of ethyl 2-aminoacetate hydrochloride (9.86 g, 70.7 mmol), magnesium sulfate (9.64 g, 80 mmol) in dichloromethane (100 mL) was stirred at 0 °C. Triethylamine (9.85 mL, 70.7 mmol) was added dropwise and and the mixture stirred at room temperature for 1 h, then benzaldehyde (5 g, 47.1 mmol) was added. After 15 h, the mixture was filtered, and the solids washed with dichloromethane (3 x 200 mL). The combined dichloromethane filtrate was washed with water (2 x 100 mL), dried (Na ₂ S0 ₄ ), and concentrated, giving the title compound (7.8 g, 36.7 mmol, 78 % yield). MS (ESI+) m/z 192.7 (M+l) ⁺ .

Example 56B

rac-4-benzyl 2-ethyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-5-phenylpyrrolidine-2,4-dicarboxylate

[0395] A solution of Example 56A (5.26 g, 27.5 mmol) and lithium bromide (1.790 g, 20.61 mmol) in tetrahydrofuran (60 mL) was cooled to -78 °C. Example 50A (3 g, 13.74 mmol) in tetrahydrofuran (10 mL) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine (3.14 g, 20.61 mmol) were added drop wise at -78 °C. The resulting mixture was stirred at -78 °C, then warmed to room temperature over 5 h. To the reaction was added saturated aqueous ammonium chloride (200 mL). The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (2 x 150 mL), dried (Na ₂ S0 ₄ ), and concentrated. The crude product was purified by combi-flash to give the title compound (3.6 g, 8.62 mmol, 62.7 % yield). MS (ESI+) m/z 410.7 (M+l) ⁺ .

Example 56C

rac-4-benzyl 1 -/e/7-butyl 2-ethyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-5-phenylpyrrolidine-l,2,4-tricarboxylat e

[0396] To a solution of Example 50B (4.1 g, 10.01 mmol) in dichloromethane (10 mL) was added triethylamine (2.026 g, 20.02 mmol) and di-/e/7-butyl dicarbonate (4.37 g, 20.02 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h, then warmed to room temperature for 3 h. Water (200 mL) was added to the reaction. The aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with brine (2 x 150 mL), dried (Na ₂ S0 ₄ ), and concentrated. The crude product was purified by column chromatography (1/10 ethyl acetate /petroleum ether) to provide the title compound (4.6607 g, 9.05 mmol, 90 % yield). ¹ H NMR (400 MHz, CDCL) d 7.50 (d, 7=7.2 Hz, 2H), 7.23-7.20 (m, 5H), 7.16-7.12 (m, 1H), 6.95 (s, 2H), 5.03- 5.01 (m, 1H), 4.50-4.47 (m, 1H), 3.34 (s, 1H), 4.21-4.16 (m, 3H), 3.39-3.35 (m, 1H), 2.84 (t, 7=5.4 Hz, 1H), 1.25 (t, 7=7.2 Hz, 3H), 0.90 (s, 9H); MS (ESI-) m/z 409.7 (M-Boc) .

Example 56D

rac-4-benzyl 2-ethyl (2i?,35',4i?,55 ^, )-3-/er/-butyl-5-phenylpyrrolidine-2,4-dicarboxylate

[0397] To a solution of Example 56C (1.036 g, 2.034 mmol) in dichloromethane (40 mL), trifluoroacetic acid (4 mL, 52.24 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was concentrated, and then a saturated aqueous NaHCCh solution and dichloromethane were added. The layers were separated on phase separator, and the organic layer was concentrated to give the title compound that was used as such in the next step. LC/MS (ESI+) m/z 410.4 (M+H) ⁺ .

Example 56E

rac-4-benzyl 2-ethyl (2i?,35 ^, ,4i?,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-phenylpyrroli dine-2,4-d icarboxylate

[0398] Example 56D was dissolved in dichloromethane (15 mL), cyclohexanecarbonyl chloride (360 pL, 2.69 mmol) and /V,/V-diisopropylethylamine (582 pL, 3.34 mmol) were added, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was concentrated to provide the title compound that was used in the next step without further purification. LC/MS (ESI+) m/z 520.4 (M+H) ⁺ .

Example 56F

rac-(2S ,3R A ,5 R )-4 e rl-bu .y\- 1 -(cyclohexanecarbonyl )-5 -(ethoxycarbonyl )-2-phenyl pyrrol idine-3- carboxylic acid

[0399] To a solution of the crude Example 56E in methanol (30 mL), palladium on charcoal 10% (240 mg, 0.23 mmol) was added, and the reaction mixture was stirred at room temperature under H ₂ for 1 h. The reaction was filtered on Celite ^® , rinsed with methanol, and the filtrate was concentrated to give the title compound (600 mg, 43% yield). LC/MS (ESI+) m/z 430.4 (M+H) ⁺ .

Example 56G

rac ethyl (2R,3S AR,5S)-3-tert-buty\- l-(cyclohexanecarbonyl)-4-(hydroxymethyl)-5- phenylpyrrolidine-2-carboxylate

[0400] To acid Example 56F (600 mg, 1.397 mmol) in tetrahydrofuran (15 mL) at -5 °C (ice/salt bath) was added triethylamine (233 pL, 1.676 mmol) and ethyl chloroformate (147 pL, 1.536 mmol). The mixture was stirred for 30 min. Thin layer chromatography confirmed the full conversion to the mixed anhydride. Then, the temperature was set to -50 °C (dry ice/acetone bath) and NaBH ₄ (158 mg, 4.19 mmol) was added, followed by addition of methanol (7 mL). The mixture was stirred at -50 °C for 60 min, and quenched with saturated aqueous NH ₄ Cl solution.

The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgS0 ₄ , and concentrated to dryness afforded the title compound (516 mg, 89%). LC/MS (ESI+) m/z 416.4 (M+H) ⁺ .

Example 56H

rac-ethyl (2R,3S R,5S)-3-tert-buty\- 1 -(cyclohexanecarbonyl)-4-formyl-5-phenylpyrrolidine-2- carboxylate

[0401] To a solution of Example 56G (500 mg, 1.2 mmol) in dichloromethane (25 mL) at 0 °C was added Dess martin periodinane (561 mg, 1.32 mmol). After 1 h at 0 °C, thin layer

chromatography monitoring (ethyl acetate/heptane 20/80) confirmed complete conversion. The reaction mixture was quenched with saturated aqueous NaHCCh solution and extracted with dichloromethane. The organic layer was separated using a phase separator, concentrated to dryness, and the residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 10/90 to 20/80) to give the title compound.

Example 561

rac-ethyl (2//,35,45,55)-3- _/< ° _/ 7-butyl- 1 -(cyclohexanecarbonyl)-5-phenyl-4-( { 2- [2- (trifluoromethyl)phenyl]pyrrolidin-l-yl}methyl)pyrrolidine-2 -carboxylate

[0402] To a solution of Example 56H (35 mg, 0.085 mmol) in methanol (1 mL) was added 2- [2-(trifluoromethyl)phenyl]pyrrolidine (20 mg, 0.093 mmol), a buffer (acetic acid/sodium acetate/methanol), and NaBFTCN (6.4 mg, 0.1 mmol). After completion, the reaction mixture was quenched with saturated aqueous NaHCCh solution, and extracted with dichloromethane. The organic layer was separated using a phase separator, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 5/95 to 60/40) to give the title compound as a mixture of diastereomers. LC/MS (ESI+) m/z 613.5 (M+H) ⁺ showed two peaks.

Example 56 J

rac-(2R, 35,45, 55)-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-phenyl-4-({(25)-2 -[2- (trifluoromethyl)phenyl]pyrrolidin-l-yl}methyl)pyrrolidine-2 -carboxylic acid

[0403] Example 561 (29 mg, 0.047 mmol) was solubilized in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (2 mL) and LiOH. Water was added (20 mg, 0.47 mmol). After 3 days, (with addition of with LiOH.H ₂ 0 (20 eq) and 24 h of heating around 50-60 °C), the reaction mixture was submitted to acid-base extraction with dichloromethane, the organic layer was separated using a phase separator, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 100/0 to 95/5) to afford each

diastereomer: Example 56J was the first eluting peak, LC/MS (ESI+) m/z 585.5 (M+H) ⁺ .

Example 57

rac-(2R, 35,45, 55)-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-phenyl-4-({(2Z?)- 2-[2- (trifluoromethyl)phenyl]pyrrolidin-l-yl}methyl)pyrrolidine-2 -carboxylic acid

[0404] The title compound was isolated from Example 56J as the second eluting peak. LC/MS (ESI+) m/z 585.5 (M+H) ⁺ .

[0405] The following Examples were prepared using similar methods to those described in Examples 1-57 (or herein) using the appropriate starting materials.

Example I- 1

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(2-methylbuta noyl)-5-phenylpyrrolidine-

2-carboxylic acid

[0406] 120 °C, DMSO- 7 ₆ :D ₂ 0 = 9: 1 (v/v)) d 7.50 - 7.27 (m, 4H), 7.17 -

7.04 (m, 3H), 7.01 - 6.85 (m, 1H), 5.65 - 5.45 (m, 1H), 4.77 - 4.66 (m, 1H), 4.66 - 4.54 (m, 1H), 3.20 - 3.11 (m, 1H), 2.43 - 2.15 (m, 1H), 1.66 - 1.15 (m, 2H), 1.00 (d, 7 = 3.2 Hz, 9H), 0.95 (d, 7 = 6.7 Hz, 2H), 0.52 (d, J = 84.0 Hz, 4H). MS (APCI+) m/z 503.8 (M+H) ⁺

Example 1-2

rac-(2R,35 ^, ,55 ^, )-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(3,3-difluoro cyclobutane-l-carbonyl)-5- phenylpyrrolidine-2-carboxylic acid

[0407] 120 °C, DMS0-7 ₆ :D ₂ 0 = 9: 1 (v/v)) d 7.47 - 7.29 (m, 4H), 7.19 -

7.07 (m, 3H), 6.94 (s, 1H), 5.53 (d, 7 = 10.0 Hz, 1H), 4.78 - 4.66 (m, 1H), 4.59 (d, 7 = 4.5 Hz, 1H), 3.25 - 3.14 (m, 2H), 2.99 - 2.82 (m, 1H), 2.82 - 2.55 (m, 2H), 2.48 - 2.29 (m, 1H), 0.99 (s, 9H).

MS (APCI+) m/z 537.9 (M+H) ⁺

Example 1-3

mc-(2R,35 ^, ,55 ^, )-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-l-(3,3-difluoro -l-methylcyclobutane-l- carbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0408] 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.49 - 7.31 (m, 3H), 7.21 -

7.04 (m, 4H), 5.52 (d, 7 = 9.8 Hz, 1H), 4.70 (dd, 7 = 9.9, 6.1 Hz, 1H), 4.63 (d, 7 = 4.9 Hz, 1H), 3.26 - 3.11 (m, 3H), 2.75 - 2.53 (m, 1H), 2.45 - 2.28 (m, 1H), 2.28 - 2.01 (m, 1H), 1.20 (s, 3H), 1.00 (s, 9H). MS (APCI+) m/z 55l.7(M+H) ⁺

Example 1-4

r _< r _/ r-(2//,3.S ^, ,4//,5.S ^, )-3-/er/-butyl-4-(2,5-dichloi _O benzoyl)- 1 -(4-fl uorobenzoyl )-5-phenyl pyrrol idine-2- carboxylic acid

[0409] 120 °C, DMS0-7 ₆ :D ₂ 0 = 9: 1 (v/v)) d 7.35 (dd, 7 = 8.5, 2.5 Hz,

1H), 7.29 (d, 7 = 8.6 Hz, 1H), 7.25 - 7.14 (m, 4H), 7.12 - 6.93 (m, 5H), 6.85 (d, 7= 2.5 Hz, 1H), 5.54 (d, 7 = 10.0 Hz, 1H), 4.71 (dd, 7 = 10.1, 4.7 Hz, 1H), 4.54 (d, 7= 3.9 Hz, 1H), 3.19 (t, 7= 4.3 Hz, 1H), 1.01 (s, 9H). MS (APCI+) m/z 542.4 (M+H) ⁺

Example 1-5 rar-(2/^, 35, 4/^, 55')-3-/° /7-butyl- 1 -(4-cyanobenzoyl )-4-(2, 5-dichlorobenzoyl )-5-phenyl pyrrol idine-2- carboxylic acid

[0410] 120 °C, DMS0-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.61 (d, 7= 7.9 Hz, 2H),

7.35 (dd, 7 = 8.6, 2.5 Hz, 1H), 7.32 - 7.24 (m, 3H), 7.14 (d, J = 7.5 Hz, 2H), 7.07 - 6.94 (m, 3H), 6.87 (d, J = 2.5 Hz, 1H), 5.50 (d, J = 10.1 Hz, 1H), 4.72 (dd, 7 = 10.1, 4.9 Hz, 1H), 4.55 (d, 7= 4.1 Hz, 1H), 3.21 (t, 7 = 4.5 Hz, 1H), 1.03 (s, 9H). MS (APCI+) m/z 549.4 (M+H) ⁺

Example 1-6

rac-(2i?,35,4i?,55)-3-/er/-butyl-4-(3-chloro-5-methoxybenzoy l)-l-(cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

[0411] ^l H NMR (400 MHz, DMSO -de) d 7.32 (d, 7= 4.8 Hz, 2H), 7.25 (d, 7= 1.8 Hz, 1H), 7.08 (d, 7= 9.8 Hz, 2H), 7.04 - 6.95 (m, 3H), 5.64 - 5.55 (d, 1H), 4.67 - 4.57 (m, 1H), 4.51 (d, 7 = 5.7 Hz, 1H), 3.77 (s, 3H), 3.12 (bs, 1H), 2.18 (t, 7 = 14.5 Hz, 1H), 1.65 (d, 7= 13.6 Hz, 2H), 1.46 (m, 2H), 1.27 (m, 2H), 1.07 (m, 3H), 0.95 (s, 9H), 0.68 (bs, 1H); MS (ESI-) m/z 524 (M-H)

Example 1-7

rac-(2R,35,4R,55)-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(3, 5-dichlorobenzoyl)-5- phenylpyrrolidine-2-carboxylic acid

[0412] NMR (400 MHz, DMSO -de) d 7.63 - 7.53 (m, 3H), 7.31 (s, 2H), 7.06 - 6.95 (m, 3H),

5.66 - 5.56 (m, 1H), 4.65 (dd, 7= 10.1, 6.0 Hz, 1H), 4.52 (d, 7 = 5.2 Hz, 1H), 3.11 (t, 7 = 5.8 Hz, 1H), 2.17 (dd, 7 = 15.1, 8.1 Hz, 1H), 1.73 - 1.61 (m, 2H), 1.46 (m, 2H), 1.27 (m, 2H), 1.07 (q, 7 = 11.5 Hz, 3H), 0.96 (d, 7 = 1.3 Hz, 9H), 0.73 (bs, 1H); MS (ESI-) m/z 528 (M-H)

Example 1-8

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-[3-chloro-5-(trifluoromethyl)benzoyl] -l-(cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

[0413] 7.92 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.30 (d, 7 =

6.0 Hz, 2H), 7.02 - 6.90 (m, 3H), 5.63 (d, 7= 10.2 Hz, 1H), 4.73 (dd, 7= 10.1, 5.5 Hz, 1H), 4.55 (d, 7= 4.8 Hz, 1H), 3.13 (bs, 1H), 2.28 - 2.15 (m, 1H), 1.67 (m, 2H), 1.46 (m, 2H), 1.27 (m, 2H), 1.18 - 1.02 (m, 3H), 0.98 (s, 9H), 0.73 (bs, 1H); MS (ESI-) m/z 562 (M-H)

Example 1-9

mc-(2R,3R,4R,55')-4-(5-chloro-2-methoxybenzoyl)-l-(cyclohexa necarbonyl)-5-phenyl-3- (trifluoromethyl)pyrrolidine-2-carboxylic acid

[0414] ^l H NMR (400 MHz, DMSO -de) d 7.49 (dd, 7= 8.9, 2.8 Hz, 1H), 7.30 (dd, 7 = 7.3, 2.1 Hz, 2H), 7.25 - 7.01 (m, 4H), 6.73 (d, 7 = 2.8 Hz, 1H), 5.64 (d, 7 = 9.4 Hz, 1H), 4.95 (t, 7= 9.3 Hz, 1H), 4.63 (d, 7 = 7.8 Hz, 1H), 3.96 (s, 4H), 2.l8 (s, 1H), 1.77 - 1.64 (m, 2H), 1.44 (dd, 7= 24.7,

12.4 Hz, 2H), 1.37 - 1.25 (m, 2H), 1.19 - 0.93 (m, 4H), 0.71 (s, 1H); MS (ESI+) m/z 560.2(M+Na) ⁺

Example I- 10

rac-(2i?,3i?,4i?,55')-l-benzoyl-4-(5-chloro-2-methoxybenzoyl )-3-(2-methoxypropan-2-yl)-5- phenylpyrrolidine-2-carboxylic acid

[0415] ^l H NMR (400 MHz, DMSO-7 ₆ ) d 7.35 - 7.25 (m, 2H), 7.25 - 7.17 (m, 2H), 7.12 (ddd, 7= 8.5, 2.9, 1.4 Hz, 4H), 7.05 - 6.92 (m, 4H), 6.50 (d, 7= 2.6 Hz, 1H), 5.46 (d, 7= 9.9 Hz, 1H), 4.76 (dd, 7 = 9.9, 6.1 Hz, 1H), 4.65 (d, 7 = 4.9 Hz, 1H), 3.86 (s, 3H), 3.40 (t, 7= 5.5 Hz, 1H), 3.14 (s, 3H), 1.21 (s, 3H), 1.17 (s, 3H), 1.11 (s, 3H). MS (ESI+) m/z 558.1 (M+Na) ⁺

Example I- 11

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(morph olin-4-yl)acetyl]-5- phenylpyrrolidine-2-carboxylic acid

[0416] 120 °C, DMSO-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.39 - 6.94 (m, 7H), 6.46 -

6.29 (m, 1H), 5.51 (d, 7 = 10.1 Hz, 1H), 4.83 - 4.71 (m, 1H), 4.68 - 4.54 (m, 1H), 3.90 (s, 3H), 3.86 - 3.78 (m, 1H), 3.79 - 3.57 (m, 5H), 3.22 - 3.10 (m, 1H), 3.03 - 2.89 (m, 4H), 0.99 (s, 9H). MS (APCI+) m/z 543.1 (M+H) ⁺

Example 1-12

mc-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(3,3-d ifluoroazetidin-l- yl)acetyl]-5-phenylpyrrolidine-2-carboxylic acid

[0417] 120 °C, DMSO-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.36 (dt, 7= 8.9, 2.4 Hz,

1H), 7.32 - 7.20 (m, 2H), 7.18 - 7.00 (m, 4H), 6.41 (s, 1H), 5.56 - 5.40 (m, 1H), 4.89 - 4.66 (m, 1H), 4.58 (dd, 7 = 4.7, 2.3 Hz, 1H), 3.99 - 3.50 (m, 8H), 3.34 - 3.11 (m, 2H), 0.99 (d, 7= 4.4 Hz, 9H). MS (APCI+) m/z 549.0 (M+H) ⁺

Example 1-13

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-/V-(metha nesulfonyl)-l-(oxane-4- carbonyl)-5-phenylpyrrolidine-2-carboxamide

[0418] ^l H NMR (501 MHz, DMSO -d ₆ ) d 12.11 (s, 1H), 7.56 (dd, 7= 8.9, 2.8 Hz, 1H), 7.44 (s, 2H), 7.22 (d, 7 = 9.0 Hz, 1H), 7.20 - 7.14 (m, 3H), 6.57 (d, 7 = 2.8 Hz, 1H), 5.55 (d, 7 = 9.9 Hz,

1H), 4.75 (dd, 7 = 11.4, 9.9 Hz, 1H), 4.34 (d, 7= 9.4 Hz, 1H), 3.98 (s, 3H), 3.79 - 3.70 (m, 1H), 3.44 - 3.35 (m, 1H), 3.27 (dd, 7= 11.5, 9.4 Hz, 1H), 3.17 (s, 3H), 3.12 (td, 7 = 11.3, 3.5 Hz, 1H), 2.55 (ddd, 7 = 12.3, 11.3, 2.2 Hz, 1H), 2.35 (ddt, 7 = 11.1, 8.4, 4.1 Hz, 1H), 1.59 - 1.46 (m, 2H), 1.04 (qd, 7 = 12.3, 4.4 Hz, 1H), 0.87 (s, 9H), 0.14 (d, 7 = 12.8 Hz, 1H); MS (ESI-) m/z 603 (M-H) Example 1-14

_/Ύ/G -(2L ^> ,36 ^, ,4L ^> ,56 ^, ₎ -3- _/< ° r/-butyl- ] -(cyclohexanecarbonyl ₎ -4-[2-methoxy-4- (trifluoromethoxy)benzoyl]-5-phenylpyrrolidine-2-carboxylic acid

[0419] NMR (400 MHz, CDCb) d 7.16 (q, 7 = 3.5, 3.0 Hz, 3H), 7.04 - 6.93 (m, 3H), 6.76

(d, 7 = 2.1 Hz, 1H), 6.66 (d, 7 = 8.7 Hz, 1H), 5.46 (d, 7 = 9.5 Hz, 1H), 4.73 - 4.58 (m, 2H), 4.01 (s, 3H), 3.88 (dd, 7 = 9.0, 6.6 Hz, 1H), 2.36 - 2.23 (m, 1H), 1.85 - 1.81 (m, 1H), 1.64 - 1.47 (m, 3H), 1.36 - 0.98 (m, 5H), 0.94 (s, 9H), 0.87 - 0.74 (m, 1H); MS (ESI+): m/z = 576 (M+H) ⁺

Example 1-15

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-[4-chloro-2-(difluoromethoxy)benzoyl] -l-(cyclohexanecarbonyl)-

5-phenylpyrrolidine-2-carboxylic acid

[0420] 4.9, 1.9 Hz, 3H), 7.09 (s, 1H), 7.01 (td, 7 =

8.2, 3.1 Hz, 4H), 6.88-6.51 (t, 1H), 5.54 (d, 7 = 9.7 Hz, 1H), 4.72 (d, 7 = 6.4 Hz, 1H), 4.51 (t, 7 =

9.2 Hz, 1H), 3.93 (dd, 7 = 8.9, 6.4 Hz, 1H), 2.33 («, 7 = 11.6, 3.2 Hz, 1H), 1.83 - 1.80 (m, 1H), 1.63 - 1.46 (m, 3H), 1.39 - 1.05 (m, 4H), 1.00 (d, 7 = 13.4 Hz, 1H), 0.93 (s, 9H), 0.82 (s, 1H); MS (ESI+) m/z 563 (M+H) ⁺

Example 1-16

mc-(2R,3R,4R,55 ^, )-4-(5-chloro-2-methoxybenzoyl)-l-[(lr,4R)-4-methoxycy clohexane-l-carbonyl]- 3-(2-methoxypropan-2-yl)-5-phenylpyrrolidine-2-carboxylic acid

[0421] 7.38 (d, 7 = 8.9 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.05 -

6.95 (m, 2H), 6.92 (d, 7= 8.8 Hz, 1H), 6.84 (s, 1H), 5.49 (d, 7= 9.6 Hz, 1H), 4.98 (d, 7 = 6.7 Hz, 1H), 4.91 - 4.79 (m, 1H), 4.08 - 4.01 (m, 1H), 3.99 (s, 3H), 3.30 (s, 2H), 3.20 (s, 3H), 3.15 - 3.02 (m, 1H), 2.37 - 2.24 (m, 1H), 2.17 (d, 7 = 11.9 Hz, 1H), 1.89 (s, 2H), 1.77 - 1.57 (m, 1H), 1.40 - 1.26 (m, 3H), 1.26 - 1.20 (m, 3H), 1.12 (s, 3H), 0.96 - 0.79 (m, 2H). MS (ESI+) m/z 572 (M+H) ⁺

Example 1-17

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(2-methoxybenzoyl)-5-phenyl-l-{ [(pyridin-3- yl)oxy] acetyl }pyrrolidine-2-carboxylic acid

MS (ESI+) m/z 517.7 (M+H) ⁺

Example 1-18

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-[2-methoxy-4- (trifluoromethyl)benzoyl]-

5-phenylpyrrolidine-2-carboxylic acid

[0422] NMR (400 MHz, CDCb) d 7.24 - 7.12 (m, 4H), 7.10 - 6.88 (m, 4H), 5.46 (d, 7 = 9.5

Hz, 1H), 4.75 - 4.58 (m, 2H), 4.05 (s, 3H), 3.94 (dd, 7= 9.2, 6.7 Hz, 1H), 2.31 (tt, 7= 11.4, 3.3 Hz, 1H), 1.81 (t, 7 = 13.8 Hz, 2H), 1.59 - 1.50 (m, 2H), 1.35 - 1.00 (m, 5H), 0.94 (s, 9H), 0.88 - 0.76 (m, 1H); MS (ESI+) m/z 560 (M+H) ⁺

Example 1-19

mc-(2i?,3i?,4i?,55')-4-(5-chloro-2-methoxybenzoyl)-l-(cycloh exanecarbonyl)-3-cyclopropyl-5- phenylpyrrolidine-2-carboxylic acid

[0423] 0.01 0.24 (m, 3H), 0.39 0.58 (m, 2H), 0.72 0.87 (m,

2H), 0.94 1.09 (m, 2H), 1.21 1.38 (m, 2H), 1.40 1.49 (m, 1H), 1.62 1.79 (m, 2H), 2.01 2.11 (m, 1H), 2.25 2.36 (m, 1H), 4.01 (s, 3H), 4.09 (d, 7 = 10.4 Hz, 1H), 4.52 (dd, 7 = 11.7, 8.8 Hz, 1H), 5.53 (d, J = 8.8 Hz, 1H), 7.04 (d, 7 = 2.8 Hz, 1H), 7.18 7.24 (m, 3H), 7.28 (d, 7 = 9.0 Hz, 1H), 7.35 7.40 (m, 2H), 7.62 (dd, J = 9.0, 2.8 Hz, 1H); MS (ESI+) m/z 510 (M+H) ⁺

Example 1-20

mc-(2i?,3i?,4i?,55 ^, )-4-(5-chloro-2-methoxybenzoyl)-3-cyclopropyl-l-[2-met hyl-2-(pyridin-2- yl)propanoyl]-5-phenylpyrrolidine-2-carboxylic acid

[0424] ^l H NMR (500 MHz, CDCb) d 8.76 (dd, 7= 5.8, 1.6 Hz, 1H), 7.82 (t, 7= 7.8 Hz, 1H), 7.51 - 7.27 (m, 4H), 7.18 - 6.97 (m, 6H), 5.67 (d, 7 = 8.0 Hz, 1H), 4.53 (d, 7 = 10.5 Hz, 1H), 4.37 (dd, 7 = 11.9, 8.0 Hz, 1H), 4.08 (s, 3H), 2.60 - 2.42 (m, 1H), 1.75 (s, 3H), 1.63 (s, 3H), 0.72 - 0.60 (m, 1H), 0.59 - 0.44 (m, 1H), 0.32 - 0.23 (m, 2H), 0.18 - 0.08 (m, 1H). MS (APCI+) m/z 546.9 (M+H) ⁺

Example 1-21

mc-(2R,35 ^, ,4R,55 ^, )-l-benzoyl-4-(5-chloro-2-methoxybenzoyl)-3-(3-methylo xetan-3-yl)-5- phenylpyrrolidine-2-carboxylic acid

[0425] ^l H NMR (400 MHz, CDCb) d 7.81 (d, 7= 2.7 Hz, 1H), 7.40 - 7.22 (m, 8H), 7.04 (qd, 7 = 8.6, 7.7, 3.6 Hz, 3H), 6.68 (d, 7= 8.7 Hz, 1H), 6.31 - 6.21 (m, 2H), 5.08 (d, 7 = 3.5 Hz, 1H), 4.74 (d, 7 = 2.5 Hz, 1H), 4.19 - 4.05 (m, 3H), 4.05 - 3.93 (m, 3H), 3.82 (dd, 7 = 11.1, 2.6 Hz, 1H), 3.73 - 3.66 (m, 1H), 3.39 (s, 3H), 1.26 (td, 7 = 7.1, 0.6 Hz, 1H), 0.97 (s, 3H). MS (ESI+) m/z 534.0 (M+H) ⁺

Example 1-22

mc-(2R,35 ^, ,4R,55 ^, )-4-(5-chloro-2-methoxybenzoyl)-l-(cyclohexanecarbonyl )-3-(3-methyloxetan-3- yl)-5 -phenylpyrrolidine-2-carboxylic acid

[0426] ^l H NMR (400 MHz, CDCb) d 7.76 (d, 7 = 2.7 Hz, 1H), 7.35 (dd, 7= 8.8, 2.7 Hz, 1H), 7.20 - 7.14 (m, 3H), 6.76 (d, 7 = 8.8 Hz, 1H), 6.61 - 6.53 (m, 2H), 4.92 (d, 7 = 4.1 Hz, 1H), 4.64 (d, 7= 3.7 Hz, 1H), 3.95 (d, 7= 6.2 Hz, 4H), 3.84 - 3.76 (m, 1H), 3.48 - 3.42 (m, 1H), 3.40 (s, 3H), 2.16 - 2.08 (m, 1H), 1.95 - 1.89 (m, 1H), 1.89 - 1.81 (m, 1H), 1.62 - 1.31 (m, 4H), 1.19 - 1.07 (m, 3H), 0.92 (s, 3H), 0.84 - 0.70 (m, 1H); MS (ESI+) m/z 540.1 (M+H) ⁺

Example 1-23

1 -[(25 ₎ - 1 -acetyl pyrrol idine-2-carbonyl]-3- _/ e _/7 -butyl-4-(5-chloi _O -2-methoxybenzoyl ₎ -5- phenylpyrrolidine-2-carboxylic acid

[0427] 9.18 (s, 1H), 7.34 (dd, J= 8.8, 2.7 Hz, 2H), 7.22 (q, 7 =

3.3 Hz, 3H), 6.89 (d, 7 = 8.9 Hz, 1H), 6.84 (d, 7 = 2.7 Hz, 1H), 5.92 (d, 7 = 9.9 Hz, 1H), 4.93 (dd, J = 9.9, 7.8 Hz, 1H), 4.82 (d, 7 = 6.8 Hz, 1H), 4.38 (dd, 7 = 8.4, 5.1 Hz, 1H), 4.03 (s, 3H), 3.69 (dt, J = 10.2, 7.1 Hz, 1H), 3.52 - 3.42 (m, 2H), 2.18 (s, 3H), 2.13 (ddd, 7 = 13.2, 7.5, 6.1 Hz, 1H), 1.69 (dp, 7 = 13.8, 7.0 Hz, 1H), 1.57 (tt, 7 = 12.8, 6.0 Hz, 1H), 1.40 - 1.23 (m, 1H), 1.13 (dq, 7 = 13.5,

7.8 Hz, 1H), 1.02 (s, 9H).MS (ESI+) m/z 555 (M+H) ⁺

Example 1-24

rac-(2R,3R S,5S ₎ -4-[ 1 -(5-chloro-2-methoxyphenyl ₎ ethenyl]- 1 -(cyclohexanecarbonyl ₎ -3-(2- methoxypropan-2-yl)-5-phenylpyrrolidine-2-carboxylic acid

[0428] NMR (501 MHz, CDCb) d 12.85 (br s, 1H), 7.29 - 7.25 (m, 3H), 7.20 (dd, J= 8.7,

2.7 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.80 (d, 7 = 8.7 Hz, 1H), 6.40 (d, 7 = 2.6 Hz, 1H), 5.20 (d, 7 = 9.1 Hz, 1H), 5.08 - 4.93 (m, 3H), 4.09 - 4.01 (m, 1H), 3.86 (s, 3H), 3.64 (dd, J = 10.8, 6.7 Hz, 1H),

3.21 (s, 3H), 2.42 - 2.29 (m, 1H), 1.78 (t, 7 = 11.9 Hz, 2H), 1.66 - 1.43 (m, 6H), 1.22 (s, 6H), 1.28 - 1.12 (m, 4H), 0.98 - 0.81 (m, 2H); MS (ESI+) m/z 540.1 (M+H) ⁺

Example 1-25

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-5-phenyl- l-[(3R)-piperidine-3- carbonyl]pyrrolidine-2-carboxylic acid

[0429] ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.43 - 7.22 (m, 3H), 7.16 - 6.95 (m, 5H), 6.47 - 6.28 (m, 1H), 5.48 (d, 7= 10.1 Hz, 1H), 4.82 - 4.68 (m, 1H), 4.56 (d, 7= 4.3 Hz, 1H), 3.90 (s, 3H), 3.16 - 3.08 (m, 1H), 3.05 - 2.91 (m, 2H), 2.70 - 2.57 (m, 2H), 1.93 - 1.84 (m, 1H), 1.81 - 1.71 (m, 1H),

1.67 - 1.52 (m, 2H), 0.98 (s, 9H); MS (ESI+) m/z 527 (M+H) ⁺

Example 1-26

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-2-methoxybenzoyl)-l-[(35 ^, )-l- (methoxycarbonyl)pyrrolidine-3-carbonyl]-5-phenylpyrrolidine -2-carboxylic acid

[0430] ^l H NMR (400 MHz, DMSO-7 ₆ ) d 7.42 - 7.25 (m, 3H), 7.05 (d, 7 = 9.2 Hz, 4H), 6.42 (s, 1H), 5.50 (d, 7 = 10.0 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.55 (d, 7= 5.0 Hz, 1H), 3.92 (s, 3H), 3.54 (s, 3H), 3.46 (dd, 7 = 10.6, 7.9 Hz, 1H), 3.26 (dd, 7= 10.5, 6.8 Hz, 2H), 3.19 - 3.11 (m, 1H), 3.08 - 2.95 (m, 2H), 1.68 - 1.53 (m, 1H), 1.25 (s, 1H), 0.97 (s, 9H), 0.88 - 0.79 (m, 1H); MS (ESI+) m/z 571 (M+H) ⁺

Example 1-27

rac-(2R,35 ^, ,45 ^, ,55 ^, )-3-/er/-butyl-4-[l-(5-chloro-2-methoxyphenyl)ethenyl] -l-(cyclohexanecarbonyl)- /V-(methanesulfonyl)-5 -phenyl pyrrol idine-2-carboxamide

[0431] NMR (400 MHz, CDCb) d 10.76 (s, 1H), 7.32 - 7.25 (m, 4H), 7.20 (dd, 7 = 8.7, 2.7

Hz, 1H), 7.03 (dd, 7 = 6.7, 2.9 Hz, 2H), 6.80 (d, 7 = 8.7 Hz, 1H), 6.31 (d, 7 = 2.6 Hz, 1H), 5.17 (d, 7 = 9.2 Hz, 1H), 5.05 (d, 7 = 14.5 Hz, 2H), 4.67 (d, 7 = 6.5 Hz, 1H), 3.87 (s, 3H), 3.54 (dd, 7 = 10.7, 6.5 Hz, 1H), 3.24 (s, 3H), 2.45 - 2.30 (m, 1H), 1.85 - 1.77 (m, 1H), 1.77 - 1.69 (m, 1H), 1.63 -

1.48 (m, 3H), 1.38 - 1.11 (m, 5H), 0.99 (s, 9H); MS (ESI+) m/z 601 (M+H) ⁺

Example 1-28

mc-(2i?,3i?,45',55 ^, )-4-[l-(5-chloro-2-methoxyphenyl)ethenyl]-3-(2-methoxy propan-2-yl)-l-(oxane-

2-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0432] 120 °C, DMSO-tfc :D ₂ 0 = 9:1 (v/v)) d 7.52 - 7.10 (m, 7H), 7.04 -

6.86 (m, 1H), 6.47 - 6.02 (m, 1H), 5.31 - 5.14 (m, 1H), 5.05 - 4.41 (m, 2H), 4.03 - 3.77 (m, 5H), 3.25 - 3.12 (m, 6H), 1.81 - 1.31 (m, 6H), 1.26 - 1.16 (m, 6H). MS (APCI+) m/z 542.1 (M+H) ⁺

Example 1-29

mc-(2R,3R,45',55 ^, )-4-[l-(5-chloro-2-methoxyphenyl)ethenyl]-3-(2-methoxy propan-2-yl)-l-(oxane-

3-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0433] 120 °C, DMSO-tfc :D ₂ 0 = 9:1 (v/v)) d 7.35 (s, 2H), 7.24 - 7.10 (m,

4H), 6.94 (dd, 7 = 8.8, 2.3 Hz, 1H), 6.23 (d, 7 = 12.1 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.94 (s, 1H),

4.84 (d, 7 = 16.8 Hz, 1H), 4.64 - 4.56 (m, 1H), 3.94 (q, 7= 8.8 Hz, 1H), 3.84 - 3.75 (m, 4H), 3.71 - 3.61 (m, 1H), 3.31 - 3.10 (m, 7H), 1.87 - 1.27 (m, 3H), 1.21 (dd, 7= 14.2, 2.4 Hz, 7H). MS

(APCI+) m/z 542.1 (M+H) ⁺

Example 1-30

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-/V-(2-methoxyet hanesulfonyl)-4-[2- methoxy-5-(trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-ca rboxamide

[0434] 120 °C, DMSO -de :D ₂ 0 = 9:1 (v/v)) d 7.82 - 7.67 (m, 1H), 7.39 -

7.23 (m, 3H), 7.20 - 7.08 (m, 3H), 6.87 (s, 1H), 5.48 (d, 7 = 10.0 Hz, 1H), 4.76 (t, 7 = 9.6 Hz, 1H),

4.48 (d, 7 = 7.3 Hz, 1H), 4.05 (s, 3H), 3.78 (t, 7 = 6.4 Hz, 2H), 3.67 - 3.53 (m, 2H), 3.47 (t, 7 = 8.4 Hz, 1H), 3.26 (s, 3H), 2.40 - 2.08 (m, 1H), 1.69 (t, 7 = 14.6 Hz, 2H), 1.59 - 0.98 (m, 7H), 0.98 - 0.61 (m, 10H). MS (APCI+) m/z 681.5 (M+H) ⁺ Example 1-31

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-/V-(cyclopropan esulfonyl)-4-[2-methoxy- 5-(trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-carboxamid e

[0435] 120 °C, DMSO-7 ₆ :D ₂ 0 = 9:1 (v/v)) d 7.79 - 7.71 (m, 1H), 7.31

(d, 7 = 8.8 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.17 - 7.03 (m, 3H), 6.87 (s, 1H), 5.47 (d, J = 9.9 Hz, 1H), 4.73 (t, 7 = 9.8 Hz, 1H), 4.48 (d, 7 = 7.5 Hz, 1H), 4.03 (s, 3H), 3.51 (t, 7 = 8.6 Hz, 1H), 2.94 - 2.83 (m, 1H), 2.26 (s, 1H), 1.76 - 1.56 (m, 2H), 1.52 - 0.95 (m, 11H), 0.91 (s, 10H). MS (APCI+) m/z 663.4 (M+H) ⁺

Example 1-32

_/g/G -(2L ^> ,35 ^, ,4L ^> ,55 ^, )-3- _/< ^o _/ 7-butyl- 1 -(cyclohexanecarbonyl)-/V-(dimethylsulfamoyl)-4-[2-methoxy-5 -

(trifluoromethyl)benzoyl]-5-phenylpyrrolidine-2-carboxami de

[0436] 120 °C, DMSO-tfc :D ₂ 0 = 9:1 (v/v)) d 7.76 (d, 7= 9.2 Hz, 1H),

7.43 - 7.20 (m, 3H), 7.ll (d, 7 = 7.9 Hz, 3H), 6.88 (s, 1H), 5.49 (d, 7 = 10.0 Hz, 1H), 4.74 (t, 7 = 9.7 Hz, 1H), 4.50 (d, 7 = 7.2 Hz, 1H), 4.05 (s, 3H), 3.54 (t, 7 = 8.5 Hz, 1H), 2.84 (s, 6H), 1.69 (t, 7 = 13.5 Hz, 2H), 1.55 - 0.98 (m, 7H), 0.93 (s, 11H). MS (APCI+) m/z 666.4 (M+H) ⁺

Example 1-33

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(2,5-dichlorobenzoyl)-5-phenyl-l-(pyr rolidine-l- carbonyl)pyrrolidine-2-carboxylic acid

[0437] 120 °C, DMSO -de :D ₂ 0 = 9:1 (v/v)) d 7.39 - 7.30 (m, 2H), 7.25 -

7.20 (m, 2H), 7.17 - 7.06 (m, 4H), 4.43 (d, 7 = 7.9 Hz, 1H), 4.22 (dd, 7= 8.0, 5.4 Hz, 1H), 3.78 (d, 7= 8.3 Hz, 1H), 3.63 - 3.39 (m, 4H), 3.21 (dd, 7 = 8.1, 5.5 Hz, 1H), 1.89 (s, 4H), 0.87 (s, 9H).MS (APCI+) m/z 517.0 (M+H) ⁺

Example 1-34

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-[di(propan-2-yl)carbamoyl]-4-(2-metho xybenzoyl)-5-(2- methoxyphenyl)pyrrolidine-2-carboxylic acid

[0438] NMR (400 MHz, CDCb) d 12.59 (bs, 1H), 7.37 (ddd, 7= 8.7, 7.3, 1.8 Hz, 1H), 7.27

(m, 1H), 7.12 (td, 7= 7.9, 1.7 Hz, 1H), 7.07 (dd, 7 = 7.8, 1.8 Hz, 1H), 6.96 - 6.87 (m, 2H), 6.78 (td, 7= 7.4, 1.0 Hz, 1H), 6.47 (dd, 7 = 8.2, 1.1 Hz, 1H), 5.60 (d, 7= 8.0 Hz, 1H), 4.62 (t, 7= 7.7 Hz,

1H), 4.48 (d, 7 = 6.6 Hz, 1H), 3.94 (s, 3H), 3.69 (p, 7 = 6.7 Hz, 2H), 3.25 (s, 3H), 3.22 (d, 7 = 7.0 Hz, 1H), 1.22 (d, 7 = 6.6 Hz, 6H), 1.15 (d, 7 = 6.6 Hz, 6H), 0.96 (s, 9H); MS (ESI-) m/z 537 (M-H)

Example 1-35

3-/er/-butyl-4-(2,5-difhiorobenzoyl)-l-[(25 ^, )-2-(2-hydroxypropan-2-yl)pyrrolidine-l-carbonyl]-5- phenylpyrrolidine-2-carboxylic acid

[0439] NMR (501 MHz, CDCb) d 7.26 - 7.09 (m, 6H), 7.06 - 6.92 (m, 2H), 5.56 (dd, J =

15.1, 9.2 Hz, 1H), 4.94 (d, 7 = 9.3 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.31 (dd, J = 9.3, 7.6 Hz, 1H), 4.26 - 4.16 (m, 1H), 3.83 - 3.65 (m, 1H), 3.54 - 3.21 (m, 1H), 3.11 - 2.84 (m, 1H), 2.10 - 1.90 (m, 2H), 1.80 - 1.58 (m, 1H), 1.58 - 1.37 (m, 1H), 1.22 (s, 2H), 1.19 (s, 2H), 1.04 (s, 5H), 0.85 (d, 7 = 8.5 Hz, 6H). MS (APCI+) m/z 543.1 (M+H) ⁺

Example 1-36

3-/er/-butyl-4-(2,5-difluorobenzoyl)-l-[(2R)-2-(2-hydroxypro pan-2-yl)pyrrolidine-l-carbonyl]-5- phenylpyrrolidine-2-carboxylic acid

[0440] NMR (400 MHz, CDCb) d 7.26 - 7.08 (m, 6H), 7.06 - 6.95 (m, 2H), 5.57 (dd, J =

14.5, 9.3 Hz, 1H), 4.94 (d, 7 = 9.3 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.35 - 4.26 (m, 1H), 4.26 - 4.15 (m, 1H), 3.83 - 3.64 (m, 1H), 3.58 - 3.26 (m, 1H), 3.06 - 2.83 (m, 1H), 2.09 - 1.89 (m, 2H), 1.89 - 1.33 (m, 1H), 1.29 - 1.15 (m, 4H), 1.04 (d, 7 = 1.5 Hz, 4H), 0.86 (d, 7 = 1.5 Hz, 7H). MS (APCI+) m/z 543.1 (M+H) ⁺

Example 1-37

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-[di(propan-2-yl)carbamoyl]-4-(2-fluor obenzoyl)-5-(2- methoxyphenyl)pyrrolidine-2-carboxylic acid

[0441] NMR (400 MHz, CDCb) d 12.65 (bs, 1H), 7.52 - 7.44 (m, 1H), 7.40 (td, 7= 7.8, 1.9

Hz, 1H), 7.32 - 7.29 (m, 1H), 7.17 (td, 7 = 8.0, 1.7 Hz, 2H), 7.10 (q, J = 8.3, 7.6 Hz, 2H), 6.96 (t, J

= 7.5 Hz, 1H), 6.53 (d, 7 = 8.2 Hz, 1H), 5.71 (d, 7 = 8.1 Hz, 1H), 4.62 (d, 7 = 6.8 Hz, 1H), 4.32 (t, J

= 8.3 Hz, 1H), 3.61 (p, J = 6.7 Hz, 2H), 3.39 (ddd, J = 8.7, 6.8, 1.9 Hz, 1H), 3.24 (s, 3H), 1.25 (d, J

= 6.6 Hz, 6H), 1.16 (d, J = 6.6 Hz, 6H), 0.95 (s, 9H); MS (ESI-) m/z 525 (M-H)

Example 1-38

rac-(2R,35 ^, ,4R,55 ^, )-4-[(benzyloxy)carbonyl]-3-/er/-butyl-l-(4-fluorobenz oyl)-5-phenylpyrrolidine-2- carboxylic acid

[0442] 7.36 (dd, J = 6.7, 2.9 Hz,

2H), 7.31 - 7.24 (m, 3H), 7.23 - 7.11 (m, 5H), 7.08 - 6.96 (m, 4H), 5.38 (d, J = 10.0 Hz, 1H), 4.58 (d, J = 12.4 Hz, 1H), 4.47 (d, J = 5.4 Hz, 1H), 4.31 (d, 7 = 12.4 Hz, 1H), 3.65 (dd, 7 = 10.0, 6.6 Hz, 1H), 2.97 - 2.86 (m, 1H), 0.95 (s, 9H). MS (APCI+) m/z 504.3 (M+H) ⁺

Example 1-39

rac-(2R,35 ^, ,4R,55 ^, )-4-[(benzyloxy)carbonyl]-3-/er/-butyl-5-phenyl-l-(2-p henylcyclopropane-l- carbonyl)pyrrolidine-2-carboxylic acid [0443] 7.77 - 7.39 (m, 2H), 7.39 -

6.86 (m, 12H), 6.76 - 6.31 (m, 1H), 5.76 - 5.35 (m, 1H), 4.57 (d, J= 12.4 Hz, 1H), 4.47 (d, 7= 5.7 Hz, 1H), 4.34 (d, J= 12.4 Hz, 1H), 3.75 - 3.50 (m, 1H), 3.03 - 2.82 (m, 1H), 2.37 - 2.08 (m, 1H), 1.97 - 1.15 (m, 2H), 1.11 - 0.66 (m, 10H). MS (APCI+) m/z 526.4 (M+H) ⁺

Example 1-40

rac-(2R,35 ^, ,4R,55 ^, )-4-[(benzyloxy)carbonyl]-3-/er/-butyl-l-(3-methylbenz oyl)-5-phenylpyrrolidine-

2-carboxylic acid

[0444] 7.43 - 7.32 (m, 2H), 7.30 -

7.24 (m, 3H), 7.20 - 7.11 (m, 5H), 7.06 - 6.80 (m, 4H), 5.32 (d, 7 = 10.0 Hz, 1H), 4.58 (d, 7 = 12.3 Hz, 1H), 4.49 (d, 7= 5.3 Hz, 1H), 4.32 (d, 7 = 12.4 Hz, 1H), 3.63 (dd, 7 = 10.0, 6.6 Hz, 1H), 2.93 (t, J= 6.0 Hz, 1H), 2.14 (s, 3H), 0.94 (s, 9H). MS (APCI+) m/z 500.4 (M+H) ⁺

Example 1-41

benzyl rac-(2R,35 ^, ,4R,55 ^, )-4-/er/-butyl-l-(cyclopentylacetyl)-5-[(methanesulfon yl)carbamoyl]-2- phenylpyrrolidine-3-carboxylate

[0445] ^l H NMR (400 MHz, DMSO -de) d 11.69 (bs, 1H), 7.60 - 7.53 (m, 2H), 7.35 - 7.18 (m, 6H), 7.13 (dd, 7 = 7.3, 2.1 Hz, 2H), 5.36 (d, J = 9.9 Hz, 1H), 4.53 (s, 2H), 4.35 (d, J = 9.0 Hz, 1H), 3.58 (t, 7 = 10.6 Hz, 1H), 3.16 (s, 3H), 3.03 (t, 7 = 10.6 Hz, 1H), 2.16 (dd, 7 = 15.6, 6.7 Hz, 1H), 1.96 (p, 7 = 7.4 Hz, 1H), 1.76 (s, 1H), 1.59 (dq, 7 = 13.0, 6.6 Hz, 1H), 1.43 (dq, 7 = 13.0, 6.8 Hz, 1H), 1.38 - 1.31 (m, 1H), 1.31 - 1.18 (m, 3H), 1.10 - 0.89 (m, 1H), 0.87 (d, J = 1.3 Hz, 9H), 0.77 - 0.62 (m, 1H); MS (ESI-) m/z 567 (M-H)

Example 1-42

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-phenyl-4-[(25 ^, )-2-(propan-2- yl)piperidine- 1 -carbonyl]pyrrolidine-2-carboxylic acid

[0446] 120 °C, DMSO -de :D ₂ 0 = 9:1 (v/v)) d 7.55 (d, 7= 7.7 Hz, 2H),

7.14 (s, 3H), 5.34 (dd, 7 = 21.2, 9.8 Hz, 1H), 4.42 (s, 1H), 3.99 - 3.90 (m, 1H), 3.74 (s, 2H), 3.16 (s, 1H), 2.79 (s, 1H), 2.23 (s, 1H), 1.72 - 0.55 (m, 30H), -0.07 (s, 2H). MS (APCI+) m/z 511.2 (M+H) ⁺

Example 1-43

mc-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-{ [(2-chloro-5-methylphenyl)methyl]carbamoyl}-l-[di(propan-2- yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylic acid

[0447] NMR (400 MHz, CDCb) d 7.26 - 7.22 (m, 2H), 7.17 - 7.10 (m, 4H), 7.00 (dd, 7 =

8.1, 2.2 Hz, 1H), 6.82 (d, 7= 2.2 Hz, 1H), 5.73 (t, 7= 5.7 Hz, 1H), 5.09 (d, 7= 7.5 Hz, 1H), 4.22 (dd, 7 = 14.5, 5.7 Hz, 1H), 4.06 (dd, 7 = 14.5, 5.6 Hz, 1H), 4.02 - 3.90 (m, 3H), 2.97 (dd, 7 = 7.6, 2.1 Hz, 1H), 2.64 (dd, 7 = 4.7, 2.1 Hz, 1H), 2.28 (s, 3H), 1.20 (d, 7 = 6.7 Hz, 6H), 1.07 - 0.98 (m, 15H). MS (APCI+) m/z 556.2 (M+H) ⁺

Example 1-44

rac-(2R,35 ^, ,4R,55 ^, )-4-[(benzyloxy)carbonyl]-3-/er/-butyl-5-phenyl-l-{ [(propan-2- yl)oxy]carbonyl}pyrrolidine-2-carboxylic acid

[0448] NMR (400 MHz, DMSO -de, 120 °C) d 7.51 - 7.45 (m, 2H), 7.25 (dd, J = 5.1, 1.9

Hz, 3H), 7.21 - 7.11 (m, 3H), 7.06 - 7.00 (m, 2H), 5.19 (d, 7= 10.1 Hz, 1H), 4.66 - 4.53 (m, 2H), 4.34 (d, 7= 12.5 Hz, 1H), 4.28 (d, 7= 5.7 Hz, 1H), 3.54 (dd, 7= 10.0, 6.8 Hz, 1H), 2.90 - 2.84 (m, 1H), 1.06 (d, 7 = 6.2 Hz, 3H), 0.93 (s, 9H), 0.89 (d, 7= 6.2 Hz, 3H); MS (ESI+) m/z 468 (M+H) ⁺

Example 1-45

_/g/G -(2L ^> ,3.n,4L ^> ,55 ^, ₎ -3- _/< ^o r _/ -butyl- 1 -(cyclohexanecarbonyl ₎ -4-[2-(4-fluorophenyl ₎ piperidine- 1 - carbonyl] -5-phenylpyrrolidine-2-carboxylic acid

[0449] 120 °C, DMSO-tfc :D ₂ 0 = 9:1 (v/v)) d 7.76 - 7.49 (m, 2H), 7.36 -

6.91 (m, 5H), 6.90 - 6.68 (m, 1H), 6.53 - 6.15 (m, 1H), 5.50 - 4.97 (m, 2H), 4.48 (s, 1H), 4.11 - 3.40 (m, 2H), 2.73 - 2.54 (m, 1H), 2.19 (d, 7 = 37.0 Hz, 2H), 1.79 - 0.45 (m, 25H).MS (APCI+) m/z

563.1 (M+H) ⁺

Example 1-46

rac-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-(2-methoxyphe nyl)-4-[(2- methoxyphenyl)methyl]pyrrolidine-2-carboxylic acid

[0450] ^l H NMR (400 MHz, DMSO -de) d 7.85 (s, 1H), 7.20 (t, 7= 7.8 Hz, 1H), 7.09 (ddd, 7 = 8.3, 5.3, 3.8 Hz, 2H), 6.99 (d, 7 = 8.2 Hz, 1H), 6.90 (t, 7 = 7.5 Hz, 1H), 6.82 (d, 7 = 8.2 Hz, 1H),

6.77 - 6.72 (m, 2H), 5.48 (d, 7 = 8.5 Hz, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 3.00 - 2.91 (m, 2H), 2.06 (s, 1H), 2.04 - 1.98 (m, 1H), 1.97 - 1.90 (m, 1H), 1.70 - 1.60 (m, 1H), 1.55 - 1.41 (m, 2H), 1.33 - 1.20 (m, 4H), 1.11 - 1.00 (m, 1H), 0.89 - 0.80 (m, 2H), 0.63 (s, 9H). MS (ESI+) m/z 508 (M+H) ⁺

Example 1-47

mc-(2R,3R,4R,55')-l-[di(propan-2-yl)carbamoyl]-3-methyl-5-ph enyl-4-({ [3- (trifluoromethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-2-carbo xylic acid

[0451] NMR (400 MHz, CDCb) d 8.26 (dd, 7= 5.2, 1.9 Hz, 1H), 7.93 (dd, 7= 7.4, 1.8 Hz,

1H), 7.29 - 7.20 (m, 5H), 7.01 (dd, 7 = 7.5, 5.1 Hz, 1H), 4.96 (d, 7 = 7.1 Hz, 1H), 4.64 (d, 7 = 9.8 Hz, 1H), 4.49 (dd, 7 = 11.0, 3.6 Hz, 1H), 3.61 - 3.44 (m, 3H), 2.61 (ddd, 7 = 12.3, 9.9, 6.2 Hz, 1H), 2.51 (tdd, 7 = 12.5, 8.7, 3.7 Hz, 1H), 1.23 (d, 7 = 6.1 Hz, 3H), 1.18 (d, 7 = 6.7 Hz, 6H), 1.15 (d, 7 = 6.6 Hz, 6H); MS (ESI-) m/z 506 (M-H)

Example 1-48

mc-(2i?,3i?,4i?,55')-l-[di(propan-2-yl)carbamoyl]-3-methyl-4 -({ [6-methyl-4- (trifluoromethyl)pyridin-2-yl]oxy}methyl)-5-phenylpyrrolidin e-2-carboxylic acid

[0452] NMR (400 MHz, CDCb) d 7.28 - 7.22 (m, 5H), 6.94 (s, 1H), 6.75 (s, 1H), 4.91 (d, J

= 13 Hz, 1H), 4.64 (d, 7 = 9.9 Hz, 1H), 4.29 (dd, 7 = 11.1, 3.7 Hz, 1H), 3.57 - 3.47 (m, 3H), 2.62 (ddt, 7 = 12.5, 9.8, 6.2 Hz, 1H), 2.53-2.44 (m, 1H), 2.46 (s, 3H), 1.25 (d, 7 = 6.2 Hz, 3H), 1.17 (d, J = 6.7 Hz, 6H), 1.15 (d, J = 6.6 Hz, 6H); MS (ESI-) m/z 520 (M-H)

Example 1-49

mc-(2i?,3i?,4i?,55')-4-[(5-chloro-2-methoxyphenoxy)methyl]-3 -cyclopropyl-l-[di(propan-2- yl)carbamoyl]-5-phenylpyrrolidine-2-carboxylic acid

[0453] ^l H NMR (400 MHz, CDCb) d 7.32 (dd, J = 6.6, 2.9 Hz, 2H), 7.23 (q, J = 2.9 Hz, 3H), 6.90 (dd, J = 8.6, 2.4 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 5.06 (d, J = 7.5 Hz, 1H), 4.86 (d, J = 9.3 Hz, 1H), 4.14 (dd, J = 9.3, 4.0 Hz, 1H), 3.90 (s, 3H), 3.52 (hept, J= 6.6 Hz, 2H), 3.07 (dd, 7 = 10.6, 9.3 Hz, 1H), 2.90 (tdd, 7= 11.1, 7.4, 3.9 Hz, 1H), 1.84 (dt, 7= 11.4, 9.3 Hz, 1H), 1.17 (d, 7 = 6.7 Hz, 6H), 1.11 (d, 7 = 6.6 Hz, 6H), 0.69 (tdd, 7 = 8.7, 6.5, 4.5 Hz, 1H), 0.62 - 0.45 (m, 3H), 0.11 - 0.03 (m, 1H); MS (ESI+) m/z 529 (M+H) ⁺

Example 1-50

mc-(2R,3R,4R,55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [2-methoxy-5-(trifluoromethyl)pyridin-3- yl]oxy}methyl)-3-methyl-5-phenylpyrrolidine-2-carboxylic acid

[0454] NMR (501 MHz, CDCb) d 8.06 (dd, 7= 2.1, 1.1 Hz, 1H), 7.29 - 7.21 (m, 5H), 6.89

(d, 7 = 2.0 Hz, 1H), 5.01 (d, 7 = 7.0 Hz, 1H), 4.67 (d, 7 = 9.2 Hz, 1H), 4.12 (s, 3H), 3.86 (dd, 7 =

9.3, 3.6 Hz, 1H), 3.54 (p, 7= 6.6 Hz, 2H), 3.20 (t, 7= 9.5 Hz, 1H), 2.73 - 2.51 (m, 2H), 1.25 (d, 7 = 6.0 Hz, 3H), 1.19 (d, 7 = 6.7 Hz, 6H), 1.15 (d, 7 = 6.6 Hz, 6H); MS (ESI-) m/z 536 (M-H)

Example 1-51

mc-(2R,3R,45 ^, ,55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [2-methoxy-5-(trifluoromethyl)pyridin-3- yl]amino}methyl)-3-methyl-5-phenylpyrrolidine-2-carboxylic acid

[0455] ^l H NMR (400 MHz, CDCb) d 7.82 - 7.72 (m, 1H), 7.33 (p, 7 = 3.0, 2.5 Hz, 3H), 7.26 (dd, 7 = 7.3, 2.4 Hz, 2H), 6.48 (d, 7= 2.2 Hz, 1H), 4.91 (d, 7= 7.5 Hz, 1H), 4.55 (d, 7= 8.3 Hz,

1H), 4.04 (s, 3H), 3.53 (p, 7 = 6.6 Hz, 2H), 2.93 (dd, 7 = 13.1, 4.7 Hz, 1H), 2.79 - 2.66 (m, 1H),

2.56 (dd, 7 = 13.2, 8.9 Hz, 1H), 2.43 - 2.23 (m, 1H), 1.24 (d, 7 = 6.5 Hz, 3H), 1.19 (d, 7 = 6.7 Hz, 6H), 1.11 (d, 7 = 6.6 Hz, 6H); MS (ESI-) m/z 535 (M-H) Example 1-52

mc-(2i?,35 ^, ,4i?,55 ^, )-l-[di(propan-2-yl)carbamoyl]-4-({ [2-methoxy-5-(trifluoromethyl)pyridin-3- yl]oxy}methyl)-3,5-diphenylpyrrolidine-2-carboxylic acid

[0456] NMR (500 MHz, CDCb) d 8.01 (dd, = 2.1, 1.1 Hz, 1H), 7.43 - 7.29 (m, 10H), 6.72

(d, / = 2.1 Hz, 1H), 5.16 (d, / = 7.5 Hz, 1H), 5.13 (d, / = 10.1 Hz, 1H), 4.10 (s, 3H), 3.73 (dd, J = 12.8, 10.0 Hz, 1H), 3.62 - 3.51 (m, 3H), 3.29 (dddd, / = 12.8, 10.8, 7.5, 3.4 Hz, 1H), 3.14 (dd, / = 10.6, 9.5 Hz, 1H), 1.23 (d, / = 6.7 Hz, 6H), 1.16 (d, /= 6.6 Hz, 6H); MS (ESI+) m/z 600 (M+H) ⁺

Example 1-54

rac-(2R,? _> S £S ,5S)- 1 -[di(propan-2-yl)carbamoyl]-4-( { [2-methoxy-5-(trifluoromethyl)pyridin-3- yl]amino}methyl)-3,5-diphenylpyrrolidine-2-carboxylic acid

[0457] NMR (400 MHz, CDCb) d 7.75 - 7.71 (m, 1H), 7.50 - 7.31 (m, 10H), 6.32 (d, J =

2.0 Hz, 1H), 5.13 (d, J= 9.2 Hz, 1H), 4.97 (d, /= 7.5 Hz, 1H), 3.99 (d, /= 1.0 Hz, 3H), 3.89 - 3.65 (m, 1H), 3.59 (p, / = 6.7 Hz, 2H), 2.93 (dq, /= 13.1, 7.4 Hz, 1H), 2.70 - 2.57 (m, 2H), 1.21 (d, / = 6.6 Hz, 6H), 1.13 (d, / = 6.6 Hz, 6H); MS (ESI-) m/z 597 (M-H)

Example 1-56

mc-(2R,35 ^, ,4R,55 ^, )-3-/er/-butyl-4-(5-chloro-l-methyl-l//-indazol-3-yl)- l-(cyclohexanecarbonyl)-5- phenylpyrrolidine-2-carboxylic acid

[0458] ^l H NMR (400 MHz, DMSO -d ₆ ) d 7.48 (d, /= 1.9 Hz, 1H), 7.28 (d, /= 8.9 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.11 (ddd, /= 8.9, 1.9, 0.9 Hz, 1H), 6.88 - 6.82 (m, 3H), 5.47 (d, / = 9.5 Hz, 1H), 4.52 (d, / = 6.9 Hz, 1H), 4.37 (t, /= 9.2 Hz, 1H), 3.72 (d, / = 0.9 Hz, 3H), 3.28 (dd, / = 9.0,

6.9 Hz, 1H), 2.33 - 2.18 (m, 1H), 1.74 (d, /= 13.3 Hz, 1H), 1.70 - 1.63 (m, 1H), 1.51 - 1.37 (m,

2H), 1.37 - 1.22 (m, 1H), 1.22 - 0.99 (m, 4H), 0.87 (s, 9H), 0.76 - 0.60 (m, 1H); MS (ESI+) m/z 522 (M+H) ⁺

Example 1-57

rac-(2R,35 ^, ,4R,55 ^, )-4-[3-(2-bromo-6-methoxyphenyl)-l,2,4-oxadiazol-5-yl] -3-/er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0459] MS (ESI+) m/z 610.3 - 612.4 (M+H) ⁺

Example 1-58

rac-(2R,35 ^, ,4R,55 ^, )-4-[3-(5-bromo-2-methoxyphenyl)-l,2,4-oxadiazol-5-yl] -3-/er/-butyl-l- (cyclohexanecarbonyl)-5-phenylpyrrolidine-2-carboxylic acid

[0460] MS (ESI+) m/z 610.7 - 612.6 (M+H) ⁺

Example 1-59 rac-(25,35,45,55)-3-/er/-butyl-l-(cyclohexanecarbonyl)-5-phe nyl-4-{5-[3- (trifluoromethyl)phenyl]-l,3,4-oxadiazol-2-yl}pyrrolidine-2- carboxylic acid

[0461] MS (ESI+) m/z 570.5 (M+H) ⁺

Example 1-60

/7/r-(25,3S,45,5S)-3-/e/7-butyl- 1 -(cyclohexanecarbonyl)-5-phenyl-4-{5-[4- (trifluoromethyl)phenyl]-l,3,4-oxadiazol-2-yl}pyrrolidine-2- carboxylic acid

[0462] MS (ESI+) m/z 570.4 (M+H) ⁺

Example 1-61

rac-(45,65,75)-N ⁴ -(6-aminopyridine-2-sulfonyl)-6-phenyl-/V ⁵ ,/V ⁵ -di(propan-2-yl)-7-[5-(propan-2- yl)-l, 3, 4-oxadiazol-2-yl]-5-azaspiro[2.4]heptane-4, 5-dicarboxamide

[0463] MS (ESI+) m/z 610.4 (M+H) ⁺

Example 1-62

(25,35,45,55 ₎ - 1 -[di (propan-2-yl /carbamoyl] -3-methyl -5-phenyl -4- { l-[4-(trifluoromethyl)phenyl]- l//-l,2,3-triazol-5-yl}pyrrolidine-2-carboxylic acid

[0464] MS (ESI+) m/z 544.7 (M+H) ⁺

[0465] The following Examples in Table 1 were prepared using similar methods to those described in Examples 1-57 (or herein) using the appropriate starting materials.

Table 1

Determination of Biological Activity

[0466] Common abbreviations well known to those with ordinary skills in the art which are used throughout: ATP for adenosine triphosphate; and SAR for structure-activity relationship.

Cell Surface Expression-Horse Radish Peroxidase (CSE-HRP) Assay

[0467] A cellular assay for measuring the F508delCFTR cell surface expression after correction with test compounds either without or with a co-corrector (2 LI M of 3-[(2R,4R)-4-({ [l- (2,2-difhioro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amin o)-7-methoxy-3,4-dihydro-2//- chromen-2-yl]benzoic acid), was developed in human lung derived epithelial cell line (CFBE4lo-) (Veit G et al, (2012) Mol Biol Cell. 23(21): 4188-4202). The development was achieved by expressing the F508delCFTR mutation along with a horseradish peroxidase (HRP) in the fourth exofacial loop, and then measuring the HRP activity using luminescence readout from these cells, CFBE4lo-F508delCFTR-HRP, that were incubated overnight with the test corrector compounds, either without or with the co-corrector. For this primary assay, the CFBE4lo-F508delCFTR-HRP cells were plated in 384- well plates (Greiner Bio-one; Cat 781080) at 4,000 cells/well along with 0.5 m g/m L doxycycline to induce the F508delCFTR-HRP expression and further incubated at 37 °C, 5% CO2 for 72 hours. The test compounds were then added either without or with a co-corrector at the required concentrations and further incubated for 18-24 hours at 33 °C. The highest

concentration tested was 20 mM with an 8-point concentration response curve using a 3-fold dilution in both the test compound without or with the co-corrector. Three replicate plates were run to determine one EC50. All plates contained negative controls (dimethyl sulfoxide, DMSO) and positive control (2 mM of 3-[(2R,4R)-4-({ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl } am ino)-7-methoxy-3,4-dihydi _O -2/7-chi _Oi uen-2-yl] benzoic acid) as well as on-plate concentration response of the positive control. Post incubation, the plates were washed 5x times with Dulbecco’s phosphate buffered saline (DPBS), followed by the addition of the HRP substrate, luminol (50 mH), and measuring the HRP activity using luminescence readout on

EnVision® Multilabel Plate Reader (Perkin Elmer; product number 2104-0010). The raw counts from the experiment were analyzed using Accelrys® Assay Explorer v3.3.

[0468] Z’ greater than 0.5 was used as passing quality control criteria for the plates.

[0469] The Z’ is defined as:

1 - [3*SDpositive Control + 3*SDNegative Control/ Absolute (Meanpostivie Control ^— MeanNegative Control)] wherein "SD" is standard deviation.

[0470] The % activity measured at each of the 8 test concentrations of the test compound added either without or with a co-corrector (2 mM of 3-[(2A,4A)-4-( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl } am ino)-7-methoxy-3,4-dihydi _O -2/7-chi _Oi uen-2-yl] benzoic acid) was normalized to the on-plate positive control using the following formulae:

% activity (Test compound without co-corrector) = [(test compound without co-corrector response - DMSO response) / (positive control response - DMSO response)] *100

% activity (Test compound with co-corrector) = [(test compound with co-corrector response - DMSO response) / (positive control response - DMSO response)] *100

[0471] The maximum % activity achieved for the test compound either without or with a co corrector at any tested concentration is presented in Table 1 along with the respective ECso’s calculated using the following general sigmoidal curve with variable Hill slope equation (described as Model 42 in the Accelrys® Assay Explorer v3.3 software):

y = (a - d) / (1 + (x / c) ^A b) + d

[0472] General sigmoidal curve with concentration, response, top, bottom, ECso and Hill slope. This model describes a sigmoidal curve with an adjustable baseline, a. The equation can be used to fit curves where response is either increasing or decreasing with respect to the independent variable, “x”.

“x” is a concentration of drug under test.

“y” is the response.

“a” is the maximum response, and“d” is the minimum response

“c” is the inflection point (ECso) for the curve. That is,“y” is halfway between the lower and upper asymptotes when x = c.

“b” is the slope-factor or Hill coefficient. The sign of b is positive when the response increases with increasing dose and is negative when the response decreases with increasing dose (inhibition).

The data is presented with the qualifiers shown below:

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Table 2

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[0473] The data provided in the present application demonstrate that the compounds of the invention demonstrate activity in vitro, and may be useful in vivo in the treatment of cystic fibrosis.

[0474] Further benefits of Applicants’ invention will be apparent to one skilled in the art from reading this patent application.

[0475] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the present disclosure, which is defined by the appended claims and their equivalents. Various changes and modifications to the described embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the present disclosure, may be made without departing from the spirit and scope thereof.