Modulators of alpha-1 antitrypsin

Abstract

Novel compounds, compositions, and methods of use and preparation thereof that may be useful in treating alpha-1 antitrypsin deficiency (AATD).

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 004,713, filed April 3, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present disclosure provides compounds capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds.

[0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments exist for AATD, there is currently no cure. AAT is primarily produced in hepatocytes and secreted into the blood, but is also made by other cell types, including lung epithelial cells and certain leukocytes. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [NE], proteinase 3, and cathepsin G), thus protecting organs such as the lungs from protease-induced damage, especially during periods of inflammation.

[0004] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene, which encodes the AAT protein. This mutation, known as the Z mutation or Z allele, leads to misfolding of the translated protein, so that it is not secreted into the bloodstream and can polymerize within the producing cells. As a result, circulating AAT levels in individuals homozygous for the Z allele (PiZZ) are significantly reduced, and only about 15% of the mutant Z-AAT protein is correctly folded and secreted by cells. An additional consequence of the Z mutation is that secreted Z-AAT has reduced activity compared to the wild-type protein, with 40% to 80% of the normal antiprotease activity (American thoracic society / European respiratory society, Am J Respir Crit Care Med. 2003;168(7):818-900, and Ogushi et al. J Clin Invest. 1987;80(5):1366-74). Accumulation of polymerized Z-AAT protein within hepatocytes results in gain-of-function cytotoxicity, which can lead to cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation can resolve spontaneously, but can be fatal in a small number of children. A lack of circulating AAT leads to unregulated protease activity, which degrades lung tissue over time and leads to emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in individuals with PiZZ, typically manifesting in middle age and resulting in a reduced quality of life and a shortened lifespan (average 68 years) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016;11:1663-9). This effect is more pronounced in individuals with PiZZ who smoke, resulting in an even further shortened lifespan (58 years) (Piitulainen and Tanash, COPD 2015;12(1):36-41). Individuals with PiZZ represent a large proportion of those with clinically relevant AATD lung disease. Thus, there is a need for additional and effective treatments for AATD. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Tanash et al.Int J Chron Obstruct Pulm Dis.2016;11:1663-9 [Non-patent document 2] Piitulainen and Tanash, COPD 2015;12(1):36-41 Summary of the Invention [Means for solving the problem]

[0006] A milder form of AATD is associated with the SZ genotype, in which the Z allele is combined with the S allele. The S allele is associated with somewhat reduced levels of circulating AAT, but does not cause cytotoxicity in liver cells. The result is clinically significant lung disease, but not liver disease. (Fregonese and Stolk, Orphanet J Rare Dis. 2008;33:16.) Similar to the ZZ genotype, the lack of circulating AAT in subjects with the SZ genotype results in unregulated protease activity, which can degrade lung tissue over time and lead to emphysema, especially in smokers.

[0007] The current standard of care for individuals with AAT deficiency who show signs of or are developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves the administration of human AAT protein concentrate purified from pooled donor plasma to enhance the deficient AAT. While plasma protein infusions have been shown to improve survival or slow the progression of emphysema, augmentation therapy is often insufficient under challenging conditions, such as during active pulmonary infection. Similarly, protein replacement therapy shows promise in slowing disease progression, but augmentation does not restore normal physiological regulation of AAT in patients, and efficacy has been difficult to demonstrate. Additionally, augmentation therapy requires weekly clinic visits for treatment and fails to address liver disease driven by the toxic gain-of-function of the Z allele. Therefore, there is a continuing need for novel and more effective treatments for AATD. DETAILED DESCRIPTION OF THE INVENTION

[0008] One aspect of the present disclosure provides compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, which may be employed in the treatment of AATD. For example, a compound of Formula (I), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, can be represented as follows: [ka] During the ceremony, V 1 and V 2 are each independently N or -CR 2 and U is —OH or —NH; X is absent, a bond, -(CR a R a )p - or -R a’ C=CR a’ - and Y is absent or a bond, -(CR b R b ) q - or -R b’ C=CR b’ - and T is -CR c R c COOH, -CR c =CR c COOH, -CN, or [ka] and R a and R b are each independently, at each occurrence, hydrogen, halogen, —OH, benzyl, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R a’ and R b’ are each independently, at each occurrence, hydrogen, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R c is, in each occurrence, independently hydrogen, halogen, —OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; Ring A is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C or C 10 aryl, or 5- to 10-membered heteroaryl; Z is -CN, [ka] and When T is not -CN, ring C is C3-C 12 Cycloalkyl, C or C 10aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; When T is -CN, ring C is C3-C 12 cycloalkyl or 3- to 12-membered heterocyclyl; R E , R F , and R G are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -CR p (=N)OR s , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s , -OC(=O)R s , or -OC(=O)NR p R q and R E , R F , and R G Any one of C1-C6 alkyl or C2-C6 alkenyl is optionally cyano, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、-OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) r R s , and -S(=O) r NR p R q and is substituted with 1 to 3 groups selected from R p , R q , and R r are each independently, at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R p , R q , and R r wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, C1-C3 alkoxy, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R p , R q , and R r wherein any one of the C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)O(C1-C2 alkyl), —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R s is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; R swherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R s wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R 1 is halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or —O—(C3-C6 cycloalkyl); R 2 is, in each occurrence, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl, or 5- or 6-membered heteroaryl; R 2 The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl may optionally be cyano, —C(═O)R k , -C(=O)OR k , -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k , -OR k , -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i ,-S(=O) s R k , and S(=O) s NR h R i and is substituted with 1 to 3 groups selected from R h , R i , and R j are each independently, at each occurrence, hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; R h , R i , and R j C1-C4 alkyl is optionally selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), substituted with 1 to 3 groups selected from -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R h , R i , and R jwherein the C3-C6 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R k is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; -OR k cannot be -OH, R k wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R k wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R 3 and R 4are, at each occurrence, independently selected from halogen, cyano, ═O, C-C alkyl, C-C alkenyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C cycloalkyl, —C(═O)R y , -C(=O)OR y , -C(=O)NR v R w , -C(=O)NR v OR y , -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y , -OR y , -OC(=O)R y , -OC(=O)OR y , -OC(=O)NR v R w , -S(=O) t R y , -S(=O) t NR v R w , -S(=O) t NR v C(=O)R y , -P(=O)R z R z , phenyl, or 5- or 6-membered heteroaryl; R 3 and R 4 Any one of C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is cyano, —C(═O)R y , -C(=O)OR y , -C(=O)NR v R w , -NR v R w , -NRv C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y , -OR y , -OC(=O)R y , -OC(=O)OR y , -OC(=O)NR v R w , -S(=O) t R y , and -S(=O) t NR v R w and is substituted with 1 to 3 groups selected from R v , R w , and R x are each independently, at each occurrence, hydrogen, C-C alkyl, C-C cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R v , R w , and R x Any one of the C1-C4 alkyl groups may optionally be selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), substituted with 1 to 3 groups selected from -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R v , R w , and R x Any one of C3-C6 cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally selected from halogen, cyano, -OH, substituted with 1 to 3 groups selected from -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R y is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R y wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R y wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R z is, in each occurrence, independently C1-C2 alkyl, —OH, or —O(C1-C2 alkyl); k, m, and n are each independently an integer selected from 0, 1, 2, and 3; p, q, r, s, and t are each independently an integer selected from 1 and 2.

[0009] The compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) are modulators of AAT activity. In some embodiments, the compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC50 of 2.0 μM or less when tested in an AAT functional assay. 50 In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC of less than 0.5 μM when tested in an AAT functional assay. 50 It has.

[0010] In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an IC of 5.0 μM or less when tested in a Z-AAT elastase activity assay. 50 In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an IC of less than 2.0 μM when tested in a Z-AAT elastase activity assay. 50 It has.

[0011] In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 of 2.0 μM or less when tested in an ATT functional assay. 50 and has an IC of 5.0 μM or less when tested in the Z-AAT elastase activity assay 50 In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 of less than 0.5 μM when tested in an ATT functional assay. 50 and has an IC of 5.0 μM or less when tested in the Z-AAT elastase activity assay 50 In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 of 2.0 μM or less when tested in an ATT functional assay. 50 and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 In some embodiments, compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 of less than 0.5 μM when tested in an ATT functional assay.50 and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 It has.

[0012] In some embodiments, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, are provided for use in the treatment of AATD. In one aspect of the present disclosure, the compound of Formula (I) is selected from compounds 1-203 and 206-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. In some embodiments, the compound of the present disclosure is selected from compounds 1-227, tautomers of compounds 1-227, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD.

[0013] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise a compound selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional pharmaceutically active ingredient and / or at least one carrier.

[0014] Another aspect of the present disclosure provides a method of treating AATD, the method comprising administering to a subject in need thereof at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0015] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition as at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In some embodiments, the method comprises administering a compound selected from Compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with the at least one additional active agent, either in the same pharmaceutical composition or in separate compositions. In some embodiments, the subject in need of treatment carries a ZZ mutation. In some embodiments, the subject in need of treatment carries an SZ mutation.

[0016] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, either in the same pharmaceutical composition or as a separate composition, at least one additional active agent, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor. In some embodiments, the method comprises administering a compound selected from compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor.

[0017] In some embodiments, a method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition as at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as a separate composition, wherein the additional active agent is recombinant AAT. In some embodiments, a method comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition as at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the additional active agent is recombinant AAT.

[0018] Also provided are methods of modulating AAT, comprising administering to a subject in need thereof at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method of modulating AAT comprises administering to a subject in need thereof at least one compound selected from Compounds 1-227, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0019] Also provided is at least one compound selected from compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, provided is a compound selected from Compounds 1-227, as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0020] Also provided are pharmaceutical compositions comprising at least one compound selected from the compounds of Formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, provided are pharmaceutical compositions comprising a compound selected from Compounds 1-227, as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0021] I. Definition As used herein, the term "AAT" refers to alpha-1 antitrypsin or a variant thereof, including but not limited to an AAT gene variant such as the Z variant. As used herein, "Z-AAT" refers to an AAT variant having a Z variant.

[0022] As used herein, "mutation" can refer to a mutation in the SERPINA1 gene (the gene encoding AAT) or the effect of an alteration in the gene sequence on the AAT protein. A "SERPINA1 gene mutation" refers to a mutation in the SERPINA1 gene, and an "AAT protein mutation" refers to a mutation that results in an alteration in the amino acid sequence of the AAT protein. A genetic defect or mutation, or a change in a nucleotide within the gene, generally results in a mutation in the AAT protein translated from that gene.

[0023] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation on each allele.

[0024] As used herein, a patient with the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein.

[0025] As used herein, the term "AATD" means alpha-1 antitrypsin deficiency, an inherited disorder characterized by low circulating levels of AAT.

[0026] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also includes lesser amounts of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0027] The compounds of the present disclosure may be optionally substituted with one or more substituents. The phrase "optionally substituted" is understood to be used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be either the same or different at all positions. Combinations of substituents envisioned by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0028] The term "isotopically enriched" refers to species whose chemical structure differs from specific compounds of this disclosure only in their isotopic composition. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon by C, are within the scope of this disclosure.

[0029] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., geometric (or conformational) isomers, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present disclosure are within the scope of the present disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0030] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0031] "Stereoisomer" refers to both enantiomers and diastereomers.

[0032] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D"). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the source of the chemicals used in synthesis. Despite this variation, the concentration of naturally occurring stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when a "deuterated derivative" of a compound of the present disclosure is referred to, at least one hydrogen is replaced with deuterium well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0033] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0034] As used herein, the term "alkyl" refers to a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that may be fully saturated or contain one or more saturated units without being fully aromatic. Unless otherwise specified, alkyl groups contain 1-12 alkyl carbon atoms. In some embodiments, alkyl groups contain 1-10 aliphatic carbon atoms. In other embodiments, alkyl groups contain 1-8 aliphatic carbon atoms. In still other embodiments, alkyl groups contain 1-6 alkyl carbon atoms, in other embodiments, alkyl groups contain 1-4 alkyl carbon atoms, and in still other embodiments, alkyl groups contain 1-3 alkyl carbon atoms and 1-2 alkyl carbon atoms.

[0035] As used herein, the term "heteroalkyl" refers to an aliphatic group in which one, two, or three carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroalkyl groups can be substituted or unsubstituted, branched or unbranched.

[0036] As used herein, the term "alkenyl" means a straight-chain (ie, linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds.

[0037] "Cycloalkyl", "cyclic alkyl", "carbocyclyl", or "carbocycle" refers to a fused, spirocyclic, or bridged monocyclic C 3-9 hydrocarbons or fused, spirocyclic, bridged bicyclic or tricyclic C rings that are fully saturated or contain one or more unsaturated units, but are not fully aromatic; 8-14" refers to a hydrocarbon, and any individual ring within the bicyclic ring system has 3 to 9 members. Typically, cycloalkyls are fully saturated, while carbocyclyls may contain one or more units of unsaturation but are not aromatic. In some embodiments, cycloalkyl or carbocyclic groups contain 3 to 12 carbon atoms. In some embodiments, cycloalkyl or carbocyclic groups contain 3 to 8 carbon atoms. In some embodiments, cycloalkyl or carbocyclic groups contain 3 to 6 carbon atoms.

[0038] As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to a fused, spirocyclic, or bridged non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are heteroatoms. In some embodiments, a "heterocycle," "heterocyclyl," or "heterocyclic" group has 3 to 14 ring members in which one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and silicon, and each ring in the system contains 3 to 9 ring members. In some embodiments, a heterocyclyl contains 3 to 12 ring atoms. In some embodiments, a heterocyclyl contains 3 to 8 ring atoms. In some embodiments, a heterocyclyl contains 3 to 6 ring atoms.

[0039] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including in the case of N-substituted pyrrolidinyl) means one or more of:

[0040] As used herein, the term "alkoxy" refers to an alkyl group, as previously defined, in which one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is connected between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, fused, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0041] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, optionally substituted with one or more halogen atoms. The term "halogen" refers to F, Cl, Br, or I. In some embodiments, halogen is selected from F, Cl, and Br. Examples of haloalkyl include perhaloalkyl, such as -CHF, -CHF, -CF, -CF-, or -CFCF.

[0042] As used herein, "=O" refers to an oxo group.

[0043] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0044] As used herein, a "hydroxy" group refers to an --OH group.

[0045] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system with delocalized pi orbitals consisting of [4n+2]p orbitals, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0046] The term "aryl" refers to monocyclic, bicyclic, and tricyclic ring systems in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members, for a total of 5 to 14 ring members. In some embodiments, an aryl contains 6 or 10 carbon atoms. A non-limiting example of an aryl group is a phenyl ring.

[0047] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems in which at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members, for a total of 5 to 10 ring members. In some embodiments, heteroaryl contains 6 or 10 ring atoms.

[0048] Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butylcarbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide (OTs).Methods for adding (a process generally referred to as "protecting") and removing (a process generally referred to as "deprotecting") such amine protecting groups are well known in the art and can be found, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994 (incorporated herein by reference in its entirety), and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999).

[0049] Examples of suitable solvents that may be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0050] Examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0051] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds, which are formed between an acidic and a base group of the compound, such as an amino acid functional group, or a basic and an acidic group of the compound, such as a carboxyl functional group.

[0052] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0053] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dione, hexylate-1,6 ... Included are dionate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0054] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4The (alkyl)4 salt is included. This disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0055] The terms "patient" and "subject" are used interchangeably and refer to animals including humans.

[0056] The terms "effective dose", "effective amount", "therapeutically effective dose", and "therapeutically effective amount" are used interchangeably herein and refer to the amount of a compound that, when administered, produces the desired effect (e.g., improvement of AATD or symptoms of AATD, reduction in the severity of AATD or symptoms of AATD, and / or reduction in the incidence or prevalence of AATD or symptoms of AATD). The exact amount of the effective dose will depend on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0057] As used herein, the term "treatment" and its cognates (e.g., "treat," "treating") refer to the improvement of AATD or its symptoms in a subject, the delay in the onset of AATD or its symptoms in a subject, or the reduction in the severity of AATD or its symptoms in a subject. As used herein, "treatment" and its cognates include, but are not limited to, improving liver and / or spleen function, reducing jaundice, improving lung function, reducing lung disease and / or lung exacerbations (e.g., emphysema), reducing skin diseases (e.g., necrotizing panniculitis), increasing growth in children, improving appetite, and reducing fatigue. Improvement or reduction in the severity of any of these symptoms can be readily assessed according to methods and techniques known or subsequently developed in the art.

[0058] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include a specific dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, recognized by those of skill in the art, that provides the equivalent pharmacological effect as that provided by the specific dose, amount, or weight percent. Typically, the term "about" refers to a variation of up to 10%, up to 5%, or up to 2% of the stated value.

[0059] Any one or more of the compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, the any one or more compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, at least one compound selected from compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, a compound selected from Compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound selected from compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, a compound selected from Compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.In some embodiments, at least one compound selected from compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily. In some embodiments, a compound selected from Compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily.

[0060] Any one or more of the compounds (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In some embodiments, the any one or more compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0061] As used herein, "AAT augmentation therapy" refers to the use of alpha-1 antitrypsin protein (AAT) from the plasma of healthy human donors to enhance (increase) circulating alpha-1 antitrypsin levels. "AAT augmentation therapy" refers to the administration of recombinant AAT.

[0062] In some embodiments, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, 400 mg to 2,500 mg, or 400 mg to 600 mg of a compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, are administered once daily, twice daily, or three times daily. In some embodiments, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, 400 mg to 2,500 mg, or 400 mg to 600 mg of a compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, are administered once daily, twice daily, or three times daily. In some embodiments, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, or 400 mg to 600 mg of a compound selected from compounds 1-227 is administered once daily, twice daily, or three times daily.

[0063] Those skilled in the art will recognize that when an amount of a compound is disclosed, the relative amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. Note that the disclosed amounts of compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts are based on the free base form of the reference compound. For example, "10 mg of at least one compound selected from the compound of formula (I) and a pharmaceutically acceptable salt thereof" includes 10 mg of the compound of formula (I) and a concentration of a pharmaceutically acceptable salt of the compound of formula (I) equivalent to 10 mg of the compound of formula (I).

[0064] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0065] References herein to methods of treatment (e.g., methods of treating AATD) using one or more compounds (e.g., compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe)), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) are intended to include, but are not limited to, references to: For example, one or more compounds for use in methods for treating AATD (e.g., compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe)), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds), and / or For example, it should be understood that reference to the use of one or more compounds (e.g., compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe)), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) in the manufacture of a medicament for treating AATD.

[0066] Exemplary embodiments: Some embodiments of the present disclosure include, but are not limited to, the following. 1. A compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: V 1 and V 2 each independently represents N or -CR2 and U is —OH or —NH; X is absent, a bond, -(CR a R a ) p - or -R a’ C=CR a’ - and Y is absent, a bond, -(CR b R b ) q - or -R b’ C=CR b’ - and T is -CR c R c COOH, -CR c =CR c COOH, -CN, or [ka] and R a and R b may each independently, in each occurrence, be hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R a’ and R b’ are each independently, at each occurrence, hydrogen, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R c is, in each occurrence, independently hydrogen, halogen, —OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; Ring A is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C or C 10 aryl, or 5- to 10-membered heteroaryl; Ring B is C4-C 12 Cycloalkyl, C or C 10aryl, benzyl, or 5- to 10-membered heteroaryl; Z is -CN, [ka] and When T is not -CN, ring C is C3-C 12 Cycloalkyl, C or C 10 aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; When T is -CN, ring C is C3-C 12 cycloalkyl or 3- to 12-membered heterocyclyl; R E , R F , and R G are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -CR p (=N)OR s , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s , -OC(=O)R s , or -OC(=O)NR p R q and R E , R F , and R G Any one of C1-C6 alkyl or C2-C6 alkenyl is optionally cyano, —C(═O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR pC(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) r R s , and -S(=O) r NR p R q and is substituted with 1 to 3 groups selected from R p , R q , and R r are each independently, in each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R p , R q , and R r Any one of C1-C4 alkyl optionally is halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2, R p , R q , and R r wherein any one of the C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)O(C1-C2 alkyl), —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R sis, in each occurrence, independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; R s wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R s wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R 1 is halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or —O—(C3-C6 cycloalkyl); R 2 are, in each occurrence, independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl, or 5- or 6-membered heteroaryl; R 2 wherein the C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is optionally cyano, —C(═O)R k , -C(=O)OR k , -C(=O)NR h R i , -NRh R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k , -OR k , -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -S(=O) s R k , and S(=O) s NR h R i and is substituted with 1 to 3 groups selected from R h , R i , and R j are each independently, at each occurrence, hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; R h , R i , and R j wherein any one of the C1-C4 alkyls is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R h , R i , and R jwherein the C3-C6 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R k is, in each occurrence, independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; -OR k But it cannot be -OH, R k wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R k wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R 3 and R 4are, at each occurrence, independently selected from halogen, cyano, ═O, C-C alkyl, C-C alkenyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C cycloalkyl, —C(═O)R y , -C(=O)OR y , -C(=O)NR v R w , -C(=O)NR v OR y , -(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y , -OC(=O)R y , -OC(=O)OR y , -OC(=O)NR v R w , -S(=O) t R y , -S(=O) t NR v R w , -S(=O) t NR v C(=O)R y , -P(=O)R z R z , phenyl, or 5- or 6-membered heteroaryl; R 3 and R 4 Any one of C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, or 5- or 6-membered heteroaryl is cyano, —C(═O)R y , -C(=O)OR y , -C(=O)NR v R w , -NRv R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y , -OR y , -OC(=O)R y , -OC(=O)OR y , -OC(=O)NR v R w , -S(=O) t R y , and -S(=O) t NR v R w and is substituted with 1 to 3 groups selected from R v , R w , and R x are each independently, at each occurrence, hydrogen, C-C alkyl, C-C cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R v , R w , and R x Any C1-C4 alkyl among these may optionally be halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, substituted with 1 to 3 groups selected from -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R v , R w , and R xwherein any one of the C3-C6 cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R y is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R y wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R y wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R z is, in each occurrence, independently C1-C2 alkyl; -OH, or -O(C1-C2 alkyl), k, n, and o are each independently an integer selected from 0, 1, 2, and 3; A compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein p, q, r, s, and t are each independently an integer selected from 1 and 2. 2. Represented by formula (IIa): [ka] During the ceremony, Y is absent or a bond, -CR b R b - or -R b’ C=CR b’ - and R b is, in each occurrence, independently hydrogen or C1-C2 alkyl; Ring B is optionally R 1 and Ring B is C4-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1. 3. Represented by formula (IIb) or (IIc): [ka] During the ceremony, Y is absent or a bond, -CR b R b - or -R b’ C=CR b’ - and R b is, in each occurrence, independently hydrogen or C1-C2 alkyl; Ring B is optionally R 1 and Ring B is C4-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1. 4. Y is absent or is a bond, -CH2-, or The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-3, wherein —HC═CH—, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 5. Represented by formula (III): [ka] During the ceremony, X is absent, a bond, or -(CR a R a ) p - and R a are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R c is, in each occurrence, independently hydrogen, F, —OH, benzyl, C1-C2 alkyl, or C1-C2 alkoxy; Ring B is optionally R 1 and Ring B is cyclobutyl, phenyl, pyridinyl, or pyrimidinyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 6. X is absent, a bond, —CH—, —CHCH—, —CHCH—, or —CHCHCH—; Ring B is optionally R 1 and Ring B is cyclobutyl, phenyl, pyridin-4-yl, or pyrimidin-4-yl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 7. Represented by formula (IV): [ka] During the ceremony, T is -CH2COOH, -CHCH3COOH, -CHC2H5COOH, -C(CH3)2COOH, -CF2COOH, -CH=CHCOOH, -C(CH3)(OH)COOH, -C(CH3)(OCH3)COOH, cyano, -CH(benzyl)COOH, or optionally R 3 and ring A is substituted with When Z is ring C, ring C may optionally be R 4 and Ring C is C3-C6 cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R 1 is halogen, C1-C2 alkyl, or C1-C2 haloalkyl; k is an integer selected from 0, 1, and 2; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-6, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 8.R 1 is F, Cl, or —CH3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 9. When T is ring A, ring A may optionally be R 3 and Ring A is C3-C7 cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-8, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 10. When T is ring A, ring A may optionally be R 3 and Ring A is C-C cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 11. When T is ring A, ring A may optionally be R 3 and ring A is substituted with [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 12. When T is ring A, ring A may optionally be R 3 and ring A is substituted with [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 13. When Z is ring C, ring C may optionally be R 4and Ring C is C-C cycloalkyl or 4-6 membered heterocyclyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 14. When Z is ring C, ring C may optionally be R 4 and ring C is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 15. When Z is ring C, ring C may optionally be R 4 and ring C is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 16.Z is, [ka] If R E , R F , and R G are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)OR s , -C(=O)NR p R q , -CR p (=N)OR s , -NR p R q , or -OR s and R E , R F, and R G Any one of C1-C6 alkyl is optionally selected from cyano and -OR s and is substituted with 1 to 3 groups selected from R p and R q are each independently, in each occurrence, hydrogen or C1-C4 alkyl; R s is, in each occurrence, independently hydrogen or C1-C4 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-12, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 17.Z is, [ka] If R E , R F , and R G are each independently hydrogen, halogen, C1-C2 alkyl, -NR p R q , or -OR s and R E , R F , and R G wherein any one of the C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from cyano, —OH, and —OCH3; R p and R q are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R s is, in each occurrence, independently hydrogen or C1-C2 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-12 and 16, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 18.Z is, [ka] If R E , R F , and R G are each independently hydrogen, F, -CHCN, -OH, -OCH, -CH, -CH, or -CHOCH; Z, [ka] If R E and R F are each independently -CH3 or -NH2, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-12, 16, and 17, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 19. Represented by formula (Va), (Vb), or (Vc): [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-18, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 20. Represented by formula (VIa), (VIb), or (VIc): [ka] 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 21. Represented by formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe): [ka] 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-20, wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 22.R 2 is, in each occurrence, independently hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -NR h R i or cyclopropyl, and R h and R i is, at each occurrence, independently hydrogen or C1-C4 alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 23.R 2 is, at each occurrence, independently hydrogen, F, Cl, —CH3, —NH2, or cyclopropyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 24.R 3 is, in each occurrence, independently selected from halogen, cyano, ═O, C-C alkyl, C-C alkoxy, C-C haloalkyl, —C(═O)OR y , -C(=O)NR v S(=O)2R y , -S(=O)2NR v R w , -S(=O)2NR v C(=O)R w , -P(=O)R z R z or 5- or 6-membered heteroaryl; R 3 wherein the C1-C6 alkyl or 5-membered heteroaryl is optionally selected from cyano, -C(=O)OR y , -ORy , and -NR v R w and is substituted with 1 to 3 groups selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C4 alkyl; R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 25.R 3 is, in each occurrence, independently selected from halogen, cyano, ═O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)OR y , -C(=O)NR v S(=O)2R y , -S(=O)2NR v R w , -S(=O)2NR v C(=O)R y or a 5-membered heteroaryl; R 3 wherein the C1-C4 alkyl or 5-membered heteroaryl is optionally selected from cyano, -C(=O)OR y , -OR y , and -NR v R w and is substituted with 1 to 3 groups selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R y is, in each occurrence, independently hydrogen or C1-C2 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-24, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 26.R3 is, in each occurrence, independently selected from halogen, cyano, ═O, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, —C(═O)OR y , -C(=O)NR v S(=O)2R y , -S(=O)2NR v R w , -S(=O)2NR v C(=O)R y , tetrazolyl, or oxadiazolyl; R 3 wherein the C1-C2 alkyl or oxadiazolyl is optionally substituted with 1 to 3 groups selected from cyano, —COOH, and —OH; R v and R w is, at each occurrence, independently hydrogen or —CH; R y is, in each occurrence, independently hydrogen or -CH3, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-25, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 27.R 3 may, in each occurrence, independently be: F, cyano, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OCH3, -OCH3, -COOH, -CH2COOH, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 26, wherein: -C(=O)NHS(=O)2CH3, -S(=O)2NHCH3, -S(=O)2NHC(=O)CH3, tetrazol-5-yl, 1,2,4-oxadiazol-5(4H)-onyl, or 1,3,4-oxadiazol-2(3H)-onyl; and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 28.R 4is, in each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C haloalkyl, -C(=O)R y , -C(=O)OR y , C(=O)NR v R w , -NR v R w , -OR y , or -P(=O)R z R z and R v and R w are each independently, in each occurrence, hydrogen or C1-C4 alkyl; R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-27, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 29.R 4 is, in each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C haloalkyl, -C(=O)R y , -C(=O)OR y , C(=O)NR v R w , -NR v R w , or -OR y and R v and R w are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-28, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 30.R 4is, in each occurrence, independently selected from halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -C(=O)OR y , or -OR y and R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-29, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 31.R 4 is, at each occurrence, —C(═O)OC(CH3)3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-31, wherein m is 0, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 33. A compound selected from compounds 1-227, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 34. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-33. 35. A method for treating alpha-1 antitrypsin (AAT) deficiency, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-33, or a therapeutically effective amount of the pharmaceutical composition of embodiment 34. 36. A method for modulating alpha-1 antitrypsin (AAT) activity, comprising contacting the AAT with a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-33, or a therapeutically effective amount of the pharmaceutical composition of embodiment 34. 37. The method of embodiment 35 or embodiment 36, wherein the therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is administered in combination with AAT augmentation therapy and / or AAT replacement therapy. II. Compounds and Compositions

[0067] In some embodiments, the compound of the present disclosure is a compound of formula (I): [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: V 1 and V 2 are each independently N or -CR 2 and U is —OH or —NH; X is absent, a bond, -(CR a R a ) p - or -R a’ C=CR a’ - and Y is absent or a bond, -(CR b R b ) q - or -R b’ C=CR b’ - and T is -CR c R c COOH, -CR c =CR c COOH, -CN, or [ka] and R a and R b are each independently, in each occurrence, hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R a’ and R b’ are each independently, at each occurrence, hydrogen, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R c is, in each occurrence, independently hydrogen, halogen, —OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; Ring A is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C or C 10 aryl, or 5- to 10-membered heteroaryl; Ring B is C4 to C 12 Cycloalkyl, C or C 10 aryl, benzyl, or 5- to 10-membered heteroaryl; Z is -CN, [ka] and When T is not -CN, ring C is C3-C 12 Cycloalkyl, C or C 10 aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; When T is -CN, ring C is C3-C 12 cycloalkyl or 3- to 12-membered heterocyclyl; R E , R F , and R G are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R s, -C(=O)OR s , -C(=O)NR p R q , -CR p (=N)OR s , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s , -OC(=O)R s , or -OC(=O)NR p R q and R E , R F , and R G Any one of C1-C6 alkyl or C2-C6 alkenyl is optionally cyano, —C(═O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) r R s , and -S(=O) r NR p R q and is substituted with 1 to 3 groups selected from R p , R q , and R rare each independently, at each occurrence, hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl; R p , R q , and R r wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, C1-C3 alkoxy, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R p , R q , and R r wherein any one of the C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)O(C1-C2 alkyl), —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R s is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; R s wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R swherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R 1 is halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or —O—(C3-C6 cycloalkyl); R 2 is, in each occurrence, independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl, or 5- or 6-membered heteroaryl; R 2 The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl may optionally be cyano, —C(═O)R k , -C(=O)OR k , -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k , -OR k , -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -S(=O) s R k , and S(=O) s NR h R i and is substituted with 1 to 3 groups selected from R h , R i , and R j are each independently, at each occurrence, hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; R h , R i , and R j wherein any one of the C1-C4 alkyls is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R h , R i , and R j wherein the C3-C6 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R k is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; -OR k cannot be -OH, R kwherein C1-C4 alkyl is optionally halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, substituted with 1 to 3 groups selected from -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R k wherein the C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, —C(═O)O(C1-C2 alkyl), —C(═O)NH2, —C(═O)NH(C1-C2 alkyl), and —C(═O)N(C1-C2 alkyl)2; R 3 and R 4 are, at each occurrence, independently selected from halogen, cyano, ═O, C-C alkyl, C-C alkenyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C cycloalkyl, —C(═O)R y , -C(=O)OR y , -C(=O)NR v R w , -C(=O)NR v OR y , -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR vS(=O) t R y 、- OR y , -OC(=O)R y , -OC(=O)OR y , -OC(=O)NR v R w , -S(=O) t R y , -S(=O) t NR v R w , -S(=O) t NR v C(=O)R y , -P(=O)R z R z , phenyl, or 5- or 6-membered heteroaryl; R 3 and R 4 Any one of C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is optionally cyano, -C(=O)R y , -C(=O)OR y , -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y 、 -OR y , -OC(=O)R y , -OC(=O)OR y , -OC(=O)NR v R w , -S(=O) t R y , and -S(=O) t NR v R w and is substituted with 1 to 3 groups selected from R v , R w , and R x are each independently, at each occurrence, hydrogen, C-C alkyl, C-C cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R v , R w , and R x wherein any one of C1-C4 alkyl is optionally halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), substituted with 1 to 3 groups selected from -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R v , R w , and R x Any one of C3-C6 cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally selected from halogen, cyano, -OH, substituted with 1 to 3 groups selected from -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; R y is, in each occurrence, independently hydrogen, C-C alkyl, C-C cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R yC1-C4 alkyl is optionally halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2, R y C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl may optionally be halogen, cyano, —OH, —NH2, NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —C(═O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2, R z is, in each occurrence, independently C1-C2 alkyl, —OH, or —O(C1-C2 alkyl); k, m, and n are each independently an integer selected from 0, 1, 2, and 3; p, q, r, s, and t are each independently an integer selected from 1 and 2.

[0068] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (IIa): [ka] During the ceremony, Y is absent or a bond, -CR b R b - or -R b’ C=CR b’ - and R b is, in each occurrence, independently hydrogen or C1-C2 alkyl; Ring B optionally comprises R 1 and Ring B is C4-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; All other variables are as defined in formula (I).

[0069] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (IIb) or Formula (IIc): [ka] During the ceremony, Y is absent or a bond, -CR b R b - or -R b’ C=CR b’ - and R b is, in each occurrence, independently hydrogen or C1-C2 alkyl; Ring B optionally comprises R 1 and Ring B is C4-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; All other variables are as defined in formula (I).

[0070] In some embodiments, Y is absent, a bond, or selected from —CH— and —HC═CH— in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula (I), (IIa), (IIb), or (IIc), and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0071] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (III): [ka] During the ceremony, X is absent, a bond, or -(CR a R a ) p - and R a are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R c is, in each occurrence, independently hydrogen, F, —OH, benzyl, C1-C2 alkyl, or C1-C2 alkoxy; Ring B optionally comprises R 1 and Ring B is cyclobutyl, phenyl, pyridinyl, or pyrimidinyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0072] In some embodiments, X is absent, a bond, or -CH2- in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formula (I), (IIa), (IIb), (IIc), or (III). -CHCH3-, -CH2CH2-, and -CHCH3CH2-; ring B is optionally selected from R 1 and Ring B is selected from cyclobutyl, phenyl, pyridin-4-yl, and pyrimidin-4-yl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0073] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (IV): [ka] During the ceremony, T is -CH2COOH, -CHCH3COOH, -CHC2H5COOH, -C(CH3)2COOH, -CF2COOH, -CH=CHCOOH, -C(CH3)(OH)COOH, -C(CH3)(OCH3)COOH, -CN, -CH(benzyl)COOH, or optionally R 3 and ring A is substituted with When z is ring C, ring C may optionally be R 4 and Ring C is C3-C6 cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R 1 is halogen, C1-C2 alkyl, or C1-C2 haloalkyl; k is an integer selected from 0, 1, and 2; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0074] In some embodiments, R 1 is F, Cl, or —CH in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Formulas (I), (IIa), (IIb), (IIc), (III), or (IV), and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0075] In some embodiments, T is ring A in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), wherein ring A is optionally selected from R 3 and Ring A is C3-C7 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl, and all other variables are as defined in any one of the preceding embodiments.

[0076] In some embodiments, ring A is optionally R 3and Ring A is C-C cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, or 4- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0077] In some embodiments of Formula (I), (IIa), (IIb), (IIc), (III), or (IV), T is optionally selected from R 3 and ring A is substituted with [ka] is selected from All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0078] In some embodiments of Formula (I), (IIa), (IIb), (IIc), (III), or (IV), T is optionally selected from R 3 and ring A is substituted with [ka] All other variables selected from and not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0079] In some embodiments of Formula (I), (IIa), (IIb), (IIc), (III), or (IV), Z is optionally selected from R 4 wherein Ring C is a 3- or 4-membered cycloalkyl or a 4- to 6-membered heterocyclyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0080] In some embodiments of Formula (I), (IIa), (IIb), (IIc), (III), or (IV), Z is optionally selected from R 4 and ring C is substituted with [ka] All other variables selected from and not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0081] In some embodiments of Formula (I), (IIa), (IIb), (IIc), (III), or (IV), Z is Ring C and optionally R 4 and ring C is substituted with [ka] All other variables selected from and not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0082] In some embodiments of Formula (I), (IIa), (IIb), (IIc), (III), or (IV), Z is [ka] and R E , R F , and R G are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)OR s , -C(=O)NR p R q , -CR p (=N)OR s , -NR p R q , or -OR s and R E , R F , and R G Any one of C1-C6 alkyl is optionally selected from cyano and -OR s and is substituted with 1 to 3 groups selected from R p and R q are each independently, in each occurrence, hydrogen or C1-C4 alkyl; R s is, in each occurrence, independently hydrogen or C1-C4 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0083] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Z is [ka] If R E , R F , and R G are each independently hydrogen, halogen, C1-C2 alkyl, -NR p R q , or -OR s and R E , R F , and R G wherein any one of the C1-C6 alkyl groups is optionally substituted with 1 to 3 groups selected from cyano, —OH, and —OCH3; R p and R q are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R s is, in each occurrence, independently hydrogen or C1-C2 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0084] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z, [ka] If R E , R F , and R G are each independently hydrogen, F, -CHCN, -OH, -OCH, -CH, -CH, or -CHOCH; Z, [ka] If R E and R F are each independently —CH or —NH, All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0085] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (Va), Formula (Vb), or Formula (Vc): [ka] All other variables are as defined in formula (I) or any one of the above embodiments.

[0086] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (VIa), Formula (VIb), or Formula (VIc): [ka] wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in formula (I) or any one of the preceding embodiments.

[0087] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (VIIa), Formula (VIIb), Formula (VIIc), Formula (VIId), or Formula (VIIe): [ka] [ka] wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in formula (I) or any one of the preceding embodiments.

[0088] In some embodiments of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), R 2 is, in each occurrence, independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -NR h R i and cyclopropyl, R h and R i is independently, at each occurrence, hydrogen or C-C alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0089] In some embodiments of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), R 2 is, at each occurrence, independently selected from F, Cl, —CH 3 , —NH 2 , and cyclopropyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0090] In some embodiments of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), R 2 is, at each occurrence, independently selected from hydrogen, halogen, cyano, C-C alkyl (optionally substituted with 1 to 3 groups selected from -CN, -OH, -OCH, and -NH), C-C haloalkyl, and C-C cycloalkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0091] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 3 is, in each occurrence, independently selected from halogen, cyano, ═O, C-C alkyl, C-C alkoxy, C-C haloalkyl, —C(═O)OR y , -C(=O)NR v S(=O)2R y , -S(=O)2NR v R w , -S(=O)2NR v C(=O)R y , -P(=O)R z R z and 5- and 6-membered heteroaryl; R 3 The C1-C6 alkyl or 5-membered heteroaryl may optionally be cyano, -OR y , and -NR v R w and is substituted with 1 to 3 groups selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C4 alkyl; R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0092] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 3 is, in each occurrence, independently selected from halogen, cyano, ═O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, —C(═O)OR y , -C(=O)NR v S(=O)2R y , -S(=O)2NR v R w , -S(=O)2NR v C(=O)R yand 5-membered heteroaryl; R 3 The C1-C4 alkyl or 5-membered heteroaryl may optionally be cyano, -OR y , and -NR v R w and is substituted with 1 to 3 groups selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R y is, in each occurrence, independently hydrogen or C1-C2 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0093] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 3 is, in each occurrence, independently selected from halogen, cyano, ═O, C-C alkyl, C-C alkoxy, C-C haloalkyl, —C(═O)OR y , -C(=O)NR v S(=O)2R y , -S(=O)2NR v R w , -S(=O)2NR v C(=O)R y , tetrazolyl, and oxadiazolyl; R 3 wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups selected from cyano and —OH; R v and R w is, at each occurrence, independently hydrogen or —CH; R y is, in each occurrence, independently hydrogen or —CH; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0094] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 3 is, in each occurrence, independently: F, cyano, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OCH3, -OCH3, All other variables selected from -COOH, -CH2COOH, -C(=O)NHS(=O)2CH3, -S(=O)2NHCH3, -S(=O)2NHC(=O)CH3, tetrazol-5-yl, 1,2,4-oxadiazol-5(4H)-onyl, and 1,3,4-oxadiazol-2(3H)-onyl, and not specifically defined in this embodiment, are as defined in any one of the preceding embodiments.

[0095] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 4 is, in each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C alkoxy, C-C haloalkyl, —C(═O)OR y , -C(=O)OR y , -OR y , and -S(=O)R y is selected from R 3 The C1-C6 alkyl is optionally cyano, -OR y , and -C(=O)OR y , and -NR v R w and is substituted with 1 to 3 groups selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C6 alkyl; R y is, in each occurrence, independently hydrogen and C1-C4 alkyl; R y wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —OCH3, and —NH2; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0096] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 4 is, in each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C haloalkyl, -C(=O)R y , -C(=O)OR y , C(=O)NR v R w , -NR v R w , -OR y , and -P(=O)R z R z is selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C4 alkyl; R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0097] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 4 is, in each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C haloalkyl, -C(=O)R y , -C(=O)OR y , C(=O)NR v R w , -NR v R w , and -OR y is selected from R v and R w are each independently, in each occurrence, hydrogen or C1-C2 alkyl; R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0098] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 4 is, in each occurrence, independently selected from halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -C(=O)OR y , and -OR y is selected from R y is, in each occurrence, independently hydrogen or C1-C4 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0099] In some embodiments, R in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure 4 is, at each occurrence, C(=O)OC(CH), and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0100] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 0, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0101] In some embodiments, the compound of any one of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) is selected from compounds 1-227 (Table I below) and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 20-1]

Table 20-2

Table 20-3

Table 20-4

Table 20-5

Table 20-6

Table 20-7

Table 20-8

Table 20-9

Table 20-10

Table 20-11

Table 20-12

Table 20-13

Table 20-14

Table 20-15

Table 20-16

Table 20-17

Table 20-18

[0102] Some embodiments of the present disclosure include derivatives of compounds 1-227 or compounds of formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), or tautomers thereof. In some embodiments, the derivatives are silicon derivatives in which at least one carbon atom in a compound selected from compounds 1-227 and compounds of formulae (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) is replaced by silicon. In some embodiments, the derivative is a boron derivative in which at least one carbon atom in a compound selected from compounds 1-227, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers thereof, is replaced by boron. In other embodiments, the derivative is a phosphate derivative in which at least one carbon atom in a compound selected from compounds 1-227, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers thereof, is replaced by phosphorus. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, the replacement of carbon with silicon, boron, or phosphorus can result in compounds with biological activity similar to the original carbon-containing compound.

[0103] In some embodiments, the derivative is a silicon derivative in which one carbon atom in a compound selected from Compounds 1-227, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers thereof, is replaced by silicon. In other embodiments, two carbon atoms are replaced by silicon. The carbon replaced by silicon may be a non-aromatic carbon. In some embodiments, a quaternary carbon atom in a tert-butyl moiety may be replaced by silicon. In some embodiments, the silicon derivatives of the present disclosure may include one or more hydrogen atoms replaced by deuterium. For example, one or more hydrogen atoms in a tert-butyl moiety in which a carbon is replaced by silicon may be replaced by deuterium. In other embodiments, silicon derivatives of compounds selected from compounds 1-227, compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), and tautomers thereof, can have silicon incorporated into a heterocycle.

[0104] In some embodiments, examples of silicon derivatives of compounds 1-227 or compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds: [ka] [ka] and any variable not specifically defined is as defined in any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0105] In some embodiments, examples of silicon derivatives of compounds 1-227 or compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds: [ka] and any variable not specifically defined is as defined in any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0106] In some embodiments, examples of boron derivatives of compounds 1-227 or compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds: [ka] and any variable not specifically defined is as defined in any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0107] In some embodiments, examples of boron derivatives of compounds 1-227 or compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds: [ka] and any variable not specifically defined is as defined in any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0108] In some embodiments, examples of phosphate derivatives of compounds 1-227 or compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds: [ka] and any variable not specifically defined is as defined in any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0109] In some embodiments, examples of phosphate derivatives of compounds 1-227 or compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds: [ka] and any variable not specifically defined is as defined in any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0110] Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound selected from compounds according to any of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) and compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

[0111] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, or lubricant.

[0112] It is also understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise at least one other active agent. Alternatively, a pharmaceutical composition comprising at least one compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered as a separate composition simultaneously with, prior to, or subsequent to a composition comprising at least one additional active agent. In some embodiments, a pharmaceutical composition comprising at least one compound selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered as a separate composition simultaneously with, prior to, or subsequent to a composition comprising at least one additional active agent.

[0113] In some embodiments, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, are combined with at least one additional active agent for simultaneous, separate, or sequential use in the treatment of AATD. In some embodiments, when the use is simultaneous, the compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and the at least one additional active agent are in separate pharmaceutical compositions. In some embodiments, when used simultaneously, the compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one additional active agent are together in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from Compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0114] In some embodiments, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided for use in a method of treating AATD, the method comprising co-administering the composition and an additional active agent. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0115] In some embodiments, a compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with an additional active agent, are provided for use in a method of treating AATD. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0116] In some embodiments, an additional active agent is provided for use in a method for treating AATD, the method comprising co-administering the additional active agent with a compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0117] In some embodiments, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided for use in methods of treating AATD, wherein the compounds are prepared for administration in combination with an additional active agent. In some embodiments, the compounds and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and the additional active agent are prepared for simultaneous administration. In some embodiments, the compounds and the additional active agent are prepared for sequential administration. In some embodiments, the compounds are selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0118] In some embodiments, compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with an additional active agent, are provided for use in methods of treating AATD. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0119] In some embodiments, an additional active agent is provided for use in the method of treating AATD, wherein the additional active agent is prepared for administration in combination with a compound of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from Compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0120] In some embodiments, the additional active agent is selected from the group consisting of alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor and recombinant AAT. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor.

[0121] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants appropriate for the desired particular dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C.B. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose), and the like. Ingredients include, but are not limited to, corn starch, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0122] In another aspect of the present invention, the compounds and pharmaceutical compositions described herein are used to treat AATD. In some embodiments, the subject in need of treatment with the compounds and compositions of the present disclosure has a ZZ mutation. In some embodiments, the subject in need of treatment with the compounds and compositions of the present disclosure has an SZ mutation.

[0123] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof a compound selected from any of the compounds of Formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound of Formula (I) is selected from compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof has a Z mutation in the alpha-1 antitrypsin gene. In some embodiments, the patient in need thereof is homozygous for a Z mutation in the alpha-1 antitrypsin gene.

[0124] Another aspect of the present disclosure provides a method of modulating alpha-1 antitrypsin activity, comprising contacting the alpha-1 antitrypsin with at least one compound of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method of modulating alpha-1 antitrypsin activity comprises contacting the alpha-1 antitrypsin with at least one compound selected from Compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0125] In some embodiments, the method of modulating alpha-1 antitrypsin activity is performed in vivo. In some embodiments, the method of modulating alpha-1 antitrypsin activity is performed ex vivo, and the alpha-1 antitrypsin is derived from a biological sample obtained from a human subject. In some embodiments, the method of modulating AAT is performed in vitro, and the alpha-1 antitrypsin is derived from a biological sample obtained from a human subject. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a sample obtained from a liver biopsy.

[0126] III. Compound Preparation All generic, subgeneric, and specific compound formulas disclosed herein are considered part of the present invention.

[0127] A. Compounds of Formula I The compounds of the present disclosure can be made according to standard chemical practices or as described herein. Throughout the synthetic schemes below, the following abbreviations are used in describing the preparation of compounds of Formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), compounds 1-227, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing: Abbreviation BrettPhos Pd G4 = Dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMA = dimethylacetamide DMAP = dimethylaminopyridine DME = dimethoxyethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOH = ethanol EtOAc = ethyl acetate HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) MeOH = methanol MP-TMT scavenger resin = macroporous polystyrene-bound trimercaptotriazine, a resin-bound equivalent of 2,4,6-trimercaptotriazine (TMT). MTBE = methyl tert-butyl ether NMM = N-methylmorpholine NMP = N-methylpyrrolidine Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2 = palladium(II) dichloride PdCl2(PPh3)2 = bis(triphenylphosphine) palladium(II) dichloride SFC = Supercritical Fluid Chromatography SPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TBAF = tetrabutylammonium fluoride tBuXPhos Pd G1 = chloro[2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) or t-BuXPhos palladium(II) phenethylamine chloride tBuXPhos Pd G3 = [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhos Pd G4 = Ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane; Dichloromethane; Methanesulfonate; N-Methyl-2-phenyl-aniline palladium(II) TFA = trifluoroacetic acid THF = tetrahydrofuran XPhos Pd G1 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride or (XPhos)palladium(II) phenethylamine chloride

[0128] In some embodiments, the process for preparing a compound of Formula (I), a tautomer thereof, a deuterated derivative of the compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing, comprises reacting a compound of Formula (I), a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof with a deprotecting reagent, as shown in Schemes 1-11 below (all variables are as defined for Formula (I) above). [ka]

[0129] Scheme 1 shows a method for the preparation of compounds of formula (I). 1 is an alcohol protecting group such as benzyl (Bn), methoxymethyl (MOM), or methyl (Me). In some instances, PG 1 When is a benzyl group, compounds of formula 1-2 can be prepared by hydrogenolysis of compounds of formula 1-1 using a palladium-carbon catalyst under an atmosphere of hydrogen. The reaction can be carried out at elevated pressure. Solvents such as MeOH, EtOH, or EtOAc can be used. PG 1 When is a group such as MOM, compounds of formula (I) can be prepared by treatment with an acid such as HCl. 1In instances where is a methyl group, the group can be removed by treatment with AlCl in the presence of octanethiol. In some instances, a reagent such as BBr can be used. Any other standard method suitable for the removal of an alcohol group can be used to prepare a compound of formula 1-2 from a compound of formula 1-1. [ka]

[0130] Scheme 2 shows a method for the preparation of compounds of formula 2-5. 1 is a halogen such as Br, I, or Cl. Compounds of formula 2-3 may be prepared by adding an alkyl group (Me) or a hydrogen group (R 20 The boronic acid or ester having the formula: 2-1 is a boronic acid or ester having the formula: 2-1. All other variables are as defined above. Compounds of formula 2-1 can be converted to compounds of formula 2-2 using any method suitable for halogenation reactions. For example, N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) in a solvent such as dichloromethane can be used. Compounds of formula 2-4 can be prepared from 2-2 and 2-3 using standard Suzuki coupling conditions. In some instances, Suzuki coupling conditions can include a catalyst such as Pd(dppf)Cl2 and a base such as Na2CO3. In some instances, a catalyst such as Pd2(dba)3 in the presence of a ligand such as Xphos can be used. Solvents such as DMF or DME can be used. The reaction is carried out with additional heat (e.g., 90°C). Compounds of formula 2-5 can be prepared from 2-4 using any method suitable for removing an alcohol protecting group. [ka]

[0131] A process for preparing compounds of formula 3-4 is shown in Scheme 3. PG 2 is any suitable carboxylic acid protecting group, for example, PG 2can be Me, Et, benzyl, or tert-butyl. All other variables are defined as above. Compounds of formula 3-2 can be prepared from compounds of formula 3-1 using any method suitable for Suzuki coupling. For example, Pd(dppf)Cl in the presence of NaCO can be used. Compounds of formula 3-3 can be prepared from compounds of formula 3-2 using any method suitable for removal of a carboxylic acid protecting group. For example, PG 2 When PG is a methyl ester, hydrolysis with a base such as LiOH or NaOH in a solvent such as THF and water can be used. 2 When is a group such as tert-butyl, treatment with an acid such as TFA or HCl provides compounds of formula 3-3. 1 and PG 2 When are both benzyl groups, compounds of formula 3-4 can be prepared directly from compounds of formula 3-2 by hydrogenation. [ka]

[0132] Scheme 4 shows a process for preparing a compound of formula 4-4. All variables are defined as above. A compound of formula 4-2 can be prepared by reductive alkylation between an indole of formula 2-1 and a ketone of formula 4-1. In some examples, the reductive alkylation can be carried out in the presence of a reagent such as triethylsilane and an acid (such as trifluoroacetic acid or methanesulfonic acid). The reaction can be carried out in a solvent such as dichloromethane. [ka]

[0133] Scheme 5 shows a method for preparing a compound of formula 5-4. All variables are defined as above. Compounds of formula 5-2 can be prepared from a ketone or aldehyde of formula 5-1 and an indole of formula 2-1 using any suitable conditions for carrying out a reductive alkylation reaction. In some examples, the reaction can be carried out in the presence of triethylsilane and trifluoroacetic acid. A solvent such as dichloromethane can be used. The reaction can also be carried out in the presence of heat (e.g., 40°C). [ka]

[0134] Scheme 6 shows a process for preparing indoles of formula 2-1. 2 and Q 3 is a halogen such as Br, Cl, or I. 1 is hydrogen or SiMe3. For example, in some processes, Q 2 is iodine, and Q 3 is bromine. In some examples, compounds of formula 6-3 can be prepared from compounds of formula 6-1 and alkynes of formula 6-2 using any conditions suitable for carrying out Sonogashira coupling. In some examples, a catalyst such as Pd(PPh3)2Cl2 in the presence of CuI can be used. A base such as triethylamine or diisopropylethylamine can be used. The reaction can be carried out in a solvent such as DMF in the presence of heat. In some examples, E 1When is SiMe3, the reaction can be carried out in the presence of TBAF. Compounds of formula 6-5 can be prepared from compounds of formula 6-3 by transition metal-catalyzed amination with amines of formula 6-4. The amination can be carried out in the presence of a palladium catalyst such as tBuXPhos Pd G3, tBuXPhos Pd G, or any other catalyst suitable for carrying out a Buchwald amination. A base such as NaOtBu can be used. The reaction can be carried out in a solvent such as xylene. The reaction can be carried out at room temperature or in the presence of heat. In some instances, cyclization to compounds of formula 2-1 occurs spontaneously in the amination reaction. In some instances, compounds of formula 2-1 from formula 6-5 are prepared by treatment with PdCl2 in a solvent such as MeCN. The reaction can be carried out with heat (e.g., 50°C). [ka]

[0135] Scheme 7 shows an alternative process for preparing compounds of formula 6-5. 4 is a halogen such as Br or I. 21 is hydrogen or an alkyl group, such as ethyl. Anilines of formula 7-1 can be arylated with boronic acids or esters 7-2 using any conditions suitable for N-arylation to give compounds of formula 7-3. In some instances, a Cu(OAc)2 catalyst can be used. The reaction can be carried out in the presence of a base such as K2CO3. A solvent such as DMSO can be used. Compounds of formula 6-5 can be prepared by Sonogashira coupling of compounds of formula 7-3 with alkynes of formula 7-4 to give compounds of formula 6-5. [ka]

[0136] Scheme 8 shows a process for preparing compounds of formula 8-7 from dihaloaryls of general formula 8-1. 5is a halogen, such as Cl, Br, or I. In some embodiments, group A is an aromatic or heteroaromatic ring. Amination of a compound of formula 8-1 with an amine of formula 8-2 provides a compound of formula 8-3. Any method suitable for the amination of aryl halides with amines can be used. For example, the reaction can be carried out in the presence of a ligand such as dppf and a catalyst such as Pd(OAc)2. In some examples, the reaction can be carried out in the presence of tBuXPhos Pd G1. The reaction can be carried out in the presence of a base such as NaOtBu. Indoles of formula 8-5 can be prepared by reacting a compound of formula 8-3 with a disubstituted alkyne of formula 8-4 in the presence of a suitable palladium catalyst. For example, a catalyst such as Pd(tBu3P)2 or JackiePhos Pd G3 can be used. In some alternative embodiments, Pd(OAc)2 can be used. The reaction is carried out in the presence of a suitable ligand. For example, dicyclohexylmethylamine (cHx)2NMe can be used. The reaction can be carried out in a solvent such as 1,4-dioxane and in the presence of heat (e.g., 60°C). [ka]

[0137] As shown in Scheme 9, any conditions suitable for the Chang-Ramm coupling of a compound of formula 9-1 with an iodide of formula 9-2 can be used to prepare a compound of formula 9-3. Compounds of formula 9-4 can be prepared from compounds of formula 9-3 using any method suitable for bromination of indoles at the C2 position. In some embodiments, the reaction is carried out in the presence of tert-butyllithium, followed by quenching with an electrophilic bromide source such as 1,2-dibromotetrachloroethane. The sp2-sp3 coupling from indoles of formula 9-4 to compounds of formula 9-5 can be carried out using photoredox cross-coupling conditions. For example, a trifluoroborate salt with an iridium-based photocatalyst is used in a flow reactor illuminated with a 450 nM Vaportech LED 124-watt lamp. Compounds of formula 9-6 can be prepared from compounds of formula 9-5 using standard methods for alcohol deprotection. [ka]

[0138] As shown in Scheme 10, any conditions suitable for the indole formation of the benzoquinone of formula 8-2 with the amine of formula 10-1 with the ketoester of formula 10-1 can be used to prepare compounds of formula 10-2. In some embodiments, the reaction is carried out in the presence of zinc chloride and acetic acid. Compounds of formula 10-3 can be prepared from compounds of formula 10-2 using standard methods for alcohol protection. [ka]

[0139] As shown in Scheme 11, any suitable conditions for the Stille cross-coupling reaction of a vinyl-stannane with an iodide of formula 2-2 can be used to prepare compounds of formula 11-1. In some embodiments, the reaction is carried out in the presence of palladium tetrakis and tetraethylammonium chloride using a solvent such as dimethylformamide. Cyclopropanation uses a reagent such as ethyl 2-diazoacetate in the presence of (R,R)-PyBox. The reaction can be carried out in a solvent such as toluene and in the presence of heat (e.g., 50 °C). Compounds of formula 11-3 can be prepared from compounds of formula 11-2 using standard methods for ester hydrolysis as described above. Compounds of formula 11-4 can be prepared from compounds of formula 11-3 using standard methods for alcohol deprotection. [Example]

[0140] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0141] Example 1. Synthesis of Compounds All specific and generic compounds, methods for making those compounds, and intermediates disclosed for making those compounds are considered to be part of this disclosure.

[0142] A. Synthesis of Starting Materials The preparation of S1-S22 illustrates synthetic routes to intermediates used in the synthesis of compounds 1-227.

[0143] [ka] Step 1. Synthesis of 4-(benzyloxy)-1-bromo-2-iodobenzene (C2) To a solution of 4-bromo-3-iodophenol (88.1 g, 291.9 mmol) in acetone (840 mL) was added K2CO3 (48.4 g, 350.3 mmol) and NaI (13.1 g, 87.6 mmol). The resulting suspension was heated to 45-50 °C. Benzyl bromide (36.7 mL, 306.5 mmol) was added dropwise, and the reaction mixture was heated at 50 °C overnight. The reaction mixture was then cooled to room temperature. The solids were removed by filtration and washed with acetone. The resulting filtrate was concentrated in vacuo, diluted with dichloromethane (400 mL), and washed with 1 M NaOH (2 × 200 mL). The aqueous phase was extracted with dichloromethane (200 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 112 g of the desired product. 4-Benzyloxy-1-bromo-2-iodo-benzene (99%). 1 H NMR (300 MHz, chloroform-d) δ 7.50-7.32 (m, 7H), 6.84 (dd, J = 8.8, 2.9 Hz, 1H), 5.02 (s, 2H).

[0144] Step 2. Synthesis of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-pyran (C3) To a solution of 4-benzyloxy-1-bromo-2-iodo-benzene C2 (141.1 g, 344.6 mmol) and trimethyl(2-tetrahydropyran-4-ylthinyl)silane (75.0 g, 407.2 mmol) in triethylamine (900 mL) was added water (13.0 mL, 721.6 mmol), followed by copper iodide (8.0 g, 42.0 mmol) and dichloropalladium; triphenylphosphane (12.0 g, 17.1 mmol). The reaction mixture was purged with nitrogen for 2 minutes and then cooled to 0 °C for 5 minutes. To the mixture was added tetrabutylammonium fluoride (430 mL of a 1 M solution in THF, 430.0 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The resulting residue was diluted with dichloromethane and filtered through a pad of silica gel. The resulting filtrate was concentrated in vacuo to give a black oil that crystallized on standing, yielding 320 grams of solid. The solid was re-diluted in dichloromethane and filtered through a silica plug using a gradient of heptane (100%) and then (1:9 EtOAc-CHCl) / heptane (0-40%) until all the product was removed. The main homogenous fraction was concentrated in vacuo and dried under vacuum to give a solid that was triturated with heptane and filtered. After drying, 81.6 g of a beige solid was obtained. The mother liquor was concentrated and repurified by MPLC-0-15% EtOAc / heptane on an 880 g silica gel column. Pure fractions gave an oil that crystallized on standing, yielding an additional 49.6 g of the desired product. 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-pyran (95%). 1 H NMR(300 MHz,chloroform-d)δ 7.38-7.04(m,6H),6.88(d,J=3.0 Hz,1H),6.59(dd,J=8.9,3.1 Hz,1H),4.83(s,2H),3.81(m,2H),3.41(m,2H),2.75(dt,J=7.8,3.7 Hz,1H),1.94-1.42(m,4H).ESI-MS m / z calculated value 370.06, measured value 372.36(M+H) + .

[0145] Step 3. 5-(Benzyloxy)-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S1) To a mixture of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-pyran C3 (3.3 g, 8.1 mmol), 4-fluoroaniline (1.0 g, 9.0 mmol), and tBuXxPhos Pd G3 (0.34 g, 0.43 mmol) in dioxane (30 mL) was added sodium tert-butoxide (8.5 mL of a 2 M solution, 17.0 mmol). The resulting mixture was stirred at 50 °C for 1 h. After cooling to room temperature, the mixture was diluted with CHCl and filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (80 g ISCO cartridge) eluting with a 0-10% EtOAc / CHCl gradient to give 4-benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline, which was used without further purification. To a solution of 4-benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline in CHCN (30 mL) was added PdCl (0.20 g, 1.13 mmol). The reaction mixture was heated at 50 °C. After the reaction was complete, the mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (80 g ISCO column) using a 0-30% CHCl / heptane gradient to give 1.2 g of product. 5-benzyloxy-1-(4-fluorophenyl)-2-tetrahydropyran-4-yl-indole (37%). 1H NMR(400 MHz,chloroform-d)δ 7.50(d,J=7.0 Hz,2H),7.45-7.22(m,7H),7.21-7.11(m,1H),6.96-6.81(m,2H),6.39(d,J=0.9 ESI-MS m / z calculated value 401.18, actual value 402.0 (M+H) + .

[0146] Compounds S2–S6 (Table 1) were made by a method similar to that of S1, substituting the appropriate aniline into the Buchwald amination reaction. [Table 1-1] [Table 1-2]

[0147] Preparation of S7 5-(Methoxymethoxy)-1-(2-methylpyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S7) [ka] Step 1. Synthesis of 1-bromo-2-iodo-4-(methoxymethoxy)benzene (C4) To a cold (0 °C) solution of 4-bromo-3-iodo-phenol (300.7 g, 1.006 mol) in CH2Cl2 (2.5 L), iPrNEt (185.0 mL, 1.062 mol) was added, followed by the addition of chloromethyl methyl ether (80 mL, 1.053 mol) at a rate that kept the temperature below 10 °C. After the addition, the reaction was removed from the cooling bath and stirred at room temperature overnight. The resulting dark red-brown solution was poured into a separatory funnel and washed with 1 N citric acid. The organic layer was separated and washed with 1 N NaOH. The organic layer was isolated, dried (MgSO), and filtered through a short plug of silica gel. The plug was eluted with CHCl, and the filtrate was evaporated in vacuo to give 309.5 g of product. 1-Bromo-2-iodo-4-(methoxymethoxy)benzene (90%). 1 H NMR (300 MHz, chloroform-d) δ 7.55 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.9 Hz, 1H), 5.12 (s, 2H), 3.46 (s, 3H).

[0148] Step 2. 4-((2-bromo-5-(methoxy)phenyl)ethynyl)tetrahydro-2H-pyran (C5) To a solution of 1-bromo-2-iodo-4-(methoxymethoxy)benzene C4 (2.0 g, 5.8 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (1.4 g, 7.6 mmol) in triethylamine (14 mL) was added water (0.21 mL, 11.68 mmol). To the mixture was added copper iodide (0.12 g, 0.65 mmol) and dichloropalladium; triphenylphosphane (0.21 g, 0.29 mmol). The mixture was purged with nitrogen for 2 minutes, and tetrabutylammonium fluoride (7.6 mL of a 1 M solution, 7.6 mmol) was added. The resulting black mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was diluted with CHCl and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the resulting crude material was purified by silica gel chromatography (80 g ISCO column) using a 0-50% EtOAc / heptane gradient to afford 1.8 g of product: 4-[2-[2-bromo-5-(methoxy)phenyl]ethynyl]tetrahydropyran (95%). 1H NMR(300 MHz,chloroform-d)δ 7.46(d,J=8.9 Hz,1H),7.15(d,J=3.0 Hz,1H),6.86(dd,J=8.8,3.0 Hz,1H),5.16(s,2H),4.01(ddd,J=11.6,6.5,3.5 Hz,2H),3.62(ddd,J=11.3,7.6,3.3 Hz,2H),3.48(s,3H),2.96(tt,J=8.0,4.2 Hz,1H),1.97(ddt,J=13.8,7.1,3.8 Hz,2H),1.89-1.71(m,2H).

[0149] Step 3. 5-(Methoxymethoxy)-1-(2-methylpyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S7) To a solution of 4-((2-bromo-5-(methoxymethoxy)phenyl)ethynyl)tetrahydro-2H-pyran C5 (5.02 g, 15.44 mmol) in tert-BuOH (50 mL) was added 2-methylpyridin-4-amine (1.70 g, 15.72 mmol), followed by NaOtBu (4.41 g, 45.89 mmol). tBuXPhos Pd G1 (0.59 g, 0.86 mmol) was added, and the mixture was heated and stirred at reflux overnight to drive the reaction to completion. The crude reaction was poured into water. The mixture was extracted with CHCl. ​​The organic phase was dried (MgSO), filtered, and evaporated in vacuo to give a dark red oil. The oil was dissolved in CHCl and filtered through a plug of silica gel. The plug was eluted with 25% EtOAc / CHCl, and the filtrate was evaporated in vacuo to give the crude product as a pale red solid. The resulting solid was dissolved in CHCl and purified by silica gel chromatography (330 g ISCO silica gel cartridge) using 10% EtOAc / CHCl to elute impurities, followed by 25% EtOAc / CHCl to elute the product as a pale yellow solid. The solid was triturated with pentane, filtered, and concentrated in vacuo to give 6.0 g of product. 5-(methoxymethoxy)-1-(2-methyl-4-pyridyl)-2-tetrahydropyran-4-yl-indole (110%). 1H NMR(400 MHz,chloroform-d)δ 8.69(d,J=5.3 Hz,1H),7.28(d,J=2.2 Hz,1H),7.18(d,J=1.9 Hz,1H),7.12(dd,J=5.3,1.6 Hz,1H),7.03(d,J=8.9 Hz,1H),6.88(dd,J=8.9,2.4 Hz,1H),6.43(s,1H),5.19(s,2H),3.98(dd,J=11.7,2.5 Hz,2H),3.51(s,3H),3.36(td,J=11.8,2.4 Hz,2H),2.90(tt,J=11.4,3.9 Hz,1H),2.67(s,3H),1.88-1.65(m,4H).ESI-MS m / z calculated value 352.18, actual value 353.33(M+1) + .

[0150] Preparation of S8 to S11 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S8) [ka] Step 1. Synthesis of 4-(benzyloxy)-1-bromo-2-(3-methylbut-1-yn-1-yl)benzene (C6) To a solution of 4-benzyloxy-1-bromo-2-iodo-benzene (172.0 g, 442.1 mmol) in triethylamine (1.5 L) in a 3 L round-bottom flask was added 3-methylbut-1-yne (40.0 g, 563.7 mmol), followed by CuI (12.0 g, 63.0 mmol) and PdCl(PPh) (17.4 g, 24.8 mmol). The solution was stirred overnight at room temperature, during which time a solid precipitated. The reaction was stripped from the solvent and suspended in 20% CHCl / heptane. A silica gel plug (approximately 1.5 kg) was loaded and eluted with heptane (2 x 1 L), followed by 20% CHCl / heptane until no pure product eluted. Pure fractions were combined to give a waxy, tan solid, which was dried to yield 140 g of product. 4-Benzyloxy-1-bromo-2-(3-methylbut-1-ynyl)benzene (92%).1 H NMR(300 MHz,chloroform-d)δ 7.51-7.31(m,6H),7.08(d,J=3.0 Hz,1H),6.78(dd,J=8.9,3.1 Hz,1H),5.04(s,2H),2.85(hept,J=6.9 Hz,1H),1.33(d,J=6.9 Hz,6H).ESI-MS m / z calculated value 328.04, actual value 338.56(M+1) + .

[0151] Step 2. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S8) To a solution of 4-benzyloxy-1-bromo-2-(3-methylbut-1-ynyl)benzene C6 (57.4 g, 165.6 mmol) in tert-BuOH (1 L) in a 1 L round-bottom flask was added 4-fluoro-3-methyl-aniline (25.0 g, 199.8 mmol). The mixture was heated to 80 °C, and NaOtBu (49.0 g, 494.6 mmol) was added. The mixture was purged with nitrogen for 10 minutes, then t-BuXPhos Pd G1 (5.3 g, 7.7 mmol) was added, and the reaction was heated to reflux overnight. The majority of the solvent was first stripped by passing nitrogen through the reaction to cool it, and then the volume was reduced to approximately 200 mL using rotary evaporation. The residue was dissolved in CHCl (500 mL) and filtered through a 500 g pad of silica gel. The silica pad was washed with CH2Cl2 (about 3 x 500 mL). The filtrate was concentrated in vacuo to give 72 g of a dark brown solid. 1H NMR indicated the material was a 2:1 mixture of the uncyclized intermediate and the closed indole S8. The residue was dissolved in DMSO (116 mL) to give a ca. 0.7 M solution, which was heated to 150 °C for 30 min and then cooled to room temperature. The reaction mixture was partitioned between saturated aqueous NaCl and 10% EtOAc / CHCl. ​​The aqueous phase was extracted multiple times with CHCl until no UV material was visible. The organic extracts were combined, dried (NaSO), filtered, and concentrated in vacuo. The resulting crude material was triturated with 1 L of 5% CHCl / heptane. The filtered solid was washed with heptane and then air-dried by passing air over the solid for 30 min. After drying, 36.2 g of a gray solid was obtained. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (62%). 1 H NMR(300 MHz,DMSO-d6)δ 7.37(ddt,J=21.3,11.8,7.2 Hz,9H),7.12(s,1H),6.77(q,J=8.8 Hz,2H),6.32(s,1H),5.10(s,2H),3.01-2.78(m,1H),2.31(s,3H),1.14(d,J=6.6 Hz,6H).ESI-MS m / z calculated value 373.18, measured value 374.41(M+1) + .

[0152] Compounds S9-S11 (Table 2) were made by a similar method to S8, substituting the appropriate aniline for the amination step. [Table 2]

[0153] Preparation of S12 2-Isopropyl-5-(methoxymethoxy)-1-(2-methylpyridin-4-yl)-1H-indole (S12) [ka] S12 is prepared in a similar manner to S8, using OMOM as a substitute for OBn and 2-methylpyridin-4-amine as a substitute for 4-fluoro-3-methyl-aniline. The core was prepared by Sonogashira-Buchwald cyclization: 1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-(methoxymethoxy)-1H-indole. 1 H NMR(300 MHz,chloroform-d)δ 8.67(dd,J=5.3,0.7 Hz,1H),7.31-7.24(m,1H),7.22-7.15(m,1H),7.13(ddd,J=5.3,2.0,0.6 Hz,1H),7.03(dt,J=8.8,0.7 Hz,1H),6.85(dd,J=8.8,2.4 Hz,1H),6.41(t,J=0.8 Hz,1H),5.19(s,2H),3.51(s,3H),3.03(pd,J=6.8,0.8 Hz,1H),2.66(s,3H),1.20(d,J=6.8 Hz,6H).ESI-MS m / z calculated 310.17, observed 311.35 (M+1) + .

[0154] Preparation of S13 to S15 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(1-methoxy-2-methylpropan-2-yl)-1H-indole (S13) [ka] Step 1. Synthesis of 4-(5-(benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yn-1-ol (C7) To a solution of 4-benzyloxy-1-bromo-2-iodo-benzene C2 (13.3 g, 34.2 mmol) and 2,2-dimethylbut-3-yn-1-ol (4.0 g, 40.8 mmol) in dioxane (75 mL) was added iPr2NEt (15.0 mL, 86.1 mmol). The reaction mixture was purged with nitrogen for 5-10 minutes. PdCl2(PPh3)2 (1.2 g, 1.7 mmol) was added, followed by CuI (0.7 g, 3.7 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and foil. The reaction was filtered with the aid of EtOAc and then concentrated in vacuo. Purification by silica gel chromatography (330 g ISCO column) using a 0-100% EtOAc / heptane gradient afforded 7.2 g of product. 4-(5-Benzyloxy-2-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (81%). 1 H NMR(400 MHz,chloroform-d)δ 7.45(d,J=8.9 Hz,1H),7.44-7.34(m,5H),7.09(d,J=3.0 Hz,1H),6.82(dd,J=8.9,3.0 Hz,1H),5.05(s,2H),3.55(d,J=7.2 Hz,2H),2.10(d,J=7.1 Hz,1H),1.35(s,6H).ESI-MS m / z calculated value 358.06, actual value 359.17(M+1) + .

[0155] Step 2. Synthesis of 4-(benzyloxy)-1-bromo-2-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)benzene (C8) To a solution / suspension of 4-(5-benzyloxy-2-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol C7 (7.2 g, 19.9 mmol) and 1-(bromomethyl)-4-methoxy-benzene (3.2 mL, 21.9 mmol) in 2-MeTHF (40 mL) was added NaH (0.8 g of 60% w / w, 20.9 mmol) at room temperature. The reaction mixture warmed to approximately 35 °C. Water and EtOAc were added, and the layers were separated. The aqueous layer was re-extracted with EtOAc, and the combined organic phases were concentrated in vacuo. The resulting residue was purified by silica gel chromatography (220 g ISCO column) using a 0-100% EtOAc / heptane gradient to afford 1.71 g of product. The methylated product was obtained. 4-Benzyloxy-1-bromo-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzene (23%). 1 H NMR(400 MHz,chloroform-d)δ 7.45-7.33(m,7H),7.09(d,J=3.1 Hz,1H),6.78(dd,J=8.9,3.0 Hz,1H),5.04(s,2H),3.47(s,3H),3.40(s,2H),1.36(s,6H).ESI-MS m / z calculated value 372.07, actual value 375.24(M+1) + .

[0156] Step 3. Synthesis of 4-(benzyloxy)-N-(4-fluoro-3-methylphenyl)-2-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)aniline (C8) A solution of 4-benzyloxy-1-bromo-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzene C7 (1.71 g, 4.58 mmol) and 4-fluoro-3-methyl-aniline (0.64 g, 5.08 mmol) in dioxane (5 mL) and tert-BuOH (5 mL) was purged with nitrogen for 5–10 minutes. During the purging, tBuXphos Pd G1 (0.20 g, 0.29 mmol) was added sequentially, followed by sodium tert-butoxide (1.00 g, 10.41 mmol). The reaction mixture was stirred at room temperature for 4 hours under nitrogen. The reaction mixture was filtered through Celite with the aid of EtOAc and then concentrated in vacuo. Purification by silica gel chromatography (80 g GOLD column) with a 0–100% EtOAc / heptane gradient afforded 1.91 g of product. 4-(Benzyloxy)-N-(4-fluoro-3-methylphenyl)-2-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)aniline (100%). 1 H NMR(400 MHz,chloroform-d)δ 7.46-7.38(m,4H),7.37-7.32(m,1H),7.05(d,J=8.9 Hz,1H),7.01(d,J=2.9 ESI-MS m / z calculated value 417.21, measured value 418.41 (M+1) + .

[0157] Step 4. 5-(Benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(1-methoxy-2-methylpropan-2-yl)-1H-indole (S13) To a solution of N-4-benzyloxy-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)phenyl]-4-fluoro-3-methyl-aniline C8 (1.23 g, 2.946 mmol) in 2-MeTHF (20 mL) was added KOt-Bu (3.25 mL of a 1 M solution, 3.25 mmol). The reaction mixture was heated at 50° C. until the reaction was complete.

[0158] Water and CH2Cl2 were added and the layers were separated with the aid of a phase separator. The aqueous layer was re-extracted with CH2Cl2, the layers were separated again with a phase separator, and the combined organics were concentrated. MTBE was added and the off-white solid was filtered to give 800 mg of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole (65%). 1 H NMR(400 MHz,chloroform-d)δ 7.48(ddt,J=7.5,1.4,0.7 Hz,2H),7.42-7.37(m,2H),7.35-7.30(m,1H),7.21(tq,J=7.5,2.1 Hz,2H),7.16-7.13(m,1H),7.12(d,J=2.3 Hz,1H),6.79(dd,J=8.8,2.4 Hz,1H),6.57(dt,J=8.9,0.6 Hz,1H),6.43(d,J=0.8 Hz,1H),5.11(s,2H),3.25(s,3H),3.19(s,2H),2.35(d,J=2.0 Hz,3H),1.30(s,3H),1.28(s,3H).ESI-MS m / z calculated value 417.21, actual value 418.41(M+1) + .

[0159] Compounds S14-S15 (Table 3) were made by a similar method to S13, substituting the appropriate alkyne in the Sonogashira coupling step. [Table 3]

[0160] Preparation of S16 Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indole (S16) [ka] To a solution of 5-benzyloxy-1H-indole (10.0 g, 44.8 mmol) and 1-fluoro-4-iodo-2-methyl-benzene (12.0 g, 50.8 mmol) in DMF (50 mL) was added CuI (0.5 g, 2.6 mmol) and CsCO (25.0 g, 76.7 mmol). The mixture was purged with nitrogen in a pressure bottle (Qian cap) for 5 minutes, then sealed and heated at 130 °C for 24 hours. The solution was diluted with EtOAc (200 mL) and the solids were filtered. The filtrate was washed with water (200 mL), the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (80 g ISCO column) eluting with 0-15% EtOAc / heptane to give 7.8 g of product as a white solid: 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indole (51%). ESI-MS m / z calculated 331.14, found 326.11 (M+1). + .

[0161] Preparation of S17 5-(benzyloxy)-4-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S17) [ka] Step 1. Synthesis of 3-(benzyloxy)-6-bromo-2-fluoroaniline (C10) To a solution of 1-benzyloxy-4-bromo-2-fluoro-3-nitro-benzene (4.96 g, 15.21 mmol), Fe (4.25 g, 76.10 mmol) in methanol (150 mL) was added NH4Cl (4.09 g, 76.46 mmol). The reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the resulting solid was washed with methanol. The filtrate was concentrated in vacuo, then diluted with HO and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (330 g ISCO column) using a 0-15% EtOAc / heptane gradient to give 4.02 g of product, which formed a white solid upon drying. 3-benzyloxy-6-bromo-2-fluoro-aniline (88%). 1 H NMR(400 MHz,chloroform-d)δ 7.48-7.29(m,5H),7.06(dd,J=8.9,1.3 Hz,1H),6.38-6.28(m,1H),5.11(s,2H),4.12(s,2H).ESI-MS m / z calculated value 295.0, actual value 296.5 (M+1) + .

[0162] Step 2. Synthesis of 1-(benzyloxy)-4-bromo-2-fluoro-3-iodobenzene (C11) To a cold (−5° C.) suspension of 3-benzyloxy-6-bromo-2-fluoroaniline C10 (3.28 g, 10.92 mmol) and TsOH—HO (6.24 g, 32.80 mmol) in acetonitrile (100 mL) was added a solution of NaNO (1.51 g, 21.89 mmol) and KI (4.53 g, 29.29 mmol) in water (7.0 mL) dropwise at a rate of 0.20 mL / min using a syringe pump. The internal temperature was <−5° C. throughout the addition. The reaction mixture turned yellow, then black, and then dark orange over time. The reaction mixture was allowed to warm slowly to room temperature overnight. The solvent was removed under reduced pressure, and the resulting crude was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (80 g ISCO column) using a 0-10% EtOAc / heptane gradient to give material that was still impure. A second purification by silica gel chromatography (80 g ISCO column) using 0-40% CHCl3 / heptane gave the product as a clear, colorless oil. 1-(benzyloxy)-4-bromo-2-fluoro-3-iodobenzene. 1 H NMR (300 MHz, chloroform-d) δ 7.45-7.29 (m, 6H), 6.88 (dd, J = 8.8, 8.3 Hz, 1H), 5.13 (s, 2H).

[0163] Step 3. Synthesis of 1-(benzyloxy)-4-bromo-2-fluoro-3-(3-methylbut-1-yn-1-yl)benzene (C12) To a solution of 1-benzyloxy-4-bromo-2-fluoro-3-iodo-benzene C11 (1.08 g, 2.63 mmol) in triethylamine (7.0 mL) purged with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (0.09 g, 0.13 mmol), CuI (0.03 g, 0.13 mmol), and 3-methylbut-1-yne (0.33 mL, 3.18 mmol) were added. The reaction mixture was heated at 40 °C overnight. LCMS indicated that the reaction was not complete. Additional 3-methylbut-1-yne (0.33 mL, 3.18 mmol), Pd(PPh3)2Cl2 (0.09 g, 0.13 mmol), and CuI (0.03 g, 0.13 mmol) were added to the reaction mixture. The reaction mixture was again heated at 40 °C overnight. The solvent was removed in vacuo. H2O was added and extracted with EtOAc. The combined organic phase was washed with 1M HCl, then brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (120 g ISCO column) using a CHCl3 / heptane gradient to give 548 mg of the desired product. 1-benzyloxy-4-bromo-2-fluoro-3-(3-methylbut-1-ynyl)benzene (60%). 1 H NMR(400 MHz,chloroform-d)δ 7.43-7.29(m,5H),7.2(dd,J=8.9,1.9 Hz,1H),6.77(dd,J=8.9,8.3 Hz,1H),5.12(s,2H),2.87(heptd,J=6.9,0.9 Hz,1H),1.31(d,J=6.9 Hz,6H).ESI-MS m / z calculated value 346.0, actual value 346.9(M+1) + .

[0164] Step 4. Synthesis of 5-(benzyloxy)-4-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S17) To a solution of 1-benzyloxy-4-bromo-2-fluoro-3-(3-methylbut-1-ynyl)benzene C12 (0.55 g, 1.58 mmol) in dioxane (7 mL) was added 4-fluoro-3-methyl-aniline (0.23 g, 1.84 mmol). The mixture was degassed with nitrogen for 10 minutes. tBuXPhos Pd G3 (0.06 g, 0.08 mmol) and NaOtBu (0.46 g, 4.74 mmol) were added to the mixture, which was then purged again with nitrogen. The reaction mixture was sealed and heated to 80 °C. After 10 minutes, the reaction was cooled to room temperature. The mixture was filtered through a pad of fluorosil and washed with CHCl / EtOAc. The filtrate was concentrated in vacuo. The resulting residue was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-20% EtOAc / heptane gradient to give 515 mg of the desired product: 5-benzyloxy-4-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (86%). ESI-MS m / z calculated 391.17, found 391.36 (M+1). + .

[0165] Compounds S18–S20 were made by a similar method to S17 using the appropriate iodoaniline (Table 4 ) via Sonogashira coupling with isopropylalkyne followed by N-arylation with 4-bromo-2-methylbromobenzene. [Table 4]

[0166] Preparation of S21 Synthesis of 5-(benzyloxy)-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S21) [ka] 6-Fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole in CH2Cl2 (25 mL) S19 To a cold (0 °C) solution of (0.8 g, 2.5 mmol) was added BBr (5.0 mL of a 1 M solution, 5.0 mmol). The reaction mixture was warmed to room temperature and stirred for 120 min. The mixture was washed with saturated aqueous NaHCO. The organic phase was dried over NaSO, filtered, and concentrated in vacuo to give 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-5-ol. The crude product was dissolved in acetone (25 mL), benzyl bromide (0.35 mL, 2.94 mmol) and CSCO (1.6 g, 4.911 mmol) were added, and the resulting solution was stirred at room temperature for 24 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic phase was dried over NaSO and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-50% EtOAc / heptane gradient to give 781 mg of the product as a white solid: 5-benzyloxy-6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (81%). 1 H NMR(400 MHz,chloroform-d)δ 7.51(d,J=7.5 Hz,2H),7.41(t,J=7.4 Hz,2H),7.34(t,J=7.3 Hz,1H),7.20-7.05(m,4H),6.75(d,J=11.5 Hz,1H),6.31(s,1H),5.17(s,2H),2.99-2.85(m,1H),2.46-2.33(m,3H),1.20(d,J=6.8 Hz,7H).ESI-MS m / z calculated value 391.17, measured value 390.69(M+1) + .

[0167] Preparation of S22 Synthesis of 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)tetrahydro-2H-thiopyran 1,1-dioxide (S22) [ka] Step 1. Synthesis of 4-ethynyltetrahydro-2H-thiopyran 1,1-dioxide (C13) To a solution of 1,1-dioxothiane-4-carbaldehyde (2.93 g, 18.06 mmol), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (5.20 g, 27.07 mmol) in methanol (20 mL) was added K2CO3 (5.00 g, 36.18 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated in vacuo, and the resulting residue was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 10-40% EtOAc / heptane gradient to give 2.28 g of the desired product. 4-Ethynylthiane 1,1-dioxide (80%). 1 H NMR (400 MHz, methanol-d₄) δ 4.92–4.76 (m, 1H), 3.14–3.04 (m, 4H), 2.44–2.33 (m, 2H), 2.10 (dtd, J = 14.2, 10.1, 3.7 Hz, 2H).

[0168] Step 2. Synthesis of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-thiopyran 1,1-dioxide (C14) To a solution of 4-benzyloxy-1-bromo-2-iodo-benzene (3.50 g, 8.99 mmol) and 4-ethynyltetrahydro-2H-thiopyran 1,1-dioxide C13 (1.98 g, 12.51 mmol) in trimethylamine (15 mL) and dioxane (15 mL) was added Pd(PPh3)2Cl2 (0.61 g, 0.87 mmol) and CuI (0.31 g, 1.62 mmol). The reaction mixture was heated at 60 °C overnight. The reaction was cooled to room temperature and then filtered through a plug of Celite. The filtrate was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 10-90% EtOAc / heptane gradient to give 2.1 g of product. 4-[2-(5-benzyloxy-2-bromo-phenyl)ethynyl]thiane 1,1-dioxide (51%) ESI-MS m / z calculated 418.02, found 419.35 (M+1) + .

[0169] Step 3. Synthesis of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-thiopyran 1,1-dioxide (C15) To a solution of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-thiopyran 1,1-dioxide C14 (2.09 g, 4.98 mmol) and 4-fluoro-3-methyl-aniline (0.65 g, 5.19 mmol) in t-BuOH (8 mL) and dioxane (8 mL) was added tBuXPhos Pd G3 (0.20 g, 0.25 mmol) and NaOtBu (1.25 g, 13.01 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the resulting residue was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 10-40% EtOAc / heptane gradient to give 2.12 g of product. N-[4-benzyloxy-2-[2-(1,1-dioxothian-4-yl)ethynyl]phenyl]-4-fluoro-3-methyl-aniline (61%). ESI-MS m / z calculated 463.16, found 464.23 (M+1). + .

[0170] Synthesis of 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)tetrahydro-2H-thiopyran 1,1-dioxide (S22) To a solution of N-4-benzyloxy-2-[2-(1,1-dioxothian-4-yl)ethynyl]phenyl]-4-fluoro-3-methyl-aniline C15 (1.12 g, 2.42 mmol) in THF (20 mL) was added KOtBu (0.27 g, 2.40 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, diluted with EtOAc, and washed with water. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 10-40% EtOAc / heptane gradient to give 820 mg of product: 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]thiane 1,1-dioxide (43%). ESI-MS m / z calculated 463.16, found 464.23 (M+1). + .

[0171] Preparation of S23 Synthesis of 2-isopropyl-5-methoxy-1-(2-methylpyrimidin-4-yl)-1H-indole (S23) [ka] Step 1. Synthesis of N-(2-iodo-4-methoxyphenyl)-2-methylpyrimidin-4-amine (C16) A mixture of 2-iodo-4-methoxy-aniline (2.52 g, 10.12 mmol), 4-chloro-2-methyl-pyrimidine (1.80 g, 14.00 mmol), and iPrNEt (4.0 mL, 22.9 mmol) in DMSO (10 mL) was microwaved at 180 °C for 20 min. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with HO, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / CHCl gradient to give 1.0 g of product. N-(2-iodo-4-methoxy-phenyl)-2-methyl-pyrimidin-4-amine (29%). ESI-MS m / z calculated 341.0, found 342.0 (M+1). + .

[0172] Step 2. Synthesis of N-(2-iodo-4-methoxyphenyl)-2-methylpyrimidin-4-amine (S23) To a solution of N-(2-iodo-4-methoxy-phenyl)-2-methyl-pyrimidin-4-amine C16 (1.00 g, 2.93 mmol) and 3-methylbut-1-yne (0.40 g, 5.87 mmol) in trimethylamine (10 mL) was added Pd(PPh3)2Cl2 (0.20 g, 0.28 mmol) and CuI (0.15 g, 0.79 mmol). The reaction mixture was heated at 50 °C for 1 h. The mixture was concentrated in vacuo, diluted with EtOAc, filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-100% EtOAc / heptane gradient to afford 420 mg of product. N-[4-methoxy-2-(3-methylbut-1-ynyl)phenyl]-2-methyl-pyrimidin-4-amine (51%). ESI-MS m / z calculated 281.2, observed 282.0 (M+1) + .

[0173] To a solution of N-[4-methoxy-2-(3-methylbut-1-ynyl)phenyl]-2-methyl-pyrimidin-4-amine (0.42 g) in THF (20 mL) was added KOtBu (0.40 g, 3.57 mmol). The reaction mixture was heated to reflux and maintained at that temperature overnight. The mixture was cooled, concentrated in vacuo, and diluted with water. The aqueous phase was extracted with CHCl, and the organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (12 g ISCO column) using a 0-30% EtOAc / CHCl gradient to afford 320 mg of product. 2-Isopropyl-5-methoxy-1-(2-methylpyrimidin-4-yl)indole (39%). 1H NMR(400 MHz,chloroform-d)δ 8.75(d,J=5.4 Hz,1H),7.44(dt,J=9.0,0.6 Hz,1H),7.33-7.23(m,1H),7.06(d,J=2.4 Hz,1H),6.83(dd,J=8.9,2.5 ESI-MS m / z calculated value 281.2, actual value 282.0 (M+1) + .

[0174] Preparation of S24 Synthesis of 5-(benzyloxy)-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S24) [ka] To a cold (0 °C) solution of 5-benzyloxy-1-(4-fluoro-3-methylphenyl)-2-isopropyl-indole (4.00 g, 10.50 mmol) in CHCl (70 mL) was added N-iodosuccinimide (2.98 g, 12.58 mmol). The solution was stirred at 0 °C for 2.5 h. The mixture was washed with saturated NaHCO, 1N aqueous NaSO, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (80 g ISCO column) using a 0-30% EtOAc / heptane gradient to give the desired product. 5-(benzyloxy)-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (87%). 1H NMR(400 MHz,chloroform-d)δ 7.52-7.47(m,2H),7.43-7.36(m,2H),7.36-7.29(m,1H),7.18-7.06(m,3H),7.01(dd,J=2.4,0.5 Hz,1H),6.84(dd,J=8.8,2.4 Hz,1H),6.74(dd,J=8.8,0.5 Hz,1H),5.14(s,2H),3.13-3.01(m,1H),2.34(d,J=2.1 Hz,3H),1.34(dd,J=7.2,3.2 Hz,6H).ESI-MS m / z calculated value 499.08, actual value 499.59(M+1) + .

[0175] Compounds S25-S26 (Table 5) were made in a similar manner to S24 from the appropriate indole intermediate. [Table 5]

[0176] Preparation of S30 and S31 Synthesis of 6-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (S30) and 7-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (S31) [ka] Step 1. Synthesis of 3-((4-fluoro-3-methylphenyl)amino)but-2-enenitrile (C17) To a solution of 3-oxobutanenitrile (4.93 g, 59.33 mmol) and 4-fluoro-3-methyl-aniline (7.42 g, 59.29 mmol) was added zinc trifluoromethanesulfonate (1.08 g, 2.97 mmol). The reaction mixture was stirred at room temperature overnight, at which point the mixture solidified. The solid was dissolved in CHCl and purified by silica gel chromatography (330 g ISCO column) using a 0-100% CHCl / heptane gradient to afford 7.9 g of product as a possible mixture of E and Z isomers. (Z) isomer: (Z)-3-(4-fluoro-3-methyl-anilino)but-2-enenitrile (68%). 1 H NMR(400 MHz,chloroform-d)δ 7.06-6.83(m,3H),5.70(s,1H),4.21(s,1H),2.26(d,J=2.1 Hz,3H),2.24(s,3H).ESI-MS m / z calculated value 190.09, measured value 191.29(M+1) + .

[0177] Step 2. Synthesis of 6-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (C18) and 7-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (C19) To a refluxing solution of 2-bromo-1,4-benzoquinone (9.07 g, 43.65 mmol) and zinc diiodide (1.33 g, 4.17 mmol) in CHCl (120 mL) was added dropwise a solution of 3-(4-fluoro-3-methyl-anilino)-but-2-enenitrile C17 (7.91 g, 41.58 mmol) in CHCl (33 mL). The mixture was heated at reflux for 1 h and then cooled to room temperature. The sample was split into two lots for purification. The resulting residue was purified by silica gel chromatography using a 0-10% EtOAc / CHCl gradient to give 1.5 g of the first product. 6-Bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carbonitrile (20%). 1H NMR(400 MHz,DMSO-d6)δ 10.15(s,1H),7.54-7.45(m,1H),7.45-7.36(m,2H),7.16(s,1H),7.10(s,1H),2.35(s,3H),2.34-2.27(m,3H).ESI-MS m / z calculated value 358.01, actual value 359.02 (M+1) + A second product was isolated: 7-bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carbonitrile (1.04 g, 14%). 1 H NMR(400 MHz,DMSO-d6)δ 9.69(s,1H),7.48-7.38(m,1H),7.38-7.29(m,2H),7.00-6.86(m,2H),2.34-2.26(m,3H),2.23(s,3H).ESI-MS m / z calculated value 358.01, actual value 359.07 (M+1) + .

[0178] Step 3a. Synthesis of 6-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (S30) To a suspension of 6-bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carbonitrile C18 (0.94 g, 2.57 mmol) and K2CO3 (0.71 g, 5.15 mmol) in DMF (6 mL) was added benzyl bromide (0.35 mL, 2.94 mmol). The reaction mixture was heated to 70 °C for 4 h. The mixture was cooled to room temperature, diluted with water, and stirred for 30 min. The brown precipitate was filtered. Triturated with heptane and filtered. The brown solid was purified by silica gel chromatography (120 g ISCO column) using CHCl to give 1.12 g of product. 5-benzyloxy-6-bromo-1-(4-fluoro-3-methyl-phenyl)-2-methyl-indole-3-carbonitrile (95%). 1H NMR(400 MHz,DMSO-d6)δ 7.55-7.48(m,3H),7.46-7.37(m,5H),7.37-7.30(m,1H),7.28(s,1H),5.31(s,2H),2.37(s,3H),2.32(d,J=1.4 Hz,3H).ESI-MS m / z calculated value 448.06, actual value 449.1(M+1) + .

[0179] Step 3b. Synthesis of 7-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (S31) To a suspension of 7-bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carbonitrile C19 (0.54 g, 1.47 mmol) and K2CO3 (0.61 g, 4.41 mmol) in DMF (3.5 mL) was added benzyl bromide (0.35 mL, 2.94 mmol). The reaction mixture was heated to 70 °C for 1 h. The mixture was cooled to room temperature and diluted with water and EtOAc. The organic phase was washed, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% CHCl2 / heptane gradient to afford 620 mg of product. 5-Benzyloxy-7-bromo-1-(4-fluoro-3-methyl-phenyl)-2-methyl-indole-3-carbonitrile (94%). 1 H NMR (400 MHz, chloroform-d) δ 7.51-7.31 (m, 5H), 7.19 (d, J = 2.3 Hz, 1H), 7.18-7.05 (m, 4H), 5.11 (s, 2H), 2.35 (d, J = 2.1 Hz, 3H), 2.30 (s, 3H).

[0180] Preparation of S32 Synthesis of 5-(benzyloxy)-2-bromo-1-(4-fluorophenyl)-1H-indole-3-carbonitrile (S32) [ka] Step 1. Synthesis of 1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carbonitrile (C20) To a solution of 5-methoxy-1H-indole-3-carbonitrile S32 (1.25 g, 7.28 mmol), 1-fluoro-4-iodo-benzene (1.76 g, 7.93 mmol) in nitrogen-purged DMF (12 mL) was added copper iodide (0.28 g, 1.45 mmol) and Cs2CO3 (3.56 g, 10.92 mmol). The reaction was sealed and heated at 120 °C for 15 h. The mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to afford 1.03 g of product. 1-(4-Fluorophenyl)-5-methoxy-indole-3-carbonitrile (53%). 1 H NMR(300 MHz,chloroform-d)δ 7.72(d,J=1.9 Hz,1H),7.58-7.40(m,2H),7.38-7.11(m,4H),6.99(dd,J=9.1,2.4 Hz,1H),3.93(d,J=2.0 Hz,3H).ESI-MS m / z calculated value 266.08, actual value 267.12 (M+1) + .

[0181] Step 2. Synthesis of 2-bromo-1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carbonitrile (C21) To a cold (-10 °C) solution of 1-(4-fluorophenyl)-5-methoxy-indole-3-carbonitrile C20 (12.05 g, 45.25 mmol) in THF (280 mL) was added dropwise a solution of tert-butyllithium (31 mL of a 1.7 M solution in pentane, 52.70 mmol). After 1 h, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (19.0 g, 58.0 mmol) in THF (60 mL) was added dropwise. After 1 h, the cooling bath was removed, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (220 g ISCO column) using a 0-20% EtOAc / heptane gradient to give 14.7 g of product. 2-Bromo-1-(4-fluorophenyl)-5-methoxy-indole-3-carbonitrile (94%). ESI-MS m / z calculated 344.0, found 345.1 (M+1) + .

[0182] Step 3. Synthesis of 2-bromo-1-(4-fluorophenyl)-5-hydroxy-1H-indole-3-carbonitrile (C22) To a cold (0 °C) solution of 2-bromo-1-(4-fluorophenyl)-5-methoxy-indole-3-carbonitrile C21 (13.2 g, 38.2 mmol) in CHCl (250 mL) was added tribromoborane (90 mL of a 1 M solution in CHCl, 90.0 mmol). After 90 min, the cooling bath was removed, and the mixture was stirred at room temperature for 1 h. Water was carefully added. The mixture was extracted three times with CHCl. ​​A white solid was present in the aqueous phase and collected by filtration. The combined organic phase was evaporated. The residue and solid were dissolved in 20% MeOH / CHCl, and the mixture was purified by silica gel chromatography (220 g ISCO column) using a 0-4% MeOH / CHCl gradient to give 11.9 g of product. 2-Bromo-1-(4-fluorophenyl)-5-hydroxy-indole-3-carbonitrile (94%). 1H NMR(300 MHz,DMSO-d6)δ 9.57(s,1H),7.83-7.58(m,2H),7.57-7.34(m,2H),6.95(dd,J=5.4,3.1 Hz,2H),6.80(dd,J=9.0,2.3 Hz,1H).ESI-MS m / z calculated value 329.98, actual value 330.65 (M+1) + .

[0183] Step 4: Synthesis of 5-(benzyloxy)-2-bromo-1-(4-fluorophenyl)-1H-indole-3-carbonitrile (S32) To a solution of 2-bromo-1-(4-fluorophenyl)-5-hydroxy-indole-3-carbonitrile C22 (1.10 g, 3.32 mmol) and CS2CO3 (3.50 g, 10.74 mmol) in acetone (25 mL) was added benzyl bromide (0.75 mL, 6.31 mmol). The reaction mixture was heated at room temperature for 18 hours at 70 °C. The solvent was removed under reduced pressure, and the resulting residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-50% EtOAc / heptane gradient to afford 870 mg of product. 5-Benzyloxy-2-bromo-1-(4-fluorophenyl)indole-3-carbonitrile (60%). ESI-MS m / z calculated 420.02, observed 420.98 (M+1) + .

[0184] Preparation of S33 2-Bromo-1-(4-fluorophenyl)-5-(methoxymethoxy)-1H-indole-3-carbonitrile (S33) [ka] S33 is made in a similar manner to S32, using OMOM instead of OBn: 2-Bromo-1-(4-fluorophenyl)-5-(methoxymethoxy)-1H-indole-3-carbonitrile. 1H NMR(300 MHz,DMSO-d6)δ 7.77-7.60(m,2H),7.58-7.40(m,2H),7.31(dd,J=2.1,0.7 Hz,1H),7.11-6.89(m,2H),5.27(s,3H),3.40(s,3H).ESI-MS m / z calculated value 374.00, actual value 375.01 (M+1) + .

[0185] Preparation S34 2-Bromo-1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carbonitrile (S34) [ka] S34 is made in a similar manner to S32, using OMe instead of OBn. 2-Bromo-1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carbonitrile. ESI-MS m / z calculated 344.0, found 345.1 (M+1). + .

[0186] Preparation of S35 5-(Benzyloxy)-2-bromo-1-phenyl-1H-indole-3-carbonitrile (S35) [ka] S35 is made in the same manner as S30 using iodobenzene. 5-(benzyloxy)-2-bromo-1-phenyl-1H-indole-3-carbonitrile. ESI-MS m / z calculated 402.04, found 403.09 (M+1). + .

[0187] Preparation of S36 Synthesis of 2-(1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (S36) [ka] Step 1. Synthesis of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (C23) To a cold (0 °C) solution of 5-methoxy-2-methyl-1H-indole (6.45 g, 40.01 mmol) in THF (80 mL) was added dropwise n-butyllithium (16 mL of a 2.5 M solution in hexanes, 40 mmol) while maintaining the internal temperature below 10 °C with an ice / ethanol bath. After 0.25 h, zinc chloride (80 mL of a 0.5 M solution in THF, 40 mmol) was added dropwise while maintaining the internal temperature between 0 and 2 °C. The cooling bath was removed, and the mixture was stirred for 2 h and then concentrated under reduced pressure to give a wax, which was dissolved in toluene (80 mL). To this solution was added bromoacetonitrile (2.75 mL, 40.01 mmol), and the mixture was stirred at room temperature for 24 h. Additional bromoacetonitrile (2.75 mL, 40.01 mmol) was added, and the mixture was stirred for an additional 1 h. The reaction mixture was quenched with 1M HCl (30 mL) and the layers were separated. The organic phase was washed with brine. The aqueous layer was extracted once more with EtOAc and then washed once with brine. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-5% EtOAc / CH2Cl2 gradient to give 4.1 g of product was obtained: 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (51%). 1 H NMR(400 MHz,DMSO-d6)δ 10.86(s,1H),7.17(d,J=8.7 Hz,1H),7.02(d,J=2.4 Hz,1H),6.68(dd,J=8.7,2.4 Hz,1H),3.93(s,2H),3.76(s,3H),2.35(s,3H).ESI-MS m / z calculated value 200.1, actual value 201.0(M+1) + .

[0188] Step 2. Synthesis of 2-(1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (S36) To a suspension of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile C23 (1.32 g, 6.59 mmol) in toluene (13.2 mL) that had been degassed with nitrogen for 10 minutes, K3PO4 (4.2 g, 19.8 mmol), copper iodide (0.75 g, 3.96 mmol), N,N'-dimethylethane-1,2-diamine (0.42 mL, 3.956 mmol), and 1-fluoro-4-iodobenzene (approximately 2.93 g, 13.18 mmol) were added. The pressure flask was sealed with a screw cap, and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a plug of Celite, rinsing with CHCl2. The filtrate was concentrated under reduced pressure to a dark oil, and the crude material was purified by silica gel chromatography using a 0–20% EtOAc / CHCl2 gradient to yield 845 mg of product. 2-[1-(4-Fluorophenyl)-5-methoxy-2-methyl-indol-3-yl]acetonitrile (44%). ESI-MS m / z calculated 294.1, found 295.2 (M+1) + .

[0189] Preparation of S37 Synthesis of 1-(4-fluoro-3-methylphenyl)-3-iodo-5-methoxy-1H-indole-2-carbonitrile (S37) [ka] Step 1. Synthesis of 1-(4-fluoro-3-methylphenyl)-5-methoxy-1H-indole-2-carbonitrile (C24) To a solution of 5-methoxy-1H-indole-2-carbonitrile (0.133 g, 0.704 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (0.219 g, 1.423 mmol), copper(II) acetate (0.270 g, 1.487 mmol), and potassium carbonate (0.225 g, 1.628 mmol) in dimethyl sulfoxide (2 mL) was added 3 Å molecular sieves (0.235 g). The reaction mixture was stirred at room temperature overnight, exposed to air. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phase was washed twice with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 88 mg of product: 1-(4-fluoro-3-methylphenyl)-3-iodo-5-methoxy-1H-indole-2-carbonitrile (44%). 1 H NMR(400 MHz,DMSO-d6)δ 7.63-7.52(m,2H),7.50-7.37(m,2H),7.28-7.17(m,2H),7.06(dd,J=9.1,2.5 Hz,1H),3.80(s,3H),2.34(d,J=2.1 Hz,3H).ESI-MS m / z calculated value 280.10, actual value 281.47(M+1) + .

[0190] Step 2. Synthesis of 1-(4-fluoro-3-methylphenyl)-3-iodo-5-methoxy-1H-indole-2-carbonitrile (S37) To a cold (0 °C) solution of 1-(4-fluoro-3-methyl-phenyl)-5-methoxy-indole-2-carbonitrile (0.088 g, 0.306 mmol) in dichloromethane (1.5 mL) was added N-iodosuccinimide (0.077 g, 0.342 mmol). The reaction mixture was stirred at 0 °C for 1 h. The ice bath was removed, and the mixture was allowed to warm to room temperature and stirred for 36 h. The reaction was quenched with water and extracted twice with CHCl. ​​The combined organic phases were washed with 1 N sodium thiosulfate, passed through a phase separator, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (24 g ISCO column) using a 0-100% EtOAc / CHCl gradient to afford 52 mg of product. 1-(4-Fluoro-3-methyl-phenyl)-3-iodo-5-methoxy-indole-2-carbonitrile (39%). 1 H NMR(400 MHz,chloroform-d)δ 7.33-7.25(m,2H),7.22(t,J=8.7 Hz,1H),7.17(dd,J=9.1,0.6 Hz,1H),7.08(dd,J=9.1,2.4 Hz,1H),6.89(dd,J=2.3,0.5 Hz,1H),3.94(s,3H),2.40(d,J=2.1 Hz,3H).ESI-MS m / z calculated value 406.0, actual value 407.3(M+1) + .

[0191] Preparation of S38 Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-3-vinyl-1H-indole (S38) [ka] Step 1. Synthesis of ethyl 1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydrofuran-2-yl)-1H-indole-3-carboxylate (C25) A suspension of 4-fluoro-3-methyl-aniline (2.00 g, 15.98 mmol) and ethyl 3-oxo-3-tetrahydrofuran-2-yl-propanoate (approximately 2.97 g, 15.98 mmol) in AcOH (0.09 mL, 1.59 mmol) in a sealed Teflon septum vial was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with CHCl, and then concentrated under reduced pressure, which was repeated two more times. The residue was then further dried under high vacuum for 1 h and then dissolved in anhydrous CHCl (62 mL) under a nitrogen atmosphere, at which time 1,4-benzoquinone (1.73 g, 15.98 mmol) was added, followed by zinc diiodide (0.51 g, 1.59 mmol), and the reaction was then heated at reflux under a nitrogen atmosphere for 24 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a 0-20% EtOAc / heptane gradient. The desired fractions were pooled and concentrated in vacuo, and the solid was triturated with EtO / hexane to give 350 mg of product: ethyl 1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydrofuran-2-yl-indole-3-carboxylate (5%). Separation of the enantiomers was achieved by SFC chiral chromatography. 1 H NMR(400 MHz,DMSO-d6)δ 9.07(s,1H),7.42(d,J=2.2 Hz,1H),7.41-7.19(m,3H),6.66(dd,J=8.9,1.8 Hz,1H),6.58(d,J=8.5 Hz,1H),5.79-5.70(m,1H),4.31(q,J=7.1 Hz,2H),3.55-3.47(m,1H),3.06-2.97(m,1H),2.30(s,3H),2.27-2.17(m,1H),1.98-1.71(m,2H),1.61-1.50(m,1H),1.37(t,J=7.1 Hz,3H).ESI-MS m / z calculated 383.1533, observed 384.5 (M+1) + .

[0192] Step 2. Synthesis of (5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-1H-indol-3-yl)methanol (C26) To a solution of ethyl 1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carboxylate C25 (0.63 g, 1.65 mmol) in DMF (6.5 mL) was added K2CO3 (0.71 g, 5.10 mmol), and the reaction was cooled to 0 °C. Bromomethylbenzene (0.26 mL, 2.14 mmol) was added slowly under a nitrogen atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 4 h. The mixture was diluted with water and diethyl ether. The aqueous phase was washed with diethyl ether. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-60% EtOAc / heptane gradient to give 725 mg of product. Ethyl 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carboxylate (93%). 1 H NMR(400 MHz,DMSO-d6)δ 7.59(d,J=2.5 Hz,1H),7.52-7.19(m,8H),6.95-6.83(m,1H),6.70(dd,J=8.9,2.0 Hz,1H),5.76(q,J=8.2 Hz,1H),5.16(s,2H),4.31(q,J=7.1 Hz,2H),3.52(dt,J=7.9,4.1 Hz,1H),3.00(p,J=7.0 Hz,1H),2.37-2.16(m,4H),1.92(dt,J=12.1,8.7 Hz,1H),1.79(dt,J=20.1,8.1 Hz,1H),1.56(s,1H),1.35(t,J=7.1 Hz,3H).ESI-MS m / z calculated value 473.20, actual value 474.37(M+1) + .

[0193] To a solution of ethyl 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carboxylate (0.70 g, 1.48 mmol) in THF (18 mL) was added lithium aluminum hydride (1.5 mL of 1 M, 1.5 mmol). The reaction mixture was stirred overnight at room temperature. Rochelle's salt and CHCl were added. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using an EtOAc / heptane gradient to give 533 mg of product. [5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-yl]methanol (84%). ESI-MS m / z calculated 431.19, found 430.78 (M+1). + .

[0194] Step 3. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-1H-indole-3-carbaldehyde (C27) To a cold (0 °C) solution of [5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-yl]methanol C26 (0.44 g, 1.02 mmol) in CHCl (12 mL) was added a solution of (1,1-diacetoxy-3-oxo-15,2-benziodoxol-1-yl)acetate (0.43 g, 1.02 mmol) in CHCl (12 mL). After 30 min, the mixture was diluted with 2 N NaOH and CHCl. ​​The phases were separated by passing through a phase separator. The resulting residue was purified by silica gel chromatography using an EtOAc / heptane gradient to give 113 mg of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carbaldehyde (18%). 1H NMR(400 MHz,DMSO-d6)δ 10.37(s,1H),7.87(d,J=2.4 Hz,1H),7.59-7.24(m,8H),6.94(dd,J=9.0,2.5 Hz,1H),6.83(d,J=8.9 Hz,1H),5.15(s,2H),4.99(dt,J=12.7,7.6 Hz,1H),3.86(dq,J=13.5,6.9 Hz,1H),3.69(q,J=7.1 Hz,1H),2.32(d,J=2.3 Hz,3H),2.17(d,J=7.0 Hz,1H),2.04-1.79(m,3H).ESI-MS m / z calculated 429.17, observed 430.31 (M+1) + .

[0195] Step 4. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-3-vinyl-1H-indole (S38) n-BuLi (0.165 mL of 2.5 M, 0.413 mmol) was added to a cold (0 °C) solution of methyl-(triphenyl)phosphonium bromide (0.131 g, 0.367 mmol) in THF (2.4 mL) under nitrogen. The resulting yellow solution was stirred at 0 °C for 2 h, and 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carbaldehyde C27 (0.113 g, 0.182 mmol) in THF (0.6 mL) was added dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous NH4Cl. The solvent was removed under reduced pressure, and the crude product was dissolved in EtOAc (200 mL) and washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography on neutral alumina using EtOAc / heptane to give 79 mg of product: 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]-3-vinyl-indole (100%). ESI-MS m / z calculated 427.19, found 428.33 (M+1). + .

[0196] Compounds S39-S44 (Table 6) were prepared from the appropriate indole intermediates as described for the preparation of S38. [Table 6-1] [Table 6-2]

[0197] Compounds 1 and 2 [ka] Step 1. Synthesis of ethyl 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohex-3-ene-1-carboxylate (C28) A solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole S5 (0.35 g, 0.84 mmol), ethyl 4-oxocyclohexanecarboxylate (0.60 g, 3.53 mmol), trifluoroacetic acid (0.30 mL, 3.89 mmol), and triethylsilane (0.54 mL, 3.38 mmol) in CHCl (7 mL) was stirred at 50° C. for 3 days. The reaction mixture was washed with water and dried over NaSO. The solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography eluting with 0–50% EtOAc / heptane to give 226 mg of product. Ethyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohex-3-ene-1-carboxylate (47%). Retention time: 0.9 min 1H NMR (400 MHz, chloroform-d) δ 7.53-7.47(m,2H),7.45-7.39(m,2H),7.34(d,J=7.3 Hz,1H),7.19-7.06(m,3H),6.98(d,J=2.3 Hz,1H),6.84(dd,J=8.8,2.4 Hz,1H),6.79-6.66(m,1H),5.81(s,1H),5.11(s,1H),4.27-4.23(m,2H),3.97(d,J=11.4 Hz,2H),3.30(t,J=12.0 Hz,2H),2.87-2.69(m,2H),2.56-2.53(m,2H),2.43(m,2H),2.37(d,J=2.0 Hz,3H),2.19-2.17(m,1H),2.11-1.92(m,3H),1.64-1.62(m,2H),1.34(t,J=7.1 Hz,3H).ESI-MS m / z calculated value 567.28, measured value 568.53(M+1) + .

[0198] Step 2. Synthesis of trans-4-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (1) and cis-4-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (2) To a nitrogen-purged solution of ethyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohex-3-ene-1-carboxylate C28 (0.20 g, 0.35 mmol) in MeOH (10 mL) was added Pd(OH)2 (0.10 g, 0.1424 mmol). The system was evacuated and purged with hydrogen (balloon) for 3 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-80% EtOAc / heptane gradient to afford 168 mg of product as a mixture of cis (major) and trans (minor) isomers. Ethyl 4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexane-carboxylate (100%). ESI-MS m / z calculated 479.25, found 480.56 (M+1) + To a solution of ethyl 4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexane-carboxylate (168 mg) in MeOH (5 mL), THF (1 mL), and water (1 mL) was added LiOH (0.10 g, 4.18 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. The crude residue was acidified with 10% HCl and extracted twice with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo.

[0199] The resulting residue was purified by silica gel chromatography with a 0-80% EtOAc / heptane gradient to give 110 mg (63%) of the major product 1 and 10 mg (6%) of the minor product 2. Major product 1 trans-4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanecarboxylic acid. 1 H NMR(400 MHz, methanol-d4)δ 7.25-7.13(m,2H),7.13-7.02(m,2H),6.59(d,J=8.7 Hz,1H),6.53(dd,J=8.7,2.3 Hz,1H),3.95(dd,J=11.6,4.1 ESI-MS m / z calculated value 451.22, actual value 452.56 (M+1) + The by-product 2cis-4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanecarboxylic acid. 1 H NMR(400 MHz, methanol-d4)δ 7.26-7.14(m,2H),7.10(dd,J=8.5,2.6 Hz,2H),6.61(d,J=8.7 Hz,1H),6.55(dd,J=8.7,2.3 Hz,1H),3.96(dd,J=11.5,4.1 Hz,2H),3.30-3.30(m,2H),3.05(m,1H),2.90-2.74(m,1H),2.55-2.45(m,1H),2.34(d,J=1.9 Hz,3H),2.23-1.98(m,7H),1.88-1.86(m,2H),1.70-1.55(m,4H).ESI-MS m / z calculated 451.22, observed 452.56 (M+1) + .

[0200] Compounds 3-104 were prepared as described for compounds 1 and 2 by reductive alkylation with the appropriate aldehyde or ketone reagent and the relevant indole intermediate.

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Table 7-15

Table 7-16

Table 7-17

[0201] compound 105 Synthesis of cis-2-(3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexyl)acetic acid (105) [ka] Step 1. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexan-1-one (C29) 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole in CH3CN (6 mL) S5To a suspension of bismuth (0.30 g, 0.69 mmol) and cyclohex-2-en-1-one (0.10 mL, 1.04 mmol), bismuth 2-methylpropane-2-sulfonate (0.06 g, 0.10 mmol) was added. The suspension was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the crude product was dissolved in EtOAc (10 mL) and washed with water. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-40% EtOAc / heptane gradient to afford 300 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone (83%). 1 H NMR(400 MHz,DMSO-d6)δ 8.74(s,1H),7.43-7.30(m,2H),7.26-7.05(m,2H),6.62(d,J=8 Hz,1H),6.56(dd,J=8.8,2.1 Hz,1H),3.85(d,J=11.0 Hz,2H),3.42(d,J=12.9 ESI-MS m / z calculated 511.25, observed 512.6 (M+1) +To a mixture of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone (0.07 g) in MeOH (5 mL) and EtOAc (2 mL) was added Pd / C, wet, Degussa (0.05 g, 0.05 mmol). The suspension was purged with nitrogen. The system was evacuated and purged with hydrogen, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to afford 60 mg of product. 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone (20%). 1 H NMR(400 MHz,DMSO-d6)δ 8.74(s,1H),7.43-7.30(m,2H),7.26-7.05(m,2H),6.62(d,J=8 Hz,1H),6.56(dd,J=8.8,2.1 Hz,1H),3.85(d,J=11.0 Hz,2H),3.42(d,J=12.9 ESI-MS m / z calculated 421.21, observed 422.59 (M+1) + .

[0202] Step 2. Synthesis of ethyl (E)-2-(3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexylidene)acetate (C30) To a solution of ethyl 2-diethoxyphosphoryl acetate (0.26 g, 1.15 mmol) in THF (5 mL) was added KOtBu (0.13 g, 1.16 mmol). The reaction mixture was stirred at room temperature for 30 min. A solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone C29 (0.30 g, 0.57 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in water (10 mL). The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 240 mg of product. Ethyl-2[3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexylidene]acetate (69%). ESI-MS m / z calculated 581.29, found 582.57 (M+1) + .

[0203] Step 3. cis-2-(3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexyl)acetic acid (105) To a solution of ethyl (2E)-2-[3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexylidene]acetate C30 (0.18 g, 0.30 mmol) in MeOH (5 mL), THF (1 mL), and water (1 mL) was added LiOH. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The crude product was dissolved in water (5 mL) and acidified with 6 N HCl. The aqueous phase was acidified with 6 M HCl. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give 160 mg of product. 2-[3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexylidene]acetic acid (96%). ESI-MS m / z calculated 553.26, found 554.49 (M+1) + The product (155 mg) was dissolved in methanol (5 mL) and Pd / C, wet, Degussa (0.10 g, 0.09 mmol) was added. The system was evacuated and purged with hydrogen, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-80% EtOAc / heptane gradient to yield 112 mg of product. Racemic cis-2-[3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexyl]acetic acid (78%). 1 H NMR(400 MHz,chloroform-d)δ 7.25-7.00(m,4H),6.61(d,J=8.7 Hz,1H),6.54(dd,J=8.8,2.2 Hz,1H),3.96(d,J=11.5 Hz,2H),3.29-3.27(m,2H),3.16-3.05(m,1H),2.81-2.75(m,1H),2.73-2.47(m,1H),2.34(s,3H),2.27(q,J=6.7,5.8 Hz,1H),2.17-1.45(m,12H),1.24-1.08(m,1H).ESI-MS m / z calculated value 465.2, actual value 466.6(M+1)+ .

[0204] Compounds 106 and 107 Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (106) and cis-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (107) [ka] Step 1. Synthesis of isopropyl 1-(hydroxymethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C31) To a cold (-78 °C) solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (10.00 g, 34.68 mmol) in THF (40 mL) was added lithium tritert-butoxyaluminum hydride (80.0 mL of a 1 M solution, 80.0 mmol). The mixture was stirred at room temperature overnight and then heated to 50 °C for 2 h. The mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with CHCl2. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 4.5 g of product. Isopropyl 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylate (56%). 1 H NMR(400 MHz,chloroform-d)δ 5.08(p,J=6.3 Hz,1H),3.83(d,J=6.6 Hz,2H),3.25-3.11(m,6H),2.61-2.48(m,2H),2.42(td,J=6.5,1.1 Hz,1H),2.26-2.14(m,2H),1.35-1.22(m,6H).

[0205] Step 2. Synthesis of isopropyl 3,3-dimethoxy-1-(methoxymethyl)cyclobutane-1-carboxylate (C32) To a solution of isopropyl 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylate C31 (1.00 g, 4.31 mmol) in DMF (10 mL) was added NaH (0.27 g of 60% w / w, 6.67 mmol). The reaction mixture was stirred for 10 min. To the mixture was added methyl iodide (4.00 mL of a 2 M solution, 8.00 mmol). The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-20% EtOAc / heptane gradient to afford 180 mg of product. Isopropyl 3,3-dimethoxy-1-(methoxymethyl)cyclobutanecarboxylate (17%). 1 H NMR(400 MHz,chloroform-d)δ 5.07(hept,J=6.2 Hz,1H),3.63(s,2H),3.36(s,3H),3.16(d,J=2.2 Hz,6H),2.62-2.51(m,2H),2.25-2.10(m,2H),1.26(d,J=6.3 Hz,6H).

[0206] Step 3. Synthesis of isopropyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylate (C33) To a vial charged with bis(trifluoromethylsulfonyl)azanilide; indium(3+) (0.045 g, 0.047 mmol), dioxane (0.5 mL) was added, and the mixture was stirred for 5 min. To the mixture was added 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole S5 (0.200 g, 0.481 mmol), isopropyl 3,3-dimethoxy-1-(methoxymethyl)cyclobutanecarboxylate C32 (0.130 g, 0.528 mmol), and methyl(diphenyl)silane (0.120 g, 0.605 mmol). The reaction mixture was heated at 47 °C for 90 min and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-30% CHCl / heptane gradient to yield 170 mg of product. ESI-MS m / z calculated 599.3, observed 600.0 (M+1) + .

[0207] Step 4. Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (106) and cis-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (107) To a solution of isopropyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylate C33 (0.169 g, 0.283 mmol) in MeOH (10 mL) was added Pd / C (0.050 g / 10 w / w, 0.047 mmol). The mixture was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 100 mg of 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylate (69%). ESI-MS m / z calculated 509.26, found 510.0 (M+1). + .

[0208] To a solution of the product in MeOH (10 mL) was added NaOH (0.50 mL of a 3 M solution, 1.50 mmol). The mixture was stirred at 50 °C for 1 hour. The reaction was neutralized with 1 N HCl and extracted with CHCl. ​​The resulting residue was purified by reverse-phase HPLC to give 10.4 mg of product: trans-3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylic acid (7%). 1 H NMR(400 MHz, methanol-d4)δ 7.44(dd,J=2.1,0.8 Hz,1H),7.28-7.15(m,2H),7.13-7.03(m,1H),6.68-6.48(m,2H),4.11(p,J=9.8 Hz,1H),4.01-3.87(m,2H),3.80(s,2H),2.84(q,J=13.8,12.5 Hz,3H),2.71-2.58(m,2H),2.34(d,J=2.0 Hz,3H),2.03(q,J=12.7 Hz,2H),1.63(d,J=13.4 Hz,2H).ESI-MS m / z calculated 467.2, observed 468.5 (M+1) +cis-3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylic acid (10.9 mg, 7%). 1 H NMR(400 MHz, methanol-d4)δ 7.28-7.18(m,3H),7.18-7.08(m,1H),4.13(tt,J=10.2,9.0 Hz,1H),3.92(dt,J=11.2,3.1 Hz,3H),3.71(s,2H),3.40(s,4H),3.36(dd,J=11.0,3.7 Hz,1H),2.94-2.77(m,4H),2.75-2.62(m,3H),2.34(d,J=2.3 Hz,3H),1.77(td,J=9.9,8.9,3.8 Hz,4H).ESI-MS m / z calculated value 467.21, actual value 468.58(M+1) + .

[0209] Preparation of C34 Isopropyl 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C34) [ka] To a cold (-78 °C) solution of isopropyl 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylate C31 (1.37 g, 5.89 mmol) in CHCl (10 mL) was added 2,6-lutidine (1.00 mL, 8.63 mmol) and trifluoromethanesulfonic anhydride (1.20 mL, 7.13 mmol). The reaction mixture was stirred at -78 °C and gradually warmed to room temperature. The reaction was quenched with water and extracted with CHCl. ​​The organic phase was washed with saturated aqueous NaHCO, saturated aqueous NHCl, and brine. The organic phase was dried over NaSO, filtered, and concentrated in vacuo to give 1.8 g of product.

[0210] Trifluoromethylsulfonyloxymethyl)cyclobutanecarboxylate. 1H NMR (400 MHz, chloroform-d) δ 5.10 (p, J = 6.3 Hz, 1H), 4.81 (s, 2H), 3.18 (d, J = 1.8 Hz, 6H), 2.65-2.55 (m, 2H), 2.29-2.20 (m, 2H), 1.28 (s, 6H). The product was dissolved in THF (10 mL) and cooled to -78 °C. To the solution was added tetrabutylammonium fluoride (9.8 mL of a 1 M solution in THF, 9.8 mmol). The reaction mixture was stirred at room temperature for 1 h, then quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-30% EtOAc / heptane gradient to give 0.8 g of product. Isopropyl 1-(fluoromethyl)-3,3-dimethoxy-cyclobutanecarboxylate (58%). 1 H NMR (400 MHz, chloroform-d) δ 5.08 (p, J = 6.3 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 3.17 (d, J = 0.6 Hz, 6H), 2.62-2.53 (m, 2H), 2.28-2.18 (m, 2H), 1.28 (d, J = 6.3 Hz, 6H).

[0211] Preparation C35 Isopropyl 3,3-dimethoxy-1-(methoxymethyl)cyclobutane-1-carboxylate (C35) [ka] To a solution of isopropyl 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylate C31 (1.00 g, 4.31 mmol) in DMF (10 mL) was added NaH (0.27 g of 60% w / w, 6.67 mmol), and the mixture was stirred for 10 min. To the mixture was added MeI (4.00 mL of 2 M, 8.00 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-20% EtOAc / heptane gradient to afford 180 mg of product. Isopropyl 3,3-dimethoxy-1-(methoxymethyl)cyclobutanecarboxylate (17%). 1 H NMR(400 MHz,chloroform-d)δ 5.07(hept,J=6.2 Hz,1H),3.63(s,2H),3.36(s,3H),3.16(d,J=2.2 Hz,6H),2.62-2.51(m,2H),2.25-2.10(m,2H),1.26(d,J=6.3 Hz,6H).

[0212] Compounds 108~122 Compounds 108-122 were prepared using the appropriate ketone or ketone and related indole intermediates using the method described for the preparation of compounds 106 and 107. Any modifications to this method are noted in the table footnotes. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] 1. Reductive alkylation: [CF3SO2)2N]3, Ph2MeSiH, dioxane, 50°C 2. Reductive alkylation: Et3SiH, TFA, CH2Cl2, 50°C 3. Hydrogenation: H2, Pd(OH)2 4. Hydrolysis conditions: NaOH, MeOH 5. Hydrogenation: H2, Pd / C, MeOH 6.SFC Chiral Chromatography 7. Hydrolysis conditions: LiOH, MeOH, THF, H2O

[0213] compound 123 Synthesis of cis-1-(difluoromethyl)-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclobutane-1-carboxylic acid (123) [ka] Step 1. Synthesis of dimethyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclobutane-1,1-dicarboxylate (C35) 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole in CH2Cl2 (7.0 mL) S5To a solution of dimethyl 3-oxocyclobutane-1,1-dicarboxylate (0.500 g, 1.203 mmol) and dimethyl 3-oxocyclobutane-1,1-dicarboxylate (0.500 g, 2.686 mmol) was added triethylsilane (0.600 mL, 3.757 mmol), followed by 2,2,2-trifluoroacetic acid (0.250 mL, 3.245 mmol). The mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with 15 mL of CHCl and washed with saturated aqueous NaHSO and brine. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to afford 210 mg of product. Dimethyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclobutane-1,1-dicarboxylate (30%). 1 H NMR(400 MHz,chloroform-d)δ 7.73(d,J=2.3 Hz,1H),7.58-7.51(m,2H),7.45-7.32(m,2H),7.20-7.03(m,4H),6.86(dd,J=8.8,2.3 Hz,1H),6.78(d,J=8.9 Hz,1H),5.22(s,2H),4.14-4.04(m,1H),3.92(s,3H),3.85(s,3H),3.48-3.26(m,2H),3.03-2.94(m,1H),2.36(d,J=2.0 Hz,3H),2.02(dtd,J=17.4,12.4,4.8 Hz,2H),1.68-1.50(m,2H).ESI-MS m / z calculated value 585.25, actual value 586.02(M+1) + .

[0214] Step 2. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-formylcyclobutane-1-carboxylate (C36) Dimethyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclobutane-1,1-dicarboxylate in CH2Cl2 (3.0 mL) C35 To a cold (-78 °C) solution of (0.100 g, 0.171 mmol) was added diisobutylaluminum hydride (0.340 mL of a 1 M solution, 0.340 mmol). The mixture was stirred at -78 °C for 3 h. The reaction was quenched with saturated aqueous NH4Cl and extracted three times with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-70% EtOAc / heptane gradient to afford 33 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-formyl-cyclobutanecarboxylate (35%). ESI-MS m / z calculated 555.24, found 556.32 (M+1). + .

[0215] Step 3. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(difluoromethyl)cyclobutane-1-carboxylate (C37) To a cold (0 °C) solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-formyl-cyclobutanecarboxylate C36 (0.032 g, 0.058 mmol) in CHCl (2 mL) was added deoxofluor (0.023 mL, 0.125 mmol), and the mixture was warmed to room temperature and stirred at that temperature for 2 h. The reaction was quenched with ice and extracted with CHCl. ​​The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 0-50% EtOAc / heptane gradient to afford 8 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(difluoromethyl)-cyclobutanecarboxylate (24%). ESI-MS m / z calculated 577.244, found 578.38 (M+1) + .

[0216] Step 4. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(difluoromethyl)cyclobutane-1-carboxylic acid (C38) To a solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(difluoromethyl)cyclobutanecarboxylate C37 (0.023 g, 0.039 mmol) in MeOH (0.6 mL), THF (0.25 mL), and HO (0.12 mL) was added, and the mixture was stirred at 25 °C for 18 h. The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (10 mL) and slowly acidified with HCl (0.43 mL of a 2 M solution, 0.86 mmol). The aqueous layer was extracted three times with EtOAc, dried (MgSO), filtered, and concentrated in vacuo to give 21 mg of product. 3-[5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(difluoro-methyl)cyclobutanecarboxylic acid (86%). ESI-MS m / z calculated 563.23, found 564.42 (M+1) + .

[0217] Step 5. Synthesis of cis-1-(difluoromethyl)-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclobutane-1-carboxylic acid (123) To a nitrogen-purged solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(difluoromethyl)cyclobutanecarboxylic acid C38 (0.021 g, 0.037 mmol) in EtOAc (1.0 mL) was added Pd / wood carbon (0.010 g / 10 w / w, 0.004 mmol). The reaction mixture was evacuated, purged with hydrogen, and stirred under a hydrogen atmosphere for 2 hours. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (12 g ISCO column) using a 0-20% EtOAc / CHCl gradient to give 9.3 mg of product. 1-(Difluoromethyl)-3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclobutanecarboxylic acid (48%). 1 H NMR(400 MHz,chloroform-d)δ 7.70(s,1H),7.17-6.94(m,4H),6.72(s,2H),6.40(t,J=56.4 Hz,1H),4.19-4.03(m,1H),4.00(dd,J=11.6,4.2 Hz,2H),3.30(t,J=11.3 Hz,4H),2.75(dt,J=22.1,12.2 Hz,3H),2.33(d,J=1.9 Hz,3H),2.02(d,J=23.2 Hz,3H),1.60(d,J=13.2 Hz,2H),1.35-1.11(m,2H).ESI-MS m / z calculated 473.18, observed 474.31 (M+1) + .

[0218] compound 124 Synthesis of trans-2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carboxylic acid (124) [ka] Step 1. Synthesis of 1-(4-fluoro-3-methylphenyl)-5-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)-3-vinyl-1H-indole (C39) To a solution of 1-(4-fluoro-3-methyl-phenyl)-3-iodo-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole S28 (0.23 g, 0.464 mmol), tetraethylammonium chloride (0.14 g, 0.85 mmol), palladium; triphenylphosphane (0.028 g, 0.024 mmol) in DMF (5 mL) was added tributyl(vinyl)stannane (0.180 mL, 0.616 mmol). The mixture was stirred under nitrogen for 5 minutes and then at 80 °C overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-20% EtOAc / heptane gradient to give 170 mg of product. 1-(4-Fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-3-vinyl-indole (93%). 1 H NMR(400 MHz,chloroform-d)δ 7.36(dd,J=2.4,0.5 Hz,1H),6.98-6.82(m,4H),6.65(dd,J=8.8,2.3 Hz,1H),6.55(dd,J=8.8,0.6 Hz,1H),5.46(dd,J=17.7,1.7 Hz,1H),5.11(dd,J=11.5,1.6 Hz,1H),4.98(s,2H),3.84-3.70(m,2H),3.29(s,3H),3.08(d,J=2.1 Hz,1H),2.13(d,J=2.0 Hz,3H),1.40(d,J=13.6 Hz,2H).

[0219] Step 2. Synthesis of trans-ethyl-2-(1-(4-fluoro-3-methylphenyl)-5-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carboxylate (124) To a suspension of 1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-3-vinyl-indole C39 (0.170 g, 0.430 mmol), (R,R)-PyBox (0.013 g, 0.043 mmol), and acridine-3,6-diamine; 10-methylacridin-10-ium-3,6-diamine; chloride (0.010 g, 0.021 mmol) in THF (10 mL) was added a solution of ethyl 2-diazoacetate (0.35 mL, 3.33 mmol) in toluene (3 mL). The reaction mixture was heated at 50 °C overnight. The mixture was concentrated, diluted with EtOAc, washed with water, dried over Na SO , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (12 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 120 mg of trans cyclopropyl trans-ethyl-2[1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-indol-3-yl]cyclopropane-carboxylate (58%) as the major isomeric product. ESI-MS m / z calculated 481.2, found 482.0 (M+1). + .

[0220] Step 3. Synthesis of trans-ethyl-2-(1-(4-fluoro-3-methylphenyl)-5-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carboxylate (124) To a solution of trans-ethyl-2[1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydro-pyran-4-yl-indol-3-yl]cyclopropanecarboxylate C40 (0.120 g, 0.249 mmol) in MeOH (1 mL) was added NaOH (1.00 mL of a 1 M solution, 1.00 mmol). The mixture was heated at 50 °C for 1 hour. The mixture was concentrated in vacuo, acidified with 4 M HCl in dioxane, and stirred for 1 hour. The HCl and dioxane were removed. The crude residue was purified by reverse-phase HPLC to give 2.8 mg of trans-2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclopropanecarboxylic acid. 1H NMR(400 MHz,chloroform-d)δ 7.01-6.78(m,4H),6.44(t,J=1.4 Hz,2H),3.87-3.70(m,2H),3.11(t,J=11.9 Hz,2H),2.76(dt,J=12.3,6.3 Hz,1H),2.48-2.36(m,1H),2.24-2.06(m,4H),2.05-1.90(m,1H),1.89-1.75(m,2H),1.58(dt,J=9.0,4.6 Hz,1H),1.42(d,J=11.7 Hz,2H),1.36-1.21(m,1H).ESI-MS m / z calculated 409.2, observed 408.6 (M+1) + .

[0221] Compounds 125~139 Compounds (125-139) in Table 9 were prepared by methods similar to those described for the preparation of compound 124. The appropriate vinyl indole intermediate was used in each example. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] 1. Cyclopropanation: Ethyl 2-diazoacetate, (R,R)-PyBox, THF, toluene at 50°C 2. Hydrolysis conditions: NaOH, MeOH 3. Hydrolysis conditions: LiOH, MeOH, THF, H2O 4. Hydrogenation: H2, Pd / C, MeOH 5. Cyclopropanation: Ethyl 2-diazopropanoate, (R,R)-PyBox, THF, toluene 50°C 6. Cyclopropanation of ethyl 2-diazopropanoate with Rh(OAc) in dichloromethane. The compound is a mixture of stereoisomers.

[0222] compound 136 Synthesis of cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (136) [ka] Step 1. Synthesis of 3-(5-(benzyloxy)-1-(3,4-difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohex-2-ene-1-carboxylic acid (C42) A solution of 5-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole S4 (0.50 g, 1.14 mmol), ethyl 3-oxocyclohexanecarboxylate (0.39 g, 2.29 mmol), phosphoric acid (0.20 mL, 3.44 mmol), and acetic anhydride (0.20 mL, 2.12 mmol) in acetic acid (2.00 mL, 35.17 mmol) was heated in a sealable tube reactor at 110 °C for several days. The solvent was removed under reduced pressure, and the sample was diluted with water (10 mL). The aqueous phase was extracted three times with EtOAc. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-80% EtOAc / heptane gradient to give 213 mg of product. 3-[5-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohex-2-ene-1-carboxylic acid (33%). ESI-MS m / z calculated 543.2, found 544.5 (M+1). + .

[0223] Step 2. Synthesis of cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (136) To a solution of 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohex-2-ene-1-carboxylic acid C42 (0.213 g, 0.469 mmol) in MeOH (8 mL) and EtOAc (2 mL) was added Pd(OH)2 (0.08 g, 0.11 mmol). The system was evacuated and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to obtain 200 mg of product. 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanecarboxylic acid (91%) as a racemic mixture of cis-isomers. ESI-MS m / z calculated 455.19, found 456.57 (M+1). + .

[0224] Compounds 137 and 138 Compounds 137-138 were prepared from S4 using the same method as described for the preparation of compound 136. [Table 10] 1. Reductive alkylation: H3PO4, Ac2O, AcOH, 110°C 2. Hydrogenation: H2, Pd(OH)2 3. Hydrolysis conditions: LiOH, THF, MeOH, H2O

[0225] compound 139 Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylic acid (139) [ka] Step 1. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylate (C43) Methyl 1-methyl-3-oxo-cyclobutanecarboxylate (0.48 g, 3.34 mmol), 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indole in CH2Cl2 (10 mL) S16 To a solution of (0.75 g, 2.21 mmol), trifluoroacetic acid (0.35 mL, 4.54 mmol) and triethylsilane (1.10 mL, 6.89 mmol) were added. The reaction mixture was stirred at 50 °C for 48 h. The mixture was diluted with water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-50% EtOAc / heptane gradient to give 0.68 g of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-1-methyl-cyclobutanecarboxylate (65%). ESI-MS m / z calculated 457.2, found 458.5 (M+1). + The mixture of cis and trans isomers was carried on to the next step without further purification.

[0226] Step 2. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(trifluoromethyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylic acid (C44) Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-1-methyl-cyclobutanecarboxylate in CH3CN (10 mL) C43To a solution of (0.68 g, 1.43 mmol) was added 1-(trifluoromethyl)-1-3,2-benziodoxol-3-one (1.2 g, 2.278 mmol) (Togni reagent). The reaction mixture was heated to 80 °C for 2 h. The solvent was removed under reduced pressure. The crude product was dissolved in EtOAc (10 mL) and washed with water. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 35 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutanecarboxylate (5%). The product was dissolved in MeOH (4.0 mL), THF (1.0 mL), and water (1.0 mL), and lithium hydroxide (0.05 g, 2.09 mmol) was added. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The crude residue was diluted with water (5 mL) and acidified with 6 N HCl. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give 25 mg of the product: 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutanecarboxylic acid. The crude product was used in the following step without further purification.

[0227] Step 3. Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylic acid (139) A solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutanecarboxylic acid C44 (0.025 g, 0.049 mmol) in MeOH (3 mL) was purged with nitrogen. Pd / C (0.010 g, 0.009 mmol) was added, followed by EtOAc (2 mL). The system was evacuated and purged with hydrogen. The reaction was stirred under a hydrogen atmosphere for 18 hours. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 12 mg of product. 3-[1-(4-Fluoro-3-methyl-phenyl)-5-hydroxy-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutanecarboxylic acid (53%). 1 H NMR(400 MHz, methanol-d4)δ 7.33(d,J=2.2 Hz,1H),7.24-7.04(m,4H),6.84-6.76(m,2H),4.13-3.98(m,1H),2.92(td,J=9.0,2.7 Hz,2H),2.58(td,J=10.0,2.7 Hz,2H),2.33(s,3H),1.52(s,3H).ESI-MS m / z calculated value 421.13, actual value 422.23(M+1) + .

[0228] compound 140 6-(1-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (140) [ka] Compound 140 was prepared from 6-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid as described for C44 in the preparation of 139. Hydrogenation with Pd / C in EtOAc gave the final product. 1H NMR(400 MHz, methanol-d4)δ 7.26(dd,J=2.2,0.7 Hz,1H),7.22-7.09(m,3H),6.86-6.72(m,2H),3.94-3.78(m,1H),3.07-3.07(m,1H),2.69-2.41(m,6H),2.35-2.28(m,5H).LCMS m / z 448.5 [M+H] + .

[0229] Compounds 141 and 142 Synthesis of trans-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (141) and cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (142) [ka] Step 1. Synthesis of methyl 3-(5-(benzyloxy)-1-(3,4-difluorophenyl)-2-isopropyl-1H-indol-3-yl)cyclobut-2-ene-1-carboxylate (C46) To a cold (0 °C) solution of 5-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-isopropyl-indole S29 (0.37 g, 0.73 mmol) in THF (2 mL) was added iPrMgCl-LiCl (0.58 mL of a 1.3 M solution, 0.75 mmol). The reaction mixture was stirred for 1 h and then allowed to warm slowly to room temperature over 30 min. A solution of methyl 3-oxocyclobutanecarboxylate (0.10 g, 0.78 mmol) in THF (0.5 mL) was added to the reaction, which was then stirred at room temperature for 2 h. The reaction was quenched with HO and extracted with CHCl. ​​The organic phase was concentrated in vacuo and used in the next step without further purification.

[0230] To a solution of the crude product dissolved in CHCl (5 mL) was added triethylamine (0.16 mL, 2.08 mmol) and triethylsilane (0.45 mL, 2.82 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-10% MeOH / CHCl gradient to give 120 mg of product. Methyl 3-[5-benzyloxy-1-(3,4-difluorophenyl)-2-isopropyl-indol-3-yl]cyclobutanecarboxylate (34%). ESI-MS m / z calculated 489.2, found 490.3 (M+1). + .

[0231] Step 2. Synthesis of trans-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (141) and cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (142) To a solution of methyl 3-[5-benzyloxy-1-(3,4-difluorophenyl)-2-isopropyl-indol-3-yl]cyclobutanecarboxylate C46 (0.12 g, 0.25 mmol) in EtOAc (10 mL) was added Pd(OH)2 (0.03 g, 0.21 mmol). The reaction mixture was evacuated, purged with hydrogen, and stirred under a hydrogen atmosphere for 2 hours. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 80 mg of crude product, which was used in the next step without further purification. Methyl 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indol-3-yl]cyclobutanecarboxylate (82%). ESI-MS m / z calculated 399.2, found 400.5 (M+1). + .

[0232] To a solution of methyl 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indol-3-yl]cyclobutanecarboxylate (80 mg) in MeOH (10 mL) was added NaOH (0.50 mL of a 3 M solution, 1.50 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography eluting with CHCN / water (0-100%, 0.1% TFA) to give: 18.6 mg of 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indol-3-yl]cyclobutanecarboxylic acid (37%). 1 H NMR(400 MHz,chloroform-d)δ 7.39-7.30(m,2H),7.22-7.12(m,1H),7.07(ddd,J=8.8,4.0,1.8 Hz,1H),6.80-6.75(m,1H),6.68(dd,J=8.7,2.4 ESI-MS m / z calculated value 385.1, actual value 386.0 (M+1) + and 18 mg of 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-3-yl]cyclobutanecarboxylic acid (18.5 mg, 37%). 1 H NMR(400 MHz,chloroform-d)δ 7.74(dd,J=2.0,0.9 Hz,1H),7.38-7.32(m,1H),7.15(ddd,J=10.5,7.1,2.5 Hz,1H),7.07(ddd,J=8.8,3.9,1.9 ESI-MS m / z calculated value 385.1, actual value 386.0 (M+1) + .

[0233] Compounds 143~146 Compounds 143-146 (Table 11) were prepared from the appropriate ketone and iodinated indole intermediates using the methods described for the preparation of compounds 141 and 142. [Table 11-1] [Table 11-2] [Table 11-3] 1. iPrMgCl-LiCl, THF, 0°C 2. Et3SiH, TFA, CH2Cl2 3. Hydrolysis conditions: NaOH, MeOH 4. Alkylation of the intermediate amine 3-(azetidin-3-yl)-5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole with benzyl 2-chloroacetate followed by removal of the benzyl group by hydrogenolysis gave the product.

[0234] Compounds 148 and 149 Synthesis of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (148) and 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (149) [ka] Step 1. Synthesis of methyl 6-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylate (C47) 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole in CH2Cl2 (12.0 mL) S8To a solution of (0.80 g, 2.14 mmol), methyl 2-oxospiro[3.3]heptane-6-carboxylate (0.56 g, 3.33 mmol), trifluoroacetic acid (0.34 mL, 4.41 mmol) and triethylsilane (1.05 mL, 6.57 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 0.94 g of product. Methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]spiro[3.3]heptane-2-carboxylate (82%) 1 H NMR(400 MHz,chloroform-d)δ 7.49-7.44(m,2H),7.43-7.35(m,2H),7.36-7.29(m,2H),7.11-7.01(m,3H),6 .81-6.62(m,2H),5.13(s,2H),3.86-3.74(m,1H),3.71(s,3H),3.11(p,J=8.5 Hz,1H),2.94(h,J=7.2 Hz,1H),2.70(dt,J=25.0,10.7 Hz,2H),2.48(dd,J=8.5,1.3 Hz,2H),2.40(dd,J=11.5,8.5 Hz,1H),2.35(d,J=5.3 Hz,5H),1.23(dt,J=7.3,1.6 Hz,6H).ESI-MS m / z calculated value 525.27, actual value 525.21(M+1) + .

[0235] Step 2. Synthesis of methyl 6-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-fluorospiro[3.3]heptane-2-carboxylate (C48) To a cold (-78 °C) solution of methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]spiro[3.3]heptane-2-carboxylate C47 (0.85 g, 1.59 mmol) in tetrahydrofuran (20 mL) was added (diisopropylamino)lithium (1.05 mL of 2 M, 2.10 mmol). The mixture was warmed to -10 °C and stirred for 30 minutes. The mixture was cooled to -78 °C, and N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (0.65 g, 2.06 mmol) in THF (2.0 mL) was added, and the mixture was allowed to warm slowly to room temperature. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 0.5 g of product: methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropenyl-indol-3-yl]-2-fluoro-spiro[3.3]heptane-2-carboxylate (58%). 1 H NMR(400 MHz,chloroform-d)δ 7.47(dd,J=8.1,1.5 Hz,2H),7.44-7.35(m,2H),7.35-7.30(m,2H),7.19-6.99(m,3H),6.92- 6.65(m,2H),5.13(s,2H),3.84-379(m,4H),2.96(ddd,J=14.7,9.4,5.5 Hz,2H),2.85-2.58(m,5H),2.59-2.41(m,2H),2.33(d,J=2.0 Hz,3H),1.23(dd,J=7.2,1.4 Hz,6H).

[0236] Step 3. Synthesis of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (C49) To a solution of methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-fluoro-spiro[3.3]heptane-2-carboxylate C48 (0.50 g, 0.92 mmol) in MeOH (10.0 mL), THF (3.0 mL), and HO (1.5 mL) was added lithium hydroxide (0.65 g, 15.49 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (10 mL) and slowly acidified with HCl (12.0 mL of 2 M, 24.0 mmol). The aqueous phase was extracted three times with EtOAc, dried (MgSO), filtered, and concentrated in vacuo to give 480 mg of product. 6-[5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-fluoro-spiro[3.3]heptane-2-carboxylic acid (95%). ESI-MS m / z calculated 529.24, found 530.51 (M+1) + A solution of the product (480.0 mg, 0.9063 mmol) in EtOAc (20.0 mL) was purged with nitrogen. To the mixture was added Pd / wood carbon (0.24 g of 10% w / w, 0.09 mmol), and the mixture was evacuated and purged with hydrogen. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% MeOH / heptane gradient to afford 0.38 g of product (89%). The crude product was submitted for SFC purification to yield: 67.5 mg of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (148), 1H NMR(400 MHz,chloroform-d)δ 7.20(d,J=2.3 Hz,1H),7.15-6.99(m,3H),6.70(d,J=8.7 Hz,1H),6.61(dd,J=8.7,2.4 Hz,1H),3.86-3.74(m,1H),3.10-2.41(m,9H),2.32(d,J=2.1 Hz,3H),1.26-1.15(m,6H), ESI-MS m / z calculated value 439.19, measured value 440.55(M+1) + and 61 mg of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (149). 1H NMR (400 MHz, chloroform-d) δ 7.20 (d, J = 2.3 Hz, 1H), 7.15-7.00 (m, 3H), 6.70 (d, J = 8.7 Hz, 1H), 6.60 (dd, J = 8.7, 2.4 Hz, 1H), 3.81 (tt, J = 10.1, 8.4 Hz, 1H), 3.09-2.41 (m, 9H), 2.32 (d, J = 1.9 Hz, 3H), 1.23 (dt, J = 7.2, 1.2 Hz, 6H).

[0237] compound 150 6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (150) [ka] Compound 150 was prepared from methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylate as described for C48 in the preparation of 148. Ester hydrolysis with sodium hydroxide in methanol, followed by hydrogenation over Pd / C in EtOAc, gave the final product. Compound 150 is isolated as a single stereoisomer of unknown absolute configuration. 1H NMR(400 MHz,chloroform-d)δ 7.71-7.60(m,1H),7.17-7.03(m,3H),6.80-6.68(m,2H),4.41(p,J=9.6 Hz,1H),3.54(dt,J=28.6,11.6 Hz,2H),2.95(p,J=7.2 Hz,1H),2.76(dddd,J=20.2,11.5,8.8,3.3 Hz,2H),2.33(d,J=2.0 Hz,3H),1.29(dd,J=7.2,1.7 Hz,6H).LCMS m / z400.3 [M+H] + .

[0238] Compound 151 Synthesis of 3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methoxy-2-methylpropanoic acid (151) [ka] Step 1. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-hydroxy-2-methylpropanoate (C50) To a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 (0.50 g, 1.34 mmol) in 1,2-dichloroethane (7.0 mL) was added methyl 2-methyloxirane-2-carboxylate (0.43 mL, 4.02 mmol) and tris(trifluoromethylsulfonyloxy)ytterbium (0.40 g, 0.65 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CHCl2. The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using 0-40% EtOAc / heptane to give 275 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-hydroxy-2-methyl-propanoate (42%). 1 H NMR(400 MHz,chloroform-d)δ 7.54-7.48(m,2H),7.47-7.38(m,2H),7.38-7.30(m,1H),7.23-7.06(m,4H),6.87-6.76(m,1H),6.64(d,J=8.8 Hz,1H),5.13(s,2H),3.74(d,J=2.8 Hz,3H),3.43-3.10(m,3H),2.35(dd,J=4.0,2.0 Hz,3H),1.60(s,3H),1.15(ddd,J=11.3,7.2,1.2 Hz,6H).

[0239] Step 2. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-methoxy-2-methylpropanoate (C51) To a cold (0 °C) solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-hydroxy-2-methyl-propanoate C50 (0.11 g, 0.22 mmol) in DMF (2 mL) was added sodium hydride (0.020 g of 60% w / w, 0.500 mmol). The reaction mixture was stirred for 30 min. Iodomethane (0.030 mL, 0.482 mmol) was added to the mixture, and the mixture was stirred at room temperature for 12 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 95 mg of product. Methyl 3-[5-benzyl-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propanoate (84%). 1 H NMR(400 MHz,chloroform-d)δ 7.56-7.45(m,2H),7.45-7.39(m,2H),7.38-7.29(m,1H),7.22(d,J=2.4 Hz,1H),7.19-7.08(m,3H),6.87-6.72(m,1H),6.63(d,J=8.7 Hz,1H),5.12(s,2H),3.76(d,J=0.5 Hz,3H),3.43-3.34(m,1H),3.29(s,3H),3.24-3.13(m,2H),2.34(d,J=1.9 Hz,3H),1.19-1.02(m,6H).

[0240] Step 3. Synthesis of 3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methoxy-2-methylpropanoic acid (151) To a solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propanoate C51 (0.090 mg, 0.178 mmol) in MeOH (2.0 mL), THF (0.6 mL), and HO (0.40 mL) was added lithium hydroxide (0.128 g, 3.050 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (10 mL) and slowly acidified with HCl (1.8 mL of 2 M, 3.6 mmol). The aqueous phase was extracted three times with EtOAc. The organic phase was dried (MgSO), filtered, and concentrated in vacuo to give 80 mg of product. 3-[5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propanoic acid (91%). 1 H NMR (400 MHz, chloroform-d) δ 7.53-7.45 (m, 2H), 7.45-7.35 (m, 2H), 7.35-7.27 (m, 1H), 7.21-7.07 (m, 4H), 6.79 (dd, J = 8.8, 2.5 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 5.12 (s, 2H), 3.38-3.22 (m, 4H), 2.40-2.26 (m, 2H), 1.16-1.03 (m, 6H). To a nitrogen-purged solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propanoic acid (0.070 g, 0.143 mmol) in EtOAc (2.0 mL) was added Pd on carbon (0.039 g of 10% w / w, 0.015 mmol), the mixture was evacuated and filled with hydrogen. The mixture was stirred under a hydrogen atmosphere for 2 h. The crude mixture was filtered through a pad of Celite, concentrated in vacuo, and purified using an ISCO (4 g gold). The resulting residue was purified by silica gel chromatography (4 g ISCO column) using 0-10% MeOH / CH2Cl2: 3-[1-(4-Fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propanoic acid (33%). 1H NMR(400 MHz,chloroform-d)δ 7.17-7.07(m,3H),7.05(d,J=2.3 Hz,1H),6.67-6.51(m,2H),3.35(s,3H),3.29(q,J=7.2 Hz,1H),3.22-3.17(m,2H),2.33-2.27(m,3H),1.54(s,3H),1.15-1.07(m,6H).ESI-MS m / z calculated value 399.18, actual value 400.31(M+1) + .

[0241] compound 152 3-[1-(4-Fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]-2-hydroxy-2-methyl-propanoic acid (152) [ka] Compound 152 was prepared from 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 as described for C51 in the preparation of 151. Ester hydrolysis using lithium hydroxide in methanol, THF, and water, followed by hydrogenation over Pd / C (wood) in EtOAc, gave the final product. 1 H NMR(400 MHz,chloroform-d)δ 7.23-7.08(m,3H),7.04(d,J=2.2 Hz,1H),6.75-6.52(m,2H),3.48(d,J=14.9 Hz,1H),3.31(p,J=7.3 Hz,1H),3.17(d,J=14.9 Hz,1H),2.34(d,J=2.1 Hz,3H),1.64(s,3H),1.16(t,J=6.5 Hz,6H).LCMS m / z386.3 [M+H] + .

[0242] Preparation 153 Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)acetic acid (153) [ka] Step 1. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole-3-carbaldehyde (C52) To a solution of oxalyl chloride (13.0 mL of a 2 M solution, 26.0 mmol) in CHCl at 0° C. was added DMF (13.0 mL, 167.9 mmol). The suspension was stirred at 0° C. for 10 min. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole in CHCl (50 mL) S8 (5.0 g, 13.4 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The solution was basified with saturated aqueous NaHCO3 and extracted three times with CHCl2. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (80 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 4.67 g of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carbaldehyde (81%). 1 H NMR(300 MHz,chloroform-d)δ 10.42(s,1H),7.95(d,J=2.5 Hz,1H),7.47-7.37(m,2H),7.40-7.21(m,3H),7.18-6.99(m,3H),6.83(dd,J=8.9,2.5 ESI-MS m / z calculated value 401.18, actual value 402.27 (M+1) + .

[0243] Step 2. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)acetonitrile (C53) To a cold (0 °C) solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carbaldehyde C52 (1.75 g, 4.36 mmol) and TOSMIC (1.13 g, 5.67 mmol) in DME (16.5 mL) and EtOH (0.5 mL) was added potassium tert-butoxide (1.21 g, 10.46 mmol) in portions. The reaction was stirred at 0 °C for 1 h. MeOH (16.5 mL) was added, and the reaction was heated to 90 °C and stirred for 30 min. The mixture was concentrated in vacuo. The residue was solubilized with an excess of saturated aqueous NH Cl and CHCl to pH = 4. The phases were separated, and the aqueous phase was extracted twice with CHCl. ​​The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 1.12 g of product: 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetonitrile (62%). 1 H NMR(400 MHz,chloroform-d)δ 7.53-7.45(m,2H),7.44-7.35(m,2H),7.35-7.28(m,1H),7.20-7.04(m,4H),6.86(dd,J=8.8,2.3 Hz,1H),6.79(dd,J=8.9,0.5 Hz,1H),5.14(s,2H),3.90(s,2H),3.00(hept,J=7.3 Hz,1H),2.34(d,J=2.0 Hz,3H),1.33(d,J=4.1 Hz,3H),1.31(d,J=4.1 Hz,3H).ESI-MS m / z calculated value 412.2, actual value 411.9(M+1) + .

[0244] Step 3. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)acetic acid (C54) To a solution of 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetonitrile C53 (0.10 g, 0.24 mmol) in EtOH (1.7 mL) was added KOH (0.79 g of 50% w / w, 7.005 mmol) in water (1.7 mL). The mixture was irradiated in a microwave at 145 °C for 45 minutes. After cooling to room temperature, the reaction mixture was poured into a solution of HCl (0.72 mL of 37% w / v, 7.276 mmol) and CHCl (20 mL) in water (20 mL). The aqueous phase was extracted twice with CHCl. ​​The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 104 mg of product. 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetic acid (97%). ESI-MS m / z calculated 431.19, found 432.45 (M+1) + The crude product was used in the next step without further purification.

[0245] Step 4: Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)acetic acid (153) To a vial containing Pd / C (wet, Degussa, 0.027 g, 0.025 mmol) was added 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetic acid C54 (0.104 g, 0.241 mmol). The vial was sealed and purged with one cycle of vacuum and nitrogen. EtOAc (4.8 mL) was added, and the reaction mixture was evacuated, purged with hydrogen, and stirred under a hydrogen atmosphere for 5 h. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-30% MeOH / CHCl gradient to afford 33 mg of product. 2-[1-(4-Fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]acetic acid (39%). 1H NMR(400 MHz,chloroform-d)δ 7.17-7.07(m,3H),6.91-6.87(m,1H),6.73(d,J=8.6 Hz,1H),6.67(d,J=8.7 Hz,1H),3.83(s,2H),3.06-2.92(m,1H),2.34(s,3H),1.30-1.21(m,6H).ESI-MS m / z calculated value 341.14, measured value 342.07(M+1) + .

[0246] Compounds 154 and 155 Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methylpropanoic acid (154) and 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propanoic acid (155) [ka] Step 1. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)propanenitrile (C55) and 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-methylpropanenitrile (C56) To a cold (0 °C) solution of 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetonitrile C53 (0.200 g, 0.485 mmol) in DMF (2.4 mL) was added sodium hydride (0.100 g, 2.425 mmol). The mixture was stirred until gas evolution ceased, and then methyl iodide (0.151 mL, 2.426 mmol) was added. The reaction was stirred at 0 °C for 30 minutes and then at room temperature for 1 hour. The mixture was then stirred at 50 °C overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution. The aqueous phase was extracted three times with CHCl2. The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to give 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methyl-propanenitrile (85 mg, 23%): ESI-MS m / z calculated 440.2, found 439.9 (M+1). + and 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]propanenitrile (56 mg, 27%): ESI-MS m / z calculated 426.21, found 427.81 (M+1) + An inseparable mixture of was obtained, which was carried on to the next step without further purification.

[0247] Step 2. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)propanoic acid (C57) and 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-methylpropanoic acid (C58) To a solution of 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methyl-propanitrile C55 (0.085 g, 0.190 mmol) and 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]propanenitrile C56 (0.056 g, 0.131 mmol) in EtOH (3.2 mL) was added a solution of KOH (0.625 g of 50% w, 5.570 mmol) in water (3.2 mL). The reaction mixture was irradiated in a microwave reactor at 180 °C for 2.5 hours. After cooling to room temperature, the reaction mixture was poured into a solution of HCl (0.570 mL of 37% w / v, 5.784 mmol) and CHCl (20 mL) in water (20 mL). The phases were separated and the aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methyl-propanamide (71 mg, 80%): ESI-MS m / z calculated 458.24, found 459.41 (M+1). + and 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]propanoic acid (71 mg, 83%): ESI-MS m / z calculated 445.21, found 446.40 (M+1) + The mixture was used in the next step without further purification.

[0248] Step 3: Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methylpropanoic acid (154) and 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propanoic acid (155) To a vial containing Pd / C (wet, Degussa, 0.027 g, 0.025 mmol) was added 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetic acid (0.104 g, 0.241 mmol). The vial was sealed and purged with one cycle of vacuum and nitrogen. EtOAc (3 mL) was added, and the reaction mixture was evacuated, purged with hydrogen, and stirred under a hydrogen atmosphere for 16 h. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]propanoic acid (4.9 mg, 9%): 1 H NMR(400 MHz,chloroform-d)δ 7.19-7.00(m,4H),6.72(d,J=8.6 Hz,1H),6.68-6.60(m,1H),4.27-4.14(m,1H),3.07-2.92(m,1H),2.33(s,3H),1.63(d,J=7.1 Hz,3H),1.34(d,J=7.2 Hz,3H),1.29(d,J=7.0 Hz,3H).ESI-MS m / z calculated value 355.1584, actual value 356.07(M+1) + and 2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]-2-methyl-propanamide (20.3 mg, 35%): 1 H NMR (400 MHz, chloroform-d) δ 7.35-7.30 (m, 1H), 7.19-7.10 (m, 3H), 6.63 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 5.77 (s, 1H), 5.47 (s, 1H), 3.31 (s, 1H), 2.33 (s, 3H), 1.81 (s, 6H), 1.07 (d, J = 7.1 Hz, 6H). ESI-MS m / z calculated 368.19, found 369.13 (M+1). + obtained.

[0249] Preparation 156 Synthesis of 2-(2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-5-hydroxy-1H-indol-3-yl)-3-phenylpropanoic acid (156) [ka] Step 1. Synthesis of methyl 2-(5-(benzyloxy)-1H-indol-3-yl)acetate (C59) To a solution of 2-(5-benzyloxy-1H-indol-3-yl)acetic acid (10.0 g, 35.6 mmol) in MeOH (50.0 mL, 1.2 mol) was added H2SO4 (2.0 mL, 37.5 mmol). The reaction mixture was heated to reflux, stirred for 3 h, and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 10-90% EtOAc / heptane gradient to give 10.1 g of product. Methyl 2-(5-benzyloxy-1H-indol-3-yl)acetate (96%). 1 H NMR(400 MHz,chloroform-d)δ 7.98(s,1H),7.51(ddd,J=6.8,1.5,0.8 Hz,2H),7.46-7.39(m,2H),7.35(d,J=7.3 ESI-MS m / z calculated value 295.12, actual value 296.09 (M+1) + .

[0250] Step 2. Synthesis of methyl 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)acetate (C60) Copper(I) iodide (3.20 g, 16.80 mmol) was added to a nitrogen-purged solution of methyl 2-(5-benzyloxy-1H-indol-3-yl)acetate C59 (10.50 g, 34.12 mmol), 1-fluoro-4-iodo-2-methyl-benzene (10.50 g, 44.49 mmol), KH2PO4 (9.30 g, 68.34 mmol), and N,N-dimethylethylenediamine (3.60 mL, 33.81 mmol) in toluene (80 mL) and DMSO (9 mL). The solution was heated at 120 °C for 20 h. The reaction mixture was cooled to room temperature and filtered. The solid was washed with EtOAc (200 mL). The filtrate was washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (120 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 6.4 g of product: methyl 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (45%). 1 H NMR(400 MHz,chloroform-d)δ 7.59-7.48(m,2H),7.44-7.33(m,4H),7.32-7.24(m,4H),7.20(d,J=2.4 Hz,1H),7.14(t,J=8.8 ESI-MS m / z calculated value 403.16, actual value 404.1 (M+1) + .

[0251] Step 3. Synthesis of methyl 2-(5-(benzyloxy)-2-bromo-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)acetate (C61) To a solution of methyl 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate C60 (0.81 g, 1.94 mmol) in CCl4 (15 mL) was added N-bromosuccinimide. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 0.32 g of product. Methyl 2-[5-benzyloxy-2-bromo-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (30%). 1 H NMR(400 MHz,chloroform-d)δ 7.48-7.40(m,2H),7.38-7.31(m,2H),7.30-7.24(m,1H),7.18-7.04(m,4H),6.94(d,J=8.9 Hz,1H),6.85(dd,J=8.9,2.4 Hz,1H),5.08(s,2H),3.76(s,2H),3.67(s,3H),2.31(d,J=2.0 Hz,3H).ESI-MS m / z calculated value 481.06888, measured value 482.0(M+1) + .

[0252] Step 4. Synthesis of methyl 2-(5-(benzyloxy)-2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)acetate (C62) Palladium(II) acetate (0.114 g, 0.508 mmol) was added to a nitrogen-purged solution of cyclopropyl(trifluoro)boranide (potassium ion (1)) (1.90 g, 12.84 mmol), methyl 2-[5-benzyloxy-2-bromo-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate C61 (1.40 g, 2.55 mmol), and X-Phos (1.89 g, 2.546 mmol) and Pd(OAc)2 (0.114 g, 0.507 mmol) in toluene (70 mL) and water (10 mL). The reaction was capped in a sealable tube (Qian Cap), and the reaction mixture was heated at 120 °C for 18 h. Additional cyclopropyl(trifluoro)boranide (potassium ion (1)) (1.90 g, 12.84 mmol), X-Phos (1.89 g, 2.55 mmol), and Pd(OAc) (0.114 g, 0.507 mmol) were added, and the reaction was heated at 120 °C for 18 h. The mixture was cooled to room temperature, and the solid was filtered. The solid was washed with EtOAc (100 mL). The combined filtrates were washed with water (50 mL), and the organic phase was separated. The organic layer was dried (MgSO), and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 0.72 g of product. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CHCN / water (0-100%, 0.1% TFA). The crude residue was purified again by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 650 mg of product: methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (57%).1H NMR(400 MHz,chloroform-d)δ 7.52-7.49(m,2H),7.44-7.38(m,2H),7.36-7.24(m,1H),7.24-7.13(m,4H),7.01(dd,J=8.9,0.5 Hz,1H),6.88(dd,J=8.8,2.4 Hz,1H),5.14(s,2H),3.71(s,3H),2.36(d,J=2.0 Hz,3H),1.79-1.76(m,,1H),0.85-0.69(m,2H),0.63-0.40(m,2H).ESI-MS m / z calculated value 443.2, measured value 444.2(M+1). + .

[0253] Step 5. Synthesis of methyl 2-(5-(benzyloxy)-2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)-3-phenylpropanoate (C63) To a cold (-78 °C) solution of methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (C62) (0.27 g, 0.60 mmol) in anhydrous THF (10 mL) was added LDA (450 μL of 2 M, 0.9000 mmol). The solution was stirred at -78 °C for 45 minutes. A solution of benzyl bromide (1.10 mL, 9.29 mmol) in THF (1 mL) was added dropwise, and the reaction was stirred at -78 °C for 2 hours, slowly warming to room temperature. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and extracted twice with EtOAc (10 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-5% EtOAc / heptane gradient to give 240 mg of product: methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propanoate (74%). 1H NMR(400 MHz,chloroform-d)δ 7.53-7.44(m,2H),7.35-7.30(m,3H),7.29-6.90(m,10H),6.81(dd,J=8.8,2.4 Hz,1H),5.11(s,2H),4.32(dd,J=9.1,6.5 Hz,1H),3.58(s,3H),3.48(dd,J=13.3,6.5 Hz,1H),3.10(dd,J=13.3,9.1 Hz, 1H), 2.26 (s, 3H), 1.11-0.90 (m, 1H), 0.62-0.60 (m, 1H), 0.51-0.47 (m, 1H), 0.43-0.26 (m, 1H), 0.04-0.05 (m, 1H). ESI-MS m / z calculated 533.2, found 534.2 (M+1). + .

[0254] Step 6. Synthesis of 2-(2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-5-hydroxy-1H-indol-3-yl)-3-phenylpropanoic acid (156) To a stirred solution of methyl 1-1[4-benzyloxy-2-cyclopropyl-2-1-2-(4-2-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propanoate C63 (0.075 g, 0.127 mmol) in THF (1 mL), MeOH (3 mL), and water (1 mL) was added LiOH (0.050 g, 2.088 mmol). The reaction mixture was stirred at room temperature for 18 hours, and the solvent was removed under reduced pressure. The residue was dissolved in water (2 mL) and acidified with 6N HCl. The white ppt was extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried and concentrated under reduced pressure to give 65 mg of product. 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propanoic acid (96%). ESI-MS m / z calculated 519.22, observed 520.25 (M+1) + .

[0255] To a solution of 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propanoic acid (0.060 mg, 0.112 mmol) in MeOH (5 mL) and EtOAc (2 mL) was added Pd / C (0.100 g, 0.094 mmol). The mixture was purged with nitrogen. The reaction mixture was evacuated, purged with hydrogen, and stirred under a hydrogen atmosphere for 1 h. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 35 mg of product. 2-[2-Cyclopropyl-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-indol-3-yl]-3-phenyl-propanoic acid (70%). 1 H NMR(400 MHz,chloroform-d)δ 7.27-7.25(m,,2H),7.21-7.12(m,3H),7.07(t,J=8.8 Hz,1H),6.95.6.93(m,,4H),6.75(dd,J=8.8,2.3 Hz,1H),4.38(dd,J=9.5,5.8 ESI-MS m / z calculated value 429.2, actual value 430.2 (M+1) + . [Table 12-1] [Table 12-2] 1. Methyl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate was used as a replacement for C62. The hydrogenation step was omitted. The OMe group was removed in the final step using BBr3.

[0256] compound 163 3-(6-Fluoro-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propanoic acid (163) [ka] Step 1. Synthesis of 6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indole-3-carbaldehyde (C64) To a cold (0 °C) solution of DMF (3.00 mL, 38.74 mmol) in CHCl (5 mL) was added oxalyl chloride (3.3 mL of 2 M, 6.600 mmol). The solution was stirred at room temperature for 30 min. A solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole S19 (1.20 g, 3.67 mmol) in CHCl (15 mL) was added. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched by the slow addition of saturated aqueous NaHCO. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-60% EtOAc / heptane gradient to give 1.12 g of product. 6-Fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole-3-carbaldehyde (89%). 1 H NMR(400 MHz,chloroform-d)δ 10.51(s,1H),8.01(d,J=8.4 Hz,1H),7.30-7.20(m,2H),7.20-7.04(m,2H),6.62(d,J=11.0 Hz,1H),4.01(s,3H),3.19(p,J=7.2 Hz,1H),2.40(d,J=2.0 Hz,3H),1.47(dd,J=7.2,2.6 Hz,6H).ESI-MS m / z calculated value 343.1384, measured value 344.19(M+1) + .

[0257] Step 2. Synthesis of ethyl (E)-3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indol-3-yl)acrylate (C65) To a solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole-3-carbaldehyde C64 (0.36 g, 1.05 mmol) in toluene (10 mL) was added ethyl 2-(triphenyl-5-phosphanylidene)acetate (0.73 g, 2.10 mmol). The reaction mixture was heated at 120 °C for 48 h. The mixture was cooled to room temperature and diluted with water. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-60% EtOAc / heptane gradient to give 0.24 g of product. Ethyl (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]prop-2-enoate (55%). 1H NMR(400 MHz,chloroform-d)δ 8.22(d,J=15.8 Hz,1H),7.43(d,J=8.0 Hz,1H),7.26-7.06(m,3H),6.63(d,J=11.2 Hz,1H),6.38(d,J=15.9 ESI-MS m / z calculated value 413.18, actual value 414.28 (M+1) + .

[0258] Step 3. Synthesis of ethyl 3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indol-3-yl)propanoate (C66) To a nitrogen-purged solution of ethyl (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]prop-2-enoate C65 (0.24 g, 0.57 mmol) in MeOH (10 mL) was added palladium hydroxide (0.05 g, 0.07 mmol). The reaction mixture was evacuated, purged with hydrogen, and stirred under a hydrogen atmosphere for 2 hours. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 220 mg of product. Ethyl 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propanoate (92%). 1 H NMR(400 MHz,chloroform-d)δ 7.23-7.04(m,4H),6.62(d,J=11.5 Hz,1H),4.21(q,J=7.1 ESI-MS m / z calculated value 415.19, actual value 416.35 (M+1) + obtained.

[0259] Step 4. Synthesis of 3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indol-3-yl)propanoic acid (C67) To a solution of ethyl 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propanoate C66 (0.14 g, 0.34 mmol) in MeOH (6.0 mL), THF (3.0 mL), and water (1.0 mL) was added lithium hydroxide (0.14 g, 3.36 mmol). After 2 hours, the solvent was concentrated in vacuo, and the crude residue was dissolved in water (10 mL) and acidified with 10% HCl. The aqueous phase was extracted three times with EtOAc. The organic phase was dried (MgSO), filtered, and concentrated in vacuo to give 130 mg of product. 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propanoic acid (99%). 1 H NMR(400 MHz,chloroform-d)δ 7.21-6.98(m,4H),6.63(d,J=11.5 Hz,1H),3.97(s,3H),3.30-3.18(m,2H),3.11-2.89(m,1H),2.82-2.62(m,2H),2.37(d,J=2.0 Hz,1H),1.30(d,J=2.4 Hz,3H),1.28(d,J=2.5 Hz,3H).ESI-MS m / z calculated value 387.16, actual value 388.26 (M+1) + .

[0260] Step 5. 3-(6-Fluoro-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propanoic acid (163) To a cold (0 °C) solution of 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propanoic acid C67 (0.130 g, 0.334 mmol) in CHCl (5.0 mL) was added tribromoborane (1.0 mL of 1 M, 1.000 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with CHCl. ​​The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CHCN / water (0–100%, 0.1% TFA) to give 112 mg of product. 3-[6-Fluoro-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]propanoic acid (86%). 1 H NMR(400 MHz,DMSO-d6)δ 12.19(s,1H),9.09(s,1H),7.32-7.28(m,2H),7.19(d,J=4.2 Hz,1H),7.00(d,J=8.5 Hz,1H),6.49(d,J=11.5 Hz,1H),5.75(s,1H),3.00-2.96(m,4H),2.30(s,3H),1.21(d,J=7.2 Hz,6H).MS m / z calculated value 373.14896, measured value 374.29(M+1) + .

[0261] compound 164 4-(1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoic acid (164) [ka] Step 1. Synthesis of 4-methoxy-3,3-dimethylbut-1-yne (C68) To a cold (0°C) solution of 2,2-dimethylbut-3-yn-1-ol (20.0 g, 203.8 mmol) in DMF (140 mL) was added NaH (8.2 g of 60% w / w, 204.0 mmol) in portions over 10 minutes. The mixture was stirred for 30 minutes. To the mixture was added dimethyl sulfate (23.5 mL, 248.4 mmol) dropwise. After 10 minutes at 0°C, the reaction was stirred at room temperature for 90 minutes. The mixture was diluted with 280 mL of cold water and stirred for 15 minutes. The organic phase was filtered to give 16 g of crude product, which was used without further purification. 4-Methoxy-3,3-dimethyl-but-1-yne (73%). 1 H NMR (300 MHz, chloroform-d) δ 3.43 (s, 3H), 3.27 (s, 2H), 2.15 (s, 1H), 1.25 (s, 6H).

[0262] Step 2. Benzyl 4-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)benzoate (C69) A solution of benzyl 4-iodobenzoate (15.00 g, 44.40 mmol), Pd(PPh3)2Cl2 (0.94 g, 1.33 mmol), and copper iodide (0.51 g, 2.66 mmol) in triethylamine (100 mL) and THF (100 mL) was purged with nitrogen for 5 minutes. To the mixture was added 4-methoxy-3,3-dimethyl-but-1-yne C68 (7.22 g, 64.37 mmol). The mixture was purged with nitrogen for 1 minute. The flask was stirred at room temperature for 5 minutes and then heated to 50 °C for 2 hours. The mixture was filtered, and the resulting solid was washed twice with EtOAc. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (330 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 13 g of product. Benzyl 4-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzoate (79%) 1 H NMR(300 MHz,chloroform-d)δ 8.04-7.94(m,2H),7.51-7.32(m,7H),5.37(s,2H),3.46(q,3H),3.36(q,2H),1.33(s,6H).ESI-MS m / z calculated value 322.2, actual value 323.1 (M+1)+ .

[0263] Step 3. Synthesis of 4-(benzyloxy)-2-bromo-N-(4-fluorophenyl)aniline (C70) A 50 mL round-bottom flask charged with 4-benzyloxy-2-bromoaniline (0.50 g, 1.78 mmol), (4-fluorophenyl)boronic acid (0.50 g, 3.55 mmol), copper(II) acetate (0.65 g, 3.55 mmol), and 4A sieves (0.50 g) in CHCl (15 mL) was stirred open to air for 15 min. Triethylamine (0.62 mL, 4.45 mmol) was added dropwise at ambient temperature, and the resulting dark blue / purple mixture was stirred open to air for 16 h. The crude reaction mixture was diluted with ethyl acetate and then washed with water and brine. The combined organic phase was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0–20% EtOAc / heptane gradient to afford 380 mg of product. 4-Benzyloxy-2-bromo-N-(4-fluorophenyl)aniline (56%). 1 H NMR(400 MHz,DMSO-d6)δ 7.47-7.37(m,5H),7.37-7.34(m,1H),7.32(d,J=2.9 Hz,1H),7.16(d,J=8.8 Hz,1H),7.00(ddd,J=8.8,5.9,3.1 Hz,3H),6.81-6.74(m,2H),5.09(s,2H).ESI-MS m / z calculated value 371.03, actual value 372.19(M+1) + .

[0264] Step 4. Synthesis of benzyl 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoate (C71) A solution of 4-benzyloxy-2-bromo-N-(4-fluorophenyl)aniline C70 (0.25 g, 0.66 mmol), benzyl 4-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzoate C69 (0.38 g, 1.05 mmol), and Pd[P(tBu)3]2 (0.017 g, 0.033 mmol) was evacuated and purged twice with nitrogen. A solution of 1,4-dioxane (4 mL) and N-cyclohexyl-N-methyl-cyclohexanamine (0.35 mL, 1.61 mmol) was bubbled with nitrogen for 2 minutes and then added to the reaction vial. The reaction vial was sealed and heated to 100 °C. LCMS after 1 hour indicated complete consumption of limited starting material. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 10-35% EtOAc / heptane gradient to afford 355 mg of product: benzyl 4-[5-benzyloxy-1-(4-fluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoate (79%). 1 H NMR(400 MHz,chloroform-d)δ 8.21-8.14(m,2H),7.59-7.49(m,4H),7.50-7.29(m,10H),7.28-7.18(m,2H),6.82(dd,J=8.8,2.4 Hz,1H),6.63-6.53(m,2H),5.45(s,2H),4.93(s,2H),3.08(s,3H),3.07(s,2H),1.12(s,6H).ESI-MS m / z calculated value 613.26, measured value 614.37(M+1) + .

[0265] Step 5. Synthesis of benzyl 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoate (164) To a slurry of Pd / C (0.06 g, 0.06 mmol) in EtOH (10 mL) was added benzyl 4-[5-benzyloxy-1-(4-fluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoate C71 (0.14 g, 0.21 mmol) in EtOAc (10 mL). The reaction vial was evacuated and backfilled with hydrogen three times, then stirred under 1 atmosphere of hydrogen for 30 minutes at room temperature. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness. The resulting material was triturated with 9:1 heptane:EtOAc, filtered, and concentrated in vacuo to give 89 mg of product. 4-[1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid (85%). 1 H NMR(400 MHz,DMSO-d6)δ 12.96(s,1H),8.67(s,1H),8.02(d,J=8.2 Hz,3H),7.61-7.36(m,7H),6.53(dd,J=8.7,2.3 Hz,1H),6.37(d,J=8.7 Hz,1H),6.26(d,J=2.3 Hz,1H),3.01(s,3H),2.99(s,4H),1.05(s,7H).ESI-MS m / z calculated value 433.17, actual value 434.32(M+1) + .

[0266] compound 165 4-(2-(1-cyano-2-methylpropan-2-yl)-1-(4-fluorophenyl)-5-hydroxy-1H-indol-3-yl)benzoic acid (165) [ka] Step 1. Synthesis of methyl 4-(4-cyano-3,3-dimethylbut-1-yn-1-yl)benzoate (C72) A solution of benzyl 4-iodobenzoate (15.00 g, 44.36 mmol), Pd(PPh3)2Cl2 (0.94 g, 1.33 mmol), and CuI (0.51 g, 2.66 mmol) in triethylamine (100 mL) and THF (100 mL) was purged with nitrogen for 5 minutes. To the mixture was added 4-methoxy-3,3-dimethyl-but-1-yne (7.22 g, 64.37 mmol). The reaction mixture was purged with nitrogen for 2 minutes. The flask was sealed and heated to 50 °C for 2 hours. The mixture was filtered, and the solid was washed twice with EtOAc. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (330 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 13 g of product. Benzyl 4-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzoate (79%) 1 H NMR(300 MHz,chloroform-d)δ 8.04-7.94(m,2H),7.51-7.32(m,7H),5.37(s,2H),3.46(q,3H),3.36(q,2H),1.33(s,6H).ESI-MS m / z calculated value 322.2, actual value 323.1 (M+1) + .

[0267] Step 2. Synthesis of 2-bromo-N-(4-fluorophenyl)-4-methoxyaniline (C73) At ambient temperature, a 50 mL round-bottom flask was charged with 2-bromo-4-methoxyaniline (0.52 g, 2.57 mmol), (4-fluorophenyl)boronic acid (0.73 g, 5.18 mmol), copper(II) acetate (0.94 g, 5.15 mmol), and 4A sieves (0.47 g). Dichloromethane (15 mL) was added to the mixture, and the slurry was stirred open to air for 15 minutes. Triethylamine (0.89 mL, 6.39 mmol) was added dropwise at ambient temperature, and the resulting dark purple mixture was stirred open to air overnight. The mixture was filtered through a pad of Celite and washed with CHCl. ​​The filtrate was washed with water and brine. The organic phase was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (80 g ISCO column) using a 0-20% EtOAc / heptane gradient to give 543 mg of product: 2-bromo-N-(4-fluorophenyl)-4-methoxy-aniline (67%). 1 H NMR(400 MHz,chloroform-d)δ 7.15(d,J=2.8 Hz,1H),7.13(s,1H),7.03-6.96(m,4H),6.82(dd,J=8.9,2.8 Hz,1H),5.65(s,1H),3.80(s,3H).ESI-MS m / z calculated value 295.01, actual value 296.12 (M+1) + .

[0268] Step 3. Synthesis of methyl 4-(2-(1-cyano-2-methylpropan-2-yl)-1-(4-fluorophenyl)-5-methoxy-1H-indol-3-yl)benzoate (C74) A vial containing methyl 4-(4-cyano-3,3-dimethyl-but-1-ynyl)benzoate C72 (0.31 g, 1.29 mmol), 2-bromo-N-(4-fluorophenyl)-4-methoxy-aniline C73 (0.25 g, 0.84 mmol), and Pd[P(tBu)3]2 (0.02 g, 0.05 mmol) was evacuated and purged with nitrogen (twice). A solution of 1,4-dioxane (5 mL) and N-cyclohexyl-N-methyl-cyclohexanamine (0.45 mL, 2.10 mmol) was added, and the reaction was stirred at 90 °C for 17 h. LCMS showed incomplete conversion to the product. The mixture was cooled to room temperature and purged with nitrogen. Another 0.05 equivalents of Pd[P(tBu)3]2 (0.02 g, 0.04 mmol) was added and the mixture was heated to 90 °C for 21 h. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to afford 155 mg of product. Methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-methoxy-indol-3-yl]benzoate (38%). 1 H NMR(400 MHz,chloroform-d)δ 8.18(d,J=8.2 Hz,2H),7.60(d,J=8.2 Hz,2H),7.54-7.47(m,1H),6.80(dd,J=8.9,2.5 Hz,1H),6.59(d,J=8.9 Hz,1H),6.48(d,J=2.4 Hz,1H),4.00(s,3H),3.72(s,3H),2.44(s,2H),1.31(s,6H).ESI-MS m / z calculated value 456.18, measured value 457.36(M+1) + .

[0269] Step 4. Methyl 4-(2-(1-cyano-2-methylpropan-2-yl)-1-(4-fluorophenyl)-5-hydroxy-1H-indol-3-yl)benzoate (C75) To a cold (0 °C) solution of methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-methoxy-indol-3-yl]benzoate C74 (0.093 g, 0.204 mmol) in dichloromethane (5.5 mL) was added tribromoborane (0.300 mL of a 1 M solution, 0.300 mmol). The reaction mixture was stirred at room temperature for 4 h. Subsequent LCMS analysis showed product (minor) and starting material (major). Additional tribromoborane (0.200 mL of a 1 M solution, 0.200 mmol) was added, and the reaction was stirred at room temperature for an additional 1 h. The reaction vial was cooled to 0 °C and quenched with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered through a phase separator, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) using a 0-20% EtOAc / heptane gradient to give 42 mg of product: methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-hydroxy-indol-3-yl]benzoate (35%). 1 H NMR(400 MHz,chloroform-d)δ 8.19-8.13(m,2H),7.61-7.55(m,2H),7.53-7.46(m,2H),7.33-7.29(m,2H),6.72(dd,J=8.7,2.5 ESI-MS m / z calculated value 442.16928, actual value 443.23(M+1) + .

[0270] Step 5. 4-(2-(1-cyano-2-methylpropan-2-yl)-1-(4-fluorophenyl)-5-hydroxy-1H-indol-3-yl)benzoic acid (165) To a solution of methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-hydroxy-indol-3-yl]benzoate C75 (0.040 g, 0.069 mmol) in water (0.5 mL), THF (0.5 mL), and MeOH (1 mL) was added lithium hydroxide ion (0.015 g, 0.626 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated, diluted with water, acidified using 6N HCl, and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The product was then triturated with 9:1 heptane:ethyl acetate to give 10 mg of product. 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-hydroxy-indol-3-yl]benzoic acid (32%). 1 H NMR(400 MHz,chloroform-d)δ 8.25-8.17(m,2H),7.63-7.56(m,2H),7.52-7.44(m,2H),7.31-7.26(m,2H),6.71(dd,J=8.7,2.5 Hz,1H),6.53(d,J=8.8 Hz,1H),6.45(d,J=2.4 Hz,1H),2.43(s,2H),1.30(s,6H).ESI-MS m / z calculated value 428.15, actual value 429.28(M+1) + .

[0271] compound 166 4-(1-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoic acid (166) [ka] Step 1. Synthesis of methyl 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoate (C76) To a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl-indole S25 (0.062 g, 0.109 mmol), (4-methoxycarbonylphenyl)boronic acid (0.022 g, 0.122 mmol), and sodium carbonate (0.110 mL of a 2 M solution, 0.220 mmol) in DMF (1 mL) was added Pd(dppf)Cl2-CHCl2 (0.009 mg, 0.011 mmol). The reaction mixture was heated to 100 °C and stirred at this temperature overnight. The mixture was diluted with EtOAc and water and filtered through Celite. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with water (twice), brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-35% EtOAc / heptane gradient to give 45 mg of product: methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoate (71%). 1 H NMR(400 MHz,chloroform-d)δ 8.15(d,J=8.2 Hz,2H),7.52(d,J=8.2 Hz,2H),7.42(d,J=7.2 Hz,2H),7.36(t,J=7.5 Hz,2H),7.31(d,J=7.0 Hz,1H),7.20(dd,J=13.7,7.0 Hz,3H),6.92(d,J=2.4 Hz,1H),6.87-6.83(m,1H),6.77(d,J=8.8 Hz,1H),5.00(s,2H),3.98(s,3H),3.83(d,J=11.5 Hz,2H),3.20(t,J=11.4 Hz,2H),3.00(d,J=12.4 Hz,1H),2.39-2.34(m,3H),1.79(d,J=13.0 Hz,2H),1.60(d,J=12.3 Hz,2H).ESI-MS m / z calculated value 549.23, measured value 550.49(M+1) + .

[0272] Step 2. Synthesis of methyl 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoate (C77) To a solution of methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoate C76 (0.045 g, 0.078 mmol) in THF (1.6 mL) / methanol (1.6 mL) was added LiOH (0.800 mL of a 1 M solution, 0.800 mmol). The reaction mixture was heated to 50 °C and stirred at this temperature overnight. The mixture was concentrated under reduced pressure. 1 mL of water was added, and the mixture was acidified to pH 5 with 1 N HCl. The mixture was extracted three times with CHCl. ​​The organic phase was dried (MgSO), filtered, and concentrated in vacuo to give 40 mg of product. 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoic acid (95%). 1 H NMR(400 MHz,chloroform-d)δ 8.20-8.14(m,2H),7.52-7.46(m,2H),7.37-7.33(m,2H),7.32-7.25(m,2H),7.26-7.19(m,1H),7.17-7.10(m,3H),6.87(d,J=2.3 Hz,1H),6.80(dd,J=8.8,2.4 Hz,1H),6.71(d,J=8.8 Hz,1H),4.94(s,2H),3.86-3.77(m,2H),3.72-3.66(m,1H),3.22-3.11(m,2H),2. 99-2.87(m,1H),2.33-2.26(m,3H),1.83-1.70(m,3H),1.60-1.48(m,2H).ESI-MS m / z calculated value 535.22, actual value 536.49 (M+1) + .

[0273] Step 3. 4-(1-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoic acid (166) To a solution of 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoic acid C77 (0.040 g, 0.074 mmol) in MeOH (1 mL) was added dihydroxypalladium (0.002 g, 0.014 mmol). The mixture was placed under 1 atmosphere of hydrogen and stirred for 1 hour. The mixture was filtered through a pad of Celite and then a pad of Florisil. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% MeOH / CHCl gradient to give 28 mg of product. 4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]benzoic acid (83%). 1 H NMR(400 MHz, methanol-d4)δ 8.16-8.06(m,2H),7.53-7.44(m,2H),7.31-7.17(m,3H),6.78(dd,J=2.0,1.0 Hz,1H),6.72-6.64(m,2H),3.83(d,J=11.2 Hz,2H),3.29-3.19(m,2H),3.07-2.96(m,1H),2.42-2.34(m,3H),1.89-1.75(m,2H),1.69-1.57(m,2H).ESI-MS m / z calculated value 445.17, actual value 446.49(M+1) + A mixture of

[0274] Compounds 167~176 Compounds 167-176 (Table 13) were prepared by Suzuki coupling of the appropriate boronic acid with the relevant iodoindole intermediate as described for the preparation of compound 166. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] 1. Suzuki coupling: Pd(dppf)Cl2-CH2Cl2, Na2CO3, H2O, DMF at 100 °C. 2. Hydrolysis conditions: LiOH, THF, MeOH, H2O 3. Hydrogenation: H2, Pd(OH)2, MeOH 4. Suzuki Coupling: Pd(Ph3P)4, K2CO3, dioxane at 110 °C 5. BBr3, CH2Cl2, 0℃ 6. Hydrolysis conditions: NaOH, MeOH 7. Hydrogenation: H2, Pd / C wood or H2, Pd / C, EtOAc 8. Suzuki coupling: Pd(Ph3P)2Cl2, Na2CO3, H2O, DME at 80 °C.

[0275] compound 177 Synthesis of 4-(6-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoic acid (177) [ka] To a solution of 4-[1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid 164 (0.025 g, 0.058 mmol) in MeCN (1.25 mL) was added 1-chloropyrrolidine-2,5-dione (0.015 g, 0.112 mmol). The reaction mixture was stirred at room temperature for 20 minutes and then at 45 °C for 1 hour. The crude mixture was purified by directly loading onto reverse-phase HPLC to give 3.3 mg of product. 4-[6-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid (12%). 1H NMR (400 MHz, chloroform-d) δ 8.23-8.17 (m, 2H), 7.62-7.56 (m, 2H), 7.49-7.42 (m, 2H), 7.29 (s, 6H), 6.67 (s, 1H), 6.63 (s, 1H), 3.09 (s, 3H), 3.07 (s, 2H), 1.14 (s, 6H).

[0276] compound 178 Synthesis of 4-(4-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoic acid (178) [ka] To a solution of 4-[1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid 164 (0.029 g, 0.067 mmol) in NaOH (1.0 mL of a 1 M solution, 1.0 mmol) was added sodium hypochlorite (0.130 mL of a 5% w / v solution, 0.087 mmol). After 1 min, the reaction mixture was diluted with water (1 mL) and HCl (1.5 mL of a 1 M solution, 1.5 mmol). The mixture was extracted three times with EtOAc. The combined organic phases were dried (MgSO), filtered, and concentrated in vacuo. The crude material was triturated with 9:1 heptane:EtOAc and filtered to give 9.8 mg of product as an off-white solid. 4-[4-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid (29%). 1 H NMR(400 MHz,chloroform-d)δ 8.17-8.09(m,2H),7.63(d,J=8.2 Hz,2H),7.49-7.41(m,2H),7.29-7.22(m,2H),6.81(d,J=8.8 Hz,1H),6.47(d,J=8.8 Hz,1H),3.11(s,3H),2.99(s,2H),1.08(s,7H).ESI-MS m / z calculated value 467.13, actual value 468.29(M+1) + .

[0277] Compound 179 4-(1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoic acid (179) [ka] Step 1. Synthesis of 4-methoxy-3,3-dimethylbut-1-yne (C78) CH 2 To a cold (0 °C) solution of oxalyl chloride (13.00 mL of 2 M, 26.00 mmol) in Cl2 was added DMF (13 mL, 167.9 mmol). The suspension was stirred at 0 °C for 10 min. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole in CHCl2 (50 mL) S8 (5.00 g, 13.39 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The solution was basified with saturated aqueous NaHCO3 and extracted three times with CHCl2. The organic phase was dried over NaSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (80 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 4.67 g of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carbaldehyde (81%). 1 H NMR(300 MHz,chloroform-d)δ 10.42(s,1H),7.95(d,J=2.5 Hz,1H),7.47-7.37(m,2H),7.40-7.21(m,3H),7.18-6.99(m,3H),6.83(dd,J=8.9,2.5 ESI-MS m / z calculated value 401.18, actual value 402.27 (M+1) + .

[0278] Step 2. Benzyl 4-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)benzoate (C79) To a cold (-78 °C) solution of methyl prop-2-ynoate (0.105 mL, 1.180 mmol) in THF (1 mL) was added n-butyllithium (0.470 mL of 2.5 M, 1.175 mmol). The reaction mixture was stirred for 30 min, and a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carbaldehyde C78 (0.335 g, 0.782 mmol) in THF (4 mL) was added dropwise. The mixture was stirred for 1 h, the -78 °C bath was switched to 0 °C, and the mixture was stirred for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-30% EtOAc / heptane gradient to give 154 mg of product. Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-hydroxy-but-2-ynoate (40%). 1 H NMR(400 MHz,chloroform-d)δ 7.56(d,J=2.3 Hz,1H),7.52-7.48(m,2H),7.41-7.36(m,2H),7.34-7.30(m,1H),7.18-7.05(m,3H),6.85(dd,J=8.9,2.4 Hz,1H),6.77(dd,J=8.8,0.5 Hz,1H),6.08(d,J=4.1 Hz,1H),5.15(s,2H),3.77(d,J=1.4 Hz,3H),3.07-3.00(m,1H),2.34(d,J=2.0 Hz,3H),2.21(d,J=4.5 Hz, 1H), 1.36-1.28 (m, 6H). ESI-MS m / z calculated 485.20, found 486.01 (M+1). + .

[0279] Step 3. Synthesis of 4-(benzyloxy)-2-bromo-N-(4-fluorophenyl)aniline (C80) Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-hydroxy-but-2-ynoate in CHCl (2 mL) C79 To a solution of (0.154 g, 0.310 mmol) was added Dess-Martin periodinane (0.160 g, 0.377 mmol). The reaction mixture was stirred for 2 hours, and 2-methyl-2-propanol (0.100 mL, 1.046 mmol) was added to expedite the reaction, which was then stirred overnight at room temperature. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 0-20% EtOAc / heptane gradient to yield 10 mg of product. Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-oxo-but-2-ynoate (6%). 1 H NMR(400 MHz,chloroform-d)δ 8.09(d,J=2.4 Hz,1H),7.49(d,J=7.7 Hz,2H),7.39(t,J=7.4 Hz,2H),7.33(d,J=7.2 Hz,1H),7.20(t,J=8.7 Hz,1H),7.14(t,J=6.5 Hz,2H),6.90(dd,J=8.7,2.5 Hz,1H),6.72(d,J=8.9 Hz,1H),5.18(s,2H),3.88(s,3H),3.68-3.58(m,1H),2.37(s,3H),1.29(d,J=2.3 Hz,6H).ESI-MS m / z calculated 483.18, observed 484.05 (M+1) + .

[0280] Step 4. Synthesis of benzyl 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoate (C81) To a solution of methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-oxo-but-2-ynoate C90 (0.010 g, 0.019 mmol) in ethanol (0.5 mL) was added hydrazine hydrate (0.005 mL, 0.102 mmol). The reaction mixture was stirred at room temperature for 4 hours, and the solvent was reduced under reduced pressure. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% EtOAc / CHCl gradient to afford 8 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylate (78%) 1 H NMR(400 MHz,chloroform-d)δ 10.34(s,1H),7.47-7.42(m,2H),7.41-7.35(m,2H),7.34-7.30(m,1H),7.21-7.12(m,3H),6.98(d,J=10.0 ESI-MS m / z calculated value 497.21, actual value 498.03 (M+1) + A mixture of

[0281] Step 5. Synthesis of benzyl 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropan-2-yl)-1H-indol-3-yl)benzoate (179) To a solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylate C81 (0.008 g, 0.015 mmol) in THF (0.3 mL) / methanol (0.3 mL) was added lithium hydroxide (0.300 mL of 1 M, 0.300 mmol). The reaction mixture was heated to 50 ° C and stirred overnight. The mixture was acidified with 1N HCl and extracted twice with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 5 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid (68%). 1 H NMR(400 MHz,chloroform-d)δ 7.44(d,J=7.4 Hz,2H),7.35(t,J=7.4 Hz,2H),7.29(d,J=7.2 Hz,1H),7.23-7.14(m,3H),7.04-7.00(m,2H),6.88(dd,J=8.9,2.3 Hz,1H),6.81(d,J=8.8 Hz,1H),5.06(s,2H),3.17-3.08(m,1H),2.37(d,J=1.9 Hz,3H),1.17(d,J=7.1 Hz,6H).ESI-MS m / z calculated value 483.2, actual value 484.2(M+1) + .

[0282] A mixture of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid (0.005 g, 0.010 mmol) and dihydroxypalladium (0.001 g, 0.007 mmol) in methanol (0.5 mL) was stirred under a hydrogen atmosphere for 1 hour. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.9 mg of product. 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid (96%). 1H NMR(400 MHz, methanol-d4)δ 7.32-7.16(m,3H),6.84(s,1H),6.72(d,J=2.2 Hz,1H),6.70-6.58(m,2H),4.12(d,J=12.2 Hz,1H),3.12-3.04(m,1H),2.36(d,J=1.9 Hz,3H),1.15(d,J=7.1 Hz,6H).ESI-MS m / z calculated value 393.15, measured value 394.07(M+1) + .

[0283] Preparation 180 Synthesis of 3-(1-(3,3-difluorocyclobutyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)benzoic acid (180) [ka] Step 1. Synthesis of 5-(benzyloxy)-1-(3,3-difluorocyclobutyl)-2-isopropyl-1H-indole (C83) To a solution of 4-benzyloxy-1-bromo-2-(3-methylbut-1-ynyl)benzene C6 (0.23 g, 0.66 mmol) in tBuOH (2.5 mL) / dioxane (1.3 mL) was added NaOtBu (0.26 g, 2.71 mmol). The mixture was purged with nitrogen, and 3,3-difluorocyclobutanamine (hydrochloride) (0.115 g, 0.801 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.050 g, 0.063 mmol) were added. The mixture was heated at 80 °C for 18 h. The reaction mixture was diluted with water (100 mL), and the aqueous layer was extracted three times with EtOAc (3 × 100 mL). The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (24 g ISCO column) using a 0-40% EtOAc / heptane gradient to afford 195 mg of product: 4-benzyloxy-N-(3,3-difluorocyclobutyl)-2-(3-methylbut-1-ynyl)aniline (83%). 1H NMR(400 MHz,chloroform-d)δ 7.39(tdd,J=16.9,11.9,8.8 Hz,5H),6.98(d,J=2.9 Hz,1H),6.85(dd,J=8.8,2.9 Hz,1H),6.39(d,J=8.9 Hz,1H),4.98(s,2H),4.41(d,J=5.6 Hz,1H),3.84(q,J=7.9,5.9 Hz,1H),3.06(dtt,J=11.4,7.9,3.7 Hz,2H),2.86(h,J=6.8 Hz,1H),2.60-2.40(m,2H),1.31(d,J=6.8 Hz,6H).ESI-MS m / z Calculated value 355.17, measured value 356.71 (M+1) + A mixture of the following compounds was obtained. Indium tribromide (0.015 g, 0.042 mmol) was added to a solution of 4-benzyloxy-N-(3,3-difluorocyclobutyl)-2-(3-methylbut-1-ynyl)aniline (0.195 g) in toluene (2 mL), and the resulting solution was heated at 80 °C for 2 h and then cooled to room temperature. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (24 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 140 mg of product. 5-benzyloxy-1-(3,3-difluorocyclobutyl)-2-isopropyl-indole (59%). 1 H NMR(400 MHz,chloroform-d)δ 7.51-7.30(m,5H),7.15(d,J=2.5 Hz,1H),6.93(dd,J=8.9,2.6 Hz,1H),6.21(t,J=0.8 ESI-MS m / z calculated value 355.17, actual value 356.24 (M+1) + A mixture of

[0284] Step 2. Synthesis of 5-(benzyloxy)-1-(3,3-difluorocyclobutyl)-3-iodo-2-isopropyl-1H-indole (C84) in CH2Cl2 (4.0 mL) N - iodosuccinimide (0.087 g, 0.387 mmol) and 5-benzyloxy-1-(3,3-difluorocyclobutyl)-2-isopropyl-indole C83 A solution of (0.140 g, 0.394 mmol) was purged with a stream of nitrogen. The reaction vial was sealed and stirred for 30 minutes. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (12 g ISCO column) using a 0-50% EtOAc / heptane gradient to afford 166 mg of product. 5-Benzyloxy-1-(3,3-difluorocyclobutyl)-3-iodo-2-isopropyl-indole (88%). 1 H NMR(400 MHz,chloroform-d)δ 7.52(ddt,J=7.5,1.4,0.7 Hz,2H),7.45-7.39(m,3H),7.38-7.34(m,1H),7.03(d,J=2.5 Hz,1H),6.98(dd,J=8.9,2.6 Hz,1H),5.16(s,2H),5.11(dt,J=8.9,4.8 Hz,1H),3.72-3.52(m,3H),3.22-3.04(m,2H),1.46(d,J=7.3 Hz,6H).

[0285] Step 3. Synthesis of methyl 3-(5-(benzyloxy)-1-(3,3-difluorocyclobutyl)-2-isopropyl-1H-indol-3-yl)benzoate (C85) A suspension of 5-benzyloxy-1-(3,3-difluorocyclobutyl)-3-iodo-2-isopropyl-indole C84 (0.160 g, 0.332 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.130 g, 0.504 mmol), and Pd(dppf)Cl2-CHCl2 (0.014 g, 0.017 mmol) was purged with nitrogen. DMF (2.0 mL) and sodium carbonate (0.500 mL of 2 M, 1.000 mmol) were added. The reaction mixture was heated at 80 °C for 20 min. The volatiles were removed under reduced pressure, and the residue was diluted with water and ethyl acetate was added. The resulting residue was purified by silica gel chromatography using a 0-50% EtOAc / heptane gradient to give 130 mg of product. Methyl 3-[5-benzyloxy-1-(3,3-difluorocyclobutyl)-2-isopropyl-indol-3-yl]benzoate (80%). 1 H NMR(400 MHz,chloroform-d)δ 8.07-8.01(m,2H),7.57-7.46(m,3H),7.46-7.29(m,5H),7.09-6.86(m,2H),5.11(pd,J=8.9,3.4 Hz,1H),5.01(s,2H),3.93(s,3H),3.83-3.66(m,2H),3.38(p,J=7.3 Hz,1H),3.13(dddd,J=16.0,13.2,9.2,4.0 Hz,2H),1.34(d,J=7.3 Hz,6H).

[0286] Step 4. Synthesis of 3-(5-(benzyloxy)-1-(3,3-difluorocyclobutyl)-2-isopropyl-1H-indol-3-yl)benzoic acid (C86) To a solution of methyl 3-[5-benzyloxy-1-(3,3-difluorocyclobutyl)-2-isopropyl-indol-3-yl]benzoate C85 (0.13 g, 0.27 mmol) in MeOH (2.20 mL), THF (0.80 mL), and HO (0.50 mL) was added lithium hydroxide (0.190 g, 4.53 mmol). The reaction mixture was stirred at 25 °C for 12 h. The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (8 mL) and slowly acidified with HCl (2.5 mL of 2 M, 5.00 mmol). The aqueous layer was extracted three times with EtOAc. The organic phase was dried (MgSO), filtered, and concentrated in vacuo to give 100 mg of product. 3-[5-Benzyloxy-1-(3,3-difluorocyclobutyl)-2-isopropyl-indol-3-yl]benzoic acid (75%). 1 H NMR(400 MHz,chloroform-d)δ 8.15-8.04(m,2H),7.67-7.47(m,3H),7.45-7.28(m,5H),7.01-6.90(m,2H),5.12(qt,J=9.1,4.5 ESI-MS m / z calculated value 475.2, actual value 476.2 (M+1) + .

[0287] Step 5. Synthesis of 3-(1-(3,3-difluorocyclobutyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)benzoic acid (180) A solution of 3-[5-benzyloxy-1-(3,3-difluorocyclobutyl)-2-isopropyl-indol-3-yl]benzoic acid C86 (0.10 g, 0.20 mmol) in EtOAc (3.0 mL) and MeOH (1.0 mL) was purged with nitrogen. Pd / wood carbon (0.06 g of 10% w / w, 0.03 mmol) was added, and the mixture was evacuated and filled with hydrogen. The mixture was stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% MeOH / CHCl gradient to give 38 mg of product. 3-[1-(3,3-difluorocyclobutyl)-5-hydroxy-2-isopropyl-indol-3-yl]benzoic acid (48%). 1H NMR(400 MHz,chloroform-d)δ 7.99(tt,J=3.7,1.9 Hz,2H),7.59-7.49(m,2H),7.44(d,J=8.6 Hz,1H),6.85-6.61(m,2H),5.20(tt,J=9.0,4.6 ESI-MS m / z Calculated value 385.15, actual value 386.22 (M+1) + .

[0288] Preparation 181 Synthesis of (E)-3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)acrylic acid (181) [ka] Step 1. Synthesis of 6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indole-3-carbaldehyde (C87) A solution of oxalyl chloride (13.0 mL of a 2 M solution (1.8 mL of 2 M, 3.6 mmol) was added to a cold (0 °C) solution of DMF (1.6 mL, 20.66 mmol) in CHCl (5 mL). The solution was stirred at room temperature for 30 min. 6-Fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole (0.65 g, 2.05 mmol) in CHCl (10 mL) was added. The resulting solution was The mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 (10 mL) was slowly added. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-60% EtOAc / heptane gradient to give 0.58 g of product. 6-Fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole-3-carbaldehyde (80%). 1 H NMR(400 MHz,chloroform-d)δ 10.50(s,1H),8.01(d,J=8.4 Hz,1H),7.27(d,J=9.8 Hz,1H),7.18-6.89(m,1H),6.62(d,J=11.0 Hz,2H),4.01(s,3H),2.40(d,J=2.0 Hz,1H),1.48(d,J=2.6 Hz,3H),1.46(d,J=2.6 Hz,3H).ESI-MS m / z calculated value 343.14, measured value 344.13(M+1) + .

[0289] Step 2. Synthesis of (E)-3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)acrylic acid (181) To a solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole-3-carbaldehyde C87 (0.05 g, 0.14 mmol) and malonic acid (0.10 g, 0.96 mmol) in pyridine (0.5 mL) was added piperidine (0.1 mL). The reaction mixture was heated in a closed vial at 100 °C for 24 hours. The mixture was poured into water (5 mL) and extracted twice with EtOAc. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-60% EtOAc / heptane gradient to give 26 mg of product. (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]prop-2-enoic acid (46%). ESI-MS m / z calculated 371.13, observed 372.16 (M+1) + .

[0290] To a solution of (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]prop-2-enoic acid (26 mg) in CHCl (3 mL) was added BBr (0.427 mL of 1 M, 0.427 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO (1 mL). The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CHCN / water (0–100%, 0.1% TFA) to afford 15 mg of product. (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]prop-2-enoic acid (27%). 1H NMR(400 MHz, methanol-d4)δ 8.21(d,J=15.8 Hz,1H),7.38(d,J=8.3 Hz,1H),7.30-7.02(m,3H),6.54(d,J=11.0 Hz,1H),6.29(d,J=15.8 Hz,1H),3.16-2.87(m,1H),2.37(d,J=2.1 Hz,3H),1.37(d,J=2.2 Hz,3H),1.35(d,J=2.2 Hz,3H).ESI-MS m / z calculated value 371.13, measured value 372.16(M+1) + .

[0291] compound 182 1-(4-Fluorophenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (182) [ka] Step 1. Synthesis of 2-(3-hydroxyphenyl)-3-oxobutanenitrile (C182) To a cold (0 °C) solution of 2-(3-hydroxyphenyl)acetonitrile (3.00 g, 20.38 mmol) in THF (30 mL) was slowly added NaH (1.06 g of 60% w / w, 26.49 mmol). The cooling bath was then removed, and the reaction mixture was stirred at room temperature for 1 h. Ethyl acetate (2.39 mL, 24.46 mmol) was added in one lot. The reaction mixture was then heated to 60 °C for 3 h. The mixture was cooled to room temperature, and two-thirds of the solvent was removed under reduced pressure. The residue was dissolved in cold water (0 °C, 50 mL). With vigorous stirring, 1 N HCl solution was added dropwise until the pH reached a neutral level. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-70% EtOAc / heptane gradient to give 3 g of product. 2-(3-hydroxyphenyl)-3-oxobutanenitrile (78%).

[0292] Step 2. Synthesis of (E)-3-((4-fluorophenyl)amino)-2-(3-hydroxyphenyl)but-2-enenitrile (C89) A mixture of 2-(3-hydroxyphenyl)-3-oxobutanenitrile C88 (1.00 g, 5.28 mmol), 4-fluoroaniline (1.02 mL, 10.57 mmol), and acetic acid (0.60 mL, 10.57 mmol) in EtOH (10.00 mL) was stirred at 50 °C. An additional 0.5 equivalents of 4-fluoroaniline and 0.5 equivalents of acetic acid were added, and the temperature was increased to 60 °C upon completion of the reaction. The mixture was evaporated to partially remove the solvent, and the residue was poured into cold water (0 °C, 40 mL) and neutralized with saturated aqueous NaHCO3. The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-70% EtOAc / heptane gradient to give 900 mg of the product (E)-3-(4-fluoroanilino)-2-(3-hydroxyphenyl)but-2-enenitrile (60%).

[0293] Step 3. Synthesis of 1-(4-fluorophenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (C90) To a solution of (E)-3-(4-fluoroanilino)-2-(3-hydroxyphenyl)but-2-enenitrile C89 (0.70 g, 2.48 mmol) in 1,2-dichloroethane (7.0 mL) was added N-chlorosuccinimide (0.36 g, 2.72 mmol) in one portion. The reaction was stirred at room temperature until total consumption of the starting material. Zn(OAc) dihydrate (3.2 mmol) was then added in one portion. The reaction temperature was gradually increased to reflux and stirred overnight. The reaction mixture was quenched with water, and the aqueous solution was extracted with EtOAc. The combined organic phases were dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 0-10% EtOAc / heptane gradient to give the desired product.

[0294] Step 4. Synthesis of 1-(4-fluorophenyl)-5-hydroxy-2-methyl-1H-indole-3-carbonitrile (182) To a cold (0 °C) solution of 1-(4-fluorophenyl)-5-hydroxy-2-methyl-indole-3-carbonitrile C90 (0.030 g, 0.107 mmol) in CHCl2 under a nitrogen atmosphere (1.2 mL), tribromoborane (1.07 mL of 1 M, 1.07 mmol) was added dropwise. The reaction mixture was stirred for 90 min. The desired product was observed. The reaction mixture was cooled to 0 °C and slowly quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl2. The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase flash chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0–100%, 0.1% TFA) to give the product. 1-(4-fluorophenyl)-5-hydroxy-2-methyl-indole-3-carbonitrile. 1 H NMR(400 MHz,DMSO-d6)δ 9.31(s,1H),7.64-7.52(m,2H),7.50-7.41(m,2H),6.94-6.85(m,2H),6.72(dd,J=8.8,2.3 Hz,1H),2.36(s,3H).ESI-MS m / z actual value 267.2(M+1) + .

[0295] compound 183 2-(1-(4-fluorophenyl)-5-hydroxy-2-methyl-1H-indol-3-yl)propanenitrile (183) [ka] Step 1. Synthesis of 2-(1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (C91) To a suspension of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile C23 (1.32 g, 6.59 mmol) in toluene (13.20 mL) degassed with nitrogen for 10 minutes, K3PO4 (4.20 g, 19.78 mmol), copper iodide (0.75 g, 3.96 mmol), N,N'-dimethylethane-1,2-diamine (0.42 mL, 3.96 mmol), and 1-fluoro-4-iodobenzene (1.52 mL, 13.18 mmol) were added. The pressure flask was sealed with a screw cap, and the reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a plug of Celite, which was further washed with CHCl2. The filt...

Claims

1. A compound represented by the following structural formula: 【Chemistry 132】 a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: V １ and V ２ But, -CR ２ and U is —OH; X is absent or -(CR ａ R ａ ) ｐ - or -R ａ’ C=CR ａ’ - and Y is absent or -(CR ｂ R ｂ ) ｑ - or -R ｂ’ C=CR ｂ’ - and T is -CR ｃ R ｃ COOH, -CR ｃ =CR ｃ COOH, —CN, or 【Chemistry 133】 and R ａ and R ｂ each occurrence independently represents hydrogen, halogen, —OH, benzyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C １ -C ６ haloalkoxy, R ａ’ and R ｂ’ are, in each occurrence, independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C １ -C ６ haloalkoxy, R ｃ is, in each occurrence, independently hydrogen, halogen, —OH, benzyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C １ -C ６ haloalkoxy, Ring A is C ３ -C １２ cycloalkyl, 3- to 12-membered heterocyclyl, C ６ Or C １０ aryl, or 5- to 10-membered heteroaryl; Ring B is C ４ -C １２ cycloalkyl, C6 aryl, or 5-10 membered heteroaryl; Z is -CN, 【Chemistry 134】 and When T is not —CN, ring C is C ３ -C １２ Cycloalkyl, C ６ Or C １０ aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; When T is —CN, ring C is C ３ -C １２ cycloalkyl or 3- to 12-membered heterocyclyl; R Ｅ , R Ｆ , and R Ｇ are each independently hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, —C(═O)R ｓ , -C(=O)OR ｓ , —C(═O)NR ｐ R ｑ , -CR ｐ (=N) OR ｓ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -OR ｓ , —OC(═O)R ｓ or —OC(═O)NR ｐ R ｑ and R Ｅ , R Ｆ , and R Ｇ Any one of the C １ -C ６ Alkyl or the C ２ -C ６ Alkenyl is optionally cyano, —C(═O)R ｓ , -C(=O)OR ｓ , —C(═O)NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (= O) ｒ R ｓ , -OR ｓ , —OC(═O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｒ R ｓ , and -S(=O) ｒ NR ｐ R ｑ and is substituted with 1 to 3 groups independently selected from R ｐ , R ｑ , and R ｒ are, in each occurrence, independently hydrogen, C １ -C ４ Alkyl, C ３ -C ６ cycloalkyl, or 3- to 6-membered heterocyclyl; R ｐ , R ｑ , and R ｒ Any one of the C １ -C ４ The alkyl is optionally selected from halogen, cyano, —OH, C １ -C ３ Alkoxy, —C(═O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｐ , R ｑ , and R ｒ Any one of the C ３ -C ６ cycloalkyl or said 3- to 6-membered heterocyclyl is optionally selected from halogen, cyano, —OH, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)O(C １ -C ２ alkyl), -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｓ may, in each occurrence, independently be hydrogen, C １ -C ４ Alkyl, C ３ -C ６ cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; R ｓ The above C １ -C ４ The alkyl is optionally selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｓ The above C ３ -C ６ cycloalkyl, said phenyl, or said 5- or 6-membered heteroaryl may optionally be selected from the group consisting of halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R １ But halogen, cyano, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ haloalkoxy, or —O—(C ３ -C ６ cycloalkyl), R ２ may, in each occurrence, independently be hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C ３ -C ６ Cycloalkyl, —NR ｈ R ｉ , phenyl, or 5- or 6-membered heteroaryl; R ２ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, or the C ３ -C ６ Cycloalkyl is optionally selected from cyano, —C(═O)R ｋ , -C(=O)OR ｋ , —C(═O)NR ｈ R ｉ , -NR ｈ R ｉ , -NR ｈ C(=O)R ｋ , -NR ｈ C(=O)OR ｋ , -NR ｈ C(=O)NR ｉ R ｊ , -NR ｈ S (= O) ｓ R ｋ , -OR ｋ , —OC(═O)R ｋ , -OC(=O)OR ｋ , -OC(=O)NR ｈ R ｉ , -S(=O) ｓ R ｋ , and S(=O) ｓ NR ｈ R ｉ and is substituted with 1 to 3 groups independently selected from R ｈ , R ｉ , and R ｊ are, in each occurrence, independently hydrogen, C １ -C ４ Alkyl, or C ３ -C ６ is cycloalkyl, R ｈ , R ｉ , and R ｊ Any one of the C １ -C ４ The alkyl is optionally selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｈ , R ｉ , and R ｊ Any one of the C ３ -C ６ Cycloalkyl is optionally selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｋ may, in each occurrence, independently be hydrogen, C １ -C ４ Alkyl, C ３ -C ６ cycloalkyl, phenyl, or 5- or 6-membered heteroaryl; -OR ｋ but cannot be —OH, R ｋ The above C １ -C ４ The alkyl is optionally selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｋ The above C ３ -C ６ cycloalkyl, said phenyl, or said 5- or 6-membered heteroaryl may optionally be selected from the group consisting of halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ３ and R ４ each occurrence independently represents halogen, cyano, ═O, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C ３ -C ６ cycloalkyl, -C(=O)R ｙ , -C(=O)OR ｙ , —C(═O)NR ｖ R ｗ , —C(═O)NR ｖ OR ｙ , -(=O)NR ｖ S (= O) ｔ R ｙ , -NR ｖ R ｗ , -NR ｖ C(=O)R ｙ , -NR ｖ C(=O)OR ｙ , -NR ｖ C(=O)NR ｗ R ｘ , -NR ｖ S (= O) ｔ R ｙ , -OR ｙ , —OC(═O)R ｙ , -OC(=O)OR ｙ , -OC(=O)NR ｖ R ｗ , -S(=O) ｔ R ｙ , -S(=O) ｔ NR ｖ R ｗ , -S(=O) ｔ NR ｖ C(=O)R ｙ , -P(=O)R ｚ R ｚ , phenyl, or 5- or 6-membered heteroaryl; R ３ and R ４ The above C １ -C ６ alkyl, the C ２ -C ６ Alkenyl, the C ３ -C ６ cycloalkyl, or said 5- or 6-membered heteroaryl is optionally selected from cyano, —C(═O)R ｙ , -C(=O)OR ｙ , —C(═O)NR ｖ R ｗ , -NR ｖ R ｗ , -NR ｖ C(=O)R ｙ , -NR ｖ C(=O)OR ｙ , -NR ｖ C(=O)NR ｗ R ｘ , -NR ｖ S (= O) ｒ R ｙ , -OR ｙ , —OC(═O)R ｙ , -OC(=O)OR ｙ , -OC(=O)NR ｖ R ｗ , -S(=O) ｔ R ｙ , and -S(=O) ｔ NR ｖ R ｗ and is substituted with 1 to 3 groups independently selected from R ｖ , R ｗ , and R ｘ are, in each occurrence, independently hydrogen, C １ -C ４ Alkyl, C ３ -C ６ cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R ｖ , R ｗ , and R ｘ Any one of the C １ -C ４ The alkyl is optionally selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｖ , R ｗ , and R ｘ Any one of the C ３ -C ６ cycloalkyl, said 5- or 6-membered heterocyclyl, or said 5- or 6-membered heteroaryl may optionally be selected from the group consisting of halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｙ may, in each occurrence, independently be hydrogen, C １ -C ４ Alkyl, C ３ -C ６ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R ｙ The above C １ -C ４ The alkyl is optionally selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｙ The above C ３ -C ６ cycloalkyl, said phenyl, said 5- or 6-membered heterocyclyl, or said 5- or 6-membered heteroaryl may optionally be selected from the group consisting of halogen, cyano, —OH, —NH ２ , NH(C １ -C ２ alkyl), -N(C １ -C ２ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, —C(═O)OH, —C(═O)O(C １ -C ２ alkyl), —C(═O)NH ２ , -C(=O)NH(C １ -C ２ alkyl), and —C(═O)N(C １ -C ２ alkyl) ２ and is substituted with 1 to 3 groups independently selected from R ｚ but, in each occurrence, independently, C １ -C ２ alkyl, —OH, or -O(C １ -C ２ alkyl), k is an integer selected from 1, 2, and 3; n and o are each independently an integer selected from 0, 1, 2, and 3; A compound, a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein p, q, r, s, and t are each independently an integer selected from 1 and 2, with the proviso that said compound of formula (I) is not 4,6-dibromo-5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carbonitrile.

2. Represented by formula (IIa): 【Chemistry 135】 During the ceremony, Y is absent or -CR ｂ R ｂ - or -R ｂ’ C=CR ｂ’ - and R ｂ is, in each occurrence, independently hydrogen or C １ -C ２ is alkyl, Ring B is R １ and ring B is substituted with C ４ -C ６ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, which is cycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

3. Y is absent or -CH ２ 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 or 2, wherein -, or -HC=CH-.

4. Represented by formula (III): 【Chemistry 137】 During the ceremony, X is absent or -(CR ａ R ａ ) ｐ - and R ａ are, in each occurrence, independently hydrogen or C １ -C ２ is alkyl, R ｃ is, in each occurrence, independently hydrogen, F, —OH, benzyl, C １ -C ２ Alkyl, or C １ -C ２ is an alkoxy; Ring B is R １ and Ring B is cyclobutyl, phenyl, pyridinyl, or pyrimidinyl.

5. X is absent or -CH ２ --, --CHCH ３ -, -CH ２ CH ２ - or -CHCH ３ CH ２ - and Ring B is R １ and Ring B is cyclobutyl, phenyl, pyridin-4-yl, or pyrimidin-4-yl.

6. Represented by formula (IV): 【Chemistry 138】 During the ceremony, T is -CH ２ COOH, -CHCH ３ COOH, -CHC ２ H ５ COOH, -C(CH ３ ) ２ COOH, -CF ２ COOH, -CH=CHCOOH, -C(CH ３ )(OH)COOH, -C(CH ３ ) (OCH ３ )COOH, cyano, —CH(benzyl)COOH, or optionally, R ３ Ring A is substituted with When Z is ring C, ring C may optionally be R ４ and ring C is substituted with C ３ -C ６ cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl; R １ But halogen, C １ -C ２ Alkyl, or C １ -C ２ is haloalkyl, 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 5, wherein k is an integer selected from 1 and 2.

7. R １ is F, Cl, or —CH ３ 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein:

8. When T is ring A, ring A may optionally be R ３ and ring A is substituted with C ３ -C ７ 8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 7, which is cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl.

9. When T is ring A, ring A may optionally be R ３ and ring A is substituted with C ３ -C ７ 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 8, which is cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms.

10. When T is ring A, ring A may optionally be R ３ and ring A is substituted with 【Chemistry 139】 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, selected from:

11. When T is ring A, ring A may optionally be R ３ and ring A is substituted with 【Chemistry 140】 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 10, selected from:

12. When Z is ring C, ring C may optionally be R ４ and ring C is substituted with C ３ -C ４ 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 11, which is cycloalkyl or 4-6 membered heterocyclyl.

13. When Z is ring C, ring C may optionally be R ４ and ring C is 【Chemistry 141】 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein:

14. When Z is ring C, ring C may optionally be R ４ and ring C is 【142】 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 13, wherein:

15. Z is, 【143】 If R Ｅ , R Ｆ , and R Ｇ are each independently hydrogen, halogen, cyano, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, —C(═O)OR ｓ , —C(═O)NR ｐ R ｑ , -CR ｐ (=N) OR ｓ , -NR ｐ R ｑ , or -OR ｓ and R Ｅ , R Ｆ , and R Ｇ Any one of the C １ -C ６ The alkyl is optionally selected from cyano and -OR ｓ and is substituted with 1 to 3 groups selected from R ｐ and R ｑ are, in each occurrence, independently hydrogen or C １ -C ４ is alkyl, R ｓ is, in each occurrence, independently hydrogen or C １ -C ４ 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein: R is alkyl.

16. Z is, 【Chemical 144】 If R Ｅ , R Ｆ , and R Ｇ are each independently hydrogen, halogen, C １ -C ２ Alkyl, —NR ｐ R ｑ , or -OR ｓ and R Ｅ , R Ｆ , and R Ｇ Any one of the C １ -C ２ Alkyl is optionally selected from cyano, —OH, and —OCH ３ and is substituted with 1 to 3 groups independently selected from R ｐ and R ｑ are, in each occurrence, independently hydrogen or C １ -C ２ is alkyl, R ｓ is, in each occurrence, independently hydrogen or C １ -C ２ 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 11 and 15, wherein:

17. Z is, 【Chemistry 145】 If R Ｅ , R Ｆ , and R Ｇ are each independently hydrogen, F, or —CH ２ CN, -OH, -OCH ３ , -CH ３ , -C ２ H ５ , or -CH ２ OCH ３ and Z is, 【Chemistry 146】 If R Ｅ and R Ｆ are each independently —CH ３ or -NH ２ 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 11, 15, and 16, wherein:

18. Formula (Va), (Vb), or (Vc): 【147】 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 17, represented by:

19. Represented by formula (VIa), (VIb), or (VIc): 【148】 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, wherein n is an integer selected from 0, 1, and 2.

20. Represented by formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe): 【149】 【Chemistry 150】 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19, wherein n is an integer selected from 0, 1, and 2.

21. R ２ may, in each occurrence, independently be hydrogen, halogen, cyano, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, —NR ｈ R ｉ or cyclopropyl, and R ｈ and R ｉ is, in each occurrence, independently hydrogen or C １ -C ４ 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 20, wherein: R is alkyl.

22. R ２ is, in each occurrence, independently hydrogen, F, Cl, —CH ３ , -NH ２ 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 21, wherein:

23. R ３ may, in each occurrence, independently be selected from halogen, cyano, ═O, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, —C(═O)OR ｙ , —C(═O)NR ｖ S (= O) ２ R ｙ , -S(=O) ２ NR ｖ R ｗ , -S(=O) ２ NR ｖ C(=O)R ｗ , -P(=O)R ｚ R ｚ or 5- or 6-membered heteroaryl; R ３ The above C １ -C ６ The alkyl or said 5-membered heteroaryl is optionally selected from cyano, —C(═O)OR ｙ , -OR ｙ , and -NR ｖ R ｗ and is substituted with 1 to 3 groups independently selected from R ｖ and R ｗ are, in each occurrence, independently hydrogen or C １ -C ４ is alkyl, R ｙ is, in each occurrence, independently hydrogen or C １ -C ４ 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 22, wherein: R is alkyl.

24. R ３ may, in each occurrence, independently be selected from halogen, cyano, ═O, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, —C(═O)OR ｙ , —C(═O)NR ｖ S (= O) ２ R ｙ , -S(=O) ２ NR ｖ R ｗ , -S(=O) ２ NR ｖ C(=O)R ｙ or a 5-membered heteroaryl; R ３ The above C １ -C ４ The alkyl or said 5-membered heteroaryl is optionally selected from cyano, —C(═O)OR ｙ , -OR ｙ , and -NR ｖ R ｗ and is substituted with 1 to 3 groups independently selected from R ｖ and R ｗ are, in each occurrence, independently hydrogen or C １ -C ２ is alkyl, R ｙ is, in each occurrence, independently hydrogen or C １ -C ２ 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein: R is alkyl.

25. R ３ may, in each occurrence, independently be selected from halogen, cyano, ═O, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, C １ -C ２ Haloalkyl, —C(═O)OR ｙ , —C(═O)NR ｖ S (= O) ２ R ｙ , -S(=O) ２ NR ｖ R ｗ , -S(=O) ２ NR ｖ C(=O)R ｙ , tetrazolyl, or oxadiazolyl; R ３ The above C １ -C ２ alkyl or said oxadiazolyl is optionally substituted with 1 to 3 groups independently selected from cyano, —COOH, and —OH; R ｖ and R ｗ are, in each occurrence, independently hydrogen or —CH ３ and R ｙ is, in each occurrence, independently hydrogen or —CH ３ 25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 24, wherein:

26. R ３ is, in each occurrence, independently selected from F, cyano, ═O, —CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ OH, -CH ２ OCH ３ , -OCH ３ , -COOH, -CH ２ COOH, -C(=O)NHS(=O) ２ CH ３ , -S(=O) ２ NHCH ３ , -S(=O) ２ NHC(=O)CH ３ , tetrazol-5-yl, 1,2,4-oxadiazol-5(4H)-onyl, or 1,3,4-oxadiazol-2(3H)-onyl, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 25.

27. R ４ may, in each occurrence, independently be selected from halogen, cyano, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —C(═O)R ｙ , -C(=O)OR ｙ , C(═O)NR ｖ R ｗ , -NR ｖ R ｗ , -OR ｙ , or -P(=O)R ｚ R ｚ and R ｖ and R ｗ are, in each occurrence, independently hydrogen or C １ -C ４ is alkyl, R ｙ is, in each occurrence, independently hydrogen or C １ -C ４ 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 26, wherein: R is alkyl.

28. R ４ may, in each occurrence, independently be selected from halogen, cyano, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, —C(═O)R ｙ , -C(=O)OR ｙ , C(═O)NR ｖ R ｗ , -NR ｖ R ｗ , or -OR ｙ and R ｖ and R ｗ are, in each occurrence, independently hydrogen or C １ -C ２ is alkyl, R ｙ is, in each occurrence, independently hydrogen or C １ -C ４ 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 27, wherein: R is alkyl.

29. R ４ may, in each occurrence, independently be selected from halogen, cyano, C １ -C ２ Alkyl, C １ -C ２ Haloalkyl, —C(═O)OR ｙ , or -OR ｙ and R ｙ is, in each occurrence, independently hydrogen or C １ -C ４ 29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 28, wherein: R is alkyl.

30. R ４ In each occurrence, -C(=O)OC(CH ３ ) ３ 30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 29, wherein:

31. 31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 30, wherein m is 0.

32. A compound selected from the following: 【Chemistry 151-1】 【Chemistry 151-2】 【Chemistry 151-3】 【Chemistry 151-4】 【Chemistry 151-5】 【Chemistry 151-6】 【Chemistry 151-7】 【Chemistry 151-8】 【Chemistry 151-9】 【Chemistry 151-10】 【Chemistry 151-11】 【Chemistry 151-12】 【Chemistry 151-13】 【Chemistry 151-14】 【Chemistry 151-15】 【Chemistry 151-16】 【Chemistry 151-17】 【Chemistry 151-18】 【Chemistry 151-19】 a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

33. 33. A pharmaceutical composition for use in treating alpha-1 antitrypsin (AAT) deficiency in a patient in need thereof, said pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1-32.

34. 33. A pharmaceutical composition for use in modulating alpha-1 antitrypsin (AAT) activity, said pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 32.

35. 35. The pharmaceutical composition of claim 33 or 34, wherein the pharmaceutical composition is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.

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